A substantial body of evidence indicates a positive correlation between dyslipidemia and an elevated risk of chronic kidney disease, with renal interstitial fibrosis frequently serving as a common pathway in the advanced stages of chronic kidney disease progression. Hydrogen has anti-inflammatory and antioxidant properties, and magnesium hydride nanoparticle is a material with high hydrogen storage capacity. Magnesium hydride -fortified feed is capable of releasing hydrogen gas steadily and continuously within the digestive tract. A 12-week high-fat diet significantly elevated the serum urea and creatinine levels in mice. In contrast, dietary addition of magnesium hydride demonstrated a notable protective effect against pathological conditions. Additionally, magnesium hydride -fortified feed was found to reduce renal fibrosis and thereby improve renal function. In support of these findings, an in vitro study utilizing human kidney cortical proximal tubule epithelial cells (HK-2 cells) exposed to palmitic acid under conditions mimicking a high-fat diet confirmed the renoprotective effects of magnesium hydride. Furthermore, the primary target phosphatase and tensin homologue deleted on chromosome 10 and the molecular mechanisms underlying the effects of magnesium hydride, specifically its ability to inhibit the transforming growth factor-beta -Smad family member 2 and 3 (Smad2/3) axis through downregulating the expression of phosphatase and tensin homologue deleted on chromosome 10, were elucidated. Additionally, overexpression of Hes family BHLH transcription factor 1 can negate the beneficial effects of magnesium hydride, suggesting that Hes family BHLH transcription factor 1 may serve as an upstream regulatory target in the context of the effects of magnesium hydride. In conclusion, this study demonstrated that magnesium hydride functions as a safe and effective hydrogen source capable of inhibiting the activation of the transforming growth factor-beta/Smad2/3 and protein kinase B/mechanistic target of rapamycin pathways by increasing the expression of phosphatase and tensin homologue deleted on chromosome 10. This mechanism counteracts the progression of high-fat diet-induced chronic renal damage.

There is strong evidence connecting increased serum lipid levels to cardiovascular disorders, including atherosclerosis. Statins is prescribed as the primary medication to decrease lipid levels. Recent research has demonstrated that hydrogen possesses anti-inflammatory and antioxidant properties by modulating the expression of peroxisome proliferator-activated receptor gamma coactivator-1α, ultimately leading to the preservation of lipid homeostasis. Magnesium hydride (MgH 2 ) is a prolonged stable hydrogen storage medium, which can be utilized to investigate its synergistic lipid-lowering effect with statins and its detailed molecular mechanism, both in vivo and in vitro . To ascertain the safety and efficacy of MgH 2 , we executed a comprehensive research of its influence on both physiological and pathological metrics. We noted a substantial diminution in lipid levels when MgH 2 was integrated with atorvastatin, as attested by oil red staining. Furthermore, we scrutinized the regulatory effect of MgH 2 on cytochrome P450 3A, which is a metabolic enzyme of statins, and discovered that it could be reduced by the MgH 2 . Concluding from our results, we propose that MgH 2 inhibits the expression of cytochrome P450 3A in the liver and exerts an auxiliary lipid-lowering effect by increasing the blood concentration of statins. By augmenting our comprehension of MgH 2 's role in ameliorating lipid metabolism, we aspire to develop more promising therapies in the future.

Hydrogen is a simple, colorless, and biologically active small molecule gas that can react with reactive oxygen species. Recent research suggests that hydrogen possesses several biological effects, including antioxidant, anti-inflammatory, and anti-apoptotic effects, while exhibiting an extremely high level of safety. Hydrogen application has shown promise in treating a range of acute and chronic diseases, both benign and malignant. Importantly, an increasing number of clinical studies on hydrogen have demonstrated its efficacy and safety in treating various diseases. This review highlights the beneficial effects of hydrogen in kidney diseases, summarizes potential mechanisms by which hydrogen may act in these diseases, and proposes several promising avenues for future research.

Acetaminophen (APAP)-induced acute kidney injury (APAP-AKI) has turned into one of reasons for clinic obtained renal insufficiency. Magnesium hydride (MgH2), as a solid-state hydrogen source, might be potentially applied in clinical practice. The current study aimed to investigate the protective effect of MgH2 against APAP-AKI. The results showed that MgH2 improved renal function and histological injury in mice of APAP-AKI. MgH2 also had protective effects on APAP-induced cytotoxicity in HK-2 cells. In addition, the increased level of reactive oxygen species (ROS) and expressions of inflammatory cytokines (TNF-alpha and IL-1 beta) and pro-apoptotic factors (Bad, Bax, Caspase3, and CytC) induced by APAP were downregulated with MgH2 treatment. Furthermore, the expressions of molecules related to TXNIP/NLRP3/NF-kappa B pathway (TXNIP, NLRP3, NF-kappa B p65 and p-NF-kappa B p65) in renal tissues and HK-2 cells were enhanced by APAP overdose, which were reduced by MgH2 administration. Collectively, this study indicated that MgH2 protects against APAP-AKI by alleviating oxidative stress, inflammation and apoptosis via inhibition of TXNIP/NLRP3/NF-kappa B signaling pathway.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). Anxiety and depression are the most common psychiatric comorbidities of MS, which seriously affect patients' quality of life, treatment compliance, and prognosis. However, current treatments for anxiety and depression in MS show low therapeutic efficacy and significant side effects. In the present study, we explored the therapeutic effects of a novel low-toxic anti-inflammatory drug, nanoparticulate magnesium hydride (MgH2), on mood disorders of MS. We observed that anxiety/depression-like behaviors in experimental autoimmune encephalomyelitis (EAE) mice were alleviated by MgH2 treatment. In addition, disease severity and inflammatory demyelination were also diminished. Furthermore, we confirmed the suppressive effect of MgH2 on depression in the acute restraint stress model. Mechanistically, MgH2 may play a therapeutic role by promoting microglial M2 polarization, inhibiting microglial M1 polarization, and reducing oxidative stress and mitochondrial damage. Therefore, nanoparticulate MgH2 may be a promising therapeutic drug for psychiatric comorbidities of MS.

OBJECTIVE:Molecular hydrogen (H2) exhibits antioxidant, anti-inflammatory and anti-apoptotic effects, and has shown benefits in glucose and lipid metabolism in certain animal metabolic disorder models. However, the potential benefits of H2 treatment in individuals with impaired fasting glucose (IFG) has seldom been studied. This randomized controlled study (RCT) aims to investigate the effects of hydrogen-rich water (HRW) on IFG subjects and explore the underlying mechanism involved.METHODS:Seventy-three patients with IFG were enrolled in a randomized, double-blind, placebo-controlled clinical study. These patients were assigned to receive either 1000 mL per day of HRW or placebo pure water (no H2 infusion) for a duration of eight weeks. Metabolic parameters and fecal gut microbiota were assessed at baseline (week 0) and at week 8. A combined analysis of metabolomics and intestinal microbiota was conducted to investigate the correlation between the effect of H2 on the metabolisms and the diversity of intestinal flora in the IGF patients.RESULTS:Both pure water and HRW demonstrated a significant reduction in fasting blood glucose in IFG patients, with a significant difference between pure water and HRW after eight weeks. Among IFG patients with abnormal pre-experimental fatty liver, 62.5% (10/16) in the HRW group and 31.6% (6/19) in the pure water group achieved remission. Furthermore, 16S RNA analysis revealed HRW-modified gut microbiota dysbiosis in the fecal samples of IGF patients. Through Pearson correlation analysis, the differential gut microbiota obtained by 16S analysis was found to be highly correlated with nine metabolites.CONCLUSION:H2 slightly improved metabolic abnormalities and gut microbiota dysbiosis, providing a novel target and theoretical basis for the prevention and treatment of blood glucose regulation in patients with IFG.

Fe-porphyrin acts as a primary molecular target/biosensor of hydrogen (H2), which can catalyze H2 to reduce •OH and carbon dioxide (CO2) into H2O and carbon monoxide (CO), respectively, for downstream signaling.1 In 1975, Dole et al.2 found that exposure to an H2/O2 (97.5%:2.5%) mixed gas at a pressure of 8 atm (1 atm = 101.325 kPa) for 2 weeks caused the marked regression of skin tumors in a skin tumor-bearing mouse model, which was speculated due to the •OH and O2- scavenging effect of H2. In 2007, Ohsawa et al.3 found that H2 can selectively reduce •OH with high oxidability rather than other reactive oxygen species, but later research indicated that the probability/efficiency of the direct reduction of •OH by H2 is considerably low.4 Increasing studies have suggested that H2 can regulate the respiration of mitochondria,5678910 which is hardly explained by the direct •OH reduction by H2, especially in terms of anticancer. It seems that H2 might play a reducer or/and CO/ nitric oxide (NO)-like gasotransmitter, which was not confirmed previously with experimental evidence. More encouragingly, Jin et al.1 experimentally identified he- matin, a kind of Fe-phorphyrins, as a molecular target/biosensor of H2. They found that in both free and protein-confining states, Fe-porphyrin can self-catalyze hydrogenation by reacting with H2 to obtain high reducibility of Fe-coordinated hydrogen atoms, which subsequently can not only neutralize •OH into H2O but also reduce CO2 into CO in the hypoxic microenvironment. Fe-porphyrin is mainly enriched in cellular mitochondria and in red blood cells, which are the two main workplaces of H2. At cellular mitochondria, H2 can efficiently reduce •OH under local catalysis of Fe-porphyrin to attenuate oxidative stress for anti­inflammation. Moreover, in the hypoxia microenvironment, such as solid tumor and heart ischemia, Fe-porphyrin-catalytically generated CO is locally coordinated with Fe-porphyrin to medi­ate the downstream CO signaling, inducing apoptosis in tumor cells and protecting myocardial cells via hypoxic alleviation. The therapeutic effects on many diseases may be related to the downstream CO signaling besides •OH scavenging. Since the other medical gasses, such as NO, CO, and hydrogen sulfide (H2S), target Fe-porphyrin (heme) to induce each signal transduction,11 it is interesting that H2 commonly targets Fe-porphyrin (hematin) to exhibit its function. Red blood cells containing plentiful amounts of Fe-porphyrin are a kind of natural H2 vehicle. In the ischemia\hypoxia mi­croenvironment, red blood cells can be a local capturer of H2 as well as a catalyst of hydrogenation for targeted H2 therapy. In the oxygen-rich blood circulation, oxygen molecules can impede the remote delivery of hydrogen to a certain extent by exhausting reactive hydrogen, but the sufficiently hydrided red blood cells can scavenge •OH in the blood circulation and even throughout the body by virtue of rapid blood flow, which implies the neces­sity of sustainable and plentiful hydrogen supply. In plants, the drug/drought/salt/heavy metals-tolerating and anti-oxidative stress effects of H21213141516 possibly derive from downstream CO. Noticeably, a moderate H2 concentration can maximize the therapeutic outcome of plant disease treatment, which may be due to CO poisoning at an excessively high con­centration of H2. Therefore, an especially high dosage of H2 will possibly cause cytotoxicity to animal cells, which can be used for anticancer and guide the exploration and avoidance of potential toxic side effects of H2. Some diseases such as chronic liver diseases and neurodegen­erative diseases are highly related to free Fe-porphyrin, which can induce Fenton reaction-dependent ferroptosis. The therapeutic effect of H2 against these diseases might be owing to the intercep­tion of a Fenton-like reaction by H2 besides catalytic scavenging of generated •OH. It can provide great inspiration for H2-based drug discovery and development. It is worth noting that Fe-porphyrin is identified as a hydro­genation biocatalyst that plays a role in hydrogen storage and transformation. As envisioned, transition metals-coordinated porphyrin and the molecules with a similar coordination structure are possibly valuable to hydrogen medicine/energy/agriculture for efficient hydrogen storage, safe/precision delivery, custom­ized transformation, and efficient utilization. Jin et al.1 found that hydrogen can enhance the effect of CO, and heme protein has the potential to store and transport hydrogen, which is undoubtedly an important breakthrough in the field of hydrogen biomedicine and puts forward a new direction for future research on the medical mechanism of hydrogen. However, once these effects are identi­fied, there is cause for concern that hydrogen may potentially block oxygen transport and lead to hypoxia in aerobic organisms. In any case, this may be an important advance in the study of the biological effects of hydrogen, which provides important evidence for understanding and analyzing the effects of hydrogen. Editor note: XS and JHZ are Editorial Board members of Medical Gas Research. They were blinded from reviewing or making decisions on the manuscript. The article was subject to the journal's standard procedures, with peer review handled independently of these Editorial Board members and their research groups.

Acute respiratory distress syndrome (ARDS) causes uncontrolled pulmonary inflammation, resulting in high morbidity and mortality in severe cases. Given the antioxidative effect of molecular hydrogen, some recent studies suggest the potential use of molecular hydrogen as a biomedicine for the treatment of ARDS. In this study, we aimed to explore the protective effects of magnesium hydride (MgH2) on two types of ARDS models and its underlying mechanism in a lipopolysaccharide (LPS)-induced ARDS model of the A549 cell line. The results showed that LPS successfully induced oxidative stress, inflammatory reaction, apoptosis, and barrier breakdown in alveolar epithelial cells (AEC). MgH2 can exert an anti-inflammatory effect by down-regulating the expressions of inflammatory cytokines (IL-1β, IL-6, and TNF-α). In addition, MgH2 decreased oxidative stress by eliminating intracellular ROS, inhibited apoptosis by regulating the expressions of cytochrome c, Bax, and Bcl-2, and suppressed barrier breakdown by up-regulating the expression of ZO-1 and occludin. Mechanistically, the expressions of p-AKT, p-mTOR, p-P65, NLRP3, and cleaved-caspase-1 were decreased after MgH2 treatment, indicating that AKT/mTOR and NF-κB/NLRP3/IL-1β pathways participated in the protective effects of MgH2. Furthermore, the in vivo study also demonstrated that MgH2-treated mice had a better survival rate and weaker pathological damage. All these findings demonstrated that MgH2 could exert an ARDS-protective effect by regulating the AKT/mTOR and NF-κB/NLRP3/IL-1β pathways to suppress LPS-induced inflammatory reaction, oxidative stress injury, apoptosis, and barrier breakdown, which may provide a potential strategy for the prevention and treatment of ARDS.

Abstract Objective This study aimed to reveal the protective effect of hydrogen storage nanomaterial MgH2 on radiation-induced male fertility impairment. Methods The characterization of MgH2 were analyzed by scanning electron microscopy (SEM) and particle size analyzer. The safety of MgH2 were evaluated in vivo and in vitro. The radioprotective effect of MgH2 on the reproductive system were analyzed in mice, including sperm quality, genetic effect, spermatogenesis, and hormone secretion. ESR, flow cytometry and western blotting assay were used to reveal the underlying mechanisms. Results MgH2 had an irregular spherical morphology and a particle size of approximately 463.2 nm, and the content of Mg reached 71.46%. MgH2 was safe and nontoxic in mice and cells. After irradiation, MgH2 treatment significantly protected testicular structure, increased sperm density, improved sperm motility, reduced deformity rates, and reduced the genetic toxicity. Particularly, the sperm motility were consistent with those in MH mice and human semen samples. Furthermore, MgH2 treatment could maintain hormone secretion and testicular spermatogenesis, especially the generation of Sertoli cells, spermatogonia and round sperm cells. In vitro, MgH2 eliminated the [·OH], suppressed the irradiation-induced increase in ROS production, and effectively alleviated the increase in MDA contents. Moreover, MgH2 significantly ameliorated apoptosis in testes and cells and reversed the G2/M phase cell cycle arrest induced by irradiation. In addition, MgH2 inhibited the activation of radiation-induced inflammation and pyroptosis. Conclusion MgH2 improved irradiation-induced male fertility impairment by eliminating hydroxyl free radicals. Graphical abstract Mice fertility and function were evaluated with or without MgH2 treatment after 5 Gy irradiation. MgH2 had the ability of hydroxyl radicals scavenging and MDA suppressing in testicular tissue induced by irradiation. Further, MgH2 could participate in spermatogenesis and protect sperm development in three stages: the generation of Sertoli cells (Sox-9+), spermatogonia (Stra8+) and round sperm cells (Crem+). Moreover, MgH2 alleviated the decrease of testosterone secreted by interstitial cells after irradiation. In addition, MgH2 suppressed apoptosis, pyroptosis and inflammatory response and alleviated cell cycle arrest by mediating IR-induced ROS.