Hydrogen as an innovative nootropic in health and disease.

Molecular hydrogen (H2, dihydrogen) is an antioxidant and signaling molecule with potent antioxidative, antiapoptotic, and anti-inflammatory properties. Despite the growing interest in H2 as a potential therapeutic agent, the evidence regarding its potential as a nootropic remains limited. Only a handful of studies on the human population have evaluated its effects, although there are suggestive indications of its efficacy. The present paper overviews H2's potential as a novel agent for improving cognitive functions in health and disease contexts, highlighting its mechanisms of action and areas for further investigation. Current evidence suggests that H2 improves executive function, alertness and memory in several clinical trials, from healthy young and elderly individuals to individuals with altered circadian rhythms, neurodegenerative disorders, and cancer. Further investigations are needed to confirm the potential positive effects of dihydrogen as a nootropic agent in both health and disease.

Malproduction of endogenous hydrogen gas in COVID-19.

The molecular footprints of COVID-19 occur everywhere, even reaching the family of biologically active gases and gasotransmitters. Besides nitric oxide and hydrogen sulfide, COVID-19 might also alter the homeostasis of dihydrogen (H2), another gaseous bioactive molecule produced endogenously by the human gut bacteria. Many studies have shown various alterations of the gut microbiota in patients with coronavirus disease 2019, including the lower abundance of hydrogen-producing bacteria that could instigate the shortage of hydrogen output. Since dihydrogen has many important bioactivities, including cytoprotective, antioxidant, anti-inflammatory, and antiapoptotic, its malproduction in COVID-19 might contribute to the disease progression and severity. On the other hand, replenishing dihydrogen by exogenous administration could be beneficial in COVID-19 for both patient- and clinical-reported outcomes. Assessing low dihydrogen along with H2 supplementation to restore normal levels could be thus combined via theranostic approaches to aid COVID-19 diagnosis and treatment.

Diagnostic and Pharmacological Potency of Creatine in Post-Viral Fatigue Syndrome.

Post-viral fatigue syndrome (PVFS) is a widespread chronic neurological disease with no definite etiological factor(s), no actual diagnostic test, and no approved pharmacological treatment, therapy, or cure. Among other features, PVFS could be accompanied by various irregularities in creatine metabolism, perturbing either tissue levels of creatine in the brain, the rates of phosphocreatine resynthesis in the skeletal muscle, or the concentrations of the enzyme creatine kinase in the blood. Furthermore, supplemental creatine and related guanidino compounds appear to impact both patient- and clinician-reported outcomes in syndromes and maladies with chronic fatigue. This paper critically overviews the most common disturbances in creatine metabolism in various PVFS populations, summarizes human trials on dietary creatine and creatine analogs in the syndrome, and discusses new frontiers and open questions for using creatine in a post-COVID-19 world.

Hydrogen Gas as an Exotic Performance-Enhancing Agent: Challenges and Opportunities.

BACKGROUND: Hydrogen gas (H2) has entered the world of experimental therapeutics approximately four and a half decades ago. Over the years, this simple molecule appears to drive more scientific attention, perhaps due to a dualism of H2 affirmative features demonstrated in numerous in vitro, animal and human studies on one side, and still puzzling mechanism(s) of its biological activity on the other. Up to this point, H2 was scrutinized for more than 170 different disease models and pathologies, and many research groups across the world have lately started to dynamically investigate its conceivable performance-enhancing potential. METHODS: We outlined here the studies indexed in leading research databases (PubMed, Web of Science, SCOPUS, JSTORE) that explored the effects of hydrogen on exercise performance, and also addressed important restraints, open questions, and windows of opportunities for forthcoming research and possible H2 enactment in exercise physiology. About two dozen trials have been identified in this domain, with most of the trials published during the past 5 years, while drinking hydrogen-rich water recognized as the most convenient method to deliver H2 in both animal and human studies. RESULTS: Either administered as an inhalational gas, enteral hydrogen-rich water, or intravenous hydrogen-rich saline, H2 seems to favorably affect various exercise performance outcomes and biomarkers of exercise-associated fatigue, inflammation, and oxidative stress. Not all studies have shown corroborative effects, and it appears that the gold-standard protocol for applying H2 in the field of exercise science does not exist at the moment, with studies markedly differ in the dose of H2 administered, the duration of treatment, and the source of hydrogen. CONCLUSION: H2 is a newfangled and rather effective performance-enhancing agent, yet its promising ergogenic potency has to be further validated and characterized in more well-controlled, appropriately sampled and longterm mechanistic trials. Also, appropriate regulation of hydrogen utilization in sport as an exotic medical gas may require distinctive legislative actions of relevant regulatory agencies in the future.

Correlation between biomarkers of creatine metabolism and serum indicators of peripheral muscle fatigue during exhaustive exercise in active men.

Exhaustive exercise induces various disturbances of homeostasis, with impaired bioenergetics often associated with strenuous muscular work. However, no study so far validated serum biomarkers of creatine metabolism vs. traditional markers of exhaustive exercise and fatigue. Here, we investigated how well changes in serum guanidinoacetic acid (GAA), creatine and creatinine correlate with responses in blood lactate, creatine kinase, interleukin-6 and cortisol in 11 young active men (age 23.2 ± 3.7 years; VO2max 49.5 ± 5.4 ml/kg/min) exposed to exhaustive exercise. All participants were subjected to running at individual running speed at anaerobic threshold until exhaustion, with venous blood drawn at baseline and during an exercise session at 5-min intervals. Running-to-exhaustion markedly affected serum GAA and creatine levels, with circulating GAA increased for 5.3 ± 8.5%(95% CI, -0.4 to 11.0), and serum creatine elevated by 33.9 ± 21.8% (95% CI, 19.3 to 48.6) compared to baseline levels (P ≤ 0.05). In addition, moderate-to-strong positive linear correlations were found between exhaustive exercise-induced changes in serum cortisol and GAA levels (r = 0.79; P = 0.03), and cortisol and creatine concentrations (r = 0.81; P = 0.03). This suggests a link between cortisol and heavy exercise-induced impaired bioenergetics, with future studies needed to evaluate a cause-and-effect interconnection between cortisol and GAA-creatine axis.

Searching for a better formulation to enhance muscle bioenergetics: A randomized controlled trial of creatine nitrate plus creatinine vs. creatine nitrate vs. creatine monohydrate in healthy men.

A novel creatine blend (creatine nitrate mixed with creatinine, CN-CRN) has been anecdotally suggested to be superior to traditional creatine formulations for bioavailability and performance. However, does CN-CRN supremely affects creatine levels in the blood and skeletal muscle of healthy humans remain currently unknown. This randomized, controlled, double-blind, crossover trial evaluated the acute effects of single-dose CN-CRN on serum creatine levels, and 5-days intervention with CN-CRN on skeletal muscle creatine and safety biomarkers in healthy men. Ten healthy young men (23.6 ± 2.9 years) were allocated to receive either CN-CRN (3 grams of creatine nitrate mixed with 3 grams of creatinine), pure creatine nitrate (3 grams, CN), or regular creatine monohydrate (3 grams, CRM) by oral administration. We found that CN-CRN resulted in a more powerful rise in serum creatine levels comparing to either CN or CRM after a single-dose intervention, as evaluated with the area under the concentration-time curve calculation (701.1 ± 62.1 (µmol/L) × min versus 622.7 ± 62.9 (µmol/L) × min versus 466.3 ± 47.9 (µmol/L) × min; p < .001). The peak serum creatine levels at 60-min sampling interval were significantly higher in CN-CRN group (183.7 ± 15.5 µmol/L), as compared to CN group (163.8 ± 12.9 µmol/L) and CRM group (118.6 ± 12.9 µmol/L) (p < .001). This was accompanied by a significantly superior increase in muscle creatine levels after CN-CRN administration at 5-days follow-up, as compared to CN and CRM, respectively (9.6% versus 8.0% versus 2.1%; p = .01). While 2 out of 10 participants were found to be nonresponsive to CN intervention (20.0%) (e.g., no amplification in muscle creatine levels found at 5-days follow-up), and 3 participants out of 10 were nonresponsive in CRM trial (30%), no nonresponders were found after CN-CRN administration, with individual upswing in total muscle creatine varied in this group from 2.0% (lowest increment) to 16.8% (highest increment). Supplemental CN-CRN significantly decreased estimated glomerular filtration rate (eGFR) at 5-days follow-up, as compared to other interventions (p = .004), with the average reduction was 14.8 ± 7.7% (95% confidence interval; from 9.3 to 20.3). Nevertheless, no single participant experienced a clinically relevant reduction in eGFR (< 60 ml/min/1.73 m2) throughout the course of the trial. Liver enzymes remained in reference ranges throughout the study, with no participant experienced high liver blood tests (e.g., AST > 40 units per L or ALT >56 units per L). Besides, no participant reported any major side effects during the trial, while the odors of CN-CRN and CN formulations were considered somewhat unpleasant in 8 out of 10 participants (80.0%). Our results suggest that CN-CRN is a preferred and relatively safe alternative to traditional creatine formulations for improved creatine bioavailability in the blood and skeletal muscle after single-dose and 5-days interventions.

Guidelines-Driven Educational Intervention Promotes Healthy Lifestyle Among Adolescents and Adults: A Serbian National Longitudinal Study.

Background and objectives: The effectiveness of short-term focused educational programs to change health behaviors across large populations seems to be poorly described so far. The main aim of the present study was to evaluate an age-specific 45-min educational program, designed in accordance with the current U.S. Department of Health and Human Services and U.S. Department of Agriculture dietary guidelines and physical activity (PA) guidelines, among adolescents and adults. Materials and Methods: We evaluated the health-promoting lifestyle habits by the Health-Promoting Lifestyle Profile (HPLP-II) at baseline and following 6⁻8 weeks post-education in a nationally representative sample of Serbian adolescents and adults (n = 3822). Results: The percentage of adolescents eating 3⁻5 servings of vegetables per day increased at follow-up (20.1% versus 23.1%, p = 0.001), with significantly more adolescents regularly reading food labels (from 12.2% at baseline to 14.2% at follow-up; p = 0.02). Taken together, mean HPLP-II scores in adolescents significantly improved for both diet (0.05 points; p < 0.0001) and PA (0.09 points; p < 0.0001), and for PA in adults (0.08 points; p < 0.0001). Hierarchical multiple regression analysis revealed that our model as a whole (including time of testing as a predictor variable, and age and gender as control variables) explained 3.0% of the variance in mean HPLP-II scores for diet (p = 0.942) and 3.0% for PA (p = 0.285) in adolescents, and 1.1% of the variance in HPLP-II scores for diet (p = 0.781) and 1.9% for PA (p = 0.075) in adults, respectively. Conclusions: It appears that a brief focused education can positively tackle unhealthy lifestyles in promoting good health in general population. Different modes of interactive communication used here appeared to strengthen participants' capacities for lifestyle changes.

Plasma creatine as a marker of mitochondrial dysfunction.

Mitochondrial dysfunction (MD) is a complex pathophysiological phenomenon, linked with many inherited and acquired diseases. A clinical evaluation of MD requires rather extensive approach, while no gold-standard circulating biomarker has been established so far. Partly produced in mitochondria, creatine thus might be considered as a sensible compound of mitochondrial bioenergetics. Increased plasma creatine perhaps is linked with MD, illustrating disturbances in its utilization in the stressed organelle.

Dietary guanidinoacetic acid increases brain creatine levels in healthy men.

OBJECTIVE: Guanidinoacetic acid (GAA) is an experimental dietary additive that might act as a creatine source in tissues with high-energy requirements. In this case study, we evaluated brain levels of creatine in white matter, gray matter, cerebellum, and thalamus during 8 wk oral GAA administration in five healthy men and monitored the prevalence and severity of side effects of the intervention. METHODS: Volunteers were supplemented daily with 36 mg/kg body weight (BW) of GAA for the first 4 wk of the intervention; afterward GAA dosage was titrated ≤60 mg/kg BW of GAA daily. At baseline, 4, and 8 wk, the participants underwent brain magnetic resonance spectroscopy, clinical chemistry studies, and open-ended questionnaire for side-effect prevalence and severity. RESULTS: Brain creatine levels increased in similar fashion in cerebellum, and white and gray matter after GAA supplementation, with an initial increase of 10.7% reported after 4 wk, and additional upsurge (7.7%) from the weeks 4 to 8 follow-up (P < 0.05). Thalamus creatine levels decreased after 4 wk for 6.5% (P = 0.02), and increased nonsignificantly after 8 wk for 8% (P = 0.09). GAA induced an increase in N-acetylaspartate levels at 8-wk follow-up in all brain areas evaluated (P < 0.05). No participants reported any neurologic adverse event (e.g., seizures, tingling, convulsions) during the intervention. CONCLUSIONS: Supplemental GAA led to a region-dependent increase of the creatine pool in the human brain. This might be relevant for restoring cellular bioenergetics in disorders characterized by low brain creatine and functional enzymatic machinery for creatine synthesis, including neurodegenerative diseases, brain tumors, or cerebrovascular disease.

Should hydrogen therapy be included in a musculoskeletal medicine routine?

Molecular hydrogen (H 2) has recently been recognized as a potential novel therapeutic agent in biomedicine. Initially proposed to be a possible treatment for certain types of neuromuscular disorders, cardio-metabolic diseases and cancer, H 2 improved clinical end-points and surrogate markers in several clinical trials, mainly acting as an anti-inflammatory agent and powerful antioxidant. In this paper, the medicinal properties of H 2 in musculoskeletal medicine are discussed with the aim to provide an updated and practical overview for health professionals working in this field.

Supplementation with Guanidinoacetic Acid in Women with Chronic Fatigue Syndrome.

A variety of dietary interventions has been used in the management of chronic fatigue syndrome (CFS), yet no therapeutic modality has demonstrated conclusive positive results in terms of effectiveness. The main aim of this study was to evaluate the effects of orally administered guanidinoacetic acid (GAA) on multidimensional fatigue inventory (MFI), musculoskeletal soreness, health-related quality of life, exercise performance, screening laboratory studies, and the occurrence of adverse events in women with CFS. Twenty-one women (age 39.3 ± 8.8 years, weight 62.8 ± 8.5 kg, height 169.5 ± 5.8 cm) who fulfilled the 1994 Centers for Disease Control and Prevention criteria for CFS were randomized in a double-blind, cross-over design, from 1 September 2014 through 31 May 2015, to receive either GAA (2.4 grams per day) or placebo (cellulose) by oral administration for three months, with a two-month wash-out period. No effects of intervention were found for the primary efficacy outcome (MFI score for general fatigue), and musculoskeletal pain at rest and during activity. After three months of intervention, participants receiving GAA significantly increased muscular creatine levels compared with the placebo group (36.3% vs. 2.4%; p < 0.01). Furthermore, changes from baseline in muscular strength and aerobic power were significantly greater in the GAA group compared with placebo (p < 0.05). Results from this study indicated that supplemental GAA can positively affect creatine metabolism and work capacity in women with CFS, yet GAA had no effect on main clinical outcomes, such as general fatigue and musculoskeletal soreness.

Oxidant-Antioxidant Capacity of Dietary Guanidinoacetic Acid.

BACKGROUND/AIMS: Guanidinoacetic acid (GAA) is an experimental nutritional additive under the functional group amino acids and derivatives, yet its use in human nutrition is hindered by limited data on GAA safety. In this double blind, placebo-controlled pilot study, we evaluated the effects of dietary GAA (3 g/day) administered for 2 weeks on the oxidant-antioxidant system in healthy men. METHODS: Twelve healthy men (age 22.3 ± 2.1 years) were recruited for blood sampling at baseline (day 0) and at the end of the intervention period (day 14). Fasting venous blood samples were assessed for plasma total antioxidant capacity, superoxide dismutase (SOD), glutathione peroxidase, total oxidant status and malondialdehyde. RESULTS: Fasting plasma SOD increased significantly from before to after administration in GAA-supplemented participants (91.4 ± 19.6 vs. 122.8 ± 25.9 ng/ml; p = 0.04). Other markers of oxidant-antioxidant system were not affected by the placebo or GAA intervention (p > 0.05). CONCLUSIONS: Oral GAA did not impact the cumulative action of antioxidants present in plasma, yet its SOD-boosting capacity might be considered beneficial when GAA is used as a dietary supplement. Further studies are needed to reveal the direct effects of GAA ingestion on markers of lipid and protein oxidation and on DNA damage.

Molecular hydrogen: An inert gas turns clinically effective.

Molecular hydrogen (H2) appeared as an experimental agent in biomedicine approximately 40 years ago, yet the past 5 years seem to confirm its medicinal value in the clinical environment. H2 improves clinical end-points and surrogate markers in several clinical trials, from metabolic diseases to chronic systemic inflammatory disorders to cancer. However, less information is available concerning its medicinal properties, such as dosage and administration, or adverse reactions and use in specific populations. The present paper overviews the clinical relevance of molecular hydrogen, and summarizes data from clinical trials on this innovative medical agent. Clinical profiles of H2 provide evidence-based direction for practical application and future research on molecular hydrogen for the wider health care community.

Effectiveness of oral and topical hydrogen for sports-related soft tissue injuries.

BACKGROUND: Because hydrogen therapy has been found beneficial for the treatment of inflammation, ischemia-reperfusion injury, and oxidative stress in humans, it seems useful to evaluate the effects of exogenously administered hydrogen as an element in the immediate management of sports-related soft tissue injuries. The main aim of this pilot study was to examine the effects of 2-week administration of hydrogen on the biochemical markers of inflammation and functional recovery in male professional athletes after acute soft tissue injury. METHOD: During the 2013 season (from March to May), 36 professional athletes were recruited as participants and examined by a certified sports medicine specialist in the first 24 hours after an injury was sustained. Subjects were allocated to 3 randomly assigned trials in a single-blind design. Those in the control group received a traditional treatment protocol for soft tissue injury. Subjects in the first experimental group followed the same procedures as the control group but with additional administration throughout the study of oral hydrogen-rich tablets (2 g per day). Subjects in the second experimental group also followed the procedures of the control group, with additional administration throughout the study of both oral hydrogen-rich tablets (2 g per day) and topical hydrogen-rich packs (6 times per day for 20 minutes). Participants were evaluated at the time of the injury report and at 7 and 14 days after baseline testing. RESULTS: Oral and topical hydrogen intervention was found to augment plasma viscosity decrease as compared with the control group (P = 0.04). Differences were found for range-of-motion recovery between the 3 groups; oral and topical hydrogen intervention resulted in a faster return to normal joint range of motion for both flexion and extension of the injured limb as compared with the control intervention (P < 0.05). CONCLUSION: These preliminary results support the hypothesis that the addition of hydrogen to traditional treatment protocols is potentially effective in the treatment of soft tissue injuries in male professional athletes. Trial identification: Clinicaltrials.gov number NCT01759498.

Co-administration of methyl donors along with guanidinoacetic acid reduces the incidence of hyperhomocysteinaemia compared with guanidinoacetic acid administration alone.

Guanidinoacetic acid (GAA) is the natural biosynthetic precursor of creatine, in a metabolic reaction that requires only a methyl group transfer. The use of GAA as a food additive for restoring creatine load in human tissues is rather unexplored and data on efficacy and safety are limited. In particular, an increase in serum homocysteine after GAA administration can be regarded as critical and should be prevented. The present study evaluated the effects of orally administered GAA with and without methyl group donors on serum and urine creatine concentrations, and the occurrence of adverse events during an intervention in healthy human subjects. A total of twenty male and female volunteers were randomised in a double-blind design to receive either GAA (2.4 g/d) or GAA with methyl donors (2.4 g/d of GAA and 1.6 g/d of betaine HCl, 5 µg/d of vitamin B12, 10 mg/d of vitamin B6 and 600 µg/d of folic acid) by oral administration for 8 weeks. Serum and urine creatine increased significantly from before to after administration in both groups (P< 0.001). The proportion of participants who reported minor adverse events was 33.3 % in the GAA group, and 10.0 % in the GAA with methyl donors group (P= 0.30). Hyperhomocysteinaemia was found in 55.6 % of participants supplemented with GAA, while no participant experienced hyperhomocysteinaemia in the group supplemented with GAA and methyl donors (P= 0.01). In summary, both interventions strongly influenced creatine metabolism, resulting in a significant increase in fasting serum creatine. The concomitant supplementation of methyl donors along with GAA largely precluded the elevation of serum homocysteine caused by GAA administration alone.

Effects of short-term dehydroepiandrosterone supplementation on body composition in young athletes.

Dehydroepiandrosterone (DHEA) is often promoted as a slimming and weight/fat loss agent and ingestion of DHEA may have hypolipidemic and anti-obesity properties. The main aim of this study was to examine the effects of acute DHEA intake on body composition and serum steroid hormones in young athletes. Twenty young (19 to 22 years) male soccer players were allocated into two randomly assigned trials in double-blind design by ingesting 100-mg daily oral DHEA or as placebo (PLA) for 28 days. Body mass was not affected by 4 weeks of DHEA supplementation (P > 0.05). No significant changes in body mass index (BMI), waist-to-hip ratio (WHR) and body fat or total muscle mass for the two groups were detected at the end of the trial (P > 0.05). There was no within- or between-group difference in arm fat index (AFI) and corrected mid-upper-arm muscle area (cAMA) (P > 0.05). Treatment with DHEA resulted in a significant increase of total testosterone, estradiol and DHEA-S levels in treated subjects versus the placebo group (P < 0.05). Results of this study suggest that DHEA supplementation has no beneficial effects on body composition in young competitive athletes.

The effects of a 4-week coffeeberry supplementation on antioxidant status, endurance, and anaerobic performance in college athletes.

The main aim of this investigation was to evaluate the changes in total antioxidant capacity (TAC) and aerobic and anaerobic performance induced by supplementation of coffeeberry (CB) formulation for 4 weeks in college athletes. Twenty college athletes (14 males and 6 females) were allocated to two randomly assigned trials. Subjects in the CB group orally ingested capsules that contained CB formulation at a dose of 800 mg per day in two equal doses for 28 days, while subjects in the placebo (P) group ingested an equal number of identical-looking caps that contained cellulose. There were no changes in glucose, cholesterol, and lipoproteins within or between trials (p > 0.05). Total antioxidant capacity (TAC) was significantly higher in the CB versus P trial at the post- supplementation trial (1.66 +/- 0.16 vs. 1.51 +/- 0.05 mmol/L; p < 0.05). There were no statistically significant changes in average anaerobic power, index of anaerobic fatigue, maximal heart rate, blood lactate, and maximal oxygen uptake within or between trials (p > 0.05). Heart rate recovery (HRR) index increased significantly in CB group as compared with baseline level (38 +/- 4 vs. 32 +/- 5 beats/min; p < 0.05). Blood lactate after 10 min of recovery (Lact(rec)) significantly decreased in the CB group after supplementation protocol as compared with initial results (7.6 +/- 4.2 vs. 5.5 +/- 2.6 mmol/L; p < 0.05). No subject reported any side effects from CB or P. The results of the present study indicate that supplementation with a CB formulation slightly increased antioxidant capacity, but there were minimal effects on recovery parameters after exercise in college athletes.