Mrakic-Sposta Dott.ssa Simona

Pubblicazioni su PubMed

• Urineprint of high-altitude: Insights from analyses of urinary biomarkers and bio-physical-chemical features of extracellular vesicles.
  Biophys Chem

  2024 Nov;316():107351. doi: 10.1016/j.bpc.2024.107351.
  
  Pilato Serena, Mrakic-Sposta Simona, Verratti Vittore, Santangelo Carmen, di Giacomo Stefano, Moffa Samanta, Fontana Antonella, Pietrangelo Tiziana, Ciampini Federica, Bonan Sofia, Pignatelli Pamela, Noce Carmine, di Profio Pietro, Ciulla Michele, Bondi Danilo, Cristiano Fabrizio
  
  Abstract
  
  Humans exposed to altitude hypoxia experience dysfunctions of the urinary system. As a non-invasive, easily manageable and informative biological sample, urine represents a relevant matrix for detecting clinical impairments of urinary system, as well as alterations of other systems and extracellular vesicles (EVs) biology during high-altitude expeditions. Nevertheless, gaps exist in the comprehensive assessment of dysfunction, molecular burden and EVs biology due to high-altitude acute exposure. This study aimed to find a biophysical and biochemical signature of urinary EVs for hypoxia-induced changes in urinary function, putatively accompanied by an oxinflammatory burden. Urine samples of 15 participants were sampled at low and high-altitude during an Alpine project (7 women and 8 men, aged 24-to-63 years and with BMI 17.93-to-30.76 kg/m) and analysed for: creatinin and albumin, lipid peroxidation, IL6, NO derivatives; atomic force microscopy and Raman spectroscopy were carried out after urinary EVs were isolated through sucrose-gradient ultracentrifugation. Albumin-to-creatinin ratio increased at high altitude, as did IL6 and 8-isoprostane. AFM showed a globular and flattened shape of EVs, although several samples were characterized by a lot of contaminants and EVs lost their prototypal spherical shape; EVs comprehensively maintained their morphology at high altitude. Raman spectroscopy revealed some typical phospholipidic-like pattern, often masked by contaminants of spectra that most often refer to high-altitude samples. Collectively, short-term exposure to altitude hypoxia increased renal concentrating ability, produced non-pathological impairment or renal function, and triggered an oxyinflammatory burden with heterogeneous response of NO system. The combination of AFM and Raman spectroscopy revealed that EVs collected at high altitude more likely are fused together and incorporated into a sediment matrix, and contain contaminants peaks that make the purification process less efficient. The combination of analytical procedures as in the present study offers novel possibilities to detect the biological and clinical effects of high altitude on renal system.
  
  Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.
  
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• Decompression Illness After Technical Diving Session in Mediterranean Sea: Oxidative Stress, Inflammation, and HBO Therapy.
  Int J Mol Sci

  2024 Oct;25(21):. doi: 11367.
  
  Mrakic-Sposta Simona, Brizzolari Andrea, Vezzoli Alessandra, Graci Carmela, Cimmino Attilio, Giacon Tommaso Antonio, Dellanoce Cinzia, Barassi Alessandra, Sesana Giovanni, Bosco Gerardo
  
  Abstract
  
  SCUBA diving poses risks due to pressure changes during descent (compression) and ascent (decompression). Decompression sickness (DCS) occurs due to gas bubble formation as the pressure decreases, causing joint pain, numbness, dizziness, or even paralysis and death. Immediate treatment involves 100% oxygen to help eliminate inert gases and hyperbaric oxygen therapy (HBOT), which is essential to reduce gas emboli formation and inflammation, thus improving symptoms. We evaluated oxy-inflammation biomarkers in the saliva and urine of nine subjects pre- and post-technical dive on the Haven wreck (GE, Italy). A case of DCS occurred during the dive. The injured diver was treated immediately with O and transported to the hyperbaric center of "ASST Ospedale Ca Granda" in Milan. He was treated following the U.S. Navy Treatment Table 5 at 2.8 ATA and the day after with Table 15 at 2.4 ATA. Venous blood and urine samples were collected before and after each HBO treatment. Our study shows that dive increased oxy-inflammation biomarkers (ROS +126%; lipid peroxidation +23%; interleukins-6 +81%, -1? +19%, and TNF? +84%) and nitric oxide metabolites levels (+36%). HBOT after a DCS episode reduced oxidative stress, lowering the very high marker of lipid peroxidation (8-iso-PGF2?), and inhibited inflammatory interleukins. Overall, HBOT improved physiological responses in the diver affected by DCS.
  
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• The Effect of Acute High-Altitude Exposure on Oral Pathogenic Bacteria and Salivary Oxi-Inflammatory Markers.
  J Clin Med

  2024 Oct;13(20):. doi: 6266.
  
  Pignatelli Pamela, Mrakic-Sposta Simona, Bondi Danilo, D'Antonio Domenica Lucia, Piattelli Adriano, Santangelo Carmen, Verratti Vittore, Curia Maria Cristina
  
  Abstract
  
  The environment can alter the homeostasis of humans and human microbiota. Oral health is influenced by high altitude through symptoms of periodontitis, barodontalgia, dental barotrauma, and a decrease in salivary flow. Microbiota and inflammatory state are connected in the oral cavity. This study aimed to explore the effect of acute high-altitude exposure on the salivary microbiome and inflammatory indicators. Fifteen healthy expeditioners were subjected to oral examination, recording the plaque index (PII), gingival index (GI), the simplified oral hygiene index (OHI-S), and the number of teeth; unstimulated saliva samples were collected at an altitude of 1191 m (T1) and 4556 m (T2). TNF-?, sICAM1, ROS, and the oral bacterial species () and () were quantified. At T2, slCAM, TNF, and ROS increased by 85.5% (IQR 74%), 84% (IQR 409.25%), and 53.5% (IQR 68%), respectively, while decreased by 92.43% (IQR 102.5%). The decrease in was greater in the presence of low OHI-S. The increase in slCAM1 correlated with the reduction in . Individuals with high GI and OHI-S had a limited increase in TNF-? at T2. Short-term exposures can affect the concentration of pathogenic periodontal bacteria and promote local inflammation.
  
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• Environmental study and stress-related biomarkers modifications in a crew during analog astronaut mission EMMPOL 6.
  Eur J Appl Physiol

  2024 Sep;():. doi: 10.1007/s00421-024-05575-3.
  
  Giacon T A, Mrakic-Sposta Simona, Bosco G, Vezzoli A, Dellanoce Cinzia, Campisi M, Narici M, Paganini M, Foing B, Ko?odziejczyk A, Martinelli M, Pavanello S
  
  Abstract
  
  PURPOSE:
  Human presence in space is increasingly frequent, but we must not forget that it is a hostile environment. We aimed to study the characteristics of experimental scenarios, to obtain data on human response to isolation, disruption of circadian rhythm and high levels of psychophysical stress.
  
  METHODS:
  In these experiments, we evaluated stress response in five young healthy subjects inside an earth-based moon-settlement-like habitat during a 1-week long analog astronaut mission. Wearable devices were used to monitor daily step count of the subjects, physical activity, heart rate during physical exercise and at rest, and sleep parameters. From saliva and urine samples collected every day at awakening, we studied oxy-inflammation biomarkers and hormones (stress and appetite) were studied too.
  
  RESULTS:
  At the end of the week, all subjects revealed an increase in oxidative stress and cortisol levels but no inflammation biomarkers variations, in conjunction with increasing time/daily exercise. Furthermore, a significant decrease in hours of sleep/day, sleep quality, and REM phase of sleep was recorded and correlated with the increase of reactive oxygen species.
  
  CONCLUSION:
  Oxidative stress increased in a short period of time and may be attributed to the influence of psychological stress during confinement, as well as increased exercise and decreased amount of sleep. On a long-term basis, this could impact performance.
  
  © 2024. The Author(s).
  
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• Consumption of Sylimarin, Pyrroloquinoline Quinone Sodium Salt and Myricetin: Effects on Alcohol Levels and Markers of Oxidative Stress-A Pilot Study.
  Nutrients

  2024 Sep;16(17):. doi: 2965.
  
  Bosco Gerardo, Vezzoli Alessandra, Brizzolari Andrea, Paganini Matteo, Giacon Tommaso Antonio, Savini Fabio, Gussoni Maristella, Montorsi Michela, Dellanoce Cinzia, Mrakic-Sposta Simona
  
  Abstract
  
  BACKGROUND:
  Alcohol abuse is one of the most common causes of mortality worldwide. This study aimed to investigate the efficacy of a treatment in reducing circulating ethanol and oxidative stress biomarkers.
  
  METHODS:
  Twenty wine-drinking subjects were investigated in a randomized controlled, single-blind trial (ClinicalTrials.gov. Identifier: NCT06548503; Ethical Committee of the University of Padova (HEC-DSB/12-2023) to evaluate the effect of the intake of a product containing silymarin, pyrroloquinoline quinone sodium salt, and myricetin (referred to as Si.Pi.Mi. for this project) on blood alcohol, ethyl glucuronide (EtG: marker for alcohol consumption) and markers of oxidative stress levels (Reactive Oxygen Species-ROS, Total Antioxidant Capacity-TAC, CoQ10, thiols redox status, 8-isoprostane, NO metabolites, neopterin, and uric acid). The effects of the treatment versus placebo were evaluated acutely and after 1 week of supplementation in blood and/or saliva and urine samples.
  
  RESULTS:
  Si.Pi.Mi intake reduced circulating ethanol after 120 min (-33%). Changes in oxidative stress biomarkers, particularly a TAC (range +9-12%) increase and an 8-isoprostane (marker of lipidic peroxidation) decrease (range -22-27%), were observed too.
  
  CONCLUSION:
  After the administration of Si.Pi.Mi, the data seemed to suggest a better alcohol metabolism and oxidative balance in response to wine intake. Further verification is requested.
  
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• A MEPS-UHPLC-MS/MS analytical platform to detect isoprostanoids and specialized pro-resolving mediators in the urinary extracellular vesicles of mountain ultramarathon runners.
  Talanta

  2024 Nov;279():126619. doi: 10.1016/j.talanta.2024.126619.
  
  Biagini Denise, Mrakic-Sposta Simona, Bondi Danilo, Ghimenti Silvia, Lenzi Alessio, Vivaldi Federico, Santangelo Carmen, Verratti Vittore, Pietrangelo Tiziana, Vezzoli Alessandra, Giardini Guido, Oger Camille, Galano Jean-Marie, Balas Laurence, Durand Thierry, D'Angelo Gennaro, Lomonaco Tommaso, Di Francesco Fabio
  
  Abstract
  
  Oxylipins are powerful signalling compounds derived from polyunsaturated fatty acids (PUFAs) and involved in regulating the immune system response. A mass spectrometry-based method was developed and validated for the targeted profiling of 52 oxylipins (e.g., isoprostanoids, prostaglandins, epoxy- and hydroxy-fatty acids, specialized pro-resolving mediators) and 4 PUFAs in small urinary extracellular vesicles (uEVs). Ultrasound-assisted extraction using a 50:50 v/v MeOH:HO mixture ensured optimal analytical performances. Limits of detection ranged between 10 and 400 pg/mL for oxylipins and 0.10-3 ng/mL for PUFAs. Satisfactory recoveries (85-116 %) and good intra- and inter-day precisions (RSD ?15 %) were obtained for all the analytes. The reliability of the procedure was tested in a real case scenario by monitoring ultramarathon runners during the world Tor des Géants® (TDG) race. Both F- and E-isoprostanes were detected in small uEVs of the ultramarathon runners, suggesting the onset of an oxidant insult. 5-F-IsoP exhibited significant pre- to post-race variations, thus potentially representing a non-invasive marker of in-vivo lipid peroxidation. The presence of specialized pro-resolving mediators suggests the activation of pro-resolution signalling cascade resolving inflammation. These outcomes may help manage post-exercise recovery and improve training.
  
  Copyright © 2024. Published by Elsevier B.V.
  
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• Physiology of deep closed circuit rebreather mixed gas diving: vascular gas emboli and biological changes during a week-long liveaboard safari.
  Front Physiol

  2024 ;15():1395846. doi: 1395846.
  
  Balestra Costantino, Lévêque Clément, Mrakic-Sposta Simona, Vezzoli Alessandra, Wauthy Pierre, Germonpré Peter, Tillmans Frauke, Guerrero François, Lafère Pierre
  
  Abstract
  
  Diving decompression theory hypothesizes inflammatory processes as a source of micronuclei which could increase related risks. Therefore, we tested 10 healthy, male divers. They performed 6-8 dives with a maximum of two dives per day at depths ranging from 21 to 122 msw with CCR mixed gas diving. Post-dive VGE were counted by echocardiography. Saliva and urine samples were taken before and after each dive to evaluate inflammation: ROS production, lipid peroxidation (8-iso-PGF2), DNA damage (8-OH-dG), cytokines (TNF-?, IL-6, and neopterin). VGE exhibits a progressive reduction followed by an increase (
  Copyright © 2024 Balestra, Lévêque, Mrakic-Sposta, Vezzoli, Wauthy, Germonpré, Tillmans, Guerrero and Lafère.
  
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• Oxy-Inflammation in Humans during Underwater Activities.
  Int J Mol Sci

  2024 Mar;25(5):. doi: 3060.
  
  Vezzoli Alessandra, Mrakic-Sposta Simona, Brizzolari Andrea, Balestra Costantino, Camporesi Enrico Maria, Bosco Gerardo
  
  Abstract
  
  Underwater activities are characterized by an imbalance between reactive oxygen/nitrogen species (RONS) and antioxidant mechanisms, which can be associated with an inflammatory response, depending on O availability. This review explores the oxidative stress mechanisms and related inflammation status (Oxy-Inflammation) in underwater activities such as breath-hold (BH) diving, Self-Contained Underwater Breathing Apparatus (SCUBA) and Closed-Circuit Rebreather (CCR) diving, and saturation diving. Divers are exposed to hypoxic and hyperoxic conditions, amplified by environmental conditions, hyperbaric pressure, cold water, different types of breathing gases, and air/non-air mixtures. The "diving response", including physiological adaptation, cardiovascular stress, increased arterial blood pressure, peripheral vasoconstriction, altered blood gas values, and risk of bubble formation during decompression, are reported.
  
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• Oxidative Stress and Cerebral Vascular Tone: The Role of Reactive Oxygen and Nitrogen Species.
  Int J Mol Sci

  2024 Mar;25(5):. doi: 3007.
  
  Salvagno Michele, Sterchele Elda Diletta, Zaccarelli Mario, Mrakic-Sposta Simona, Welsby Ian James, Balestra Costantino, Taccone Fabio Silvio
  
  Abstract
  
  The brain's unique characteristics make it exceptionally susceptible to oxidative stress, which arises from an imbalance between reactive oxygen species (ROS) production, reactive nitrogen species (RNS) production, and antioxidant defense mechanisms. This review explores the factors contributing to the brain's vascular tone's vulnerability in the presence of oxidative damage, which can be of clinical interest in critically ill patients or those presenting acute brain injuries. The brain's high metabolic rate and inefficient electron transport chain in mitochondria lead to significant ROS generation. Moreover, non-replicating neuronal cells and low repair capacity increase susceptibility to oxidative insult. ROS can influence cerebral vascular tone and permeability, potentially impacting cerebral autoregulation. Different ROS species, including superoxide and hydrogen peroxide, exhibit vasodilatory or vasoconstrictive effects on cerebral blood vessels. RNS, particularly NO and peroxynitrite, also exert vasoactive effects. This review further investigates the neuroprotective effects of antioxidants, including superoxide dismutase (SOD), vitamin C, vitamin E, and the glutathione redox system. Various studies suggest that these antioxidants could be used as adjunct therapies to protect the cerebral vascular tone under conditions of high oxidative stress. Nevertheless, more extensive research is required to comprehensively grasp the relationship between oxidative stress and cerebrovascular tone, and explore the potential benefits of antioxidants as adjunctive therapies in critical illnesses and acute brain injuries.
  
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• Pulsed Hyperoxia Acts on Plasmatic Advanced Glycation End Products and Advanced Oxidation Protein Products and Modulates Mitochondrial Biogenesis in Human Peripheral Blood Mononuclear Cells: A Pilot Study on the "Normobaric Oxygen Paradox".
  Int J Mol Sci

  2024 Feb;25(4):. doi: 2394.
  
  Balestra Costantino, Baldelli Sara, Virgili Fabio, Salvagno Michele, Mrakic-Sposta Simona, Fratantonio Deborah
  
  Abstract
  
  The "normobaric oxygen paradox" (NOP) describes the response to the return to normoxia after a hyperoxic event, sensed by tissues as an oxygen shortage, up-regulating redox-sensitive transcription factors. We have previously characterized the time trend of oxygen-sensitive transcription factors in human PBMCs, in which the return to normoxia after 30% oxygen is sensed as a hypoxic trigger, characterized by hypoxia-induced factor (HIF-1) activation. On the contrary, 100% and 140% oxygen induce a shift toward an oxidative stress response, characterized by NRF2 and NF-kB activation in the first 24 h post exposure. Herein, we investigate whether this paradigm triggers Advanced Glycation End products (AGEs) and Advanced Oxidation Protein Products (AOPPs) as circulating biomarkers of oxidative stress. Secondly, we studied if mitochondrial biogenesis was involved to link the cellular response to oxidative stress in human PBMCs. Our results show that AGEs and AOPPs increase in a different manner according to oxygen dose. Mitochondrial levels of peroxiredoxin (PRX3) supported the cellular response to oxidative stress and increased at 24 h after mild hyperoxia, MH (30% O), and high hyperoxia, HH (100% O), while during very high hyperoxia, VHH (140% O), the activation was significantly high only at 3 h after oxygen exposure. Mitochondrial biogenesis was activated through nuclear translocation of PGC-1? in all the experimental conditions. However, the consequent release of nuclear Mitochondrial Transcription Factor A (TFAM) was observed only after MH exposure. Conversely, HH and VHH are associated with a progressive loss of NOP response in the ability to induce TFAM expression despite a nuclear translocation of PGC-1? also occurring in these conditions. This study confirms that pulsed high oxygen treatment elicits specific cellular responses, according to its partial pressure and time of administration, and further emphasizes the importance of targeting the use of oxygen to activate specific effects on the whole organism.
  
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• Nutritional physiology and body composition changes during a rapid ascent to high altitude.
  Appl Physiol Nutr Metab

  2024 Jun;49(6):723-737. doi: 10.1139/apnm-2023-0338.
  
  Santangelo Carmen, Verratti Vittore, Mrakic-Sposta Simona, Ciampini Federica, Bonan Sofia, Pignatelli Pamela, Pietrangelo Tiziana, Pilato Serena, Moffa Samanta, Fontana Antonella, Piccinelli Raffaela, Donne Cinzia Le, Lobefalo Lucio, Beccatelli Matteo, Rizzini Pierluigi Lodi, Seletti Davide, Mecca Rocco, Beccatelli Tommaso, Bondi Danilo
  
  Abstract
  
  Exposure to high altitude might cause the body to adapt with negative energy and fluid balance that compromise body composition and physical performance. In this field study involving 12 healthy adults, sex-balanced, and aged 29 ± 4 years with a body mass index of 21.6 ± 1.8 kg/m, we investigated the effects of a 4-day trekking up to 4556 m a.s.l. on Monte Rosa (Alps, Italy). The food intake was recorded using food diaries and nutrient averages were calculated. The bio-impedance analysis was performed at low and high altitudes, and a wearable biosensor (Swemax) was used to track hydro-saline losses in two participants. Daily total energy intake was 3348 ± 386 kcal for males and 2804 ± 415 kcal for females (13%-14% protein, 35% fat, 44%-46% carbohydrates). Although there was a significant body weight loss (65.0 ± 9.3 vs. 64.2 ± 9.10 kg,  
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• Commentary: Is obesity associated with taste alterations? a systematic review.
  Front Endocrinol (Lausanne)

  2023 ;14():1282276. doi: 1282276.
  
  Alessandrini Marco, Vezzoli Alessandra, Mrakic-Sposta Simona, Malacrida Sandro, Micarelli Alessandro
  
  
  
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• Hyperbaric Oxygen Therapy Counters Oxidative Stress/Inflammation-Driven Symptoms in Long COVID-19 Patients: Preliminary Outcomes.
  Metabolites

  2023 Sep;13(10):. doi: 1032.
  
  Mrakic-Sposta Simona, Vezzoli Alessandra, Garetto Giacomo, Paganini Matteo, Camporesi Enrico, Giacon Tommaso Antonio, Dellanoce Cinzia, Agrimi Jacopo, Bosco Gerardo
  
  Abstract
  
  Long COVID-19 patients show systemic inflammation and persistent symptoms such as fatigue and malaise, profoundly affecting their quality of life. Since improving oxygenation can oppose inflammation at multiple tissue levels, we hypothesized that hyperbaric oxygen therapy (HBOT) could arrest inflammation progression and thus relieve symptoms of COVID-19. We evaluated oxy-inflammation biomarkers in long COVID-19 subjects treated with HBOT and monitored with non-invasive methods. Five subjects (two athletes and three patients with other comorbidities) were assigned to receive HBOT: 100% inspired O at 2.4 ATA in a multiplace hyperbaric chamber for 90 min (three athletes: 15 HBOT × 5 days/wk for 3 weeks; two patients affected by Idiopathic Sudden Sensorineural Hearing Loss: 30 HBOT × 5 days/wk for 6 weeks; and one patient with osteomyelitis: 30 HBOT × 5 days/wk for week for 6 weeks and, after a 30-day break, followed by a second cycle of 20 HBOT). Using saliva and/or urine samples, reactive oxygen species (ROS), antioxidant capacity, cytokines, lipids peroxidation, DNA damage, and renal status were assessed at T1_pre (basal level) and at T2_pre (basal level after treatment), and the results showed attenuated ROS production, lipid peroxidation, DNA damage, NO metabolites, and inflammation biomarker levels, especially in the athletes post-treatment. Thus, HBOT may represent an alternative non-invasive method for treating long COVID-19-induced long-lasting manifestations of oxy-inflammation.
  
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• Effects of Electrical Stimulation on Delayed Onset Muscle Soreness (DOMS): Evidences from Laboratory and In-Field Studies.
  J Funct Morphol Kinesiol

  2023 Oct;8(4):. doi: 146.
  
  Gussoni Maristella, Moretti Sarah, Vezzoli Alessandra, Genitoni Valerio, Giardini Guido, Balestra Costantino, Bosco Gerardo, Pratali Lorenza, Spagnolo Elisabetta, Montorsi Michela, Mrakic-Sposta Simona
  
  Abstract
  
  Intense, long exercise can increase oxidative stress, leading to higher levels of inflammatory mediators and muscle damage. At the same time, fatigue has been suggested as one of the factors giving rise to delayed-onset muscle soreness (DOMS). The aim of this study was to investigate the efficacy of a specific electrical stimulation (ES) treatment (without elicited muscular contraction) on two different scenarios: in the laboratory on eleven healthy volunteers (56.45 ± 4.87 years) after upper limbs eccentric exercise (Study 1) and in the field on fourteen ultra-endurance athletes (age 47.4 ± 10.2 year) after an ultra-running race (134 km, altitude difference of 10,970 m+) by lower exercising limbs (Study 2). Subjects were randomly assigned to two experimental tasks in cross-over: Active or Sham ES treatments. The ES efficacy was assessed by monitoring the oxy-inflammation status: Reactive Oxygen Species production, total antioxidant capacity, IL-6 cytokine levels, and lactate with micro-invasive measurements (capillary blood, urine) and scales for fatigue and recovery assessments. No significant differences ( > 0.05) were found in the time course of recovery and/or pre-post-race between Sham and Active groups in both study conditions. A subjective positive role of sham stimulation (VAS scores for muscle pain assessment) was reported. In conclusion, the effectiveness of ES in treating DOMS and its effects on muscle recovery remain still unclear.
  
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• Oxygen Variations-Insights into Hypoxia, Hyperoxia and Hyperbaric Hyperoxia-Is the Dose the Clue?
  Int J Mol Sci

  2023 Aug;24(17):. doi: 13472.
  
  Balestra Costantino, Mrakic-Sposta Simona, Virgili Fabio
  
  Abstract
  
  Molecular oxygen (O) is one of the four most important elements on Earth (alongside carbon, nitrogen and hydrogen); aerobic organisms depend on it to release energy from carbon-based molecules [...].
  
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• Smell, taste and food habits changes along body mass index increase: an observational study.
  Eur Arch Otorhinolaryngol

  2023 Dec;280(12):5595-5606. doi: 10.1007/s00405-023-08204-5.
  
  Micarelli Alessandro, Malacrida Sandro, Vezzoli Alessandra, Micarelli Beatrice, Misici Ilaria, Carbini Valentina, Caputo Sara, Mrakic-Sposta Simona, Alessandrini Marco
  
  Abstract
  
  PURPOSE:
  To evaluate the changes in gustatory and olfactory sensitivity and dietary habits between healthy lean subjects (LS) and participants affected by overweight (OW), stage I and II obesity and to estimate possible impact of these factors on body mass index (BMI).
  
  METHODS:
  After a general and ear-nose-throat evaluation, taste and olfactory function testing by means of taste strips and sniffin' stick tests, respectively, and food habits analysis by means of food frequency questionnaire (FFQ), 221 participants (68 LS [33 female; mean age?=?53.01?±?7.54 years]; 51 OW [26 female; mean age?=?51.5?±?12.16 years]; 50 stage I obesity [24 female; mean age?=?50.78?±?13.71 years] and 52 stage II obesity [24 female; mean age?=?52.21?±?13.35 years]) were enrolled in the study.
  
  RESULTS:
  Significant (p?0.008) reductions in total and subtest taste and smell scores were found in stage I and II obesity when compared to LS and OW participants. FFQ depicted a progressive intake increase of nutrients along the BMI stages. Significant associations were found between BMI and taste/smell subtests sugar taste carbs, saturated, monounsaturated and polyunsaturated fatty acids.
  
  CONCLUSIONS:
  These data demonstrated for the first time a parallel impairment in smell and taste in a large sample size of participants from lean to stage II obesity and could reinforce those previous theories claiming that the greater the ability in taste or smell qualities perception, the lower the preference for them, resulting in a lower intake of specific foods.
  
  © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
  
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• Oxidative Stress Response Kinetics after 60 Minutes at Different (1.4 ATA and 2.5 ATA) Hyperbaric Hyperoxia Exposures.
  Int J Mol Sci

  2023 Aug;24(15):. doi: 12361.
  
  Leveque Clément, Mrakic Sposta Simona, Theunissen Sigrid, Germonpré Peter, Lambrechts Kate, Vezzoli Alessandra, Bosco Gerardo, Lévénez Morgan, Lafère Pierre, Guerrero François, Balestra Costantino
  
  Abstract
  
  Hyperbaric oxygen therapy (HBOT) is a therapeutical approach based on exposure to pure oxygen in an augmented atmospheric pressure. Although it has been used for years, the exact kinetics of the reactive oxygen species (ROS) between different pressures of hyperbaric oxygen exposure are still not clearly evidenced. In this study, the metabolic responses of hyperbaric hyperoxia exposures for 1 h at 1.4 and 2.5 ATA were investigated. Fourteen healthy non-smoking subjects (2 females and 12 males, age: 37.3 ± 12.7 years old (mean ± SD), height: 176.3 ± 9.9 cm, and weight: 75.8 ± 17.7 kg) volunteered for this study. Blood samples were taken before and at 30 min, 2 h, 24 h, and 48 h after a 1 h hyperbaric hyperoxic exposure. The level of oxidation was evaluated by the rate of ROS production, nitric oxide metabolites (NOx), and the levels of isoprostane. Antioxidant reactions were assessed through measuring superoxide dismutase (SOD), catalase (CAT), cysteinylglycine, and glutathione (GSH). The inflammatory response was measured using interleukine-6, neopterin, and creatinine. A short (60 min) period of mild (1.4 ATA) and high (2.5 ATA) hyperbaric hyperoxia leads to a similar significant increase in the production of ROS and antioxidant reactions. Immunomodulation and inflammatory responses, on the contrary, respond proportionally to the hyperbaric oxygen dose. Further research is warranted on the dose and the inter-dose recovery time to optimize the potential therapeutic benefits of this promising intervention.
  
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• Chelation Therapy Associated with Antioxidant Supplementation Can Decrease Oxidative Stress and Inflammation in Multiple Sclerosis: Preliminary Results.
  Antioxidants (Basel)

  2023 Jun;12(7):. doi: 1338.
  
  Vezzoli Alessandra, Mrakic-Sposta Simona, Dellanoce Cinzia, Montorsi Michela, Vietti Daniele, Ferrero Maria Elena
  
  Abstract
  
  An imbalance of oxy-inflammation status has been involved in axonal damage and demyelination in multiple sclerosis (MS). The aim of this study was to investigate the efficacy of an antioxidant treatment (calcium disodium ethylenediaminetetracetic acid-EDTA) chelation therapy associated with a micronutrient complex in MS patients. A total of 20 MS patients and 20 healthy subjects, enrolled as a control group (CTR), were recruited. We measured the plasma ROS production and total antioxidant capacity (TAC) by a direct assessment using Electron Paramagnetic Resonance; activities of the antioxidant system (thiols' redox status and enzymes); and the urinary presence of biomarkers of oxidative stress by immunoenzymatic assays. We also evaluated the levels of inflammation by plasmatic cytokines (TNF?, IL-1?, and IL-6) and assessed the sICAM levels, as well as the nitric oxide (NO) catabolism and transthyretin (TTR) concentration. Comparing CTR and MS, in the latter ROS production, oxidative damage, inflammatory biomarkers, and NO metabolite concentrations results were significantly higher, while TAC was significantly lower. Treatment in MS induced significant (
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• Oxidative Stress Response Kinetics after 60 Minutes at Different Levels (10% or 15%) of Normobaric Hypoxia Exposure.
  Int J Mol Sci

  2023 Jun;24(12):. doi: 10188.
  
  Leveque Clément, Mrakic Sposta Simona, Theunissen Sigrid, Germonpré Peter, Lambrechts Kate, Vezzoli Alessandra, Gussoni Maristella, Levenez Morgan, Lafère Pierre, Guerrero François, Balestra Costantino
  
  Abstract
  
  In this study, the metabolic responses of hypoxic breathing for 1 h to inspired fractions of 10% and 15% oxygen were investigated. To this end, 14 healthy nonsmoking subjects (6 females and 8 males, age: 32.2 ± 13.3 years old (mean ± SD), height: 169.1 ± 9.9 cm, and weight: 61.6 ± 16.2 kg) volunteered for the study. Blood samples were taken before, and at 30 min, 2 h, 8 h, 24 h, and 48 h after a 1 h hypoxic exposure. The level of oxidative stress was evaluated by considering reactive oxygen species (ROS), nitric oxide metabolites (NOx), lipid peroxidation, and immune-inflammation by interleukin-6 (IL-6) and neopterin, while antioxidant systems were observed in terms of the total antioxidant capacity (TAC) and urates. Hypoxia abruptly and rapidly increased ROS, while TAC showed a U-shape pattern, with a nadir between 30 min and 2 h. The regulation of ROS and NOx could be explained by the antioxidant action of uric acid and creatinine. The kinetics of ROS allowed for the stimulation of the immune system translated by an increase in neopterin, IL-6, and NOx. This study provides insights into the mechanisms through which acute hypoxia affects various bodily functions and how the body sets up the protective mechanisms to maintain redox homeostasis in response to oxidative stress.
  
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• Glutamatergic dysfunction, neuroplasticity, and redox status in the peripheral blood of patients with motor conversion disorders (functional movement disorders): a first step towards potential biomarkers discovery.
  Transl Psychiatry

  2023 Jun;13(1):212. doi: 212.
  
  Demartini Benedetta, Nisticò Veronica, Benayoun Caroline, Cigognini Anna Chiara, Ferrucci Roberta, Vezzoli Alessandra, Dellanoce Cinzia, Gambini Orsola, Priori Alberto, Mrakic-Sposta Simona
  
  Abstract
  
  Functional movement disorders (FMD) are characterized by the presence of neurological symptoms that cannot be explained by typical neurological diseases or other medical conditions. First evidence showed that, compared to healthy controls (CTR), FMD patients presented increased levels of glutamate+glutamine in the anterior cingulate cortex/medial prefrontal cortex, and decreased levels of glutamate in the cerebrospinal fluid, suggesting that a glutamatergic dysfunction might play a role in FMD pathophysiology. In this study, 12 FMD patients and 20 CTR were recruited and underwent venous blood sampling and urine collection: levels of glutamate, BDNF, dopamine, oxidative stress, creatinine, neopterin, and uric acid were analyzed. Participants also underwent a psychometric assessment investigating depression, anxiety, and alexithymia. We found that levels of glutamate, BDNF, and dopamine were significantly lower in the blood of FMD patients than CTR. Glutamate and dopamine levels were positively associated with levels of alexithymia. Our findings give further evidence that glutamatergic dysfunction might be involved in the pathophysiology of FMD, possibly representing a biomarker of disease; moreover, since glutamatergic and dopaminergic systems are closely interconnected, our results might have a relevance in terms of treatment options for FMD patients.
  
  © 2023. The Author(s).
  
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• Comparative Effectiveness of an Artificial Air Pocket Device to Delay Asphyxiation in Supine Individuals Critically Buried in Avalanche Debris.
  JAMA Netw Open

  2023 May;6(5):e2313376. doi: 10.1001/jamanetworkopen.2023.13376.
  
  Strapazzon Giacomo, Rauch Simon, Malacrida Sandro, Dal Cappello Tomas, Governo Enrica, Catuzzo Bruna, Mrakic-Sposta Simona, Urgesi Margherita, Falla Marika, Cavoretto Gianluca, Visetti Enrico, Giardini Guido, Brugger Hermann, Prato Federico
  
  Abstract
  
  IMPORTANCE:
  Approximately 70% of individuals critically buried in avalanche debris die within 35 minutes as a result of asphyxial cardiac arrest. An artificial air-pocket device (AAPD) that separates inhaled air from exhaled air may delay the onset of severe hypoxemia and eventual asphyxia during snow burial.
  
  OBJECTIVE:
  To investigate the efficacy of a new AAPD during snow burial in a supine position.
  
  DESIGN, SETTING, AND PARTICIPANTS:
  This comparative effectiveness trial was performed in winter 2016 with data analysis in November 2016 and November 2022. Each trial used a simulated critical avalanche burial scenario, in which a trough was dug in a snow pile and an additional air pocket of 0.5 L volume was punched into the lateral wall for each control trial. All participants were buried in a supine position. Trials could be voluntarily terminated at any time, with a maximum length of 60 minutes; trials were automatically terminated if the participant's peripheral oxygen saturation (Spo2) dropped to less than 84%.
  
  EXPOSURES:
  Each participant conducted 2 trials, one in which they breathed into the AAPD (intervention trial) and the other in which they breathed into the prepared air pocket (control trial).
  
  MAIN OUTCOMES AND MEASURES:
  Measurements included Spo2, cerebral oxygenation, ventilatory parameters, respiratory gas concentrations, and visual-analogue scales. Kaplan-Meier survival curves and rank test for matched survival data were used to analyze the total burial time in each trial.
  
  RESULTS:
  A total of 13 volunteers (9 men; mean [SD] age, 33 [8] years) were exposed to the intervention and control trials. Intervention trials were terminated less often (2 of 13 trials) as a result of hypoxemia than control trials (11 of 12 trials). Similarly, survival curves showed a longer duration of burial in the intervention compared with the control trials for the time to reach an Spo2 less than 84% (rank test for matched survival data: P?=?.003). The intervention trials, compared with the control trials, also had slower rates of decrease in fraction of inspired oxygen (mean [SD] rate, -0.8 [0.4] %/min vs -2.2 [1.2] %/min) and of increase in fraction of inspired carbon dioxide (mean [SD] rate, 0.5 [0.3] %/min vs 1.4 [0.6] %/min) and expired ventilation per minute (mean [SD] rate, 0.5 [1.0] L/min2 vs 3.9 [2.6] L/min2).
  
  CONCLUSIONS AND RELEVANCE:
  This comparative effectiveness trial found that the new AAPD was associated with delaying the development of hypoxemia and hypercapnia in supine participants in a critical burial scenario. Use of the AAPD may allow a longer burial time before asphyxial cardiac arrest, which might allow longer times for successful rescue by companions or by prehospital emergency medical services.
  
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• Editorial: Women in environmental physiology 2022.
  Front Physiol

  2023 ;14():1175366. doi: 1175366.
  
  Eftedal Ingrid, Mrakic-Sposta Simona, Lang Morin
  
  
  
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• Taste Function in Adult Humans from Lean Condition to Stage II Obesity: Interactions with Biochemical Regulators, Dietary Habits, and Clinical Aspects.
  Nutrients

  2023 Feb;15(5):. doi: 1114.
  
  Micarelli Alessandro, Vezzoli Alessandra, Malacrida Sandro, Micarelli Beatrice, Misici Ilaria, Carbini Valentina, Iennaco Ilaria, Caputo Sara, Mrakic-Sposta Simona, Alessandrini Marco
  
  Abstract
  
  Differences in gustatory sensitivity, nutritional habits, circulating levels of modulators, anthropometric measures, and metabolic assays may be involved in overweight (OW) development. The present study aimed at evaluating the differences in these aspects between 39 OW (19 female; mean age = 53.51 ± 11.17), 18 stage I (11 female; mean age = 54.3 ± 13.1 years), and 20 II (10 female; mean age = 54.5 ± 11.9) obesity participants when compared with 60 lean subjects (LS; 29 female; mean age = 54.04 ± 10.27). Participants were evaluated based on taste function scores, nutritional habits, levels of modulators (leptin, insulin, ghrelin, and glucose), and bioelectrical impedance analysis measurements. Significant reductions in total and subtests taste scores were found between LS and stage I and II obesity participants. Significant reductions in total and all subtests taste scores were found between OW and stage II obesity participants. Together with the progressive increase in plasmatic leptin levels, insulin, and serum glucose, decrease in plasmatic ghrelin levels, and changes in anthropometric measures and nutritional habits along with body mass index, these data for the first time demonstrated that taste sensitivity, biochemical regulators, and food habits play a parallel, concurring role along the stages evolving to obesity.
  
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• The "ON-OFF" Switching Response of Reactive Oxygen Species in Acute Normobaric Hypoxia: Preliminary Outcome.
  Int J Mol Sci

  2023 Feb;24(4):. doi: 4012.
  
  Mrakic-Sposta Simona, Gussoni Maristella, Marzorati Mauro, Porcelli Simone, Bosco Gerardo, Balestra Costantino, Montorsi Michela, Lafortuna Claudio, Vezzoli Alessandra
  
  Abstract
  
  Exposure to acute normobaric hypoxia (NH) elicits reactive oxygen species (ROS) accumulation, whose production kinetics and oxidative damage were here investigated. Nine subjects were monitored while breathing an NH mixture (0.125 FO in air, about 4100 m) and during recovery with room air. ROS production was assessed by Electron Paramagnetic Resonance in capillary blood. Total antioxidant capacity, lipid peroxidation (TBARS and 8-iso-PFG2?), protein oxidation (PC) and DNA oxidation (8-OH-dG) were measured in plasma and/or urine. The ROS production rate (?mol·min) was monitored (5, 15, 30, 60, 120, 240 and 300 min). A production peak (+50%) was reached at 4 h. The on-transient kinetics, exponentially fitted (t = 30 min = 0.995), were ascribable to the low O tension transition and the mirror-like related SpO decrease: 15 min: -12%; 60 min: -18%. The exposure did not seem to affect the prooxidant/antioxidant balance. Significant increases in PC (+88%) and 8-OH-dG (+67%) at 4 h in TBARS (+33%) one hour after hypoxia offset were also observed. General malaise was described by most of the subjects. Under acute NH, ROS production and oxidative damage resulted in time and SpO-dependent reversible phenomena. The experimental model could be suitable for evaluating the acclimatation level, a key element in the context of mountain rescues in relation to technical/medical workers who have not had enough time for acclimatization-as, for example, during helicopter flights.
  
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• Seasonal Oxy-Inflammation and Hydration Status in Non-Elite Freeskiing Racer: A Pilot Study by Non-Invasive Analytic Method.
  Int J Environ Res Public Health

  2023 Feb;20(4):. doi: 3157.
  
  Brizzolari Andrea, Bosco Gerardo, Vezzoli Alessandra, Dellanoce Cinzia, Barassi Alessandra, Paganini Matteo, Cialoni Danilo, Mrakic-Sposta Simona
  
  Abstract
  
  Freeskiing is performed in an extreme environment, with significant physical effort that can induce reactive oxygen species (ROS) generation and dehydration. This study aimed to investigate the evolution of the oxy-inflammation and hydration status during a freeskiing training season with non-invasive methods. Eight trained freeskiers were investigated during a season training: T0 (beginning), T1-T3 (training sessions), and T4 (after the end). Urine and saliva were collected at T0, before (A) and after (B) T1-T3, and at T4. ROS, total antioxidant capacity (TAC), interleukin-6 (IL-6), nitric oxide (NO) derivatives, neopterin, and electrolyte balance changes were investigated. We found significant increases in ROS generation (T1A-B +71%; T2A-B +65%; T3A-B +49%;
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• Oxidative Stress Response's Kinetics after 60 Minutes at Different (30% or 100%) Normobaric Hyperoxia Exposures.
  Int J Mol Sci

  2022 Dec;24(1):. doi: 664.
  
  Leveque Clément, Mrakic-Sposta Simona, Lafère Pierre, Vezzoli Alessandra, Germonpré Peter, Beer Alexandre, Mievis Stéphane, Virgili Fabio, Lambrechts Kate, Theunissen Sigrid, Guerrero François, Balestra Costantino
  
  Abstract
  
  Oxygen is a powerful trigger for cellular reactions and is used in many pathologies, including oxidative stress. However, the effects of oxygen over time and at different partial pressures remain poorly understood. In this study, the metabolic responses of normobaric oxygen intake for 1 h to mild (30%) and high (100%) inspired fractions were investigated. Fourteen healthy non-smoking subjects (7 males and 7 females; age: 29.9 ± 11.1 years, height: 168.2 ± 9.37 cm; weight: 64.4 ± 12.3 kg; BMI: 22.7 ± 4.1) were randomly assigned in the two groups. Blood samples were taken before the intake at 30 min, 2 h, 8 h, 24 h, and 48 h after the single oxygen exposure. The level of oxidation was evaluated by the rate of reactive oxygen species (ROS) and the levels of isoprostane. Antioxidant reactions were observed by total antioxidant capacity (TAC), superoxide dismutase (SOD), and catalase (CAT). The inflammatory response was measured using interleukin-6 (IL-6), neopterin, creatinine, and urates. Oxidation markers increased from 30 min on to reach a peak at 8 h. From 8 h post intake, the markers of inflammation took over, and more significantly with 100% than with 30%. This study suggests a biphasic response over time characterized by an initial "permissive oxidation" followed by increased inflammation. The antioxidant protection system seems not to be the leading actor in the first place. The kinetics of enzymatic reactions need to be better studied to establish therapeutic, training, or rehabilitation protocols aiming at a more targeted use of oxygen.
  
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• The Normobaric Oxygen Paradox-Hyperoxic Hypoxic Paradox: A Novel Expedient Strategy in Hematopoiesis Clinical Issues.
  Int J Mol Sci

  2022 Dec;24(1):. doi: 82.
  
  Salvagno Michele, Coppalini Giacomo, Taccone Fabio Silvio, Strapazzon Giacomo, Mrakic-Sposta Simona, Rocco Monica, Khalife Maher, Balestra Costantino
  
  Abstract
  
  Hypoxia, even at non-lethal levels, is one of the most stressful events for all aerobic organisms as it significantly affects a wide spectrum of physiological functions and energy production. Aerobic organisms activate countless molecular responses directed to respond at cellular, tissue, organ, and whole-body levels to cope with oxygen shortage allowing survival, including enhanced neo-angiogenesis and systemic oxygen delivery. The benefits of hypoxia may be evoked without its detrimental consequences by exploiting the so-called normobaric oxygen paradox. The intermittent shift between hyperoxic-normoxic exposure, in addition to being safe and feasible, has been shown to enhance erythropoietin production and raise hemoglobin levels with numerous different potential applications in many fields of therapy as a new strategy for surgical preconditioning aimed at frail patients and prevention of postoperative anemia. This narrative review summarizes the physiological processes behind the proposed normobaric oxygen paradox, focusing on the latest scientific evidence and the potential applications for this strategy. Future possibilities for hyperoxic-normoxic exposure therapy include implementation as a synergistic strategy to improve a patient's pre-surgical condition, a stimulating treatment in critically ill patients, preconditioning of athletes during physical preparation, and, in combination with surgery and conventional chemotherapy, to improve patients' outcomes and quality of life.
  
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• Dopamine/BDNF loss underscores narcosis cognitive impairment in divers: a proof of concept in a dry condition.
  Eur J Appl Physiol

  2023 Jan;123(1):143-158. doi: 10.1007/s00421-022-05055-6.
  
  Bosco Gerardo, Giacon Tommaso Antonio, Paolocci Nazareno, Vezzoli Alessandra, Noce Cinzia Della, Paganini Matteo, Agrimi Jacopo, Garetto Giacomo, Cialoni Danilo, D'Alessandro Natalie, Camporesi Enrico M, Mrakic-Sposta Simona
  
  Abstract
  
  PURPOSE:
  Divers can experience cognitive impairment due to inert gas narcosis (IGN) at depth. Brain-derived neurotrophic factor (BDNF) rules neuronal connectivity/metabolism to maintain cognitive function and protect tissues against oxidative stress (OxS). Dopamine and glutamate enhance BDNF bioavailability. Thus, we hypothesized that lower circulating BDNF levels (via lessened dopamine and/or glutamate release) underpin IGN in divers, while testing if BDNF loss is associated with increased OxS.
  
  METHODS:
  To mimic IGN, we administered a deep narcosis test via a dry dive test (DDT) at 48 msw in a multiplace hyperbaric chamber to six well-trained divers. We collected: (1) saliva samples before DDT (T0), 25 msw (descending, T1), 48 msw (depth, T2), 25 msw (ascending, T3), 10 min after decompression (T4) to dopamine and/or reactive oxygen species (ROS) levels; (2) blood and urine samples at T0 and T4 for OxS too. We administered cognitive tests at T0, T2, and re-evaluated the divers at T4.
  
  RESULTS:
  At 48 msw, all subjects experienced IGN, as revealed by the cognitive test failure. Dopamine and total antioxidant capacity (TAC) reached a nadir at T2 when ROS emission was maximal. At decompression (T4), a marked drop of BDNF/glutamate content was evidenced, coinciding with a persisting decline in dopamine and cognitive capacity.
  
  CONCLUSIONS:
  Divers encounter IGN at - 48 msw, exhibiting a marked loss in circulating dopamine levels, likely accounting for BDNF-dependent impairment of mental capacity and heightened OxS. The decline in dopamine and BDNF appears to persist at decompression; thus, boosting dopamine/BDNF signaling via pharmacological or other intervention types might attenuate IGN in deep dives.
  
  © 2022. The Author(s).
  
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• Fertility Impairment after Trekking at High Altitude: A Proof of Mechanisms on Redox and Metabolic Seminal Changes.
  Int J Mol Sci

  2022 Aug;23(16):. doi: 9066.
  
  Verratti Vittore, Mrakic-Sposta Simona, Fusi Jonathan, Sabovic Iva, Franzoni Ferdinando, Pietrangelo Tiziana, Bondi Danilo, Dall'Acqua Stefano, Daniele Simona, Scarfò Giorgia, Di Giulio Camillo, Garolla Andrea
  
  Abstract
  
  Many authors described negative but reversible effects of high-altitude hypoxic exposure on animal and human fertility in terms of sperm concentration, function, and biochemical alterations. The aim of this study was to evaluate the acute and chronic effects of high-altitude exposure on classical sperm parameters, redox status, and membrane composition in a group of travellers. Five healthy Italian males, all lowlanders not accustomed to the altitude, were evaluated after 19 days-trekking through low, moderate, and high altitudes in the Himalayas. Sperm samples were collected before (Pre), 10 days after (Post), and 70 days after the end of the expedition (Follow-up). Sperm concentration, cholesterol and oxysterol membrane content, and redox status were measured. Hypoxic trek led to a significant reduction in sperm concentration (p
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• Redox-based Disruption of Cellular Hormesis and Promotion of Degenerative Pathways: Perspectives on Aging Processes.
  J Gerontol A Biol Sci Med Sci

  2022 Nov;77(11):2195-2206. doi: 10.1093/gerona/glac167.
  
  Bevere Michele, Di Cola Giulia, Santangelo Carmen, Grazioli Elisa, Marramiero Lorenzo, Pignatelli Pamela, Bondi Danilo, Mrakic-Sposta Simona
  
  Abstract
  
  The present work aims to link the redox and cell-centric theories of chronic processes in human biology, focusing on aging. A synthetic overview of cellular redox pathways will be integrated by the concept of hormesis, which disruption leads to several physiopathological processes. The onset of age-related diseases due to the restriction of homeodynamic capacity will be herein considered in a redox fashion. Up-to-date arguments on hormetic agents, such as geroprotectors, dietary interventions, and physical exercise are refining the presented theoretical framework, integrated by insights from extracellular vesicles, microbiota, pollutants, and timing mechanisms. The broad concepts of exposome encompass the redox-based alteration of cellular hormesis for providing meaningful perspectives on redox biogerontology.
  
  © The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
  
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• Smell Impairment in Stage I-II Obesity: Correlation with Biochemical Regulators and Clinical Aspects.
  Laryngoscope

  2022 Oct;132(10):2028-2035. doi: 10.1002/lary.30325.
  
  Micarelli Alessandro, Mrakic-Sposta Simona, Micarelli Beatrice, Malacrida Sandro, Misici Ilaria, Carbini Valentina, Iennaco Ilaria, Caputo Sara, Vezzoli Alessandra, Alessandrini Marco
  
  Abstract
  
  OBJECTIVE:
  To evaluate the differences in olfactory sensitivity, nutritional habits, levels of modulators of feeding and smell, bioelectrical impedance analysis (BIA) measures and metabolic assays between two groups of participants with stage I and II obesity and reciprocal relationships between these parameters.
  
  METHODS:
  Eighteen participants with stage I (11 female; mean age = 54.3?±?13.1?years) and 20 participants with stage II (10 female; mean age = 54.5?±?11.9) obesity underwent a food frequency questionnaire and Sniffin' Sticks® test battery, anthropometric parameters, and BIA measurements as well as metabolic assays (including plasma levels of leptin, insulin, ghrelin, glucose, insulin-like growth factor-1 [IGF-1] and usual laboratory parameters).
  
  RESULTS:
  The stage II obesity participants demonstrated significant higher levels of insulin and leptin and lower levels of ghrelin and IGF-1, a reduction in odor identification (OI) and in total olfactory score, and an increase in visceral and total fat percentage. Among a mosaic of multiple correlations, ghrelin was found to positively correlate with OI and leptin negatively with odor discrimination.
  
  CONCLUSION:
  The present study expands the notions positing the olfactory perception - and its connections with metabolic cues, foods habits and BIA measures - changes across the two most important obesity stages. This could ameliorate clinical and research deepening of obesity-related olfactory behavior with possible consequences on diagnosis, treatment and prevention of onset and development of obesity, thus opening possible future strategies involving multidisciplinary contributions.
  
  LEVEL OF EVIDENCE:
  3 Laryngoscope, 132:2028-2035, 2022.
  
  © 2022 The American Laryngological, Rhinological and Otological Society, Inc.
  
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• Lifespan and ROS levels in different Drosophila melanogaster strains after 24?h hypoxia exposure.
  Biol Open

  2022 Jun;11(6):. doi: bio059386.
  
  Malacrida Sandro, De Lazzari Federica, Mrakic-Sposta Simona, Vezzoli Alessandra, Zordan Mauro A, Bisaglia Marco, Menti Giulio Maria, Meda Nicola, Frighetto Giovanni, Bosco Gerardo, Dal Cappello Tomas, Strapazzon Giacomo, Reggiani Carlo, Gussoni Maristella, Megighian Aram
  
  Abstract
  
  During recent decades, model organisms such as Drosophila melanogaster have made it possible to study the effects of different environmental oxygen conditions on lifespan and oxidative stress. However, many studies have often yielded controversial results usually assigned to variations in Drosophila genetic background and differences in study design. In this study, we compared longevity and ROS levels in young, unmated males of three laboratory wild-type lines (Canton-S, Oregon-R and Berlin-K) and one mutant line (Sod1n1) as a positive control of redox imbalance, under both normoxic and hypoxic (2% oxygen for 24?h) conditions. Lifespan was used to detect the effects of hypoxic treatment and differences were analysed by means of Kaplan-Meier survival curves and log-rank tests. Electron paramagnetic resonance spectroscopy was used to measure ROS levels and analysis of variance was used to estimate the effects of hypoxic treatment and to assess ROS differences between strains. We observed that the genetic background is a relevant factor involved in D. melanogaster longevity and ROS levels. Indeed, as expected, in normoxia Sod1n1 are the shortest-lived, while the wild-type strains, despite a longer lifespan, show some differences, with the Canton-S line displaying the lowest mortality rate. After hypoxic stress these variances are amplified, with Berlin-K flies showing the highest mortality rate and most evident reduction of lifespan. Moreover, our analysis highlighted differential effects of hypoxia on redox balance/unbalance. Canton-S flies had the lowest increase of ROS level compared to all the other strains, confirming it to be the less sensitive to hypoxic stress. Sod1n1 flies displayed the highest ROS levels in normoxia and after hypoxia. These results should be used to further standardize future Drosophila research models designed to investigate genes and pathways that may be involved in lifespan and/or ROS, as well as comparative studies on specific mutant strains.
  
  © 2022. Published by The Company of Biologists Ltd.
  
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• Editorial: Human Molecular and Physiological Responses to Hypoxia.
  Front Physiol

  2022 ;13():888005. doi: 888005.
  
  Malacrida Sandro, Strapazzon Giacomo, Mrakic-Sposta Simona, Pun Matiram, Cogo Annalisa
  
  
  
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• Effects of Prolonged Exposure to Hypobaric Hypoxia on Oxidative Stress: Overwintering in Antarctic Concordia Station.
  Oxid Med Cell Longev

  2022 ;2022():4430032. doi: 4430032.
  
  Mrakic-Sposta Simona, Montorsi Michela, Porcelli Simone, Marzorati Mauro, Healey Beth, Dellanoce Cinzia, Vezzoli Alessandra
  
  Abstract
  
  Concordia Station is the permanent, research station on the Antarctic Plateau at 3230?m. During the eleventh winter-over campaign (DC11-2015; February 2015 to November 2015) at Antarctic Concordia Station, 13 healthy team members were studied and blood samples were collected at six different time points: baseline measurements (T0), performed at sea level before the departure, and during the campaign at 3, 7, 20, 90, and 300 days after arrival at Concordia Station. Reducing the partial pressure of O as barometric pressure falls, hypobaric hypoxia (HH) triggers several physiological adaptations. Among the others, increased oxidative stress and enhanced generation of reactive oxygen/nitrogen species (ROS/RNS), resulting in severe oxidative damage, were observed, which can share potential physiopathological mechanisms associated with many diseases. This study characterized the extent and time-course changes after acute and chronic HH exposure, elucidating possible fundamental mechanisms of adaptation. ROS, oxidative stress biomarkers, nitric oxide, and proinflammatory cytokines significantly increased (range 24-135%) during acute and chronic hypoxia exposure (peak 20 day) with a decrease in antioxidant capacity (peak 90 day: -52%). Results suggest that the adaptive response of oxidative stress balance to HH requires a relatively long time, more than 300 days, as all the observed variables do not return to the preexposition level. These findings may also be relevant to patients in whom oxygen availability is limited through disease (i.e., chronic heart and lung and/or kidney disease) and/or during long-duration space missions.
  
  Copyright © 2022 Simona Mrakic-Sposta et al.
  
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• Lower miR-21/ROS/HNE levels associate with lower glycemia after habit-intervention: DIAPASON study 1-year later.
  Cardiovasc Diabetol

  2022 Mar;21(1):35. doi: 35.
  
  La Sala Lucia, Tagliabue Elena, Mrakic-Sposta Simona, Uccellatore Anna Chiara, Senesi Pamela, Terruzzi Ileana, Trabucchi Emilio, Rossi-Bernardi Luigi, Luzi Livio
  
  Abstract
  
  BACKGROUND:
  The prevalence of prediabetes is increasing in the global population and its metabolic derangements may expose to a higher risk to develop type 2 diabetes (T2D) and its cardiovascular burden. Lifestyle modifications might have considerable benefits on ameliorating metabolic status. Alternative biomarkers, such as circulating miR-21, has been recently discovered associated with dysglycemia. Here we evaluated, in a longitudinal cohort of dysglycemic population the relation between the circulating miR-21/ROS/HNE levels and the habit-intervention (HI) after 1 year of follow-up.
  
  METHODS:
  1506 subjects from DIAPASON study were screened based on the Findrisc score. Of them, 531 subjects with Findrisc???9 were selected for dysglycemia (ADA criteria) and tested for circulating miR-21, ROS and HNE levels, as damaging-axis. 207 subjects with dysglycemia were re-evaluated after 1-year of habit intervention (HI). Repeated measures tests were used to evaluate changes from baseline to 1-year of follow-up. The associations between glycemic parameters and miR-21/ROS/HNE were implemented by linear regression and logistic regression models.
  
  RESULTS:
  After HI, we observed a significant reduction of miR-21/ROS/HNE axis in dysglycemic subjects, concomitantly with ameliorating of metabolic parameters, including insulin resistance, BMI, microalbuminuria, reactive hyperemia index and skin fluorescence. Significant positive interaction was observed between miR-21 axis with glycaemic parameters after HI. Lower miR-21 levels after HI, strongly associated with a reduction of glycemic damaging-axis, in particular, within-subjects with values of 2hPG?200 mg/dL.
  
  CONCLUSIONS:
  Our findings demonstrated that HI influenced the epigenetic changes related to miR-21 axis, and sustain the concept of reversibility from dysglycemia. These data support the usefulness of novel biological approaches for monitoring glycemia as well as provide a screening tool for preventive programmes.
  
  © 2022. The Author(s).
  
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• OxInflammation at High Altitudes: A Proof of Concept from the Himalayas.
  Antioxidants (Basel)

  2022 Feb;11(2):. doi: 368.
  
  Mrakic-Sposta Simona, Biagini Denise, Bondi Danilo, Pietrangelo Tiziana, Vezzoli Alessandra, Lomonaco Tommaso, Di Francesco Fabio, Verratti Vittore
  
  Abstract
  
  High-altitude locations are fascinating for investigating biological and physiological responses in humans. In this work, we studied the high-altitude response in the plasma and urine of six healthy adult trekkers, who participated in a trek in Nepal that covered 300 km in 19 days along a route in the Kanchenjunga Mountain and up to a maximum altitude of 5140 m. Post-trek results showed an unbalance in redox status, with an upregulation of ROS (+19%), NOx (+28%), neopterin (+50%), and pro-inflammatory prostanoids, such as PGE (+120%) and 15-deoxy-delta12,14-PGJ (+233%). The isoprostane 15-F-IsoP was associated with low levels of TAC (-18%), amino-thiols, omega-3 PUFAs, and anti-inflammatory CYP450 EPA-derived mediators, such as DiHETEs. The deterioration of antioxidant systems paves the way to the overload of redox and inflammative markers, as triggered by the combined physical and hypoxic stressors. Our data underline the link between oxidative stress and inflammation, which is related to the concept of OxInflammation into the altitude hypoxia fashion.
  
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• Oxidative stress and motion sickness in one crew during competitive offshore sailing.
  Sci Rep

  2022 Jan;12(1):1142. doi: 1142.
  
  Giacon Tommaso Antonio, Bosco Gerardo, Vezzoli Alessandra, Dellanoce Cinzia, Cialoni Danilo, Paganini Matteo, Mrakic-Sposta Simona
  
  Abstract
  
  Competitive Offshore Ocean Sailing is a highly demanding activity in which subjects are exposed to psychophysical stressors for a long time. To better define the physiological adaptations, we investigated the stress response of subjects exposed to 3-days long ocean navigation with disruption of circadian rhythms. 6 male subjects were involved in the study and provided urine and saliva samples before setting sail, during a single day of inshore sailing, during 3-days long ocean navigation, and at the arrival, to measure oxidative stress, cortisol, nitric oxide metabolites (NOx) and metabolic response. Motion Sickness questionnaires were also administered during the navigation. The crew suffered a mean weight loss of 1.58 kg. After the long navigation, a significant increase in ROS production and decrease in total antioxidant capacity and uric acid levels were observed. Lipid peroxidation, NO metabolites, ketones, creatinine, and neopterin levels were also increased. Furthermore, a significant increase in cortisol levels was measured. Finally, we found a correlation between motion sickness questionnaires with the increase of NOx, and no correlation with cortisol levels. Physical and psychological stress response derived from offshore sailing resulted in increased oxidative stress, nitric oxide metabolites, and cortisol levels, unbalanced redox status, transient renal function impairment, and ketosis. A direct correlation between motion sickness symptoms evaluated through questionnaires and NOx levels was also found.
  
  © 2022. The Author(s).
  
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• Full-Face Mask Use during SCUBA Diving Counters Related Oxidative Stress and Endothelial Dysfunction.
  Int J Environ Res Public Health

  2022 Jan;19(2):. doi: 965.
  
  Levenez Morgan, Lambrechts Kate, Mrakic-Sposta Simona, Vezzoli Alessandra, Germonpré Peter, Pique Hadrien, Virgili Fabio, Bosco Gerardo, Lafère Pierre, Balestra Costantino
  
  Abstract
  
  Impaired flow mediated dilation (FMD), an index of vascular stress, is known after SCUBA diving. This is related to a dysfunction of nitric oxide (NO) availability and a disturbance of the redox status, possibly induced by hyperoxic/hyperbaric gas breathing. SCUBA diving is usually performed with a mask only covering "half face" (HF) and therefore forcing oral breathing. Nasal NO production is involved in vascular homeostasis and, as consequence, can significantly reduce NO possibly promoting vascular dysfunction. More recently, the utilization of "full-face" (FF) mask, allowing nasal breathing, became more frequent, but no reports are available describing their effects on vascular functions in comparison with HF masks. In this study we assessed and compared the effects of a standard shallow dive (20 min at 10 m) wearing either FF or a HF mask on different markers of vascular function (FMD), oxidative stress (ROS, 8-iso-PGF2?) and NO availability and metabolism (NO, NOx and 3-NT and iNOS expression). Data from a dive breathing a hypoxic (16% O at depth) gas mixture with HF mask are shown allowing hyperoxic/hypoxic exposure. Our data suggest that nasal breathing might significantly reduce the occurrence of vascular dysfunction possibly due to better maintenance of NO production and bioavailability, resulting in a better ability to counter reactive oxygen and nitrogen species. Besides the obvious outcomes in terms of SCUBA diving safety, our data permit a better understanding of the effects of oxygen concentrations, either in normal conditions or as a strategy to induce selected responses in health and disease.
  
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• JAB1 deletion in oligodendrocytes causes senescence-induced inflammation and neurodegeneration in mice.
  J Clin Invest

  2022 Feb;132(3):. doi: e145071.
  
  Rivellini Cristina, Porrello Emanuela, Dina Giorgia, Mrakic-Sposta Simona, Vezzoli Alessandra, Bacigaluppi Marco, Gullotta Giorgia Serena, Chaabane Linda, Leocani Letizia, Marenna Silvia, Colombo Emanuela, Farina Cinthia, Newcombe Jia, Nave Klaus-Armin, Pardi Ruggero, Quattrini Angelo, Previtali Stefano C
  
  Abstract
  
  Oligodendrocytes are the primary target of demyelinating disorders, and progressive neurodegenerative changes may evolve in the CNS. DNA damage and oxidative stress are considered key pathogenic events, but the underlying molecular mechanisms remain unclear. Moreover, animal models do not fully recapitulate human diseases, complicating the path to effective treatments. Here we report that mice with cell-autonomous deletion of the nuclear COP9 signalosome component CSN5 (JAB1) in oligodendrocytes develop DNA damage and defective DNA repair in myelinating glial cells. Interestingly, oligodendrocytes lacking JAB1 expression underwent a senescence-like phenotype that fostered chronic inflammation and oxidative stress. These mutants developed progressive CNS demyelination, microglia inflammation, and neurodegeneration, with severe motor deficits and premature death. Notably, blocking microglia inflammation did not prevent neurodegeneration, whereas the deletion of p21CIP1 but not p16INK4a pathway ameliorated the disease. We suggest that senescence is key to sustaining neurodegeneration in demyelinating disorders and may be considered a potential therapeutic target.
  
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• Changes in Factors Regulating Serum Sodium Homeostasis During Two Ultra-Endurance Mountain Races of Different Distances: 69km vs. 121km.
  Front Physiol

  2021 ;12():764694. doi: 764694.
  
  Schenk Kai, Rauch Simon, Procter Emily, Grasegger Katharina, Mrakic-Sposta Simona, Gatterer Hannes
  
  Abstract
  
  Overdrinking and non-osmotic arginine vasopressin release are the main risk factors for exercise-associated hyponatremia (EAH) in ultra-marathon events. However, particularly during ultra-marathon running in mountainous regions, eccentric exercise and hypoxia, which have been shown to modulate inflammation, hormones regulating fluid homeostasis (hypoxia), and oxidative stress, could contribute to serum sodium changes in a dose-dependent manner. To the best of our knowledge, the contribution of these factors, the extent of which depends on the duration and geographical location of the race, has not been well studied. Twelve male participants (11 finishers) of the short (69km, 4,260m elevation-gain) and 15 male participants (seven finishers) of the long (121km, 7,554m elevation-gain) single-stage Südtirol Ultra Sky-Race took part in this observational field study. Venous blood was drawn immediately before and after the race. Analyses included serum sodium concentration, copeptin (a stable marker for vasopressin), markers of inflammation, muscle damage and oxidative stress. Heart rate was measured during the race and race time was obtained from the race office. During the short and the long competition two and one finishers, respectively showed serum sodium concentrations >145mmol/L. During the long competition, one athlete showed serum sodium concentrations
  Copyright © 2021 Schenk, Rauch, Procter, Grasegger, Mrakic-Sposta and Gatterer.
  
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• Impact of Nutritional Intervention on Taste Perception-A Scoping Review.
  Foods

  2021 Nov;10(11):. doi: 2747.
  
  Micarelli Alessandro, Malacrida Sandro, Strapazzon Giacomo, Mrakic-Sposta Simona, Micarelli Beatrice, Alessandrini Nicolò, Carbini Valentina, Caputo Sara, Falla Marika, Alessandrini Marco
  
  Abstract
  
  The aim of the present scoping review was to evaluate the impact of experimental meal loads or observational diet changes/habits on taste tests in both healthy subjects and patients. A systematic search performed in PubMed, Scopus, and Institute for Scientific Information (ISI) Web of Science electronic databases retrieved, respectively 2981, 6258, and 7555 articles from January 2000 to December 2020. A total of 17 articles were included for full-text review. Literature results were stratified according to the observational/interventional approach, the involvement of healthy subjects or patients, the taste test, and the meal/dietary changes. The present scoping review reinforced the notions postulating that certain taste tests (for example focusing on fatty acid, salt, or sugar) might be specifically influenced by the nutritional intervention and that other ones might be susceptible to a wide span of changes beyond the extent of tastant included in the specific food changes. This could also depend on the inhomogeneity of literature trend: The short duration of the intervention or the random type of meal load, unsuitability of the taste test chosen, and the presence of underlying disorders. Future studies for a better comprehension of taste tests reliability in relation to specific food changes are thus to be fostered.
  
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• Oxidative Stress and Inflammation, MicroRNA, and Hemoglobin Variations after Administration of Oxygen at Different Pressures and Concentrations: A Randomized Trial.
  Int J Environ Res Public Health

  2021 Sep;18(18):. doi: 9755.
  
  Bosco Gerardo, Paganini Matteo, Giacon Tommaso Antonio, Oppio Alberto, Vezzoli Alessandra, Dellanoce Cinzia, Moro Tatiana, Paoli Antonio, Zanotti Federica, Zavan Barbara, Balestra Costantino, Mrakic-Sposta Simona
  
  Abstract
  
  Exercise generates reactive oxygen species (ROS), creating a redox imbalance towards oxidation when inadequately intense. Normobaric and hyperbaric oxygen (HBO) breathed while not exercising induces antioxidant enzymes expression, but literature is still poor. Twenty-two athletes were assigned to five groups: controls; 30%, or 50% O; 100% O (HBO) at 1.5 or 2.5 atmosphere absolute (ATA). Twenty treatments were administered on non-training days. Biological samples were collected at T0 (baseline), T1 (end of treatments), and T2 (1 month after) to assess ROS, antioxidant capacity (TAC), lipid peroxidation, redox (amino-thiols) and inflammatory (IL-6, 10, TNF-?) status, renal function (i.e., neopterin), miRNA, and hemoglobin. At T1, O mixtures and HBO induced an increase of ROS, lipid peroxidation and decreased TAC, counterbalanced at T2. Furthermore, 50% O and HBO treatments determined a reduced state in T2. Neopterin concentration increased at T1 breathing 50% O and HBO at 2.5 ATA. The results suggest that 50% O treatment determined a reduced state in T2; HBO at 1.5 and 2.5 ATA similarly induced protective mechanisms against ROS, despite the latter could expose the body to higher ROS levels and neopterin concentrations. HBO resulted in increased Hb levels and contributed to immunomodulation by regulating interleukin and miRNA expression.
  
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• Hypoxic and Hyperoxic Breathing as a Complement to Low-Intensity Physical Exercise Programs: A Proof-of-Principle Study.
  Int J Mol Sci

  2021 Sep;22(17):. doi: 9600.
  
  Balestra Costantino, Lambrechts Kate, Mrakic-Sposta Simona, Vezzoli Alessandra, Levenez Morgan, Germonpré Peter, Virgili Fabio, Bosco Gerardo, Lafère Pierre
  
  Abstract
  
  Inflammation is an adaptive response to both external and internal stimuli including infection, trauma, surgery, ischemia-reperfusion, or malignancy. A number of studies indicate that physical activity is an effective means of reducing acute systemic and low-level inflammation occurring in different pathological conditions and in the recovery phase after disease. As a proof-of-principle, we hypothesized that low-intensity workout performed under modified oxygen supply would elicit a "metabolic exercise" inducing a hormetic response, increasing the metabolic load and oxidative stress with the same overall effect expected after a higher intensity or charge exercise. Herein, we report the effect of a 5-week low-intensity, non-training, exercise program in a group of young healthy subjects in combination with the exposure to hyperoxia (30% and 100% pO, respectively) or light hypoxia (15% pO) during workout sessions on several inflammation and oxidative stress parameters, namely hemoglobin (Hb), redox state, nitric oxide metabolite (NOx), inducible nitric oxide synthase (iNOS), inflammatory cytokine expression (TNF-?, interleukin (IL)-6, IL-10), and renal functional biomarkers (creatinine, neopterin, and urates). We confirmed our previous reports demonstrating that intermittent hyperoxia induces the normobaric oxygen paradox (NOP), a response overlapping the exposure to hypoxia. Our data also suggest that the administration of modified air composition is an expedient complement to a light physical exercise program to achieve a significant modulation of inflammatory and immune parameters, including cytokines expression, iNOS activity, and oxidative stress parameters. This strategy can be of pivotal interest in all those conditions characterized by the inability to achieve a sufficient workload intensity, such as severe cardiovascular alterations and articular injuries failing to effectively gain a significant improvement of physical capacity.
  
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• Comment on Menzel et al. Common and Novel Markers for Measuring Inflammation and Oxidative Stress Ex Vivo in Research and Clinical Practice-Which to Use Regarding Disease Outcomes? 2021, , 414.
  Antioxidants (Basel)

  2021 May;10(6):. doi: 836.
  
  Mrakic-Sposta Simona, Gussoni Maristella, Montorsi Michela, Vezzoli Alessandra
  
  Abstract
  
  Recently, Menzel A et al. published a review titled "Origin and Physiological Aspects of Oxidative Stress (OS), inflammation and markers of OS, relation to disease and practical aspects" [...].
  
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• A Prospective Evaluation of the Acute Effects of High Altitude on Cognitive and Physiological Functions in Lowlanders.
  Front Physiol

  2021 ;12():670278. doi: 670278.
  
  Falla Marika, Papagno Costanza, Dal Cappello Tomas, Vögele Anna, Hüfner Katharina, Kim Jenny, Weiss Elisabeth M, Weber Bernhard, Palma Martin, Mrakic-Sposta Simona, Brugger Hermann, Strapazzon Giacomo
  
  Abstract
  
  Cognitive function impairment due to high altitude exposure has been reported with some contradictory results regarding the possible selective cognitive domain involvement. We prospectively evaluated in 36 lowlanders, exposed for 3 consecutive days to an altitude of 3,269 m, specific cognitive abilities (attention, processing speed, and decision-making) required to safely explore the mountains, as well as to work at altitude. We simultaneously monitored the physiological parameters. Our study provides evidence of a reduced processing speed in lowlanders when exposed to altitude in the first 24 h. There was a fairly quick recovery since this impairment was no more detectable after 36 h of exposure. There were no clinically relevant effects on decision-making, while psychomotor vigilance was unaffected at altitude except for individuals with poor sleep. Significant changes were seen in physiological parameters (increased heart rate and reduced peripheral oxygen saturation). Our results may have practical implications, suggesting that individuals should practice prudence with higher ascent when performing risky activities in the first 24-36 h, even at altitudes below 3,500 m, due to an impairment of the cognitive performance that could worsen and lead to accidents.
  
  Copyright © 2021 Falla, Papagno, Dal Cappello, Vögele, Hüfner, Kim, Weiss, Weber, Palma, Mrakic-Sposta, Brugger and Strapazzon.
  
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• Sulfonate-Conjugated Polyelectrolytes as Anode Interfacial Layers in Inverted Organic Solar Cells.
  Molecules

  2021 Feb;26(3):. doi: 763.
  
  Lassi Elisa, Squeo Benedetta Maria, Sorrentino Roberto, Scavia Guido, Mrakic-Sposta Simona, Gussoni Maristella, Vercelli Barbara, Galeotti Francesco, Pasini Mariacecilia, Luzzati Silvia
  
  Abstract
  
  Conjugated polymers with ionic pendant groups (CPEs) are receiving increasing attention as solution-processed interfacial materials for organic solar cells (OSCs). Various anionic CPEs have been successfully used, on top of ITO (Indium Tin Oxide) electrodes, as solution-processed anode interlayers (AILs) for conventional devices with direct geometry. However, the development of CPE AILs for OSC devices with inverted geometry is an important topic that still needs to be addressed. Here, we have designed three anionic CPEs bearing alkyl-potassium-sulfonate side chains. Their functional behavior as anode interlayers has been investigated in P3HT:PCBM (poly(3-hexylthiophene): [6,6]-phenyl C61 butyric acid methyl ester) devices with an inverted geometry, using a hole collecting silver electrode evaporated on top. Our results reveal that to obtain effective anode modification, the CPEs' conjugated backbone has to be tailored to grant self-doping and to have a good energy-level match with the photoactive layer. Furthermore, the sulfonate moieties not only ensure the solubility in polar orthogonal solvents, induce self-doping via a right choice of the conjugated backbone, but also play a role in the gaining of hole selectivity of the top silver electrode.
  
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• Beet on Alps: Time-course changes of plasma nitrate and nitrite concentrations during acclimatization to high-altitude.
  Nitric Oxide

  2021 Feb;107():66-72. doi: 10.1016/j.niox.2020.12.004.
  
  Rasica Letizia, Porcelli Simone, Limper Ulrich, Mrakic-Sposta Simona, Mazzolari Raffaele, Gelmini Fabrizio, Beretta Giangiacomo, Marzorati Mauro
  
  Abstract
  
  Nitric oxide seems to be involved in the altitude acclimatization process due to its ability to regulate pulmonary, cardiovascular and muscular responses to hypoxia. In this study, we investigated the plasma nitrate (NO) and nitrite (NO) response to hypobaric hypoxia in two groups of lowlanders exposed at different altitudes. For seven days, fourteen subjects were evaluated at Casati Hut (3269 m a.s.l. M.CEVEDALE) and eleven individuals were studied at Capanna Regina Margherita (4554 m a.s.l. M.ROSA). Before expeditions and at different time points during high-altitude sojourn, plasma NO and NO concentrations were measured by chemiluminescence. Resting peripheral arterial oxygen saturation (SpO), heart rate (HR) and mean arterial blood pressure (MAP) were monitored during the experimental period. Possible confounding factors such as dietary NO intake, physical activity and altitude changes were controlled. Sea level plasma NO and NO concentrations significantly increased at altitude in both M.CEVEDALE group (+26.2 ?M, p ? 0.0001, 95% CI [+17.6, +34.8] and +559.2 nM, p ? 0.0001, [+332.8, +785.6]) and M.ROSA group (+18.7 ?M, p ? 0.0001, [+10.8, +26.5] and +463.7 nM, p ? 0.0001, [+314.3, +613.0]). Average peak value in NO metabolites concentration occurred earlier in M.CEVEDALE group vs M.ROSA group (NO, day 3 vs day 5, p = 0.007; NO, day 3 vs day 5, p = 0.019). In both groups, resting SpO, HR and MAP values changed according to altitude levels. This study shows that exposure to hypobaric hypoxia affects nitric oxide metabolites, resulting in a significant increase in plasma NO and NO concentrations from sea level values. Interestingly, the higher the altitude reached, the longer the time taken to reach a peak in plasma concentrations of nitric oxide metabolites.
  
  Copyright © 2020 Elsevier Inc. All rights reserved.
  
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• Antioxidant Activity with Increased Endogenous Levels of Vitamin C, E and A Following Dietary Supplementation with a Combination of Glutathione and Resveratrol Precursors.
  Nutrients

  2020 Oct;12(11):. doi: 3224.
  
  Biswas Priscilla, Dellanoce Cinzia, Vezzoli Alessandra, Mrakic-Sposta Simona, Malnati Mauro, Beretta Alberto, Accinni Roberto
  
  Abstract
  
  The effects of two different dietary supplements on the redox status of healthy human participants were evaluated. The first supplement (GluS, Glutathione Synthesis) contains the precursors for the endogenous synthesis of glutathione and the second (GluReS, Glutathione and Resveratrol Synthesis) contains in addition polydatin, a precursor of resveratrol. To assess the influence of GluS and GluReS on the redox status, ten thiol species and three vitamins were measured before (t0) and after 8 weeks (t1) of dietary supplementation. An inflammatory marker, neopterin, was also assessed at the same time points. Both supplements were highly effective in improving the redox status by significantly increasing the reduced-glutathione (GSH) content and other reduced thiol species while significantly decreasing the oxidized species. The positive outcome of the redox status was most significant in the GluRes treatment group which also experienced a significant reduction in neopterin levels. Of note, the endogenous levels of vitamins C, E and A were significantly increased in both treatment groups, with best results in the GluReS group. While both dietary supplements significantly contributed to recognized antioxidant and anti-inflammatory outcomes, the effects of GluReS, the combination of glutathione and resveratrol precursors, were more pronounced. Thus, dietary supplementation with GluReS may represent a valuable strategy for maintaining a competent immune status and a healthy lifespan.
  
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• Change in Oxidative Stress Biomarkers During 30 Days in Saturation Dive: A Pilot Study.
  Int J Environ Res Public Health

  2020 Sep;17(19):. doi: 7118.
  
  Mrakic-Sposta Simona, Vezzoli Alessandra, D'Alessandro Federica, Paganini Matteo, Dellanoce Cinzia, Cialoni Danilo, Bosco Gerardo
  
  Abstract
  
  Saturation diving allows divers to reduce the risk of decompression sickness while working at depth for prolonged periods but may increase reactive oxygen species (ROS) production. Such modifications can affect endothelial function by exacerbating oxidative stress. This study investigated the effects of saturation diving on oxidative stress damage. Redox status was evaluated through: ROS production; total antioxidant capacity (TAC); nitric oxide metabolites (NOx); nitrotyrosine (3-NT); and lipid peroxidation (8-iso-PGF2?) assessment. Creatinine and neopterin were analyzed as markers of renal function and damage. Measurements were performed on saliva and urine samples obtained at four time points: pre; deep; post; and 24 h post. Four divers were included in the study. After the saturation dive (post), significant (
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• Influence of Dietary Supplementation for Hyperhomocysteinemia Treatments.
  Nutrients

  2020 Jun;12(7):. doi: 1957.
  
  Vezzoli Alessandra, Dellanoce Cinzia, Caimi Teresa Maria, Vietti Daniele, Montorsi Michela, Mrakic-Sposta Simona, Accinni Roberto
  
  Abstract
  
  Hyperhomocysteinemia is recognized as risk factor for cardiovascular and age-associated diseases. Folic acid supplementation efficiently lowers plasma homocysteine (Hcy) levels, but high intake may negatively affect health because of unnatural levels of unmetabolized folic acid in the systemic circulation. Oxoproline (Oxo) provides by glutamic acid production an increase of intracellular folic acid trapping. Aim of this study was to compare the efficacy of three supplementation protocols: (1) traditional therapy (5-methyl-tetrahydrofolate: 15 mg/day); (2) 5 mL/day of Oxo with 300 ?g folic acid (oxifolic); (3) 5 mL/day of Oxo alone (magnesio+) in a 90 days randomized trial on thirty-two moderate hyperhomocysteinemic (18.6 ± 2.4 ?mol.L) patients (age 48 ± 14 yrs). Thiols: cysteine (Cys), cysteinylglycine (Cys-Gly) and glutathione levels were assessed too. Every supplementation induced significant ( range
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• High-altitude mountain telemedicine.
  J Telemed Telecare

  2022 Feb;28(2):135-145. doi: 10.1177/1357633X20921020.
  
  Martinelli Massimo, Moroni Davide, Bastiani Luca, Mrakic-Sposta Simona, Giardini Guido, Pratali Lorenza
  
  Abstract
  
  INTRODUCTION:
  An innovative teleconsultation platform has been designed, developed and validated between summer 2017 and winter 2018, in five mountain huts and in three remote outpatient clinical centres of the Italian region Valle d'Aosta of the Mont Blanc massif area.
  
  METHODS:
  An ad-hoc videoconference system was developed within the framework of the e-Rés@MONT (Interreg ALCOTRA) European project, to tackle general health problems and high-altitude diseases (such as acute mountain sickness, high-altitude pulmonary and cerebral oedema). The system allows for contacting physicians at the main hospital in Aosta to perform a specific diagnosis and to give specific advice and therapy to the patients in an extreme environment out-hospital setting. At an altitude between 1500-3500 m, five trained nurses performed clinical evaluations (anamnesis, blood pressure, heart rate, oxygen saturation), electrocardiographic and echography monitoring on both tourists and residents as necessary; all of the collected data were sent to the physicians in Aosta.
  
  RESULTS:
  A total of 702 teleconsultation cases were performed: 333 dismissed (47%), 356 observed (51%) and 13 immediate interventions (2%). In 30 cases the physicians decided there was no need for helicopter and ambulance rescue intervention and hospital admissions. The main physiological measures, the classified pathologies, the severe cases and the cost savings are described in this article.
  
  DISCUSSION:
  The e-Rés@MONT teleconsultation platform has been discussed in terms of treated cases, feasibility, proactivity in reducing complexities, direct and indirect advantages, and diagnostics help; moreover, general and specific pros and cons have been debated, and future steps have been exposed.
  
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• Commentary on: "Targeted and untargeted metabolomics applied to occupational exposure to hyperbaric atmosphere".
  Toxicol Lett

  2020 May;330():71-72. doi: 10.1016/j.toxlet.2020.05.021.
  
  Mrakic-Sposta Simona, Bosco Gerardo, Vezzoli Alessandra
  
  
  
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• Acute Effects of Triathlon Race on Oxidative Stress Biomarkers.
  Oxid Med Cell Longev

  2020 ;2020():3062807. doi: 3062807.
  
  Mrakic-Sposta Simona, Gussoni Maristella, Vezzoli Alessandra, Dellanoce Cinzia, Comassi Mario, Giardini Guido, Bruno Rosa Maria, Montorsi Michela, Corciu Anca, Greco Fulvia, Pratali Lorenza
  
  Abstract
  
  The response to strenuous exercise was investigated by reactive oxygen species (ROS) production, oxidative damage, thiol redox status, and inflammation assessments in 32 enrolled triathlon athletes (41.9 ± 7.9 yrs) during Ironman® (IR), or half Ironman® (HIR) competition. In biological samples, inflammatory cytokines, aminothiols (glutathione (GSH), homocysteine (Hcy), cysteine (Cys), and cysteinylglycine (CysGly)), creatinine and neopterin, oxidative stress (OxS) biomarkers (protein carbonyl (PC), thiobarbituric acid-reactive substances (TBARS)), and ROS were assessed. Thirteen HIR and fourteen IR athletes finished the race. Postrace, ROS (HIR +20%; IR +28%;
  Copyright © 2020 Simona Mrakic-Sposta et al.
  
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• Moderate Intensity Resistive Training Reduces Oxidative Stress and Improves Muscle Mass and Function in Older Individuals.
  Antioxidants (Basel)

  2019 Sep;8(10):. doi: 431.
  
  Vezzoli Alessandra, Mrakic-Sposta Simona, Montorsi Michela, Porcelli Simone, Vago Paola, Cereda Ferdinando, Longo Stefano, Maggio Marcello, Narici Marco
  
  Abstract
  
  An innovative moderate-intensity resistive exercise-training (RT) program was tested in thirty-five sarcopenic elders (SAR). The subjects were randomized into two groups: SAR training (SAR-RT), n = 20, 73.0 ± 5.5 years, or SAR non-training (SAR-NT), n = 15, 71.7 ± 3.4 years. The training consisted of 12-week progressive RT, thrice/week, at 60% one-repetition maximum (1RM), 3 sets, 14-16 repetitions for both upper and lower limbs. The pre and post intervention measurements included: the skeletal muscle index (SMI%); strength (1RM); stair-climbing power (SCP); muscle thickness (MT) of vastus lateralis (VL) and elbow flexors (EF), VL pennation angle (PA), rectus femoris (RF) anatomical cross-sectional area (ACSA); reactive oxygen species (ROS), total antioxidant capacity (TAC), protein carbonyls (PC), thiobarbituric acid-reactive substances (TBARS), 8-isoprostane (8-iso-PGF2-?), 8-OH-2-deoxyguanosine (8-OH-dG), as markers of oxidative stress/damage (OxS). In SAR-RT, SCP increased by 7.7% ( 0.01), MT increased by 5.5% for VL, 10.4% for EF and PA increased by 13.4% for VL ( 0.001 for all). The RF ACSA increased by 14.5% ( 0.001). 1RM significantly increased by at least 67% for all muscles tested. Notably muscle strength (1RM) positively correlated ( 0.001) with TAC and negatively with PC ( 0.001). In conclusion, moderate intensity RT is an effective strategy to increase muscle mass and strength in SAR, while minimizing OxS.
  
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• Oxidative stress assessment in breath-hold diving.
  Eur J Appl Physiol

  2019 Dec;119(11-12):2449-2456. doi: 10.1007/s00421-019-04224-4.
  
  Mrakic-Sposta Simona, Vezzoli Alessandra, Rizzato Alex, Della Noce Cinzia, Malacrida Sandro, Montorsi Michela, Paganini Matteo, Cancellara Pasqua, Bosco Gerardo
  
  Abstract
  
  PURPOSE:
  Breath-hold diving results in significant changes in blood gases' levels. Challenging variations in oxygen partial pressures may induce reactive oxygen species (ROS) production that exacerbate oxidative stress and, consequently, affect endothelial function. The aim of this study was to investigate the effects of breath-hold diving on oxidative stress damage, assessing ROS production. Nitric oxide metabolites, inducible nitric oxide synthase (iNOS), aminothiols, and renal function were evaluated too as markers of redox status and renal damage.
  
  METHODS:
  ROS production was assessed with electron paramagnetic resonance. Oxidative status values were measured at pre- and post-40 m dive in a deep swimming pool (Y-40) from six divers (mean age 46.6?±?9.3 years; height 176?±?4 cm; BMI 25?±?2.9 kg/m).
  
  RESULTS:
  Significant (p?0.05) increases at post-dive of ROS production rate (0.158?±?0.003 vs 0.195?±?0.006 ?mol min), lipid peroxidation (8-isoprostane: 375.67?±?195.62 vs 420.49?±?232.31 pg mg creatinine), nitrate (27.91?±?19.71 vs 30.80?±?20.44 ?M), iNOS (31.30?±?4.52 vs 35.68?±?6.72 IU mL) and neopterin concentration (96.20?±?40.41 vs 118.76?±?27.84 ?mol mol creatinine) were recorded. Conversely, the antioxidant capacity significantly decreased (3.423?±?0.089 vs 3.015?±?0.284 mM) after immersion.
  
  CONCLUSION:
  Overproduction of ROS and consequent oxidative damage to lipids of membrane and antioxidant capacity decreasing reflect also a hypoxic condition, which in the breath-hold diving typically occurs in the last few meters below the surface. iNOS produces NO in large quantities under the examined extreme conditions. Neopterin and creatinine concentration level increased, suggesting an "impairment of renal function" as a likely physiological response to PaO variations during dive activity.
  
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• Urinary physiology and hypoxia: a pilot study of moderate-altitude trekking effects on urodynamic indexes.
  Am J Physiol Renal Physiol

  2019 Oct;317(4):F1081-F1086. doi: 10.1152/ajprenal.00333.2019.
  
  Verratti Vittore, Mrakic-Sposta Simona, Moriggi Manuela, Tonacci Alessandro, Bhandari Suwas, Migliorelli Danilo, Bajracharya Ashok, Bondi Danilo, Agrò Enrico Finazzi, Cerretelli Paolo
  
  Abstract
  
  Exposure to high altitude is one of the most widely used models to study the adaptive response to hypoxia in humans. However, little is known about the related effects on micturition. The present study addresses the adaptive urinary responses in four healthy adult lowlanders, comparing urodynamic indexes at Kathmandu [1,450 m above sea level (a.s.l.); K] and during a sojourn in Namche Bazar (3,500 m a.s.l.; NB). The urodynamic testing consisted of cistomanometry and bladder pressure/flow measurements. Anthropometrics, electrocardiographic, and peripheral capillary oxygen saturation data were also collected. The main findings consisted of significant reductions in bladder power at maximum urine flow by ~30%, bladder contractility index by 13%, and infused volume both at first (by 57%) and urgency sensation (by 14%) to urinate, indicating a reduced cystometric capacity, at NB. In addition to the urinary changes, we found that oxygen saturation, body mass index, body surface area, and median RR time were all significantly reduced at altitude. We submit that the hypoxia-related parasympathetic inhibition could be the underlying mechanism of both urodynamic and heart rate adaptive responses to high-altitude exposure. Moreover, increased diuresis and faster bladder filling at altitude may trigger the anticipation of being able to void, a common cause of urgency. We believe that the present pilot study represents an original approach to the study of urinary physiology at altitude.
  
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• Transcription Factors Regulation in Human Peripheral White Blood Cells during Hypobaric Hypoxia Exposure: an in-vivo experimental study.
  Sci Rep

  2019 Jul;9(1):9901. doi: 9901.
  
  Malacrida Sandro, Giannella Alessandra, Ceolotto Giulio, Reggiani Carlo, Vezzoli Alessandra, Mrakic-Sposta Simona, Moretti Sarah, Turner Rachel, Falla Marika, Brugger Hermann, Strapazzon Giacomo
  
  Abstract
  
  High altitude is a natural laboratory, within which the clinical study of human physiological response to hypobaric hypoxia (HH) is possible. Failure in the response results in progressive hypoxemia, inflammation and increased tissue oxidative stress (OxS). Thus, investigating temporal changes in key transcription factors (TFs) HIF-1?, HIF-2?, NF-?B and NRF2 mRNA levels, relative to OxS and inflammatory markers, may reveal molecular targets which contrast deleterious effects of hypoxia. Biological samples and clinical data from 15 healthy participants were collected at baseline and after rapid, passive ascent to 3830?m (24?h and 72?h). Gene expression was assessed by qPCR and ROS generation was determined by EPR spectroscopy. Oxidative damage and cytokine levels were estimated by immuno or enzymatic methods. Hypoxia transiently enhanced HIF-1? mRNA levels over time reaching a peak after 24?h. Whereas, HIF-2? and NRF2 mRNA levels increased over time. In contrast, the NF-?B mRNA levels remained unchanged. Plasma levels of IL-1? and IL-6 also remained within normal ranges. ROS production rate and markers of OxS damage were significantly increased over time. The analysis of TF-gene expression suggests that HIF-1? is a lead TF during sub-acute HH exposure. The prolongation of the HH exposure led to a switch between HIF-1? and HIF-2?/NRF2, suggesting the activation of new pathways. These results provide new insights regarding the temporal regulation of TFs, inflammatory state, and ROS homeostasis involved in human hypoxic response, potentially also relevant to the mediation of diseases that induce a hypoxic state.
  
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• Circulating microRNA-21 is an early predictor of ROS-mediated damage in subjects with high risk of developing diabetes and in drug-naïve T2D.
  Cardiovasc Diabetol

  2019 Feb;18(1):18. doi: 18.
  
  La Sala Lucia, Mrakic-Sposta Simona, Tagliabue Elena, Prattichizzo Francesco, Micheloni Stefano, Sangalli Elena, Specchia Claudia, Uccellatore Anna Chiara, Lupini Silvia, Spinetti Gaia, de Candia Paola, Ceriello Antonio
  
  Abstract
  
  BACKGROUND:
  Impaired glucose tolerance (IGT) is a risk factor for the development of diabetes and related complications that ensue. Early identification of at-risk individuals might be beneficial to reduce or delay the progression of diabetes and its related complications. Recently, microRNAs emerged as potential biomarkers of diseases. The aim of the present study was to evaluate microRNA-21 as a potential biomarker for the risk of developing diabetes in adults with IGT and to investigate its downstream effects as the generation of reactive oxygen species (ROS), the induction of manganese-superoxide dismutase-2 (SOD2), and the circulating levels of 4-HNE (4-hydroxynonenal).
  
  METHODS:
  To evaluate the prognostic and predictive values of plasmatic microRNA-21 in identifying metabolic derangements, we tested a selected cohort (n?=?115) of subjects enrolled in the DIAPASON Study, whom were selected on ADA criteria for 2hPG. Statistical analysis was performed using ANOVA or the Kruskal-Wallis test as appropriate. ROC curves were drawn for diagnostic accuracy of the tests; positive and negative predictive values were performed, and Youden's index was used to seek the cut-off optimum truncation point. ROS, SOD2 and 4-HNE were also evaluated.
  
  RESULTS:
  We observed significant upregulation of microRNA-21 in IGT and in T2D subjects, and microRNA-21 was positively correlated with glycaemic parameters. Diagnostic performance of microRNA-21 was high and accurate. We detected significant overproduction of ROS by electron paramagnetic resonance (EPR), significant accumulation of the lipid peroxidation marker 4-HNE, and defective SOD2 antioxidant response in IGT and newly diagnosed, drug-naïve T2D subjects. In addition, ROC curves demonstrated the diagnostic accuracy of markers used.
  
  CONCLUSIONS:
  our data demonstrate that microRNA-21 is associated with prediabetic status and exhibits predictive value for early detection of glucose imbalances. These data could provide novel clues for miR-based biomarkers to evaluate diabetes.
  
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• Pemetrexed-loaded nanoparticles targeted to malignant pleural mesothelioma cells: an in vitro study.
  Int J Nanomedicine

  2019 ;14():773-785. doi: 10.2147/IJN.S186344.
  
  Cova Emanuela, Pandolfi Laura, Colombo Miriam, Frangipane Vanessa, Inghilleri Simona, Morosini Monica, Mrakic-Sposta Simona, Moretti Sarah, Monti Manuela, Pignochino Ymera, Benvenuti Silvia, Prosperi Davide, Stella Giulia, Morbini Patrizia, Meloni Federica
  
  Abstract
  
  PURPOSE:
  Malignant pleural mesothelioma (MPM) is an aggressive tumor characterized by poor prognosis. Its incidence is steadily increasing due to widespread asbestos exposure. There is still no effective therapy for MPM. Pemetrexed (Pe) is one of the few chemotherapeutic agents approved for advanced-stage disease, although the objective response to the drug is limited. The use of gold nanoparticles (GNPs) as a drug delivery system promises several advantages, including specific targeting of malignant cells, with increased intracellular drug accumulation and reduced systemic toxicity, and, in the case of MPM, direct treatment administration into the pleural space. This study aims at exploring CD146 as a potential MPM cell-specific target for engineered Pe-loaded GNPs and to assess their effectiveness in inhibiting MPM cell line growth.
  
  METHODS:
  MPM cell lines and primary cultures obtained by pleural effusions from MPM patients were assayed for CD146 expression by flow cytometry. Internalization by MPM cell lines of fluorescent dye-marked GNPs decorated with a monoclonal anti CD146 coated GNPs (GNP-HC) was proven by confocal microscopy. The effects of anti CD146 coated GNPs loaded with Pe (GNP-HCPe) on MPM cell lines were evaluated by cell cycle (flow cytometry), viability (MTT test), clonogenic capacity (soft agar assay), ROS production (electric paramagnetic resonance), motility (wound healing assay), and apoptosis (flow cytometry).
  
  RESULTS:
  GNP-HC were selectively uptaken by MPM cells within 1 hour. MPM cell lines were blocked in the S cell cycle phase in the presence of GNP-HCPe. Both cell viability and motility were significantly affected by nanoparticle treatment compared to Pe. Apoptotic rate and ROS production were significantly higher in the presence of nanoparticles. Clonogenic capacity was completely inhibited following nanoparticle internalization.
  
  CONCLUSION:
  GNP-HCPe treatment displays in vitro antineoplastic action and is more effective than Pe alone in inhibiting MPM cell line malignant phenotype. The innovative use of specifically targeted GNPs opens the perspective of local intrapleural administration to avoid normal cell toxicity and enhance chemotherapy efficacy.
  
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• Behavioral and Neurophysiological Effects of Transcranial Direct Current Stimulation (tDCS) in Fronto-Temporal Dementia.
  Front Behav Neurosci

  2018 ;12():235. doi: 235.
  
  Ferrucci Roberta, Mrakic-Sposta Simona, Gardini Simona, Ruggiero Fabiana, Vergari Maurizio, Mameli Francesca, Arighi Andrea, Spallazzi Marco, Barocco Federica, Michelini Giovanni, Pietroboni Anna Margherita, Ghezzi Laura, Fumagalli Giorgio Giulio, D'Urso Giordano, Caffarra Paolo, Scarpini Elio, Priori Alberto, Marceglia Sara
  
  Abstract
  
  Fronto-temporal dementia (FTD) is the clinical-diagnostic term that is now preferred to describe patients with a range of progressive dementia syndromes associated with focal atrophy of the frontal and anterior temporal cerebral regions. Currently available FTD medications have been used to control behavioral symptoms, even though they are ineffective in some patients, expensive and may induce adverse effects. Alternative therapeutic approaches are worth pursuing, such as non-invasive brain stimulation with transcranial direct current (tDCS). tDCS has been demonstrated to influence neuronal excitability and reported to enhance cognitive performance in dementia. The aim of this study was to investigate whether applying Anodal tDCS (2 mA intensity, 20 min) over the fronto-temporal cortex bilaterally in five consecutive daily sessions would improve cognitive performance and behavior symptoms in FTD patients, also considering the neuromodulatory effect of stimulation on cortical electrical activity measured through EEG. We recruited 13 patients with FTD and we tested the effect of Anodal and Sham (i.e., placebo) tDCS in two separate experimental sessions. In each session, at baseline (T0), after 5 consecutive days (T1), after 1 week (T2), and after 4 weeks (T3) from the end of the treatment, cognitive and behavioral functions were tested. EEG (21 electrodes, 10-20 international system) was recorded for 5 min with eyes closed at the same time points in nine patients. The present findings showed that Anodal tDCS applied bilaterally over the fronto-temporal cortex significantly improves (1) neuropsychiatric symptoms (as measured by the neuropsychiatric inventory, NPI) in FTD patients immediately after tDCS treatment, and (2) simple visual reaction times (sVRTs) up to 1 month after tDCS treatment. These cognitive improvements significantly correlate with the time course of the slow EEG oscillations (delta and theta bands) measured at the same time points. Even though further studies on larger samples are needed, these findings support the effectiveness of Anodal tDCS over the fronto-temporal regions in FTD on attentional processes that might be correlated to a normalized EEG low-frequency pattern.
  
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• Effects of Combined Physical and Cognitive Virtual Reality-Based Training on Cognitive Impairment and Oxidative Stress in MCI Patients: A Pilot Study.
  Front Aging Neurosci

  2018 ;10():282. doi: 282.
  
  Mrakic-Sposta Simona, Di Santo Simona G, Franchini Flaminia, Arlati Sara, Zangiacomi Andrea, Greci Luca, Moretti Sarah, Jesuthasan Nithiya, Marzorati Mauro, Rizzo Giovanna, Sacco Marco, Vezzoli Alessandra
  
  Abstract
  
  The growing elderly population and the increased incidence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) call for the improvement of the quality and the efficacy of the healthcare and social support services. Exercise and cognitive stimulation have been demonstrated to mitigate cognitive impairment and oxidative stress (OxS) has been recognized as a factor that contributes to the advancement of neurodegenerative diseases. Taking these aspects into account, the impact of a novel virtual reality (VR)-based program combining aerobic exercise and cognitive training has been evaluated in the pilot study proposed here. Ten patients (aged 73.3 ± 5.7 years) with MCI (Mini-Mental State Examination, MMSE: 23.0 ± 3.4) were randomly assigned to either 6 weeks physical and cognitive training (EXP) or control (CTR) group. Evaluations of cognitive profile, by a neuropsychological tests battery, and OxS, by collection of blood and urine samples, were performed before and at the end of the experimental period. The assessment of the patients' opinions toward the intervention was investigated through questionnaires. EXP group showed a tendency towards improvements in the MMSE, in visual-constructive test and visuo-spatial tests of attention, while CTR worsened. EXP group showed a greater improvement than CTR in the executive test, memory functions and verbal fluency. No statistical significance was obtained when comparing within and between both the groups, probably due to small number of subjects examined, which amplifies the effect of the slight heterogeneity in scores recorded. Despite a greater worsening of Daily Living Activities tests, all participants reported a better performance in real life, thanks to the elicited self-perceived improvement. After training intervention OxS (i.e., reactive oxygen species (ROS) production, oxidative damage of lipids and DNA) decreased resulting in significantly (range
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• Hyperbaric oxygen therapy ameliorates osteonecrosis in patients by modulating inflammation and oxidative stress.
  J Enzyme Inhib Med Chem

  2018 Dec;33(1):1501-1505. doi: 10.1080/14756366.2018.1485149.
  
  Bosco Gerardo, Vezzani Giuliano, Mrakic Sposta Simona, Rizzato Alex, Enten Garrett, Abou-Samra Abdullah, Malacrida Sandro, Quartesan Silvia, Vezzoli Alessandra, Camporesi Enrico
  
  Abstract
  
  Early stages of avascular necrosis of the femoral head (AVNFH) can be conservatively treated with hyperbaric oxygen therapy (HBOT). This study investigated how HBOT modulates inflammatory markers and reactive oxygen species (ROS) in patients with AVNFH. Twenty-three male patients were treated with two cycles of HBOT, 30 sessions each with a 30 days break between cycles. Each session consisted of 90?minutes of 100% inspired oxygen at 2.5 absolute atmospheres of pressure. Plasma levels of tumor necrosis factor alfa (TNF-?), interleukin 6 (IL-6), interleukin 1 beta (IL-1?) and ROS production were measured before treatment (T0), after 15 and 30 HBOT sessions (T1 and T2), after the 30-day break (T3), and after 60 sessions (T4). Results showed a significant reduction in TNF-? and IL-6 plasma levels over time. This decrease in inflammatory markers mirrored observed reductions in bone marrow edema and reductions in patient self-reported pain.
  
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• Acute Cardiovascular Adaptation to Strenuous Exercise: An Integrative Ultrasound Study.
  J Ultrasound Med

  2019 Feb;38(2):463-470. doi: 10.1002/jum.14719.
  
  Bianchini Elisabetta, Bruno Rosa Maria, Di Lascio Nicole, Vezzoli Alessandra, Mrakic-Sposta Simona, Corciu Anca Irina, Comassi Mario, Pratali Lorenza
  
  Abstract
  
  OBJECTIVES:
  The aim of this study was to evaluate the acute effects of participation in an Ironman distance triathlon competition on arterial function by ultrasound, in relation to cardiac function and body water content.
  
  METHODS:
  Twenty-eight male triathletes participating in an Ironman distance competition underwent carotid, femoral, and cardiac ultrasound examinations. Moreover, the presence of extravascular lung water was identified by lung echo B-lines (echogenic coherent wedge-shaped signal with a narrow origin from the hyperechoic pleural line) at rest and within 20 minutes of arrival.
  
  RESULTS:
  At the end of the competition, athletes showed an increased heart rate (mean?±?SD, from 60.2?±?13.1 to 82.8?±?15.6 beats/min; P?.0001) and unchanged mean blood pressure (from 93?±?14 to 91?±?10?mm Hg; P?>?.05) in the presence of negligible dehydration (total body water from 48.0?±?4.0 to 46.5?±?3.9?kg; P?>?.05). Cardiac output increased (from 5.5?±?1.2 to 6.7?±?2.4?L/min; P?.05) in the presence of an unchanged stroke volume (from 64?±?14 to 59?±?16?mL; P?>?.05) and unchanged left ventricular elastance (from 1.52?±?0.48 to 1.39?±?0.48?mm Hg/mL/m ; P?>?.05). The mean carotid diameter increased (from 7.19?±?0.65 to 7.61?±?0.76?mm; P?.05), whereas the mean femoral diameter was unchanged at the end of the competition (from 10.41?±?0.83 to 10.49?±?0.82?mm; P?>?.05). Carotid intima-media thickness was significantly reduced (from 537?±?70 to 495?±?70??m; P?.05), whereas B-lines increased significantly after the competition (from 1 [0-4] to 12 [5-23]; P?.0001).
  
  CONCLUSIONS:
  These data suggest different acute functional adaptation in central arteries with respect to peripheral leg vessels.
  
  © 2018 by the American Institute of Ultrasound in Medicine.
  
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• Glucose-sensing microRNA-21 disrupts ROS homeostasis and impairs antioxidant responses in cellular glucose variability.
  Cardiovasc Diabetol

  2018 Jul;17(1):105. doi: 105.
  
  La Sala Lucia, Mrakic-Sposta Simona, Micheloni Stefano, Prattichizzo Francesco, Ceriello Antonio
  
  Abstract
  
  BACKGROUND:
  Antioxidant enzymes play a fundamental role in counteracting oxidative stress induced by high glucose. Although mitochondrial superoxide dismutase (SOD2) is the principal defence against the toxicity of superoxide anions, the mechanism of its inactivation in diabetic subjects is still poorly understood. Recently, microRNA-21 has been associated with diabetes, although its function remains unclear. We sought to explore the mechanism underlying defective SOD2 antioxidant response in HUVECs during exposures to constant high glucose and oscillating glucose (as glucose variability model, GV) and the role of miR-21 in increasing the susceptibility to oxidative stress by disrupting reactive oxygen species (ROS) homeostasis.
  
  METHODS:
  HUVECs exposed for 1 week to constant high glucose and GV were subjected to quantitative electron paramagnetic resonance for ROS measurements. Superoxide anions, SOD2 protein levels and mitochondrial membrane potential (??m) were also evaluated. Endogenous miR-21 and its putative ROS-homeostatic target genes (KRIT1, FoxO1, NFE2L2 and SOD2) were tested using mimic-miR-21 and quantified by qPCR. Luciferase assays were performed to test miR-21/3'-UTR-SOD2 binding.
  
  RESULTS:
  We observed upregulation of microRNA-21, overproduction of superoxide anions and total ROS generation, depolarisation of the mitochondrial membrane potential (??m) and defective SOD2 antioxidant response in HUVECs subjected to constant high glucose and GV exposures. We also found that exogenous mimic-microRNA-21 targeted putative microRNA-21 ROS-homeostatic target genes, e.g., KRIT1, NRF2 and SOD2, which were significantly downregulated. All these effects were reverted by a microRNA-21 inhibitor, which improved SOD2 and KRIT1 expression, reduced the levels of ROS production and ameliorated ??m.
  
  CONCLUSIONS:
  Our data demonstrate the association of microRNA-21 with oscillating and high glucose and early mitochondrial dysfunction. We found that microRNA-21 may promote the suppression of homeostatic signalling that normally limits ROS damage. These data provide novel clues about the inhibition of microRNA-21 as a new therapeutic approach to protect against cellular oxidative injury in glucose variability and diabetes.
  
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• Oxidative stress as a biomarker for monitoring treated celiac disease.
  Clin Transl Gastroenterol

  2018 Jun;9(6):157. doi: 157.
  
  Moretti Sarah, Mrakic-Sposta Simona, Roncoroni Leda, Vezzoli Alessandra, Dellanoce Cinzia, Monguzzi Erika, Branchi Federica, Ferretti Francesca, Lombardo Vincenza, Doneda Luisa, Scricciolo Alice, Elli Luca
  
  Abstract
  
  INTRODUCTION:
  High levels of reactive oxygen species (ROS) and impaired antioxidant defense systems lead to oxidative stress (OxS) and tissue injury in different intestinal and extra intestinal conditions, including celiac disease (CD). The aim of the present study was to investigate the role and potential use of ROS and other biomarkers of OxS in the clinical management of CD.
  
  METHODS:
  We collected duodenal specimens and blood samples from naïve patients (N-CD), patients on a gluten free diet (GFD) including responders (CD-GFD) and non-responders (NRCD). We measured plasmatic ROS production (electron paramagnetic resonance, EPR), lipid peroxidation (thiobarbituric acid-reactive substances, TBARS), protein oxidation (protein carbonyl, PC), total antioxidant capacity (TAC), nitric oxides and glutathione (GSH) in erythrocytes.
  
  RESULTS:
  Fifty-four patients affected by CD were enrolled (17 N-CD, 18 CD-GFD and 19 NRCD; 44?F; age 44?±?13 years). A significant increase of plasmatic OxS biomarkers (ROS, peroxidated lipids, oxidized proteins, and nitrate concentrations) and decrease of antioxidant species (TAC and GSH levels) were found in NRCD and N-CD compared to CD-GFD. Comparably, a significant direct relationship between the severity of duodenal atrophy, ROS production rates and TBARS was found; conversely, TAC and GSH presented an inverse correlation.
  
  DISCUSSION:
  OxS is involved in CD tissue damage and correlates with the degree of duodenal atrophy. These findings suggest the possible role of OxS biomarkers as indicators of CD activity during the clinical follow-up.
  
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• R(+)-Thioctic Acid Effects on Oxidative Stress and Peripheral Neuropathy in Type II Diabetic Patients: Preliminary Results by Electron Paramagnetic Resonance and Electroneurography.
  Oxid Med Cell Longev

  2018 ;2018():1767265. doi: 1767265.
  
  Mrakic-Sposta Simona, Vezzoli Alessandra, Maderna Luca, Gregorini Francesca, Montorsi Michela, Moretti Sarah, Greco Fulvia, Cova Emanuela, Gussoni Maristella
  
  Abstract
  
  OBJECTIVES:
  Diabetic neuropathy is the most common complication of diabetes. The idea of alterations in energy metabolism in diabetes is emerging. The biogenic antioxidant R(+)-thioctic acid has been successfully used in the treatment of diabetic polyneuropathic (DPN) patients.
  
  METHODS:
  The effects of R(+)-thioctic acid (1 tablet, 1.6?g) administration were evaluated in 12 DPN patients at baseline and at 15, 30, 60, and 120 administration days throughout the assessment of oxidative stress (OxS); ROS production rate by electron paramagnetic resonance (EPR) technique; and oxidative damage biomarkers (thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PC)), electroneurography (ENG) and visual analogue scale.
  
  RESULTS:
  Supplementation induced significant changes (
  CONCLUSION:
  The results strongly indicate that an increased antioxidant capacity plays an important role in OxS, nerve conduction velocity, pain, and general wellness improvement. Nevertheless, the effects of the antioxidant compound were found positive up to 60 days. Then, a hormesis effect was observed. Novelty of the research would be a challenge for investigators to carefully address issues, including dose range factors, appropriate administration time, and targeting population to counteract possible "boomerang effects." The great number of monitored parameters would firmly stress these conclusions.
  
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• Spirometry and oxidative stress after rebreather diving in warm water.
  Undersea Hyperb Med

  2018 ;45(2):191-198.
  
  Bosco Gerardo, Rizzato Alex, Quartesan Silvia, Camporesi Enrico, Mrakic-Sposta Simona, Moretti Sarah, Balestra Costantino, Rubini Alessandro
  
  Abstract
  
  INTRODUCTION:
  Hyperbaric oxygen (HBO?) therapy and use of enriched air can result in oxidative injury affecting the brain, lungs and eyes. HBO? exposure during diving can lead to a decrease in respiratory parameters. However, the possible effects of acute exposure to oxygen-enriched diving on subsequent spirometric performance and oxidative state in humans have not been recently described recently. We aim to investigate possible effects of acute (i) hyperbaric and (ii) hyperbaric hyperoxic exposure using scuba or closed-circuit rebreather (CCR) on subsequent spirometry and to assess the role of oxidative state after hyperoxic diving.
  
  METHODS:
  Spirometry and urine samples were obtained from six well-trained divers (males, mean ± SD, age: 43.33 ± 9.16 years; weight: 79.00 ± 4.90 kg; height: 1.77 ± 0.07 meters) before (CTRL) and after a dive breathing air, and after a dive using CCR (PO? 1.4). In the crossover design (two dives separated by six hours) each subject performed a 20-minute session of light underwater exercise at a depth of 15 meters in warm water (31-32°C). We measured urinary 8-isoprostane and 8-OH-2-deoxyguanosine evaluating lipid and DNA oxidative damages.
  
  RESULTS:
  Different breathing conditions (air vs. CCR) did not significantly affect spirometry. A significant increase of 8-OH-dG (1.85 ± 0.66 vs. 4.35 ± 2.12; P ? 0.05) and 8-isoprostane (1.35 ± 0.20 vs. 2.59 ± 0.61; P ? 0.05) levels after CCR dive with respect to the CTRL was observed. Subjects did not have any ill effects during diving.
  
  CONCLUSIONS:
  Subjects using CCR showed elevated oxidative stress, but this did not correlate with a reduction in pulmonary function.
  
  Copyright© Undersea and Hyperbaric Medical Society.
  
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• Effects of the Ketogenic diet in overweight divers breathing Enriched Air Nitrox.
  Sci Rep

  2018 Feb;8(1):2655. doi: 2655.
  
  Bosco Gerardo, Rizzato Alex, Quartesan Silvia, Camporesi Enrico, Mangar Devanand, Paganini Matteo, Cenci Lorenzo, Malacrida Sandro, Mrakic-Sposta Simona, Moretti Sara, Paoli Antonio
  
  Abstract
  
  Central Nervous System Oxygen Toxicity (CNS-OT) is one of the most harmful effects of Enriched Air Nitrox (EAN) diving. Protective factors of the Ketogenic Diet (KD) are antioxidant activity, the prevention of mitochondrial damage and anti-inflammatory mechanisms. We aimed to investigate if a short-term KD may reduce oxidative stress and inflammation during an hyperoxic dive. Samples from six overweight divers (mean?±?SD, age: 55.2?±?4.96 years; BMI: 26.7?±?0.86?kg/m) were obtained a) before and after a dive breathing Enriched Air Nitrox and performing 20-minute mild underwater exercise, b) after a dive (same conditions) performed after 7 days of KD. We measured urinary 8-isoprostane and 8-OH-2-deoxyguanosine and plasmatic IL-1?, IL-6 and TNF-? levels. The KD was successful in causing weight loss (3.20?±?1.31?Kgs, p?0.01) and in limiting lipid peroxidation (3.63?±?1.16 vs. 1.11?±?0.22; p?0.01) and inflammatory response (IL-1??=?105.7?±?25.52 vs. 57.03?±?16.32, p?0.05; IL-6?=?28.91?±?4.351 vs. 14.08?±?1.74, p?0.001; TNF-??=?78.01?±?7.69 vs. 64.68?±?14.56, p?0.05). A short-term KD seems to be effective in weight loss, in decreasing inflammation and protective towards lipid peroxidation during hyperoxic diving.
  
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• Cathodal Transcranial Direct Current Stimulation Improves Focal Hand Dystonia in Musicians: A Two-Case Study.
  Front Neurosci

  2017 ;11():508. doi: 508.
  
  Marceglia Sara, Mrakic-Sposta Simona, Fumagalli Manuela, Ferrucci Roberta, Mameli Francesca, Vergari Maurizio, Barbieri Sergio, Priori Alberto
  
  Abstract
  
  Focal hand dystonia (FHD) in musicians is a movement disorder causing abnormal movements and irregularities in playing. Since weak electrical currents applied to the brain induce persistent excitability changes in humans, cathodal tDCS was proposed as a possible non-invasive approach for modulating cortical excitability in patients with FHD. However, the optimal targets and modalities have still to be determined. In this pilot study, we delivered cathodal (2 mA), anodal (2 mA) and sham tDCS over the motor areas bilaterally for 20 min daily for five consecutive days in two musicians with FHD. After cathodal tDCS, both patients reported a sensation of general wellness and improved symptoms of FHD. In conclusion, our pilot results suggest that cathodal tDCS delivered bilaterally over motor-premotor (M-PM) cortex for 5 consecutive days may be effective in improving symptoms in FHD.
  
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• Enhanced Right-Chamber Remodeling in Endurance Ultra-Trail Athletes Compared to Marathon Runners Detected by Standard and Speckle-Tracking Echocardiography.
  Front Physiol

  2017 ;8():527. doi: 527.
  
  Ujka Kristian, Bastiani Luca, D'Angelo Gennaro, Catuzzo Bruna, Tonacci Alessandro, Mrakic-Sposta Simona, Vezzoli Alessandra, Giardini Guido, Pratali Lorenza
  
  Abstract
  
  Strenuous and endurance exercise training have been associated with morphological and functional heart remodeling. Two-dimensional speckle-tracking echocardiography (STE) is a novel technique that allows an accurate quantification of global myocardium deformation. Our aim was to evaluate together left and right cardiac remodeling in different long-distance running athletes: marathon runners (42 km) (M) and endurance mountain runners (>300 Km) (UT). A total of 92 athletes (70 males, 76%) including 47 M [age 45 ± 7 years; training: 18 (9-53) yearsdays/week], 45 UT [age 42 ± 9, training: 30 (15-66) yearsdays/week] underwent conventional echocardiography and STE (Beyond Diogenes 2.0, AMID) during the agonistic season. Right ventricle (RV) end-diastolic area ( = 0.026), fractional area changing (FAC) ( = 0.008) and RV global longitudinal strain (GLS) were significantly increasedin UT athletes. Furthermore, UT showed larger right atrium (RA) volume ( = 0.03), reduced RA GLS and significantly increased RA global circumferential strain (GCS) compared to M. After adjustment for age, sex, and HR as covariates, UT showed a reduced RA GLS (OR 0.907; CI 0.856-0.961) and increased RV FAC (OR 1.172; CI: 1.044-1.317) compared to M. Athletes enrolled in UT endurance activities showed RV and RA morphological and functional remodeling to increased preload in comparison with M runners characterized by increased RV FAC and reduced RA GLS. Follow-up studies are needed to better assess the long-term clinical impact of these modifications. 2D STE is a useful tool for investigating the deformation dynamic in different sports specialties.
  
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• "Direct" and "Indirect" Methods to Detect Oxidative Stress During Acute or Chronic High-Altitude Exposure.
  High Alt Med Biol

  2017 Sep;18(3):303-304. doi: 10.1089/ham.2017.0067.
  
  Mrakic-Sposta Simona, Vezzoli Alessandra, Malacrida Sandro, Falla Marika, Strapazzon Giacomo
  
  
  
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• Neurosensory and Cognitive Modifications in Europe's Toughest RandoRaid Competition: the Transpyrénéa Extreme Study.
  Front Physiol

  2017 ;8():201. doi: 201.
  
  Tonacci Alessandro, Mrakic-Sposta Simona, Ujka Kristian, Sansone Francesco, Ferrisi Alice, Giardini Guido, Conte Raffaele, Pratali Lorenza
  
  Abstract
  
  Given the wide proliferation of ultra-long endurance races, it is important to understand the physiological response of the athletes to improve their safety. We evaluated the cognitive and neurosensory effects on ultra-endurance athletes during the Transpyrénéa (866 Km, 65,000 m positive slope), held on the French Pyrenees. 40 athletes were enrolled (age 43.8 ± 8.8 years; 36 males). Olfactory and cognitive tests were performed before the race (T0, = 40), at 166 kms (T1, = 28), at 418 kms (T2, = 20), and after the race (T3, 866 kms, = 13). The effect of dehydration and sleep deprivation on cognitive features were also studied. Olfactory function decreased during the race (T0: 24.9 ± 4.3 vs. T3: 22.8 ± 3.5, = -2.678, = 0.007), language fluency increased (T0: 10.8 ± 2.9; T1: 11.4 ± 2.7; T2: 12.9 ± 2.8; T3: 12.9 ± 3.0; ? = 11.132, = 0.011 for combined samples), whereas the Trail Making Test did not show any changes between pre- and post-race (T0 vs. T3 = 0.697 for TMT-A, = 0.977 for TMT-B). The mean aggregate sleeping time was 9.3 ± 5.4 h at T1, 22.4 ± 10.0 h at T2, 29.5 ± 20.5 h at T3, with a correlation with olfactory function ( = 0.644, = 0.018), while Total Body Water (TBW) was not correlated with olfactory or cognitive scores. Physical activity and sleep restriction in ultra-endurance could transiently affect olfactory function, while verbal fluency improved, demonstrating a dissimilar mechanism of activation/deactivation in different cortical areas. Body water loss was uncorrelated to cognition. Further studies should clarify whether cognitive and sensory deficits occur even in absence of sleep restriction.
  
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• Bioengineered gold nanoparticles targeted to mesenchymal cells from patients with bronchiolitis obliterans syndrome does not rise the inflammatory response and can be safely inhaled by rodents.
  Nanotoxicology

  2017 May;11(4):534-545. doi: 10.1080/17435390.2017.1317862.
  
  Cova Emanuela, Inghilleri Simona, Pandolfi Laura, Morosini Monica, Magni Sara, Colombo Miriam, Piloni Davide, Finetti Chiara, Ceccarelli Gabriele, Benedetti Laura, Cusella Maria Gabriella, Agozzino Manuela, Corsi Fabio, Allevi Raffaele, Mrakic-Sposta Simona, Moretti Sarah, De Gregori Simona, Prosperi Davide, Meloni Federica
  
  Abstract
  
  The use of gold nanoparticles (GNPs) as drug delivery system represents a promising issue for diseases without effective pharmacological treatment due to insufficient local drug accumulation and excessive systemic toxicity. Bronchiolitis obliterans syndrome (BOS) represents about 70% of cases of chronic lung allograft dysfunction, the main challenge to long-term lung transplantation. It is believed that due to repeated insults to epithelial bronchiolar cells local inflammatory response creates a milieu that favors epithelial-mesenchymal transition and activation of local mesenchymal cells (MCs) leading to airway fibro-obliteration. In a previous work, we engineered GNPs loaded with the mammalian target of rapamycin inhibitor everolimus, specifically decorated with an antibody against CD44, a surface receptor expressed by primary MCs isolated from bronchoalveolar lavage of BOS patients. We proved in vitro that these GNPs (GNP-HCe) were able to specifically inhibit primary MCs without affecting the bronchial epithelial cell. In the present work, we investigated the effect of these bioengineered nanoconstructs on inflammatory cells, given that a stimulating effect on macrophages, neutrophils or lymphocytes is strongly unwanted in graft airways since it would foster fibrogenesis. In addition, we administered GNP-HCe by the inhalatory route to normal mice for a preliminary assessment of their pulmonary and peripheral (liver, spleen and kidney) uptake. By these experiments, an evaluation of tissue toxicity was also performed. The present study proves that our bioengineered nanotools do not rise an inflammatory response and, under the tested inhalatory conditions that were used, are non-toxic.
  
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• Quantitative EEG for Predicting Upper Limb Motor Recovery in Chronic Stroke Robot-Assisted Rehabilitation.
  IEEE Trans Neural Syst Rehabil Eng

  2017 Jul;25(7):1058-1067. doi: 10.1109/TNSRE.2017.2678161.
  
  Trujillo Paula, Mastropietro Alfonso, Scano Alessandro, Chiavenna Andrea, Mrakic-Sposta Simona, Caimmi Marco, Molteni Franco, Rizzo Giovanna
  
  Abstract
  
  Stroke is a leading cause for adult disability, which in many cases causes motor deficits. Despite the developments in motor rehabilitation techniques, recovery of upper limb functions after stroke is limited and heterogeneous in terms of outcomes, and knowledge of important factors that may affect the outcome of the therapy is necessary to make a reasonable prediction for individual patients. In this paper, we assessed the relationship between quantitative electroencephalographic (QEEG) measures and the motor outcome in chronic stroke patients that underwent a robot-assisted rehabilitation program to evaluate the utility of QEEG indices to predict motor recovery. For this purpose, we acquired resting-state electroencephalographic signals from which the power ratio index (PRI), delta/alpha ratio, and brain symmetry index were calculated. The outcome of the motor rehabilitation was evaluated using upper limb section of the Fugl-Meyer Assessment. We found that PRI was significantly correlated with the motor recovery, suggesting that this index may provide useful information to predict the rehabilitation outcome.
  
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• Oxidative stress response to acute hypobaric hypoxia and its association with indirect measurement of increased intracranial pressure: a field study.
  Sci Rep

  2016 Aug;6():32426. doi: 32426.
  
  Strapazzon Giacomo, Malacrida Sandro, Vezzoli Alessandra, Dal Cappello Tomas, Falla Marika, Lochner Piergiorgio, Moretti Sarah, Procter Emily, Brugger Hermann, Mrakic-Sposta Simona
  
  Abstract
  
  High altitude is the most intriguing natural laboratory to study human physiological response to hypoxic conditions. In this study, we investigated changes in reactive oxygen species (ROS) and oxidative stress biomarkers during exposure to hypobaric hypoxia in 16 lowlanders. Moreover, we looked at the potential relationship between ROS related cellular damage and optic nerve sheath diameter (ONSD) as an indirect measurement of intracranial pressure. Baseline measurement of clinical signs and symptoms, biological samples and ultrasonography were assessed at 262?m and after passive ascent to 3830?m (9, 24 and 72?h). After 24?h the imbalance between ROS production (+141%) and scavenging (-41%) reflected an increase in oxidative stress related damage of 50-85%. ONSD concurrently increased, but regression analysis did not infer a causal relationship between oxidative stress biomarkers and changes in ONSD. These results provide new insight regarding ROS homeostasis and potential pathophysiological mechanisms of acute exposure to hypobaric hypoxia, plus other disease states associated with oxidative-stress damage as a result of tissue hypoxia.
  
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• Oxidative Stress Assessment in Response to Ultraendurance Exercise: Thiols Redox Status and ROS Production according to Duration of a Competitive Race.
  Oxid Med Cell Longev

  2016 ;2016():6439037. doi: 6439037.
  
  Vezzoli Alessandra, Dellanoce Cinzia, Mrakic-Sposta Simona, Montorsi Michela, Moretti Sarah, Tonini Annamaria, Pratali Lorenza, Accinni Roberto
  
  Abstract
  
  Purpose. Response to an ultraendurance competitive race on thiols redox status, reactive oxygen species (ROS) production, and oxidative stress (OxS) was investigated according to duration. Methods. Twenty-four elite runners were examined: six completed 50?km and eighteen 100?km. Blood and urine samples were collected before and immediately after the race. Erythrocytes and plasma aminothiols by high-performance liquid chromatography, total antioxidant capacity (TAC), and OxS biomarkers (protein carbonyl (PC), thiobarbituric acid-reactive substances (TBARS), 8-isoprostane (8-iso-PGF2?), and 8-OH-2-deoxyguanosine (8-OH-dG)) by immunoenzymatic assays and ROS production by Electron Paramagnetic Resonance were assessed. Results. Significant increases (P between
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• Transcranial Direct Current Stimulation Modulates Cortical Neuronal Activity in Alzheimer's Disease.
  Front Neurosci

  2016 ;10():134. doi: 134.
  
  Marceglia Sara, Mrakic-Sposta Simona, Rosa Manuela, Ferrucci Roberta, Mameli Francesca, Vergari Maurizio, Arlotti Mattia, Ruggiero Fabiana, Scarpini Elio, Galimberti Daniela, Barbieri Sergio, Priori Alberto
  
  Abstract
  
  Quantitative electroencephalography (qEEG) showed that Alzheimer's disease (AD) is characterized by increased theta power, decreased alpha and beta power, and decreased coherence in the alpha and theta band in posterior regions. These abnormalities are thought to be associated with functional disconnections among cortical areas, death of cortical neurons, axonal pathology, and cholinergic deficits. Since transcranial Direct Current Stimulation (tDCS) over the temporo-parietal area is thought to have beneficial effects in patients with AD, in this study we aimed to investigate whether tDCS benefits are related to tDCS-induced changes in cortical activity, as represented by qEEG. A weak anodal current (1.5 mA, 15 min) was delivered bilaterally over the temporal-parietal lobe to seven subjects with probable AD (Mini-Mental State Examination, MMSE score >20). EEG (21 electrodes, 10-20 international system) was recorded for 5 min with eyes closed before (baseline, t0) and 30 min after anodal and cathodal tDCS ended (t1). At the same time points, patients performed a Word Recognition Task (WRT) to assess working memory functions. The spectral power and the inter- and intra-hemispheric EEG coherence in different frequency bands (e.g., low frequencies, including delta and theta; high frequencies, including alpha and beta) were calculated for each subject at t0 and t1. tDCS-induced changes in EEG neurophysiological markers were correlated with the performance of patients at the WRT. At baseline, qEEG features in AD patients confirmed that the decreased high frequency power was correlated with lower MMSE. After anodal tDCS, we observed an increase in the high-frequency power in the temporo-parietal area and an increase in the temporo-parieto-occipital coherence that correlated with the improvement at the WRT. In addition, cathodal tDCS produced a non-specific effect of decreased theta power all over the scalp that was not correlated with the clinical observation at the WRT. Our findings disclosed that tDCS induces significant modulations in the cortical EEG activity in AD patients. The abnormal pattern of EEG activity observed in AD during memory processing is partially reversed by applying anodal tDCS, suggesting that anodal tDCS benefits in AD patients during working memory tasks are supported by the modulation of cortical activity.
  
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• A Novel Application for Cognitive Evaluation in Mountain Ultramarathons: Olfactory Assessment.
  Wilderness Environ Med

  2016 Mar;27(1):131-5. doi: 10.1016/j.wem.2015.11.013.
  
  Tonacci Alessandro, Billeci Lucia, Tartarisco Gennaro, Mastorci Francesca, Borghini Andrea, Mrakic-Sposta Simona, Moretti Sarah, Vezzoli Alessandra, Faraguna Ugo, Pioggia Giovanni, Guido Giardini, Pratali Lorenza
  
  Abstract
  
  OBJECTIVE:
  Olfactory function, a cognitive impairment biomarker, was evaluated in mountain ultramarathon (MUM) runners during the Tor des Géants race (332.5 km with an overall altitude gain of 24,000 m; altitude range 330-3296 m above the sea).
  
  METHODS:
  An Odor Identification Test was administered before (T0; n = 53), at 148.7 kms (T1; n = 32) and after the race (T2; n = 28). The effect of dehydration and sleep deprivation on olfactory function was assessed. Olfactory function was also assessed in non-MUM athletes and sedentary controls (C) at rest.
  
  RESULTS:
  A majority of the athletes completed the olfactory test at all time intervals. Olfactory function decreased throughout the race (T0: 13.8 ± 1.9, T1: 13.7 ± 1.6, T2: 13.1 ± 1.8; T0 vs T2 P = .01). There was no relationship with race time or sleep deprivation on the sense of smell throughout the competition. However, there was a combined effect with decreased olfaction during the second half of the race, while a poor relationship was seen between olfaction and total body water at midterm (T1: rs = -0.427; P = .019), but not at baseline or after the race. MUM athletes had similar olfactory scores to C (13.8 ± 1.9 vs 13.7 ± 1.4) and non-MUM (13.8 ± 1.9 vs 13.9 ± 1.6) athletes.
  
  CONCLUSIONS:
  This pilot study showed the feasibility of olfactory evaluation as a minimally invasive cognitive impairment assessment. The test can be used in logistically difficult environments, adding scientific value to this promising method. Although olfaction decreased after prolonged physical activity, further studies are warranted to make the relationship between cognition and external factors (eg, sleep deprivation, dehydration) more clear.
  
  Copyright © 2016 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.
  
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• Effects of Mountain Ultra-Marathon Running on ROS Production and Oxidative Damage by Micro-Invasive Analytic Techniques.
  PLoS One

  2015 ;10(11):e0141780. doi: e0141780.
  
  Mrakic-Sposta Simona, Gussoni Maristella, Moretti Sarah, Pratali Lorenza, Giardini Guido, Tacchini Philippe, Dellanoce Cinzia, Tonacci Alessandro, Mastorci Francesca, Borghini Andrea, Montorsi Michela, Vezzoli Alessandra
  
  Abstract
  
  PURPOSE:
  Aiming to gain a detailed insight into the physiological mechanisms involved under extreme conditions, a group of experienced ultra-marathon runners, performing the mountain Tor des Géants® ultra-marathon: 330 km trail-run in Valle d'Aosta, 24000 m of positive and negative elevation changes, was monitored. ROS production rate, antioxidant capacity, oxidative damage and inflammation markers were assessed, adopting micro-invasive analytic techniques.
  
  METHODS:
  Forty-six male athletes (45.04±8.75 yr, 72.6±8.4 kg, 1.76±0.05 m) were tested. Capillary blood and urine were collected before (Pre-), in the middle (Middle-) and immediately after (Post-) Race. Samples were analyzed for: Reactive Oxygen Species (ROS) production by Electron Paramagnetic Resonance; Antioxidant Capacity by Electrochemistry; oxidative damage (8-hydroxy-2-deoxy Guanosine: 8-OH-dG; 8-isoprostane: 8-isoPGF2?) and nitric oxide metabolites by enzymatic assays; inflammatory biomarkers (plasma and urine interleukin-6: IL-6-P and IL-6-U) by enzyme-linked immunosorbent assays (ELISA); Creatinine and Neopterin by HPLC, hematologic (lactate, glucose and hematocrit) and urine parameters by standard analyses.
  
  RESULTS:
  Twenty-five athletes finished the race, while twenty-one dropped out of it. A significant increase (Post-Race vs Pre) of the ROS production rate (2.20±0.27 vs 1.65±0.22 ?mol.min-1), oxidative damage biomarkers (8-OH-dG: 6.32±2.38 vs 4.16±1.25 ng.mg-1 Creatinine and 8-isoPGF2?: 1404.0±518.30 vs 822.51±448.91 pg.mg-1Creatinine), inflammatory state (IL-6-P: 66.42±36.92 vs 1.29±0.54 pg.mL-1 and IL-6-U: 1.33±0.56 vs 0.71±0.17 pg.mL1) and lactate production (+190%), associated with a decrease of both antioxidant capacity (-7%) and renal function (i.e. Creatinine level +76%) was found.
  
  CONCLUSIONS:
  The used micro-invasive analytic methods allowed us to perform most of them before, during and immediately after the race directly in the field, by passing the need of storing and transporting samples for further analysis. Considered altogether the investigated variables showed up that exhaustive and prolonged exercise not only promotes the generation of ROS but also induces oxidative stress, transient renal impairment and inflammation.
  
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• Chronic and acute effects of endurance training on telomere length.
  Mutagenesis

  2015 Sep;30(5):711-6. doi: 10.1093/mutage/gev038.
  
  Borghini Andrea, Giardini Guido, Tonacci Alessandro, Mastorci Francesca, Mercuri Antonella, Mrakic-Sposta Simona, Moretti Sarah, Andreassi Maria Grazia, Pratali Lorenza
  
  Abstract
  
  Telomere shortening is considered a cellular marker of health status and biological ageing. Exercise may influence the health and lifespan of an individual by affecting telomere length (TL). However, it is unclear whether different endurance exercise levels may have beneficial or detrimental effects on biological aging. The aims of the study were to assess both chronic and acute effects of endurance training on TL after an exceptional and extreme trail race. TL was assessed in 20 endurance athletes (17 males; age = 45.4 ± 9.2 years) and 42 age- and gender-matched sedentary controls (32 males; age = 45.9 ± 9.5 years) with quantitative real-time PCR at baseline conditions. Of the 20 runners enrolled in the 'Tor des Géants ®' ultra-distance trail race, 15 athletes (12 males; age = 47.2 ± 8.5 years) were re-evaluated at the intermediate point and 14 athletes (11 males; age = 47.1 ± 8.8 years) completed the competition and were analysed at the final point. Comparison between the two groups (endurance athletes vs. sedentary controls) revealed a significant difference in TL (1.28 ± 0.4 vs. 1.02 ± 0.3, P = 0.005). TL was better preserved in elder endurance runners compared with the same age control group (1.3 ± 0.27 vs. 0.91 ± 0.21, P = 0.003). TL was significantly reduced at the intermediate (0.88 ± 0.36 vs. 1.11 ± 0.34, P = 0.002) and final point compared with baseline measurements (0.86 ± 0.4 vs. 1.11 ± 0.34, P = 0.0006) for athletes engaged in the ultra-marathon race. Our data suggest that chronic endurance training may provide protective effects on TL attenuating biological aging. Conversely, acute exposure to an ultra-distance endurance trail race implies telomere shortening probably caused by oxidative DNA damage.
  
  © The Author 2015. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
  
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• Training effects on ROS production determined by electron paramagnetic resonance in master swimmers.
  Oxid Med Cell Longev

  2015 ;2015():804794. doi: 804794.
  
  Mrakic-Sposta Simona, Gussoni Maristella, Porcelli Simone, Pugliese Lorenzo, Pavei Gaspare, Bellistri Giuseppe, Montorsi Michela, Tacchini Philippe, Vezzoli Alessandra
  
  Abstract
  
  Acute exercise induces an increase in Reactive Oxygen Species (ROS) production dependent on exercise intensity with highest ROS amount generated by strenuous exercise. However, chronic repetition of exercise, that is, exercise training, may reduce exercise-induced oxidative stress. Aim of this study was to evaluate the effects of 6-weeks high-intensity discontinuous training (HIDT), characterized by repeated variations of intensity and changes of redox potential, on ROS production and antioxidant capacity in sixteen master swimmers. Time course changes of ROS generation were assessed by Electron Paramagnetic Resonance in capillary blood by a microinvasive approach. An incremental arm-ergometer exercise (IE) until exhaustion was carried out at both before (PRE) and after (POST) training (Trg) period. A significant (P
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• A quantitative method to monitor reactive oxygen species production by electron paramagnetic resonance in physiological and pathological conditions.
  Oxid Med Cell Longev

  2014 ;2014():306179. doi: 306179.
  
  Mrakic-Sposta Simona, Gussoni Maristella, Montorsi Michela, Porcelli Simone, Vezzoli Alessandra
  
  Abstract
  
  The growing interest in the role of Reactive Oxygen Species (ROS) and in the assessment of oxidative stress in health and disease clashes with the lack of consensus on reliable quantitative noninvasive methods applicable. The study aimed at demonstrating that a recently developed Electron Paramagnetic Resonance microinvasive method provides direct evidence of the "instantaneous" presence of ROS returning absolute concentration levels that correlate with "a posteriori" assays of ROS-induced damage by means of biomarkers. The reliability of the choice to measure ROS production rate in human capillary blood rather than in plasma was tested (step I). A significant (P
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• Structure-function paradigm in human myoglobin: how a single-residue substitution affects NO reactivity at low pO2.
  J Am Chem Soc

  2013 May;135(20):7534-44. doi: 10.1021/ja400213t.
  
  Scorciapino Mariano Andrea, Spiga Enrico, Vezzoli Alessandra, Mrakic-Sposta Simona, Russo Rosaria, Fink Bruno, Casu Mariano, Gussoni Maristella, Ceccarelli Matteo
  
  Abstract
  
  This work is focused on the two more expressed human myoglobin isoforms. In the literature, their different overexpression in high-altitude natives was proposed to be related to alternative/complementary functions in hypoxia. Interestingly, they differ only at residue-54, lysine or glutamate, which is external and far from the main binding site. In order to ascertain whether these two almost identical myoglobins might exert different functions and to contribute to a deeper understanding about myoglobin's oxygen-level dependent functioning, they have been compared with respect to dynamics, heme electronic structure, and NO reactivity at different O2 levels. Electron paramagnetic resonance (EPR) spectroscopy was employed to investigate the electronic structure of the nitrosyl-form, obtaining fundamental clues about a different bond interaction between the heme-iron and the proximal histidine and highlighting striking differences in NO reactivity, especially at a very low pO2. The experimental results well matched with the information provided by molecular dynamics simulations, which showed a significantly different dynamics for the two proteins only in the absence of O2. The single mutation differentiating the two myoglobins resulted in strongly affecting the plasticity of the CD-region (C-helix-loop-D-helix), whose fluctuations, being coupled to the solvent, were found to be correlated with the dynamics of the distal binding site. In the absence of O2, on the one hand a significantly different probability for the histidine-gate opening has been shown by MD simulations, and on the other a different yield of myoglobin-NO formation was experimentally observed through EPR.
  
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• Assessment of a standardized ROS production profile in humans by electron paramagnetic resonance.
  Oxid Med Cell Longev

  2012 ;2012():973927. doi: 973927.
  
  Mrakic-Sposta Simona, Gussoni Maristella, Montorsi Michela, Porcelli Simone, Vezzoli Alessandra
  
  Abstract
  
  Despite the growing interest in the role of reactive oxygen species (ROS) in health and disease, reliable quantitative noninvasive methods for the assessment of oxidative stress in humans are still lacking. EPR technique, coupled to a specific spin probe (CMH: 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine) is here presented as the method of choice to gain a direct measurement of ROS in biological fluids and tissues. The study aimed at demonstrating that, differently from currently available "a posteriori" assays of ROS-induced damage by means of biomolecules (e.g., proteins and lipids) spin-trapping EPR provides direct evidence of the "instantaneous" presence of radical species in the sample and, as signal areas are proportional to the number of excited electron spins, lead to absolute concentration levels. Using a recently developed bench top continuous wave system (e-scan EPR scanner, Bruker) dealing with very low ROS concentration levels in small (50 ?L) samples, we successfully monitored rapid ROS production changes in peripheral blood of athletes after controlled exercise and sedentary subjects after antioxidant supplementation. The correlation between EPR results and data obtained by various enzymatic assays (e.g., protein carbonyls and thiobarbituric acid reactive substances) was determined too. Synthetically, our method allows reliable, quick, noninvasive quantitative determination of ROS in human peripheral blood.
  
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• Conflict-dependent dynamic of subthalamic nucleus oscillations during moral decisions.
  Soc Neurosci

  2011 ;6(3):243-56. doi: 10.1080/17470919.2010.515148.
  
  Fumagalli Manuela, Giannicola Gaia, Rosa Manuela, Marceglia Sara, Lucchiari Claudio, Mrakic-Sposta Simona, Servello Domenico, Pacchetti Claudio, Porta Mauro, Sassi Marco, Zangaglia Roberta, Franzini Angelo, Albanese Alberto, Romito Luigi, Piacentini Sylvie, Zago Stefano, Pravettoni Gabriella, Barbieri Sergio, Priori Alberto
  
  Abstract
  
  Although lesional, neuroimaging, and brain stimulation studies have provided an insight into the neural mechanisms of judgement and decision-making, all these works focused on the cerebral cortex, without investigating the role of subcortical structures such as the basal ganglia. Besides being an effective therapeutic tool, deep brain stimulation (DBS) allows local field potential (LFP) recordings through the stimulation electrodes thus providing a physiological "window" on human subcortical structures. In this study we assessed whether subthalamic nucleus LFP oscillations are modulated by processing of moral conflictual, moral nonconflictual, and neutral statements. To do so, in 16 patients with Parkinson's disease (8 men) bilaterally implanted with subthalamic nucleus (STN) electrodes for DBS, we recorded STN LFPs 4 days after surgery during a moral decision task. During the task, recordings from the STN showed changes in LFP oscillations. Whereas the 14--30 Hz band (beta) changed during the movement executed to perform the task, the 5--13 Hz band (low-frequency) changed when subjects evaluated the content of statements. Low-frequency band power increased significantly more during conflictual than during nonconflictual or neutral sentences. We conclude that STN responds specifically to conflictual moral stimuli, and could be involved in conflictual decisions of all kinds, not only those for moral judgment. LFP oscillations provide novel direct evidence that the neural processing of conflictual decision-making spreads beyond the cortex to the basal ganglia and encompasses a specific subcortical conflict-dependent component.
  
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• The effects of levodopa and ongoing deep brain stimulation on subthalamic beta oscillations in Parkinson's disease.
  Exp Neurol

  2010 Nov;226(1):120-7. doi: 10.1016/j.expneurol.2010.08.011.
  
  Giannicola Gaia, Marceglia Sara, Rossi Lorenzo, Mrakic-Sposta Simona, Rampini Paolo, Tamma Filippo, Cogiamanian Filippo, Barbieri Sergio, Priori Alberto
  
  Abstract
  
  Local field potentials (LFPs) recorded through electrodes implanted in the subthalamic nucleus (STN) for deep brain stimulation (DBS) in patients with Parkinson's disease (PD) show that oscillations in the beta frequency range (8-20 Hz) decrease after levodopa intake. Whether and how DBS influences the beta oscillations and whether levodopa- and DBS-induced changes interact remains unclear. We examined the combined effect of levodopa and DBS on subthalamic beta LFP oscillations, recorded in nine patients with PD under four experimental conditions: without levodopa with DBS turned off; without levodopa with DBS turned on; with levodopa with DBS turned on; and with levodopa with DBS turned off. The analysis of STN-LFP oscillations showed that whereas levodopa abolished beta STN oscillations in all the patients (p=0.026), DBS significantly decreased the beta oscillation only in five of the nine patients studied (p=0.043). Another difference was that whereas levodopa completely suppressed beta oscillations, DBS merely decreased them. When we combined levodopa and DBS, the levodopa-induced beta disruption prevailed and combining levodopa and DBS induced no significant additive effect (p=0.500). Our observations suggest that levodopa and DBS both modulate LFP beta oscillations.
  
  Copyright © 2010 Elsevier Inc. All rights reserved.
  
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• Multicenter study report: electrophysiological monitoring procedures for subthalamic deep brain stimulation surgery in Parkinson's disease.
  Neurol Sci

  2010 Aug;31(4):449-57. doi: 10.1007/s10072-010-0254-0.
  
  Marceglia Sara, Mrakic-Sposta Simona, Tommasi Giorgio, Bartolomei Luigi, Foresti Camillo, Valzania Franco, Galati Salvatore, Stefani Alessandro, Tamma Filippo, Priori Alberto,
  
  Abstract
  
  Despite the wide diffusion of subthalamic deep brain stimulation (STN-DBS) for Parkinson's disease, systematic practical recommendations for intraoperative electrophysiological monitoring are still lacking. In this paper, a shared protocol for intraoperative electrophysiological monitoring arising from the meetings of a panel of neurophysiologists of the DBS Study Group of the Italian Neurological Society is proposed. Intraoperative monitoring is composed by microrecordings and functional stimulation. In microrecordings, it is recommended to use at least 2-3 electrodes, descending with steps of 0.5-1 mm and waiting at least 60 s before changing the position. Functional stimulation is used to assess the clinical efficacy and the side effects induced by STN-DBS at different positions. Based on the therapeutic window, an algorithm to find the optimal target is proposed. The procedures for intraoperative monitoring for STN-DBS proposed here are safe, relatively cheap, take approximately 30-40 min per side and could offer valuable additional information to the surgeon.
  
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• Dorsolateral prefrontal cortex specifically processes general - but not personal - knowledge deception: Multiple brain networks for lying.
  Behav Brain Res

  2010 Aug;211(2):164-8. doi: 10.1016/j.bbr.2010.03.024.
  
  Mameli Francesca, Mrakic-Sposta Simona, Vergari Maurizio, Fumagalli Manuela, Macis Margherita, Ferrucci Roberta, Nordio Francesco, Consonni Dario, Sartori Giuseppe, Priori Alberto
  
  Abstract
  
  Despite intensive research into ways of detecting deception in legal, moral and clinical contexts, few experimental data are available on the neural substrate for the different types of lies. We used transcranial direct current stimulation (tDCS) to modulate dorsolateral prefrontal cortex (DLPFC) function and to assess its influence on various types of lies. Twenty healthy volunteers were tested before and after tDCS (anodal and sham). In each session the Guilty Knowledge Task and Visual Attention Task were administered at baseline and immediately after tDCS ended. A computer-controlled task was used to evaluate truthful responses and lie responses to questions referring to personal information and general knowledge. Dependent variables collected were reaction times (RTs) and accuracy. At baseline the RTs were significantly longer for lies than for truthful responses. After sham stimulation, lie responses remained unchanged (p = 0.24) but after anodal tDCS, RTs decreased significantly only for lies involving general knowledge (p = 0.02). tDCS left the Visual Attention Task unaffected. These findings show that manipulating DLPFC function with tDCS specifically modulates deceptive responses for general information leaving those on personal information unaffected. Multiple cortical networks intervene in deception involving general and personal knowledge. Deception referring to general and personal knowledge probably involves multiple cortical networks.
  
  Copyright 2010 Elsevier B.V. All rights reserved.
  
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• Brain switches utilitarian behavior: does gender make the difference?
  PLoS One

  2010 Jan;5(1):e8865. doi: e8865.
  
  Fumagalli Manuela, Vergari Maurizio, Pasqualetti Patrizio, Marceglia Sara, Mameli Francesca, Ferrucci Roberta, Mrakic-Sposta Simona, Zago Stefano, Sartori Giuseppe, Pravettoni Gabriella, Barbieri Sergio, Cappa Stefano, Priori Alberto
  
  Abstract
  
  Decision often implies a utilitarian choice based on personal gain, even at the expense of damaging others. Despite the social implications of utilitarian behavior, its neurophysiological bases remain largely unknown. To assess how the human brain controls utilitarian behavior, we delivered transcranial direct current stimulation (tDCS) over the ventral prefrontal cortex (VPC) and over the occipital cortex (OC) in 78 healthy subjects. Utilitarian judgment was assessed with the moral judgment task before and after tDCS. At baseline, females provided fewer utilitarian answers than males for personal moral dilemmas (p = .007). In males, VPC-tDCS failed to induce changes and in both genders OC-tDCS left utilitarian judgments unchanged. In females, cathodal VPC-tDCS tended to decrease whereas anodal VPC-tDCS significantly increased utilitarian responses (p = .005). In males and females, reaction times for utilitarian responses significantly decreased after cathodal (p<.001 but not after anodal .735 vpc-tdcs. we conclude that ventral prefrontal tdcs interferes with utilitarian decisions influencing the evaluation of advantages and disadvantages each option in both sexes does so more strongly females. whereas cathodal alters time for reasoning stimulation incisively women modifying possible consequent actions. gender-related tdcs-induced changes suggest vpc differentially controls females males. gender-specific functional organization brain areas involved behavior could be a correlate moral social behavioral differences between two sexes.>
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• Thalamic single-unit and local field potential activity in Tourette syndrome.
  Mov Disord

  2010 Feb;25(3):300-8. doi: 10.1002/mds.22982.
  
  Marceglia Sara, Servello Domenico, Foffani Guglielmo, Porta Mauro, Sassi Marco, Mrakic-Sposta Simona, Rosa Manuela, Barbieri Sergio, Priori Alberto
  
  Abstract
  
  Deep brain stimulation (DBS) of the ventralis oralis (VO) complex of the thalamus improves tics in patients with Tourette syndrome (TS). To neurophysiologically describe the VO complex we recorded, in seven patients with TS undergoing DBS electrode implantation, single-unit activity during surgery and local field potentials (LFPs) a few days after surgery. Single unit recordings showed that the VO complex is characterized by a localized pattern of bursting neuronal activity. LFP spectra demonstrated that VO of TS patients has a prominent oscillatory activity at low frequencies (2-7 Hz) and in the alpha-band (8-13 Hz), and a virtually absent beta activity. In each patient, the main LFP frequency significantly correlated with single-unit interburst frequency. In conclusion, we observed an oscillatory bursting activity in the VO as target region in patients with severe TS undergoing DBS surgery.
  
  (c) 2010 Movement Disorder Society.
  
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• Time dependent subthalamic local field potential changes after DBS surgery in Parkinson's disease.
  Exp Neurol

  2010 Apr;222(2):184-90. doi: 10.1016/j.expneurol.2009.12.013.
  
  Rosa Manuela, Marceglia Sara, Servello Domenico, Foffani Guglielmo, Rossi Lorenzo, Sassi Marco, Mrakic-Sposta Simona, Zangaglia Roberta, Pacchetti Claudio, Porta Mauro, Priori Alberto
  
  Abstract
  
  Local field potentials (LFPs) recorded through electrodes implanted in patients with Parkinson's disease (PD) for deep brain stimulation (DBS) provided physiological information about the human basal ganglia. However, LFPs were always recorded 2-7 days after electrode implantation ("acute" condition). Because changes in the tissue surrounding the electrode occur after DBS surgery and could be relevant for LFPs, in this work we assessed whether impedance and LFP pattern are a function of the time interval between the electrode implant and the recordings. LFPs and impedances were recorded from 11 patients with PD immediately after (T-0h), 2 h after (T-2h), 2 days after (T-48h), and 1 month after (T-30d, "chronic" condition) surgery. Impedances at T-0h were significantly higher than at all the other time intervals (T-2h, p=0.0005; T-48h, p=0.0002; T-30d, p=0.003). Correlated with this change (p=0.005), the low-frequency band (2-7 Hz) decreased at all time intervals (p=0.0005). Conversely, the low- (8-20 Hz) and the high-beta (21-35 Hz) bands increased in time (low-beta, p=0.003; high beta, p=0.022), but did not change between T-48h and T-30d. Our results suggest that DBS electrode impedance and LFP pattern are a function of the time interval between electrode implant and LFP recordings. Impedance decrease could be related to changes in the electrode/tissue interface and in the low-frequency band. Conversely, beta band modulations could raise from the adaptation of the neural circuit. These findings confirm that results from LFP analysis in the acute condition can be extended to the chronic condition and that LFPs can be used in novel closed-loop DBS systems.
  
  Copyright 2010 Elsevier Inc. All rights reserved.
  
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• Transcranial direct current stimulation in two patients with Tourette syndrome.
  Mov Disord

  2008 Nov;23(15):2259-61. doi: 10.1002/mds.22292.
  
  Mrakic-Sposta Simona, Marceglia Sara, Mameli Francesca, Dilena Robertino, Tadini Laura, Priori Alberto
  
  
  
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• Extracellular spike microrecordings from the subthalamic area in Parkinson's disease.
  J Clin Neurosci

  2008 May;15(5):559-67. doi: 10.1016/j.jocn.2007.02.091.
  
  Mrakic-Sposta Simona, Marceglia Sara, Egidi Marcello, Carrabba Giorgio, Rampini Paolo, Locatelli Marco, Foffani Guglielmo, Accolla Ettore, Cogiamanian Filippo, Tamma Filippo, Barbieri Sergio, Priori Alberto
  
  Abstract
  
  Intraoperative neuronal microrecordings can help in localizing the subthalamic nucleus (STN) during stereotactic neurosurgery for deep-brain stimulation (DBS) in Parkinson's disease. To obtain quantitative information on neuronal spike descriptors, we systematically analysed neuronal spikes in the STN and substantia nigra pars reticulata (SNr) in 31 sides of the brain in awake patients undergoing stereotactic neurosurgery for DBS electrode implantation. In these two structures we evaluated spike amplitude, area, duration, rise time and mean total firing rate. The recording spike density was higher in the STN than in the SNr (94% vs. 28%). Microelectrode recordings showed a larger spike area and amplitude in the SNr than in the STN ([mean+/-SD] amplitude: 46.7+/-31.1 vs. 36.3+/-29.6 microV; area: 25.6+/-24.2 vs. 36.7+/-21.4 microVmsec), a higher total firing rate at rest in the SNr than in the STN (78.6+/-53.5 vs. 61.9+/-40.8 Hz), and a longer duration and rise time in the SNr than in the STN (duration: 2.0+/-1 vs. 1.3+/-0.6 ms; rise time: 0.95+/-0.6 vs. 0.67+/-0.3 ms). Our analysis also revealed sex-related differences in the studied spike descriptors, paralleling recent findings from deep electroencephalography recordings. In the STN, males had larger spike area and amplitude (amplitude: 41.97+/-32.57 vs. 26.2+/-19.7 microV; area: 31.8+/-26.4 vs. 13.0+/-10.6 microVmsec), whereas females had higher mean total firing rate (66.7+/-53.4 vs. 82.8+/-50.8 Hz). Our results have implications for clinical practice and the development of algorithms for the neurophysiological identification of the STN during stereotactic neurosurgery for Parkinson's disease, based on the on-line automated computation of multiple spike-variables.
  
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• Interaction between rhythms in the human basal ganglia: application of bispectral analysis to local field potentials.
  IEEE Trans Neural Syst Rehabil Eng

  2007 Dec;15(4):483-92. doi: 10.1109/TNSRE.2007.907893.
  
  Marceglia Sara, Bianchi Anna Maria, Baselli Giuseppe, Foffani Guglielmo, Cogiamanian Filippo, Modugno Nicola, Mrakic-Sposta Simona, Priori Alberto, Cerutti Sergio
  
  Abstract
  
  The application of deep brain stimulation (DBS) for the treatment of Parkinson's disease offered a direct "insight" into the human electrical activity in subcortical structures. The analysis of the oscillatory activity [local field potentials (LFPs)] disclosed the importance of rhythms and of interactions between rhythms in the human basal ganglia information processing. The aim of this study was to investigate the existence of possible nonlinear interactions between LFP rhythms characterizing the output structure of the basal ganglia, the globus pallidus internus, by means of bispectral analysis. The results of this study disclosed that the rhythms expressed in the globus pallidus internus of the untreated parkinsonian patient are not independent and, in particular, the low-beta (13-20 Hz) band generates harmonics that are included in the high-beta (20-35 Hz) band. Conversely, in the dystonic globus pallidus, as well as in the parkinsonian globus pallidus after dopaminergic medication (i.e., in the more "normal" condition), the rhythms are substantially independent and characterized by a strong activity in the low-frequency band that generates a second harmonic (4-14 Hz), mostly included in the same band. The interactions between rhythms in the human globus pallidus are therefore different in different pathologies and in different patient's states. The interpretation of these interactions is likely critical for fully understanding the role of LFP rhythms in the pathophysiology of human basal ganglia.
  
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• Gender differences in patients with Parkinson's disease treated with subthalamic deep brain stimulation.
  Mov Disord

  2007 Jun;22(8):1150-6.
  
  Accolla Ettore, Caputo Elena, Cogiamanian Filippo, Tamma Filippo, Mrakic-Sposta Simona, Marceglia Sara, Egidi Marcello, Rampini Paolo, Locatelli Marco, Priori Alberto
  
  Abstract
  
  We investigated gender-differences in clinical phenomenology and response to deep brain stimulation (DBS) of the subthalamic nucleus (STN) in a group of patients with advanced Parkinson's disease (PD). Thirty-eight consecutive patients with PD (22 men and 16 women), bilaterally implanted for DBS of the STN, were evaluated 1 month before and 11 to 14 months after surgery. Gender differences in severity of the disease (HY and UPDRS), ability in the activities of daily living (ADL, UPDRS II), tremor and rigidity (UPDRS III), bradykinesia (UPDRS III and hand tapping test), levodopa-induced dyskinesias (LIDs, UPDRS IV), and levodopa equivalent daily dosage (LEDD) were analyzed before and after intervention. We found a predominantly male population, with no gender-related differences in age at onset, disease progression rate, or severity of disease. Nevertheless, women had more severe LIDs than men, only before the intervention. Bradykinesia was significantly less responsive to any kind of treatment (pharmacologic and neurosurgical) in women than in men. Finally, although STN-DBS induced similar total benefits in both genders, postoperative assessment suggested that the ADL improved more in women than in men. Women and men with advanced PD appear to differ in some clinical features and in response to dopaminergic and STN-DBS treatment.
  
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