Endogenous Hydrogen Sulfide Production Research Articles

Complex Pathophysiology of Acute Kidney Injury (AKI) in Aging: Epigenetic Regulation, Matrix Remodeling, and the Healing Effects of H2S.

The kidney is an essential excretory organ that works as a filter of toxins and metabolic by-products of the human body and maintains osmotic pressure throughout life. The kidney undergoes several physiological, morphological, and structural changes with age. As life expectancy in humans increases, cell senescence in renal aging is a growing challenge. Identifying age-related kidney disorders and their cause is one of the contemporary public health challenges. While the structural abnormalities to the extracellular matrix (ECM) occur, in part, due to changes in MMPs, EMMPRIN, and Meprin-A, a variety of epigenetic modifiers, such as DNA methylation, histone alterations, changes in small non-coding RNA, and microRNA (miRNA) expressions are proven to play pivotal roles in renal pathology. An aged kidney is vulnerable to acute injury due to ischemia-reperfusion, toxic medications, altered matrix proteins, systemic hemodynamics, etc., non-coding RNA and miRNAs play an important role in renal homeostasis, and alterations of their expressions can be considered as a good marker for AKI. Other epigenetic changes, such as histone modifications and DNA methylation, are also evident in AKI pathophysiology. The endogenous production of gaseous molecule hydrogen sulfide (H2S) was documented in the early 1980s, but its ameliorative effects, especially on kidney injury, still need further research to understand its molecular mode of action in detail. H2S donors heal fibrotic kidney tissues, attenuate oxidative stress, apoptosis, inflammation, and GFR, and also modulate the renin-angiotensin-aldosterone system (RAAS). In this review, we discuss the complex pathophysiological interplay in AKI and its available treatments along with future perspectives. The basic role of H2S in the kidney has been summarized, and recent references and knowledge gaps are also addressed. Finally, the healing effects of H2S in AKI are described with special emphasis on epigenetic regulation and matrix remodeling.

Pharmacological Inhibition of Endogenous Hydrogen Sulfide Production Slows Bladder Cancer Progression in an Intravesical Murine Model.

Present bladder cancer therapies have relatively limited therapeutic impact and account for one of the highest lifetime treatment costs per patient. Therefore, there is an urgent need to explore novel and optimized treatment strategies. The present study investigated the effects of inhibiting endogenous hydrogen sulfide (H2S) production on bladder cell viability and in vivo tumor progression. We targeted the H2S-producing enzyme, cystathionine γ-lyase, in 5637 cells using propargylglycine (H2S inhibitor) and performed cytofluorimetric analysis to evaluate cell viability. We then tested the efficacy of propargylglycine alone or in combination with gemcitabine (conventional chemotherapy) in an intravesical murine model of bladder cancer. Magnetic resonance imaging and immunohistochemical staining for cell proliferation, apoptosis, immune-cell infiltration, and neovascularization were performed to evaluate tumor response. Compared to control conditions or cohorts, propargylglycine administration significantly attenuated bladder cancer cell viability in vitro (p < 0.0001) and tumor growth (p < 0.002) and invasion in vivo. Furthermore, propargylglycine enhanced the anti-cancer effects of gemcitabine, resulting in tumor regression (p < 0.0001). Moreover, propargylglycine induced cleaved PARP-1-activated apoptosis (p < 0.05), as well as intratumoral CD8+ T cell (p < 0.05) and F4/80+ macrophage (p < 0.002) infiltration. Propargylglycine also reduced intratumoral neovascularization (p < 0.0001) and cell proliferation (p < 0.0002). Importantly, the pro-apoptotic and anti-neovascularization effects of gemcitabine were enhanced by propargylglycine co-administration. Our findings suggest that inhibition of endogenous H2S production can be protective against bladder cancer by enhancing the chemotherapeutic action of gemcitabine and may be a novel pharmacological target and approach for improved bladder cancer diagnosis and treatments in the future.

Evolutionary Rate Shifts in Coding and Regulatory Regions Underpin Repeated Adaptation to Sulfidic Streams in Poeciliid Fishes.

Adaptation to extreme environments often involves the evolution of dramatic physiological changes. To better understand how organisms evolve these complex phenotypic changes, the repeatability and predictability of evolution, and possible constraints on adapting to an extreme environment, it is important to understand how adaptive variation has evolved. Poeciliid fishes represent a particularly fruitful study system for investigations of adaptation to extreme environments due to their repeated colonization of toxic hydrogen sulfide-rich springs across multiple species within the clade. Previous investigations have highlighted changes in the physiology and gene expression in specific species that are thought to facilitate adaptation to hydrogen sulfide-rich springs. However, the presence of adaptive nucleotide variation in coding and regulatory regions and the degree to which convergent evolution has shaped the genomic regions underpinning sulfide tolerance across taxa are unknown. By sampling across seven independent lineages in which nonsulfidic lineages have colonized and adapted to sulfide springs, we reveal signatures of shared evolutionary rate shifts across the genome. We found evidence of genes, promoters, and putative enhancer regions associated with both increased and decreased convergent evolutionary rate shifts in hydrogen sulfide-adapted lineages. Our analysis highlights convergent evolutionary rate shifts in sulfidic lineages associated with the modulation of endogenous hydrogen sulfide production and hydrogen sulfide detoxification. We also found that regions with shifted evolutionary rates in sulfide spring fishes more often exhibited convergent shifts in either the coding region or the regulatory sequence of a given gene, rather than both.

Fur-mediated regulation of hydrogen sulfide synthesis, stress response, and virulence in Edwardsiella piscicida

The production of endogenous hydrogen sulfide (H2S) is an important phenotype of bacteria. H2S plays an important role in bacterial resistance to ROS and antibiotics, which significantly contributes to bacterial pathogenicity. Edwardsiella piscicida, the Gram-negative pathogen causing fish edwardsiellosis, has been documented to produce hydrogen sulfide. In the study, we revealed that Ferric uptake regulator (Fur) controlled H2S synthesis by activating the expression of phsABC operon. Besides, Fur participated in the bacterial defense against ROS and cationic antimicrobial peptides and modulated T3SS expression. Furthermore, the disruption of fur exhibited a significant in vivo colonization defect. Collectively, our study demonstrated the regulation of Fur in H2S synthesis, stress response, and virulence, providing a new perspective for better understanding the pathogenesis of Edwardsiella.

Catalytic specificity and crystal structure of cystathionine γ-lyase from Pseudomonas aeruginosa

The escalating drug resistance among microorganisms underscores the urgent need for innovative therapeutic strategies and a comprehensive understanding of bacteria's defense mechanisms against oxidative stress and antibiotics. Among the recently discovered barriers, the endogenous production of hydrogen sulfide (H2S) via the reverse transsulfuration pathway, emerges as a noteworthy factor. In this study, we have explored the catalytic capabilities and crystal structure of cystathionine γ-lyase from Pseudomonas aeruginosa (PaCGL), a multidrug-opportunistic pathogen chiefly responsible for nosocomial infections. In addition to a canonical l-cystathionine hydrolysis, PaCGL efficiently catalyzes the production of H2S using l-cysteine and/or l-homocysteine as alternative substrates. Comparative analysis with the human enzyme and counterparts from other pathogens revealed distinct structural features within the primary enzyme cavities. Specifically, a distinctly folded entrance loop could potentially modulate the access of substrates and/or inhibitors to the catalytic site. Our findings offer significant insights into the structural evolution of CGL enzymes across different pathogens and provide novel opportunities for developing specific inhibitors targeting PaCGL.

Inhibition of endogenous hydrogen sulfide production reduces activation of hepatic stellate cells via the induction of cellular senescence

ABSTRACT In chronic liver injury, quiescent hepatic stellate cells (HSCs) transdifferentiate into activated myofibroblast-like cells and produce large amounts of extracellular matrix components, e.g. collagen type 1. Cellular senescence is characterized by irreversible cell-cycle arrest, arrested cell proliferation and the acquisition of the senescence-associated secretory phenotype (SASP) and reversal of HSCs activation. Previous studies reported that H2S prevents induction of senescence via its antioxidant activity. We hypothesized that inhibition of endogenous H2S production induces cellular senescence and reduces activation of HSCs. Rat HSCs were isolated and culture-activated for 7 days. After activation, HSCs treated with H2S slow-releasing donor GYY4137 and/or DL-propargylglycine (DL-PAG), an inhibitor of the H2S-producing enzyme cystathionine γ-lyase (CTH), as well as the PI3K inhibitor LY294002. In our result, CTH expression was significantly increased in fully activated HSCs compared to quiescent HSCs and was also observed in activated stellate cells in a in vivo model of cirrhosis. Inhibition of CTH reduced proliferation and expression of fibrotic markers Col1a1 and Acta2 in HSCs. Concomitantly, DL-PAG increased the cell-cycle arrest markers Cdkn1a (p21), p53 and the SASP marker Il6. Additionally, the number of β-galactosidase positive senescent HSCs was increased. GYY4137 partially restored the proliferation of senescent HSCs and attenuated the DL-PAG-induced senescent phenotype. Inhibition of PI3K partially reversed the senescence phenotype of HSCs induced by DL-PAG. Inhibition of endogenous H2S production reduces HSCs activation via induction of cellular senescence in a PI3K-Akt dependent manner. Our results show that cell-specific inhibition of H2S could be a novel target for anti-fibrotic therapy via induced cell senescence.

Allicin Promotes Glucose Uptake by Activating AMPK through CSE/H2S-Induced S-Sulfhydration in a Muscle-Fiber Dependent Way in Broiler Chickens.

Allicin, a product of enzymatic reaction when garlic is injured, plays an important role in maintaining glucose homeostasis in mammals. However, the effect of allicin on glucose homeostasis in the state of insulin resistance remains to be elucidated. This study investigates the effect of allicin on glucose metabolism using different muscle fibers in a chicken model. Day-old male Arbor Acres broilers are randomly divided into three groups and fed a basal diet supplemented with 0, 150, or 300mgkg-1 allicin for 42 days. Results show that allicin improves the zootechnical performance of broilers at the finishing stage. The glucose loading test (2gkg-1 body mass) indicates the regulatory role of allicin on glucose homeostasis. In vitro results demonstrate allicin increases glutathione (GSH) level and the expression of cystathionine γ lyase (CSE), leading to endogenous hydrogen sulfide (H2S) production in M. pectoralis major (PM) muscle-derived myotubes. Allicin stimulates adenosine monophosphate-activated protein kinase (AMPK) S-sulfhydration and AMPK phosphorylation to promote glucose uptake, which is suppressed in the presence of d,l-propargylglycine (PAG, a CSE inhibitor). This study demonstrates that allicin induces AMPK S-sulfhydration and AMPK phosphorylation to promote glucose uptake via the CSE/H2S system in a muscle fiber-dependent manner.

The bitter taste receptor (TAS2R) agonist denatonium promotes a strong relaxation of rat corpus cavernosum

Bitter taste receptors (TAS2R) are found in numerous extra-oral tissues, including smooth muscle (SM) cells in both vascular and visceral tissues. Upon activation, TAS2R stimulate the relaxation of the SM. Nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway is involved in penile erection, and type 5 phosphodiesterase (PDE5) inhibitors, a cGMP-specific hydrolase are used as first-line treatments for erectile dysfunction (ED). Nevertheless, PDE5 inhibitors are ineffective in a considerable number of patients, prompting research into alternative pharmacological targets for ED. Since TAS2R agonists regulate SM contractility, this study investigates the role of TAS2Rs in rat corpus cavernosum (CC). We performed immunohistochemistry to detect TAS2R10, isometric force recordings for TAS2R agonists denatonium and chloroquine, the slow-release H2S donor GYY 4137, the NO donor SNAP, the β-adrenoceptor agonist isoproterenol and electrical field stimulation (EFS), as well as measurement of endogenous hydrogen sulfide (H2S) production. The immunofluorescence staining indicated that TAS2R10 was broadly expressed in the CC SM and to some extent in the nerve fibers. Denatonium, chloroquine, SNAP, and isoproterenol cause potent dose-dependent SM relaxations. H2S production was decreased by NO and H2S synthase inhibitors, while it was enhanced by denatonium. In addition, denatonium increased the relaxations induced by GYY 4137 and SNAP but failed to modify EFS- and isoproterenol-induced responses. These results suggest neuronal and SM TAS2R10 expression in the rat CC, where denatonium induces a strong SM relaxation per se and promotes the H2S- and NO-mediated inhibitory gaseous neurotransmission. Thus, TAS2R10 might represent a valuable therapeutic target in ED.

A time-course investigation of the human urinary excretion of the hydrogen sulfide biomarker trimethylsulfonium

Hydrogen sulfide is a toxic gas but also recognized as an endogenously produced metabolite in humans playing key roles. We previously identified trimethylsulfonium, which can be a methylation product of hydrogen sulfide but the stability in the production of trimethylsulfonium has not been investigated. In the present work, the intra- and inter-individual variability in the excretion of trimethylsulfonium over 2 months in a group of healthy volunteers was investigated. Urinary levels of trimethylsulfonium (mean: 56 nM, 95% CI: 48–68 nM) were > 100-fold lower than the conventional hydrogen sulfide biomarker thiosulfate (13 µM, 12–15 µM) and the precursor for endogenous hydrogen sulfide production cystine (47 µM, 44–50 µM). There was no correlation between urinary trimethylsulfonium and thiosulfate. Higher intra-individual variability in the excretion of trimethylsulfonium (generally 2-8 fold) than that for cystine (generally 2-3 fold) was found. Trimethylsulfonium displayed significant inter-individual variability with two concentration clusters at 117 nM (97−141) and 27 nM (22−34). In conclusion, the observed inter- and intra-individual variability must be considered when using urinary trimethylsulfonium as a biomarker.

Inhibition of endogenous hydrogen sulfide production suppresses the growth of nasopharyngeal carcinoma cells.

Hydrogen sulfide (H2 S) has been widely recognized as one of gasotransmitters. Endogenous H2 S plays a crucial role in the progression of cancer. However, the effect of endogenous H2 S on the development of nasopharyngeal carcinoma (NPC) is still unknown. In this study, aminooxyacetic acid (AOAA, an inhibitor of cystathionine-β-synthase), dl-propargylglycine (PAG, an inhibitor of cystathionine-γ-lyase), and l-aspartic acid (l-Asp, an inhibitor of 3-mercaptopyruvate sulfurtransferase) were adopted to detect the role of endogenous H2 S in NPC growth. The results indicated that the combine (PAG + AOAA + l-Asp) group had higher inhibitory effect on the growth of NPC cells than the PAG, AOAA, and l-Asp groups. There were similar trends in the levels of apoptosis and reactive oxygen species (ROS). In addition, the combine group exhibited lower levels of phospho (p)-extracellular signal-regulated protein kinase but higher expressions of p-p38 and p-c-Jun N-terminal kinase than those in the AOAA, PAG, and l-Asp groups. Furthermore, the combine group exerted more potent inhibitory effect on NPC xenograft tumor growth without obvious toxicity. In summary, suppression of endogenous H2 S generation could dramatically inhibit NPC growth via the ROS/mitogen-activated protein kinase pathway. Endogenous H2 S may be a novel therapeutic target in human NPC cells. Effective inhibitors for H2 S-producing enzymes could be designed and developed for NPC treatment.

Choline induced cardiac dysfunction by inhibiting the production of endogenous hydrogen sulfide in spontaneously hypertensive rats

To investigate the exact effects of dietary choline on hypertensive heart disease (HHD) and explore the potential mechanisms, male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were randomly divided into five groups as follows: WKY group, WKY + Choline group, SHR group, SHR + Choline group, and SHR + Choline + NaHS group. In choline treatment groups, rats were fed with 1.3% (w/v) choline in the drinking water for 3 months. The rats in the SHR + Choline + NaHS group were intraperitoneally injected with NaHS (100 μmol/kg/day, a hydrogen sulfide (H2S) donor) for 3 months. After 3 months, left ventricular ejection fraction (LVEF) and fractional shortening (LVFS), the indicators of cardiac function measured by echocardiography, were increased significantly in SHR as compared to WKY, although there was no significant difference in collagen volumes and Bax/Bcl-2 ratio between the two groups, indicating the early stage of cardiac hypertrophy. There was a significant decrease in LVEF and LVFS and an increase in collagen volumes and Bax/Bcl-2 ratio in SHR fed with choline, meanwhile, plasma H2S levels were significantly decreased significantly in SHR fed with choline accompanying by the decrease of cystathionine-γ-lyase (CSE) activity. Three months of NaHS significantly increased plasma H2S levels, ameliorated cardiac dysfunction and inhibited cardiac fibrosis and apoptosis in SHR fed with choline. In conclusion, choline aggravated cardiac dysfunction in HHD through inhibiting the production of endogenous H2S, which was reversed by supplementation of exogenous H2S donor.

Targeting hepatic sulfane sulfur/hydrogen sulfide signaling pathway with α-lipoic acid to prevent diabetes-induced liver injury via upregulating hepatic CSE/3-MST expression

BackgroundDiabetes-induced liver injury is a complication of diabetes mellitus of which there are no approved drugs for effective treatment or prevention. This study investigates possible hepatoprotective effect of alpha-lipoic acid (ALA), and sulfane sulfur/hydrogen sulfide pathway as a novel protective mechanism in a rat model of type 2 diabetes-induced liver injury.MethodsThirty Sprague–Dawley rats underwent fasting for 12 h after which fasting blood glucose was measured and rats were randomly assigned to diabetic and non-diabetic groups. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). Diabetic rats were treated daily with ALA (60 mg/kg/day p.o.) or 40 mg/kg/day DL-propargylglycine (PPG, an inhibitor of endogenous hydrogen sulfide production) for 6 weeks and then sacrificed. Liver, pancreas and blood samples were collected for analysis. Untreated T2DM rats received distilled water.ResultsHypoinsulinemia, hyperglycemia, hepatomegaly and reduced hepatic glycogen content were observed in untreated T2DM rats compared to healthy control group (p < 0.001). Also, the pancreas of untreated T2DM rats showed severely damaged pancreatic islets while liver damage was characterized by markedly increased hepatocellular vacuolation, sinusoidal enlargement, abnormal intrahepatic lipid accumulation, severe transaminitis, hyperbilirubinemia, and impaired hepatic antioxidant status and inflammation compared to healthy control rats (p < 0.01). While pharmacological inhibition of hepatic sulfane sulfur/hydrogen sulfide with PPG administration aggravated these pathological changes (p < 0.05), ALA strongly prevented these changes. ALA also significantly increased hepatic expression of hydrogen sulfide-producing enzymes (cystathionine γ-lyase and 3-mecaptopyruvate sulfurtransferase) as well as hepatic sulfane sulfur and hydrogen sulfide levels compared to all groups (p < 0.01).ConclusionsTo the best of our knowledge, this is the first experimental evidence showing that ALA prevents diabetes-induced liver injury by activating hepatic sulfane sulfur/hydrogen sulfide pathway via upregulation of hepatic cystathionine γ-lyase and 3-mecaptopyruvate sulfurtransferase expressions. Therefore, ALA could serve as a novel pharmacological agent for the treatment and prevention of diabetes-induced liver injury, with hepatic sulfane sulfur/hydrogen sulfide as a novel therapeutic target.

Engineered Carbon Nanostructures for Preventing Alzheimer’s Disease

Alzheimer’s disease (AD) is an aging-associated devastating disease that affects over 5 million Americans and imposes an annual economic burden of $236 billion. Currently, all efforts to develop remedies to AD have failed. This unfortunate situation calls for the development of new research directions. One of the common pathological features of AD is the decline in endogenous production of hydrogen sulfide (H2S), a gaseous signaling molecule. H2S in the brain is historically believed to be solely derived via enzymatic production and deficiencies in H2S producing enzymes, such as cystathionine-γ-lyase (CGL) and cystathionine-β-synthase (CBS) are associated with neurodegenerative diseases. Exogenous administration of H2S and H2S donors have shown to attenuate Alzheimer’s and Parkinson’s disease phenotypes in rodent models. However, exogenous H2S gas and donor molecules are short-lived, highly reactive, and display acute toxicity at elevated levels, and delivery to the intended tissue may be challenging to achieve in the clinic. Thus, discovering new technologies that regulate and/or augment endogenous enzymatic H2S pose novel scientific and therapeutic avenues particularly for the treatment of neurodegenerative disorders such as Alzheimer’s disease.We are designing enzyme-mimicking carbon nanostructures (EMCNs) that can augment the production of H2S using biological substrates present in the body and compensate for the declining enzyme activity and prevent the progression of Alzheimer’s disease. Carbon nanostructures with sp2 carbons are composed of multiple electron-deficient double bonds, which can be systematically replaced with functional groups to create a heterogeneous surface that is fundamentally different from that originally present. Based on the sp2 site engineering concept, we selected and synthesized EMCNs capable of interacting with the sulfur-containing biomolecules, catalyzing their breakdown into H2S and other products, thus mimicking CGL and CBS enzymes.The ability of EMCNs to mimic enzymes was evaluated with lead acetate saturated paper-based assay. EMCNs break down cysteine to produce H2S, which reacts with lead acetate to form lead sulfide. The concentration of H2S generated is calculated by using sodium hydrosulfide as an equimolar H2S donor for calibration. The H2S generation from EMCNs can be matched with the CBS enzyme. Further, EMCNs are stable and demonstrate long-term activity. In a repeated exposure experiment, H2S production was constant over a 20 day period where the substrate was added every day without replenishing ECMNs. If EMCNs were a reactant, the H2S production should have decreased with repeated substrate addition until all the EMCN was consumed.The efficacy of EMCNs to produce H2S in vitro was demonstrated with murine neuronal cells. P3 multi-photon fluorescent probe was utilized to detect intracellular H2S levels. The fluorescence intensity of the neuronal cells exposed to EMCN increased in a concentration-dependent manner. Neither cells nor EMCN exhibited auto-fluorescence under multi-photon microscopy. Beta-amyloid (Aβ) plaques, a hallmark of brain pathology in Alzheimer's disease patients, is formed by aggregation of β-amyloid peptides. The role of EMCNs in the AD model was evaluated with β-amyloid toxicity assay using Aβ1-42, which is selectively toxic to neurons. Preliminary studies suggest that EMCNs protect neuronal cells against the toxicity induced by Aβ1-42 by 19%. The ability of EMCNs to produce H2S under physiological conditions thus offers potential for rescuing enzyme deficiencies in Alzheimer’s disease.

Gibberellic acid maintains postharvest quality of Agaricus bisporus mushroom by enhancing antioxidative system and hydrogen sulfide synthesis.

The application of gibberellic acid (GA3 ) treatment to the postharvest quality maintenance of white button mushroom (Agaricus bisporus) was investigated. The optimum concentration of exogenous GA3 was 100mg/L. At this concentration, the color change was inhibited, the firmness was maintained, and the weight loss and respiratory rates were reduced. The GA3 group had significantly lower malonaldehyde (MDA) content and membrane permeability. Reactive oxygen species accumulation was reduced due to the regulation of polyphenol oxidase (PPO), peroxidase (POD), and superoxide dismutase (SOD) enzyme activities. Moreover, the production of endogenous gaseous signaling molecule hydrogen sulfide (H2 S) was triggered by GA3 treatment, which enhanced cystathionine γ-lyase (AbCSE) and cystathionine β-synthase (AbCBS) activities alongside the corresponding gene expressions. The preservation of button mushroom postharvest storage quality by GA3 was most likely due to the regulation of reactive oxygen species metabolism and hydrogen sulfide biosynthesis. PRACTICAL APPLICATIONS: Mushroom is rich in nutrients and functional substances. However, due to the lack of cuticle, high respiration rate, and moisture content, mushroom's postharvest quality deteriorates rapidly. A safe and effective reagent that prevents the senescence and quality deterioration of harvested mushroom is urgently needed. The effects of plant hormone GA3 on the postharvest quality of edible fungi remain unclear. The present study provided convincing evidence that 100mgL-1 of GA3 effectively maintained postharvest button mushroom quality by regulating reactive oxygen species metabolism and hydrogen sulfide biosynthesis.

Exercise training ameliorates early diabetic kidney injury by regulating the H2 S/SIRT1/p53 pathway.

Exercise training exerts protective effects against diabetic nephropathy. This study aimed to investigate whether exercise training could attenuate diabetic renal injury via regulating endogenous hydrogen sulfide (H2 S) production. First, C57BL/6 mice were allocated into the control, diabetes, exercise, and diabetes+exercise groups. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ). Treadmill exercise continued for four weeks. Second, mice was allocated into the control, diabetes, H2 S and diabetes+H2 S groups. H2 S donor sodium hydrosulfide (NaHS) was intraperitoneally injected once daily for four weeks. STZ-induced diabetic mice exhibited glomerular hypertrophy, tissue fibrosis and increased urine albumin levels, urine protein- and albumin-to-creatinine ratios, which were relieved by exercise training. Diabetic renal injury was associated with apoptotic cell death, as evidenced by the enhanced caspase-3 activity, the increased TdT-mediated dUTP nick-end labeling -positive cells and the reduced expression of anti-apoptotic proteins, all of which were attenuated by exercise training. Exercise training enhanced renal sirtuin 1 (SIRT1) expression in diabetic mice, accompanied by an inhibition of the p53-#ediated pro-apoptotic pathway. Furthermore, exercise training restored the STZ-mediated downregulation of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) and the reduced renal H2 S production. NaHS treatment restored SIRT1 expression, inhibited the p53-mediated pro-apoptotic pathway and attenuated diabetes-associated apoptosis and renal injury. In high glucose-treated MPC5 podocytes, NaHS treatment inhibited the p53-mediated pro-apoptotic pathway and podocyte apoptosis in a SIRT1-dependent manner. Collectively, exercise training upregulated CBS/CSE expression and enhanced the endogenous H2 S production in renal tissues, thereby contributing to the modulation of the SIRT1/p53 apoptosis pathway and improvement of diabetic nephropathy.

Giving antibiotics an assist.

Inhibiting endogenous hydrogen sulfide production makes bacteria more susceptible to antibiotics

Hydrogen Sulfide Attenuated Sepsis-Induced Myocardial Dysfunction Through TLR4 Pathway and Endoplasmic Reticulum Stress.

Aims: We examined the change in endogenous hydrogen sulfide (H2S) production and its role in sepsis-induced myocardial dysfunction (SIMD).Results: Significant elevations in plasma cardiac troponin I (cTnI), creatine kinase (CK), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were noted in SIMD patients, whereas left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and plasma H2S were significantly decreased relative to those in the controls. Plasma H2S was linearly related to LVEF and LVFS. Subsequently, an SIMD model was developed in mice by injecting lipopolysaccharide (LPS), and NaHS, an H2S donor, was used to elucidate the pathophysiological role of H2S. The mice showed decreased ventricular function and increased levels of TNF-α, IL-1β, cTnI, and CK after LPS injections. Toll-like receptor (TLR) 4 protein and endoplasmic reticulum stress (ERS) proteins were over expressed in the SIMD mice. All of the parameters above showed more noticeable variations in cystathionine γ-lyase knockout mice relative to those in wild type mice. The administration of NaHS could improve ventricular function and attenuate inflammation and ERS in the heart.Conclusion: Overall, these findings indicated that endogenous H2S deficiency contributed to SIMD and exogenous H2S ameliorated sepsis-induced myocardial dysfunction by suppressing inflammation and ERS via inhibition of the TLR4 pathway.

Physiologic Responses to Dietary Sulfur Amino Acid Restriction in Mice Are Influenced by Atf4 Status and Biological Sex

ABSTRACTBackgroundDietary sulfur amino acid restriction (SAAR) improves body composition and metabolic health across several model organisms in part through induction of the integrated stress response (ISR).ObjectiveWe investigate the hypothesis that activating transcription factor 4 (ATF4) acts as a converging point in the ISR during SAAR.MethodsUsing liver-specific or global gene ablation strategies, in both female and male mice, we address the role of ATF4 during dietary SAAR.ResultsWe show that ATF4 is dispensable in the chronic induction of the hepatokine fibroblast growth factor 21 while being essential for the sustained production of endogenous hydrogen sulfide. We also affirm that biological sex, independent of ATF4 status, is a determinant of the response to dietary SAAR.ConclusionsOur results suggest that auxiliary components of the ISR, which are independent of ATF4, are critical for SAAR-mediated improvements in metabolic health in mice.

A naphthalimide-based peptide conjugate for concurrent imaging and apoptosis induction in cancer cells by utilizing endogenous hydrogen sulfide.

The excessive production of endogenous hydrogen sulfide (H2S) in cancer cells leads to enhanced tumor growth and metastasis. On the other hand, decreased endogenous H2S suppresses tumor growth. The reported approaches for inhibiting tumor growth are selective silencing of the tumor-promoting genes and pharmacological inhibition of these proteins. To enhance the antitumor efficacy of frontline chemotherapeutic agents, herein, we synthesized a highly sensitive endogenous H2S responsive fluorescent probe, i.e., a hydrogen sulfide-sensing naphthalimide-based peptide conjugate (HSNPc), which showed selective inhibition of proliferation of cancer cells due to apoptosis induction. Furthermore, HSNPc suppressed the glycolytic reserve, a critical energy source for the proliferation of cancer cells. HSNPc also decreased the Young's modulus of HeLa cells compared to the control cells, which demonstrated a direct relation between cell apoptosis and cell stiffness. Taken together, we demonstrated the dual function of detection and killing of cancer cells by HSNPc that can be likened to a theranostic role.

Retracted] Artificial Intelligence Imaging to Observe the Protective Effect of Hydrogen Sulfide on Acute Kidney Injury Caused by Urinary Sepsis

With the development of medical technology products and the rapid development of computer technology, medical AI has become a hotbed in scientific research and clinical practice. Some medical AI‐assisted diagnosis has been applied to the clinic to assist doctors in formulating treatment plans. The traditional method of clinical diagnosis and treatment is that the physician makes an intentional diagnosis and then performs ancillary tests. The clinician performs diagnosis and treatment by identifying clinical symptoms and analyzing auxiliary examination results. Modern medical AI is based on big data collection and analyzes the test results through artificial intelligence and computer algorithms. It can output diagnostic results with high sensitivity and specificity for clinical tests. Acute kidney injury (AKI) is a common clinical emergency. The main clinical features are elevated blood creatinine, decreased urine output, and sharp decline in renal function within a short period of time, and it is a hot spot worldwide. In this experiment, a rabbit sepsis model was replicated by inoculating E. coli bacteria into the rabbit’s unilateral ureteral lumen and ligation. NaHS was used as an exogenous hydrogen sulfide donor to observe the effects of hydrogen sulfide on UTIs. The protective effect of oxidative stress and inflammatory response in acute kidney injury with hyperemia. In the experiment, the production of endogenous hydrogen sulfide was decreased in the Sepsis group, and the renal CSE activity was decreased, while the content of endogenous hydrogen sulfide in the NaHS group was higher than that of the Sepsis group, and the CSE activity of renal tissue was increased. It can be seen that the plasma hydrogen sulfide and renal tissue SCE levels in septic acute kidney injury increased after NaHS intervention, and the renal tissue damage was reduced, suggesting that hydrogen sulfide is mainly generated endogenously through the action of CSE, which causes damage to the kidneys. The expressions of iNOS and HO‐1 in renal tissues of urinary sepsis are increased. H2S can play a certain protective effect on acute kidney injury in urinary sepsis by down‐regulating iNOS and up‐regulating the expression of HO‐1.