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Hydrogen sulfide (H 2 S) has profound biological effects within living organisms and is now increasingly being considered alongside other gaseous signalling molecules, such as nitric oxide (NO) and carbon monoxide (CO). Conventional use of pharmacological and molecular approaches has spawned a rapidly growing research field that has identified H 2 S as playing a functional role in cell-signalling and post-translational modifications. Recently, a number of laboratories have reported the use of siRNA methodologies and genetic mouse models to mimic the loss of function of genes involved in the biosynthesis and degradation of H 2 S within tissues. Studies utilising these systems are revealing new insights into the biology of H 2 S within the cardiovascular system, inflammatory disease, and in cell signalling. In light of this work, the current review will describe recent advances in H 2 S research made possible by the use of molecular approaches and genetic mouse models with perturbed capacities to generate or detoxify physiological levels of H 2 S gas within tissues.

The recognition of hydrogen sulfide (H2S) has been evolved from a toxic gas to a physiological mediator, exhibiting properties similar to NO and CO. On the one hand, H2S is produced from L-cysteine by enzymes of cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3MST) in combination with aspartate aminotransferase (AAT) (also called as cysteine aminotransferase, CAT); on the other hand, H2S is produced from D-cysteine by enzymes of D-amino acid oxidase (DAO). Besides sulfide salt, several sulfide-releasing compounds have been synthesized, including organosulfur compounds, Lawesson’s reagent and analogs, and plant-derived natural products. Based on garlic extractions, we synthesized S-propargyl-L-cysteine (SPRC) and its analogs to contribute our endeavors on drug development of sulfide-containing compounds. A multitude of evidences has presented H2S is widely involved in the roles of physiological and pathological process, including hypertension, atherosclerosis, angiogenesis, and myocardial infarcts. This review summarizes current sulfide compounds, available H2S measurements, and potential molecular mechanisms involved in cardioprotections to help researchers develop further applications and therapeutically drugs.

Cardiac fibrosis is a common cause of most cardiovascular diseases. Leonurine, an alkaloid from Herba leonuri , had been indicated to treat cardiovascular diseases due to its cardioprotective effects. Recently, pyroptosis, a programmed form of cell death that releases inflammatory factors, has been shown to play an important role in cardiovascular diseases, especially cardiac fibrosis. This study examined the novel mechanism by which leonurine protects against cardiac fibrosis. In rats with isoprenaline-induced cardiac fibrosis, leonurine inhibited the expression of proteins related to pyroptosis and improved cardiac fibrosis. In vitro , leonurine inhibited the expression of proteins related to pyroptosis and fibrosis. Additionally, leonurine regulated the TGF-β/Smad2 signalling pathway and inhibited pyroptosis to protect cardiomyocytes and improve cardiac fibrosis. Therefore, leonurine might improve cardiac fibrosis induced by isoprenaline by inhibiting pyroptosis via the TGF-β/Smad2 signalling pathway.

Myocardial infarction (MI) triggers an inflammatory reaction, in which macrophages are of key importance for tissue repairing. Infiltration and/or migration of macrophages into the infarct area early after MI is critical for infarct healing, vascularization and cardiac function. Hydrogen sulfide (H 2 S) has been demonstrated to possess cardioprotective effects post MI and during the progress of cardiac remodeling. However, the specific molecular and cellular mechanisms involved in macrophage recruitment by H 2 S remain to be identified. In this study, the NaHS (exogenous sources of H 2 S) treatment exerted an increased infiltration of macrophages into the infarcted myocardium at early stage of MI cardiac tissues in both wild type (WT) and cystathionine-γ-lyase-knockout (CSE-KO) mice. And NaHS accelerated the migration of macrophage cells in vitro . While, the inhibitors not only significantly diminished the migratory ability in response to NaHS, but also blocked the activation of phospho-Src, -Pyk2, -FAK 397 and -FAK 925 . Furthermore, NaHS induced the internalization of integrin β1 on macrophage surface, but, integrin β1 silencing inhibited macrophage migration and Src signaling activation. These results indicate that H 2 S may have the potential as an anti-infarct of MI by governing macrophage migration, which was achieved by accelerating internalization of integrin β1 and activating downstream Src-FAK/Pyk2-Rac pathway.

Alliums and allied plant species are rich sources of sulfur compounds that have effects on vascular homeostasis and the control of metabolic systems linked to nutrient metabolism in mammals. In view of the multiple biological effects ascribed to these sulfur molecules, researchers are now using these compounds as inspiration for the synthesis and development of novel sulfur-based therapeutics. This research has led to the chemical synthesis and biological assessment of a diverse array of sulfur compounds representative of derivatives of S-alkenyl-l-cysteine sulfoxides, thiosulfinates, ajoene molecules, sulfides, and S-allylcysteine. Many of these synthetic derivatives have potent antimicrobial and anticancer properties when tested in preclinical models of disease. Therefore, the current review provides an overview of advances in the development and biological assessment of synthetic analogs of allium-derived sulfur compounds.

Background Ischemic stroke is well‐known for its high mortality and morbidity, but its treatment remains to be explored due to the current limitations. For example, severe neuroinflammation occurs after ischemic stroke; however, effective neuroinflammatory inhibitors are still lacking. Thus, the development of new therapeutic targets of inhibiting neuroinflammation is urgent. CD24 is a small heavy glycosylated protein, which plays a critical role in neural development and acts as an inflammatory suppressor in tumors and autoimmune diseases. But the role of CD24 in ischemic stroke remains unknown. Aims The role of CD24 in ischemic stroke should be explored. Additionally, the potential relationship between the H2S donor, S‐propargyl‐cysteine (SPRC) and CD24 in ischemic stroke should be revealed. Methods Mechanism studies have been performed both in vitro and in vivo to verify the CD24‐mediated inflammation and migration. SPRC has been applied to treat ischemic stroke, and its potential association with CD24 has been studied. Results The overexpression of CD24 can inhibit the nuclear factor kappa B (NF‐κB) inflammatory signaling pathway and promote the migration ability of M2 microglia cells via Src/Fak/Pyk2 signaling pathway in an inflammatory model of BV2 cells. SPRC can upregulate the level of endogenous H2S via cystathionase‐β‐synthase (CBS) and it indirectly plays a role in upregulating CD24. Conclusions CD24 could be a potential target of inhibiting neuroinflammation. SPRC reduces inflammation in ischemic stroke by regulating the CD24/Iκ‐Bα/NF‐κB inflammatory signaling pathway and improves the migration ability of M2 microglia via CD24/Src/Fak/Pyk2 signaling pathway, which further alleviates the inflammatory response at the lesion. CD24 may be a potential innovative target of ischemic stroke for alleviating neuroinflammation via NF‐κB pathway and Src pathway. The treatment of SPRC on ischemic stroke is associated with CD24 via CBS/H2S pathway.

Hydrogen sulfide (H S), the third endogenous gaseous signaling molecule alongside nitric oxide (NO) and carbon monoxide, is synthesized by multiple enzymes in cardiovascular system. Similar to other gaseous mediators, H S has demonstrated a variety of biological activities, including anti-oxidative, anti-apoptotic, pro-angiogenic, vasodilating capacities and endothelial NO synthase modulating activity, and regulates a wide range of pathophysiological processes in cardiovascular disorders. However, the underlying mechanisms by which H S mediates cardiovascular homeostasis are not fully understood. This review focuses on the recent progress on functional and mechanistic aspects of H S in the inflammatory and immunoregulatory processes of cardiovascular disorders, importantly myocardial ischemia, heart failure, and atherosclerosis. Moreover, we highlight the challenges for developing H S-based therapy to modulate the pathological processes in cardiovascular diseases. A better understanding of the immunomodulatory and biochemical functions of H S might provide new therapeutic strategies for these cardiovascular diseases.

Introduction Stroke, predominantly ischemic, is a leading cause of mortality and disability worldwide. Despite advances in intervention strategies, effective treatments to mitigate neurological injury post‐ischemic stroke remain limited. Hydrogen sulfide (H2S), a gas signaling molecule, has been implicated in neuroprotection, but its role in stroke is controversial. S‐propargyl‐cysteine (SPRC), an H2S donor, has shown great potential in protecting against neurological injuries, but its mechanisms in ischemic stroke are not fully understood. This study investigates the neuroprotective potential of SPRC and its mechanisms, focusing on the interplay between H2S and autophagy in modulating the cerebral microenvironment post‐stroke. Methods We conducted a comprehensive single‐cell RNA sequencing analysis on ischemic brain tissue to elucidate the cellular heterogeneity and specific responses related to H2S synthesis and autophagy. We utilized the GEO repository dataset GSE174574, applying stringent filtering and batch effect correction using the Harmony R package. Cellular subpopulations were identified using established markers, and H2S and autophagy scores were calculated using the JASMINE package. We also measured serum H2S levels, evaluated the pharmacodynamics of SPRC in rats, and constructed a cerebral ischemia–reperfusion (I/R) injury model to assess the neuroprotective effects of SPRC. Additionally, we examined the role of SPRC in CBS and 3‐MST knockout mice to determine the dependency on these H2S synthetases. Results Our findings revealed a dysregulation in the expression of H2S and autophagy‐related genes in central nervous system cells, particularly in neurons, following stroke. SPRC administration significantly improved neurological behavior, metabolic activity, reduced brain infarction size, and ameliorated ultrastructure changes in stroke‐affected rats. Interestingly, SPRC continued to provide neuroprotection even after the knockdown of CBS and 3‐MST, indicating a CBS/3‐MST‐independent mechanism. Furthermore, SPRC preserved the endogenous H2S level and strongly upregulated protective autophagy. Conclusion This study is the first to reveal the neuroprotection of SPRC in cerebral I/R injury in a classical enzymatic CBS/3‐MST independent manner. The potential cellular and molecular mechanisms may rely on the promotion of SPRC to activated protective autophagy. Our results suggest that SPRC could be a promising therapeutic candidate for enhancing neuroprotection and modulating autophagy in ischemic stroke. Stroke is one of the major contributors to mortality and long‐term disability. Treatments aiming at regulating endogenous protective mechanisms to reduce neurological injury after ischemic stroke are still urgently needed. Herein, we investigated the neuroprotective potential of S‐propargyl‐cysteine (SPRC), a novel water‐soluble donor of H2S, and its possible mechanisms. Histologically, it was observed that the percentage of cells expressing hydrogen sulfide‐related genes in stroke‐affected brain tissues was lower compared to those in healthy brain samples. Autophagy, an emerging area of research in stroke studies, has been shown to modulate the cerebral microenvironment. Nevertheless, the relationship of hydrogen sulfide and autophagy levels remains elusive, which reason is partly due to the inherent heterogeneity in cellular populations present in stroke lesions. This investigation provides a thorough examination of the single‐cell transcriptomic profiles pertaining to hydrogen sulfide synthesis and autophagy across a spectrum of cellular phenotypes within ischemic brain tissue. Our findings reveal dysregulation in the expression of hydrogen sulfide and autophagy‐related genes, particularly in the central nervous system, such as microglial cells, astrocytes, glial cells, and neurons. Moreover, the significant increase in correlation between hydrogen sulfide and autophagy levels was greater in neurons of stroke compared to the control group. Experimental results showed that neurological behavior assays, metabolic activity, brain infarction size, and ultrastructure changes were significantly ameliorated by SPRC administration. After knockdown of cystathionine‐β‐synthase (CBS) and 3‐mercaptopyruvat sulfurtransferase (3‐MST), SPRC could still alleviate neurological injury. Meanwhile, SPRC could preserve the endogenous balance of H2S levels. Furthermore, protective autophagy was strongly upregulated by SPRC administration. Our results first revealed the neuroprotection of SPRC in cerebral I/R injury in a classical enzymatic CBS/3‐MST‐independent manner, and the potential cellular and molecular mechanisms may rely on the promotion of SPRC to the activated protective autophagy.

Hydrogen sulfide (H₂S) has been shown to have cytoprotective effects in models of hypertension, ischemia/reperfusion and Alzheimer's disease. However, little is known about its effects or mechanisms of action in atherosclerosis. Therefore, in the current study we evaluated the pharmacological effects of H₂S on antioxidant defenses and mitochondria protection against hydrogen peroxide (H₂O₂) induced endothelial cells damage. H₂S, at non-cytotoxic levels, exerts a concentration dependent protective effect in human umbilical vein endothelial cells (HUVECs) exposed to H₂O₂. Analysis of ATP synthesis, mitochondrial membrane potential (ΔΨm) and cytochrome c release from mitochondria indicated that mitochondrial function was preserved by pretreatment with H₂S. In contrast, in H₂O₂ exposed endothelial cells mitochondria appeared swollen or ruptured. In additional experiments, H₂S was also found to preserve the activities and protein expressions levels of the antioxidants enzymes, superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase in H₂O₂ exposed cells. ROS and lipid peroxidation, as assessed by measuring H₂DCFDA, dihydroethidium (DHE), diphenyl-l-pyrenylphosphine (DPPP) and malonaldehyde (MDA) levels, were also inhibited by H₂S treatment. Interestingly, in the current model, D, L-propargylglycine (PAG), a selective inhibitor of cystathionine γ-lyase (CSE), abolished the protective effects of H₂S donors. This study is the first to show that H₂S can inhibit H₂O₂ mediated mitochondrial dysfunction in human endothelial cells by preserving antioxidant defences. H₂S may protect against atherosclerosis by preventing H₂O₂ induced injury to endothelial cells. These effects appear to be mediated via the preservation of mitochondrial function and by reducing the deleterious effects of oxidative stress.

Immune checkpoint inhibitors (ICIs) have significantly advanced the field of cancer immunotherapy. However, clinical data has shown that many patients have a low response rate or even resistance to immune checkpoint inhibitor alone. The underlying reasons for its poor efficacy include the deficiency of immune infiltration and effective CD28/CD80 costimulatory signal in tumor. Discoidin domain receptor 1 (DDR1) has been reported to be negatively related to immune cell infiltration in tumors. Herein, we constructed a soluble fusion protein using CD80, the natural ligand of CD28, in combination with DDR1 inhibitor. Our results demonstrated that CD80-Fc effectively activated T cells and inhibited tumor growth in vivo, even in tumors with poor efficacy of ICIs. Importantly, CD80-Fc fusion protein had a milder affinity against the targets which suggested a potential higher safety than CD28 agonists. Further, in order to promote tumor immune infiltration, we attempted to combine CD80-Fc fusion protein with DDR1 inhibitor for treatment. Our results indicated that using CD80-Fc fusion protein along with DDR1 inhibitor significantly promoted T cell infiltration in tumor microenvironment and more strongly inhibited tumor growth. Therefore, the combination use of CD80 fusion protein and DDR1 inhibitor could become an effective tumor immunotherapy strategy, potentially benefiting a larger number of patients. Key points • We successfully constructed, expressed, and purified the recombinant CD80-Fc fusion protein • We demonstrated that CD80-Fc fusion protein has good safety and anti-tumor activity • We demonstrated that using CD80-Fc fusion protein along with DDR1 inhibitor can significantly promote immune infiltration of T cells in tumor microenvironment and more strongly inhibit tumor growth