Endogenous H2S Research Articles

Depletion and Downregulation of Hydrogen Sulfide Using an Activatable Probe for Promoting Photothermal Therapy toward Colorectal Cancers.

Since hydrogen sulfide (H2S) is an important endogenous gaseous mediator, therapeutic manipulation of H2S is promising for anticancer treatment. In this work, we develop a novel theranostic nanoplatform with H2S-specific and photocontrolled synergistic activation for imaging-guided H2S depletion and downregulation along with promoted photothermal therapy. Such a nanoplatform is fabricated by integration of a H2S-responsive molecule probe that can generate a cystathionine-β-synthase (CBS) inhibitor AOAA and a photothermal transducer into an NIR-light-responsive container. Our nanoplatform can turn on NIR fluorescence specifically in H2S-rich cancers, guiding further laser irradiation. Furthermore, prominent conversion of photoenergy into heat guarantees special container melting with controllable AOAA release for H2S-level downregulation. This smart regulation of the endogenous H2S level amplifies the PTT therapeutic effect, successfully suppressing colorectal tumor in living mice under NIR fluorescence imaging guidance. Thus, we believe that this nanoplatform may provide a powerful tool toward H2S-concerned cancer treatment with an optimized diagnostic and therapeutic effect.

Multifunctional iron oxide‐hydroxide based nanorods for hydrogen sulfide scavenging assisted synergistic photothermal-chemotherapy of colon cancer

The tumor microenvironment responsive multifunctional nanoplatforms with integrated diagnosis and therapy have recently received great attention in anti-cancer treatment. In this study, we developed biocompatible iron oxide-hydroxide-based nanorods (DOX-FPT NRs) for MR imaging and H2S scavenging assisted synergistic photothermal-chemotherapy of colon cancer, which is fabricated by modifying polydopamine (PDA) and transferrin (Tf) on the surface of iron oxide hydroxide (FeOOH) nanorods. The prepared DOX-FPT NRs could precisely target the colon cancer cells through transferrin ligand-receptor-mediated targeting and effectively scavenge endogenous H2S to prohibit the growth of colon cancer. Meanwhile, the considerable drug loading capability and outstanding photothermal conversion efficiency are permitted by the PDA shell modification. In addition, the H2S scavenging assisted photothermal-chemotherapy showed an excellent therapeutic effect on CT26 cells via in vitro cell test. Therefore, the prepared DOX-PFT NRs will be a promising nanoplatform to enhance the therapeutic effect of colon cancer through the treatment strategy of H2S scavenging-assisted synergistic photothermal chemotherapy.

Curcumin reduces myocardial ischemia-reperfusion injury, by increasing endogenous H2S levels and further modulating m6A.

Our previous research shows that Curcumin (CUR) attenuates myocardial ischemia-reperfusion injury (MIRI) by reducing intracellular total RNA m6A levels. However, the mechanism remains unknown. For ischemia-reperfusion (IR), H9c2 cells were cultured for 6h in serum-free low-glycemic (1g/L) medium and a gas environment without oxygen, and then cultured for 6h in high-glycemic (4.5g/L) medium supplemented with 10% FBS and a 21% oxygen environment. The effects of different concentrations of CUR (5, 10, and 20 µM) treatments on signaling molecules in conventionally cultured and IR-treated H9c2 cells were examined. CUR treatment significantly up-regulated the H2S levels, and the mRNA and protein expression of cystathionine γ-lyase (CSE), and down-regulated the mRNAs and proteins levels of thiosulfate sulfurtransferase (TST) and ethylmalonic encephalopathy 1 (ETHE1) in H9c2 cells conventionally cultured and subjected to IR. Exogenous H2S supply (NaHS and GYY4137) significantly reduced intracellular total RNA m6A levels, and the expression of RNA m6A "writers" METTL3 and METTL14, and increased the expression of RNA m6A "eraser" FTO in H9c2 cells conventionally cultured and subjected to IR. CSE knockdown counteracted the inhibitory effect of CUR treatment on ROS production, promotion on cell viability, and inhibition on apoptosis of H9c2 cells subjected to IR. CUR attenuates MIRI by regulating the expression of H2S level-regulating enzymes and increasing the endogenous H2S levels. Increased H2S levels could regulate the m6A-related proteins expression and intracellular total RNA m6A levels.

Garlic oil supplementation blocks inflammatory pyroptosis-related acute lung injury by suppressing the NF-κB/NLRP3 signaling pathway via H2S generation.

Acute lung injury (ALI) is a major cause of acute respiratory failure with a high morbidity and mortality rate, and effective therapeutic strategies for ALI remain limited. Inflammatory response is considered crucial for the pathogenesis of ALI. Garlic, a globally used cooking spice, reportedly exhibits excellent anti-inflammatory bioactivity. However, protective effects of garlic against ALI have never been reported. This study aimed to investigate the protective effects of garlic oil (GO) supplementation on lipopolysaccharide (LPS)-induced ALI models. Hematoxylin and eosin staining, pathology scores, lung myeloperoxidase (MPO) activity measurement, lung wet/dry (W/D) ratio detection, and bronchoalveolar lavage fluid (BALF) analysis were performed to investigate ALI histopathology. Real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were conducted to evaluate the expression levels of inflammatory factors, nuclear factor-κB (NF-κB), NLRP3, pyroptosis-related proteins, and H2S-producing enzymes. GO attenuated LPS-induced pulmonary pathological changes, lung W/D ratio, MPO activity, and inflammatory cytokines in the lungs and BALF. Additionally, GO suppressed LPS-induced NF-κB activation, NLRP3 inflammasome expression, and inflammatory-related pyroptosis. Mechanistically, GO promoted increased H2S production in lung tissues by enhancing the conversion of GO-rich polysulfide compounds or by increasing the expression of H2S-producing enzymes in vivo. Inhibition of endogenous or exogenous H2S production reversed the protective effects of GO on ALI and eliminated the inhibitory effects of GO on NF-κB, NLRP3, and pyroptotic signaling pathways. Overall, these findings indicate that GO has a critical anti-inflammatory effect and protects against LPS-induced ALI by suppressing the NF-κB/NLRP3 signaling pathway via H2S generation.

Abstract LB343: Golgihi T cells exhibit reduced susceptibility to exhaustion and improved tumor control

Abstract The role of tumor microenvironment mediated disruption of Golgi architecture and function,termed Golgi stress, in the regulation of T cell survival and function are largely unknown. Here weshow that the disruption of Golgi architecture, identified by the decreased expression of GM130,was reverted upon treatment with hydrogen sulfide (H2S) donor GYY4137, or over-expressingcystathionine β-synthase (Cbs), an enzyme involved in the biosynthesis of endogenous H2S -that promoted stemness, antioxidant capacity and exhibited increased protein translationmediated in part by ER-Golgi shuttling of Peroxiredoxin-4. In in vivo models of melanoma andlymphoma, anti-tumor T cells conditioned ex vivo with exogenous H2S or overexpressing Cbsdemonstrated superior tumor control upon adoptive transfer. Further, Golgihi T cells, with highGolgi content, exhibited unique metabolic and glycation signature with enhanced anti-tumorcapacity. These data suggest that strategies to mitigate Golgi network stress or using Golgihitumor-reactive T cells can improve tumor control upon adoptive transfer. Citation Format: Nathaniel Oberholtzer, Paramita Chakraborty, Mohamed Faisal Kassir, James Dressman, Zacharia Hedley, Gina Scurti, Monika Gooz, Lauren E. Ball, Elizabeth Hill, Anand S. Mehta, Eduardo N. Maldonado, Michael I. Nishimura, Besim Ogretmen, Shikhar Mehrotra. Golgihi T cells exhibit reduced susceptibility to exhaustion and improved tumor control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB343.

Synergistic role of melatonin and hydrogen sulfide in modulating secondary metabolites and metal uptake/sequestration in arsenic-stressed tomato plants

The multifunctional roles of melatonin (ML) and hydrogen sulfide (H2S) as plant gasotransmitters are well understood. However, their interaction in defensive responses is still unclear. Here, we assessed how the ML-H2S interaction impacts tomato plants exposed to arsenic (As, 10 mg/L) toxicity. The results showed that ML and ML+H2S treatments alleviated As toxicity by inducing the transcription of ANS, PAL, DFR, CHS, F3H, and CHI and an enhanced accumulation of phenolic and anthocyanin compounds. ML and ML+H2S led to a drop in the transcription of PT2 and Lsi1, resulting in reduced As uptake and subsequent movement to the leaves. ML and ML+H2S treatments resulted in high GSH1, PCS, and ABC1 transcription. This led to elevated levels of glutathione and phytochelatins, facilitating As sequestration in the roots and protecting root and leaf cells against As. ML and ML+H2S treatments enhanced tomato growth under As treatments by optimizing chlorophyll metabolism, increasing internal H2S, and amplifying the antioxidant machinery function. In contrast to the sole use of ML treatment, ML+H2S exhibited more pronounced positive impacts on As-stressed tomatoes, indicating synergistic/interactive effects between these two substances. On the other hand, the use of hypotaurine, an H2S scavenger, demonstrated the inhibition of the beneficial impact of ML and ML+H2S treatments in stimulating defensive responses, which highlights the substantial involvement of H2S in the signaling pathway activated by ML during As stress. Hence, we can conclude that ML requires the presence of endogenous H2S to mitigate the adverse effects of As on tomato seedlings.

A novel iridium(III) complex-based ratiometric luminescence probe for monitoring hydrogen sulfide in living cells and zebrafish

Hydrogen sulfide exhibits crucial functions in many biological and physiological processes. The abnormal levels of H2S have been revealed to be associated with numerous human diseases. The majority of existing fluorescent probes toward H2S may still need to be improved in terms of single output signal, water solubility, biotoxicity and photostability. The construction of a ratiometric fluorescent probe based on metal complex is one effective strategy for avoiding the mentioned problems for precisely detecting H2S. Herein, we report an iridium(III) complex-based ratiometric luminescence probe (Ir-PNBD), which is designed by coupling the 7-nitro-2,1,3-benzoxadiazoles (NBD) to one of the bipyridine ligands of Ir (III) complex luminophore through a piperazition moiety. Ir-PNBD owns high selectivity and sensitivity toward H2S, and an excellent ability to target mitochondria. Moreover, Ir-PNBD was further successfully utilized to visualize exogenous and endogenous H2S in HeLa cells and zebrafish. Our work offers new opportunities to gain deeper insights into the construction of transition metal complex-based ratiometric luminescent probes and expands their applications in biomedical imaging and disease diagnosis.

Tobacco Transcription Factor NtWRKY70b Facilitates Leaf Senescence via Inducing ROS Accumulation and Impairing Hydrogen Sulfide Biosynthesis.

Leaf senescence is the terminal stage of leaf development, and its initiation and progression are closely controlled by the integration of a myriad of endogenous signals and environmental stimuli. It has been documented that WRKY transcription factors (TFs) play essential roles in regulating leaf senescence, yet the molecular mechanism of WRKY-mediated leaf senescence still lacks detailed elucidation in crop plants. In this study, we cloned and identified a tobacco WRKY TF gene, designated NtWRKY70b, acting as a positive regulator of natural leaf senescence. The expression profile analysis showed that NtWRKY70b transcript levels were induced by aging and hydrogen peroxide (H2O2) and downregulated upon hydrogen sulfide (H2S) treatment. The physiological and biochemical assays revealed that overexpression of NtWRKY70b (OE) clearly promoted leaf senescence, triggering increased levels of reactive oxygen species (ROS) and decreased H2S content, while disruption of NtWRKY70b by chimeric repressor silencing technology (SRDX) significantly delayed the onset of leaf senescence, leading to a decreased accumulation of ROS and elevated concentration of H2S. The quantitative real-time PCR analysis showed that the expression levels of various senescence-associated genes and ROS biosynthesis-related genes (NtRbohD and NtRbohE) were upregulated in OE lines, while the expression of H2S biosynthesis-related genes (NtDCD and NtCYSC1) were inhibited in OE lines. Furthermore, the Yeast one-hybrid analysis (Y1H) and dual luciferase assays showed that NtWRKY70b could directly upregulate the expression of an ROS biosynthesis-related gene (NtRbohD) and a chlorophyll degradation-related gene (NtPPH) by binding to their promoter sequences. Accordingly, these results indicated that NtWYKY70b directly activated the transcript levels of NtRbohD and NtPPH and repressed the expression of NtDCD and NtCYCS1, thereby promoting ROS accumulation and impairing the endogenous H2S production, and subsequently accelerating leaf aging. These observations improve our knowledge of the regulatory mechanisms of WRKY TFs controlling leaf senescence and provide a novel method for ensuring high agricultural crop productivity via genetic manipulation of leaf senescence in crops.

A Novel DNBS-based Fluorescent Probe for the Detection of H2S in Cells and on Test Strips.

Hydrogen sulfide (H2S) plays a key role in the physiology and pathology of organisms, and H2S in the environment is easily absorbed and harmful to health. It is of great significance to develop a probe with good selectivity, high sensitivity and good stability that can detect hydrogen sulfide inside and outside organisms. In this work, we designed a novel "turn-on" fluorescent probe CIM-SDB for the detection of H2S. The probe CIM-SDB used indene-carbazole as the fluorophore and 2,4-dinitrobenzenesulfonyl as the recognition site. The probe CIM-SDB exhibited high selectivity and sensitivity to H2S (detection limit as low as 123 nM). Moreover, the probe CIM-SDB was successfully applied to the detection of intracellular exogenous and endogenous H2S, and the test strips prepared by the probe CIM-SDB could realize the convenient and rapid detection of H2S.

Background-Free SERS Nanosensor for Endogenous Hydrogen Sulfide Detection Based on Prussian Blue-Coated Gold Nanobipyramids.

Surface-enhanced Raman scattering (SERS) has great potential in biological analysis due to its specificity, sensitivity, and non-invasive nature. However, effectively extracting Raman information and avoiding spectral overlapping from biological background interference remain major challenges. In this study, we developed a background-free SERS nanosensor consisting of gold nanobipyramids (Au NBPs) core-Prussian blue (PB) shell (Au NBPs@PB), for endogenous H2S detection. The PB shell degraded quickly upon contact with endogenous H2S, generating a unique Raman signal response in the Raman silent region (1800-2800 cm-1). By taking advantage of the high SERS-activity of Au NBPs and H2S-triggered spectral changes of PB, these SERS nanosensors effectively minimize potential biological interferences. The nanosensor exhibits a detection range of 2.0 μM to 250 μM and a limit of detection (LOD) of 0.34 μM, with good reproducibility and minimal interference. We successfully applied this background-free SERS platform to monitor endogenous H2S concentrations in human serum samples with satisfied results.

Improved Immune Response for Colorectal Cancer Therapy Triggered by Multifunctional Nanocomposites with Self-Amplifying Antitumor Ferroptosis.

Ferroptosis, as a type of regulated cell death, can trigger the release of damage-associated molecular patterns from cancer cells and lead to the enhancement of immune recognition. Fenton reaction-mediated chemodynamic therapy could initiate ferroptosis by generating lipid peroxides, but its efficiency would be greatly restricted by the insufficient H2O2 and antioxidant system within the tumor. Herein, this work reports the successful preparation of H2O2 self-supplied and glutathione (GSH)-depletion therapeutic nanocomposites (Cu2O@Au) through in situ growth of Au nanoparticles on the surface of cuprous oxide (Cu2O) nanospheres. Upon delivery into cancer cells, the released Cu2O could consume endogenous H2S within colorectal cancer cells to form Cu31S16 nanoparticles, while the released Au NPs could catalyze glucose to generate H2O2 and gluconic acid. The self-supplying endogenous H2O2 and lower acidity could amplify the Cu ion-induced Fenton-like reaction. Meanwhile, the consumption of glucose would reduce GSH generation by disrupting the pentose phosphate pathway. Additionally, the Cu2+/Cu+ catalytic cycle promotes the depletion of GSH, leading to lipid peroxide accumulation and ferroptosis. It was found that the onset of ferroptosis triggered by Cu2O@Au could initiate immunologic cell death, promote dendritic cell maturation and T-cell infiltration, and finally enhance the antitumor efficacy of the PD-L1 antibody. In summary, this collaborative action produces a remarkable antitumor effect, which provides a promising treatment strategy for colorectal cancer.

Natural H2S-donors: A new pharmacological opportunity for the management of overweight and obesity.

The prevalence of overweight and obesity has progressively increased in the last few years, becoming a real threat to healthcare systems. To date, the clinical management of body weight gain is an unmet medical need, as there are few approved anti-obesity drugs and most require an extensive monitoring and vigilance due to risk of adverse effects and poor patient adherence/persistence. Growing evidence has shown that the gasotransmitter hydrogen sulfide (H2S) and, therefore, H2S-donors could have a central role in the prevention and treatment of overweight/obesity. The main natural sources of H2S-donors are plants from the Alliaceae (garlic and onion), Brassicaceae (e.g., broccoli, cabbage, and wasabi), and Moringaceae botanical families. In particular, polysulfides and isothiocyanates, which slowly release H2S, derive from the hydrolysis of alliin from Alliaceae and glucosinolates from Brassicaceae/Moringaceae, respectively. In this review, we describe the emerging role of endogenous H2S in regulating adipose tissue function and the potential efficacy of natural H2S-donors in animal models of overweight/obesity, with a final focus on the preliminary results from clinical trials. We conclude that organosulfur-containing plants and their extracts could be used before or in combination with conventional anti-obesity agents to improve treatment efficacy and reduce inflammation in obesogenic conditions. However, further high-quality studies are needed to firmly establish their clinical efficacy.

Effect of hydrogen sulfide (H2S) on the growth and development of tobacco seedlings in absence of stress

BackgroundHydrogen sulfide (H2S) is a novel signaling molecule involved in the growth and development of plants and their response to stress. However, the involvement of H2S in promoting the growth and development of tobacco plants is still unclear.ResultsIn this study, we explored the effect of pre-soaking or irrigating the roots of tobacco plants with 0.0, 2.0, 4.0, 6.0, and 8.0 mM of sodium hydrosulfide (NaHS) on endogenous H2S production, antioxidant enzymatic and cysteine desulfhydrase activities, seed germination, agronomic traits, photosynthetic pigments contents, and root vigor. The results revealed that exogenous NaHS treatment could significantly promote endogenous H2S production by inducing gene expression of D/L-CD and the activities of D/L-CD enzymes. Additionally, a significant increase in the agronomic traits and the contents of photosynthetic pigments, and no significant difference in carotenoid content among tobacco plants treated with 0.0 to 8.0 mM of NaHS was observed. Additionally, a significant increase in the germination speed, dry weight, and vigor of tobacco seeds, whereas no significant effect on the percentage of seed germination was observed on NaHS treatment. Furthermore, NaHS treatment could significantly increase the activity of superoxide dismutase (SOD) and peroxidase (POD) enzymes, which reduces damage due to oxidative stress by maintaining reactive oxygen species homeostasis.ConclusionsThese results would aid in enhancing our understanding of the involvement of H2S, a novel signaling molecule to promote the growth and development of tobacco plants.

H2S donor S-propargyl-cysteine for skin wound healing improvement via smart transdermal delivery.

Hydrogen sulfide for wound healing has drawn a lot of attention recently. In this research, the S-propargyl-cysteine (SPRC), an endogenous H2S donor, was loaded on carbomerhydrogel, and a copper sheet rat burn model was developed. Pathological changes in rat skin tissue were examined using hematoxylin-eosin (HE) and Masson staining. The immunohistochemistry (IHC) staining was performed to detect the expression of Collagen I (Col I) and Collagen III (Col III). The mRNA levels of interleukin (IL)-6, Col Iα2, Col IIIα1, tissue inhibitors of metalloproteinase (TIMP)-1, matrix metalloproteinase (MMP)-9, vascular endothelial growth factor (VEGF), and transforming growth factor (TGF)-β1 were examined by quantitative real-time chain polymerase reaction. The findings demonstrated that the collagen layer was thicker in the SPRC group during the proliferative phase, SPRC hydrogel promoted VEGF expression. In the late stage of wound healing, the expression of IL-6, TIMP-1, MMP-9, and TGF-β1 was inhibited, and the Col I content was closer to that of normal tissue. These results surface that SPRC hydrogel can promote wound healing and play a positive role in reducing scar formation. Our results imply that SPRC can facilitate wound healing and play a positive role in reducing scar formation.

β-Aminobutyric Acid Effectively Postpones Senescence of Strawberry Fruit by Regulating Metabolism of NO, H2S, Ascorbic Acid, and ABA

Current researchis focused on the influence of β-aminobutyric acid (BABA) on the metabolism of nitric oxide (NO), hydrogen sulfide (H2S), ascorbic acid, and abscisic acid (ABA) in strawberry fruit. The increases in ion leakage and malondialdehyde (MDA) concentration in strawberry fruit and the degradation of chlorophyll in the sepals of the fruit were markedly inhibited by BABA at 20 mM. BABA-immersed fruit exhibited lower activities and expressions of polygalacturonase (PG), pectinmethylesterase (PME), and ethylene biosynthetic enzymes compared to the control. Furthermore, BABA immersion evidently upgraded the metabolic levels of NO and H2S, including the enzymatic activities and intermediary contents of metabolites, which collectively enhanced the levels of endogenous NO and H2S contents in strawberry fruit. The high enzymatic activities and gene expressions of the AsA biosynthesis pathway jointly maintained AsA accumulation in the BABA-treated sample. The application of BABA led to a decrease in ABA concentration, which was associated with reduced activities and gene expression levels of key enzymes participating in ABA metabolism. Our experimental observations showed that immersion with BABA may be a highly promising means to delay senescence and reduce natural decay in strawberry fruit, and the alleviation in senescence using BABA may be attributed to the modulation of NO, H2S, AsA, and ABA metabolism.

Neuromodulator hydrogen sulfide attenuates sickness behavior induced by lipopolysaccharide

Sickness behavior reflects a state of altered physiology and central nervous system function that occurs during systemic infection or inflammation, serving as an adaptive response to illness. This study aims to elucidate the role of hydrogen sulfide (H2S) in regulating sickness behavior and neuroinflammatory responses in a rat model of systemic inflammation. Adult male Wistar rats were treated with lipopolysaccharide (LPS) to induce sickness behavior. Intracerebroventricular (i.c.v.) pretreatments included aminooxyacetic acid (AOAA), an inhibitor of H2S synthesis, and sodium sulfide (NaHS), an H2S donor. Behavioral assays were conducted, along with the assessment of astrocyte activation, as indicated by GFAP expression in the hypothalamus. Pretreatment with NaHS mitigated LPS-induced behavioral changes, including hypophagia, social and exploratory deficits, without affecting peripheral cytokine levels, indicating a central modulatory effect. AOAA, conversely, accentuated certain behavioral responses, suggesting a complex role of endogenous H2S in sickness behavior. These findings were reinforced by a lack of effect on plasma interleukin levels but significant reduction in GFAP expression. Our findings support the central role of H2S in modulating neuroinflammation and sickness behavior, highlighting the therapeutic potential of targeting H2S signaling in neuroinflammatory conditions.

Auxin and hydrogen peroxide (H2O2) interaction differentially regulate seedling growth, Na+/K+ ratio and H2S homeostasis accompanying NaCl stress in etiolated sunflower (Helianthus annuus L. cv. Microgreen) seedling roots and cotyledons

Although H2S has been reported to modulate auxin and H2O2 signaling during abiotic stress, no reports decipher the interactive roles of exogenous auxin and H2O2 on the regulation of endogenous H2S homeostasis. In the present work, auxin (IAA) and hydrogen peroxide (H2O2) interaction appear to be crucial in regulating Na+/K+ homeostasis, recovery in seedling growth and H2S accumulation in NaCl-stressed sunflower seedlings. Interestingly, impairment in endogenous IAA transport (TIBA application) also impacts H2S accumulation in the roots and cotyledons. IAA supplementation is effective in reducing Na+/K+ ratio and electrolytic leakage in roots, which reverses in the presence of TIBA (polar auxin transport inhibitor) application. IAA and H2O2-mediated modulation of H2S content corroborates with l-DES activity in seedling roots and cotyledons. In contrast to cotyledons, roots exhibited a reduction in H2S content in the presence of treatments (IAA and H2O2). H2O2 supplementation seems to partially circumvent the changes caused by the disruption of auxin transport. Thus, we hypothesize that auxin might imply H2O2 as a crucial signaling component in the regulation of H2S levels in sunflower tissues. To sum up, IAA and H2O2 interaction regulates root growth, LR proliferation, Na+/K+ ratio, and H2S metabolism in sunflower seedling roots.

Therapeutic potential of hydrogen sulfide in osteoarthritis development.

The pathological mechanisms and treatments of osteoarthritis (OA) are critical topics in medical research. This paper reviews the regulatory mechanisms of hydrogen sulfide (H2S) in OA and the therapeutic potential of H2S donors. The review highlights the importance of changes in the endogenous H2S pathway in OA development and systematically elaborates on the role of H2S as a third gaseous transmitter that regulates inflammation, oxidative stress, and pain associated with OA. It also explains how H2S can lessen bone and joint inflammation by inhibiting leukocyte adhesion and migration, reducing pro-inflammatory mediators, and impeding the activation of key inflammatory pathways such as nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK). Additionally, H2S is shown to mitigate mitochondrial dysfunction and endoplasmic reticulum stress, and to modulate Nrf2, NF-κB, PI3K/Akt, and MAPK pathways, thereby decreasing oxidative stress-induced chondrocyte apoptosis. Moreover, H2S alleviates bone and joint pain through the activation of Kv7, K-ATP, and Nrf2/HO-1-NQO1 pathways. Recent developments have produced a variety of H2S donors, including sustained-release H2S donors, natural H2S donors, and synthetic H2S donors. Understanding the role of H2S in OA can lead to the discovery of new therapeutic targets, while innovative H2S donors offer promising new treatments for patients with OA.

An asymmetrical flavylium based probe with large Stokes shift and near infrared emission for highly sensitive detecting and visualizing cellular drug induced H2S fluctuations

Hydrogen sulfide (H2S) has been recognized as an important gaseous signaling molecule in living systems, and is of great significance in many pathological and physiological processes. Misregulation of endogenous H2S is implicated in various diseases in the neuronal, gastrointestinal, circulatory, and endocrine systems. Fluorescent probe with large Stokes shift and near infrared emission, is ideal candidate for imaging applications to prevent excitation scattering, autofluorescence interference, matrix absorption caused signal loss, and sample destruction. In this study, a dual-side expansion approach was performed to develop spectra tunable hydroxyl functional flavylium derivative named HN8 with enlarged Stokes shift of 81 nm, lengthened emission of 671 nm, satisfied quantum yield of 0.23, and good fluorescence enhancement factor of 14.3-fold. Moreover, based on HN8, the screened probe HN8DNP displayed 225-fold fluorescence enhancement containing linear correlations to H2S from 0 to 50 μM with good limit of detection (LOD) of 0.31 μM. Therefore, HN8DNP was then applied for imaging exogenous H2S and drug induced enzymatic H2S generation in living cells with satisfied results, revealing the relationship between intracellular H2S levels and related enzyme activities. In a word, the present work provided a potential fluorescence probe for highly selective and sensitive detecting H2S in vitro and in living cells. And the promising dual-side expansion strategy for regulation optical feature of traditional fluorophore may meet the increasing requirements of sensing and imaging applications.

Hydrogen sulfide protects cardiomyocytes from doxorubicin-induced ferroptosis through the SLC7A11/GSH/GPx4 pathway by Keap1 S-sulfhydration and Nrf2 activation

Recent studies have demonstrated that ferroptosis, a novel form of nonapoptotic regulated cell death plays an important role in doxorubicin (DOX)-induced cardiotoxicity (DoIC). Hydrogen sulfide (H2S) is emerging as the third important gaseous mediator in cardiovascular system. However, whether H2S has an effect on DOX-induced ferroptosis remains unknown. Here, we found that DOX not only triggered cardiomyocyte ferroptosis but also significantly inhibited the synthesis of endogenous H2S in the murine model of chronic DoIC. Application of NaHS, an H2S donor obviously activated the SLC7A11/GSH/GPx4 antioxidant pathway and thus alleviated DOX-induced ferroptosis and cardiac injury in mice. In contrast, cardiac-specific knockout of cystathionine γ-lyase gene (Cse) in mice (Csef/f/Cre+) to abolish the cardiac synthesis of endogenous H2S evidently exacerbated DOX-induced ferroptosis and cardiac dysfunction. A further suppression of SLC7A11/GSH/GPx4 pathway was obtained in Csef/f/Cre+ mice with DoIC, as compared to Csef/f/Cre− mice with DoIC. The aggravation caused by cardiac-specific Cse deficiency was remarkably rescued by exogenous supplementation of NaHS. Moreover, in DOX-stimulated H9c2 cardiomyocytes, pretreatment with NaHS dose-dependently enhanced the activity of SLC7A11/GSH/GPx4 pathway and subsequently mitigated ferroptosis and mitochondrial impairment. On the contrary, transfection with Cse siRNA in DOX-stimulated H9c2 cardiomyocytes markedly inhibited SLC7A11/GSH/GPx4 pathway, thus leading to aggravated ferroptosis and more damage to mitochondrial structure and function. In addition, the protective effect of NaHS on DOX-induced ferroptosis was closely related to the S-sulfhydrated Keap1, which in turn promoted nuclear translocation of Nrf2 and the transcription of SLC7A11 and GPx4. In conclusion, our findings suggest that H2S may exert protective effect on DoIC by inhibiting DOX-induced ferroptosis via Keap1/Nrf2-dependent SLC7A11/GSH/GPx4 antioxidant pathway.