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1.
Hydrogen sulfide (H 2S) is an endogenously generated and putative signaling/effector molecule. Despite its numerous reported functions, the chemistry by which it elicits its functions is not understood. Moreover, recent studies allude to the existence of other sulfur species besides H 2S that may play critical physiological roles. Herein, the basic chemical biology of H 2S as well as other related or derived species is discussed and reviewed. This review particularly focuses on the per- and polysulfides which are likely in equilibrium with free H 2S and which may be important biological effectors themselves. 相似文献
2.
Hydrogen sulfide (H 2S) is a versatile molecule with different functions in living organisms: it can work as a metabolite of sulfur and energetic metabolism or as a signaling molecule in higher Eukaryotes. H 2S is also highly toxic since it is able to inhibit heme cooper oxygen reductases, preventing oxidative phosphorylation. Due to the fact that it can both inhibit and feed the respiratory chain, the immediate role of H 2S on energy metabolism crucially relies on its bioavailability, meaning that studying the central players involved in the H 2S homeostasis is key for understanding sulfide metabolism.Two different enzymes with sulfide oxidation activity (sulfide dehydrogenases) are known: flavocytochrome c sulfide dehydrogenase (FCSD), a sulfide:cytochrome c oxidoreductase; and sulfide:quinone oxidoreductase (SQR).In this work we performed a thorough bioinformatic study of SQRs and FCSDs and integrated all published data. We systematized several properties of these proteins: (i) nature of flavin binding, (ii) capping loops and (iii) presence of key amino acid residues. We also propose an update to the SQR classification system and discuss the role of these proteins in sulfur metabolism. 相似文献
3.
Recognized as a novel and important gasotransmitter, hydrogen sulfide (H 2S) is widely present in various tissues and organs. Cystathionine gamma-lyase (CSE)-derived H 2S has been shown to regulate oxidative stress and lipid metabolism. The aim of the present study is to examine the role of H 2S in ferroptosis and lipid peroxidation in mouse myoblasts and skeletal muscles. Ferroptosis agonist RSL3 inhibited the expressions of Gpx4 and reduced CSE/H 2S signaling, which lead to increased oxidative stress, lipid peroxidation, and ferroptotic cell death. In addition, ferroptosis antagonist ferrostatin-1 (Fer-1) up-regulated the expression of CSE, scavenged the generation of reactive oxygen species (ROS) and lipid peroxidation, and improved cell viability. Exogenously applied NaHS was also able to block RSL3-induced ferroptotic cell death. Neither RSL3 nor H 2S affected cell apoptosis. Furthermore, H 2S reversed RSL3-induced Drp1 expression and mitochondrial damage, which lead to abnormal lipid metabolism as evidenced by altered expressions of ACSL4, FAS, ACC and CPT1 as well as higher acetyl-CoA contents in both cytoplasm and mitochondria. RSL3 promoted the protein expression and acetylation of ALOX12, a key protein in initiating membrane phospholipid oxidation, while the addition of NaHS attenuated ALOX12 acetylation and protected from membrane lipid peroxidation. Moreover, we observed that CSE deficiency alters the expressions of ferroptosis and lipid peroxidation-related proteins and enhances global protein acetylation in mouse skeletal muscles under aging or injury conditions. These results indicate that downregulation of CSE/H 2S signaling would contribute to mitochondrial damage, abnormal lipid metabolism, membrane lipid peroxidation, and ferroptotic cell death. CSE/H 2S system can be a target for preventing ferroptosis in skeletal muscle. 相似文献
4.
硫化氢(H_2S)是继一氧化氮(NO)和一氧化碳(CO)后发现的第3种气态信号分子,但其细菌生理学研究才刚刚起步。本文根据作者对奥内达希瓦氏菌的研究,结合新近文献,就细菌的H_2S产生机理及其生理功能作了较为全面的阐述。细菌的H_2S产生途径主要有2条,一是通过降解半胱氨酸产生,二是通过厌氧呼吸产生。产生的H_2S除可为互生性微生物提供能源、供氢体和无机矿质营养外,还具有抑制竞争性微生物的生长,有效占领生态位的作用。H_2S在氧化应答中也起着重要的作用,一方面可抑制过氧化氢酶活性,增加过氧化氢对细菌的杀灭效果;另一方面可作为信号分子激活细菌的氧化应答,诱导拮抗系统的表达,保护细胞免受氧化损伤。这两种看似"矛盾"的作用与H_2S的处理时间有关:短时间处理以抑制为主,而延长处理时间则以保护为主。细菌H_2S产生机理及生理功能的阐明可为硫元素生物地球化学循环规律的揭示和感染性病原细菌的控制提供有益的参考。 相似文献
6.
BackgroundEpithelial ovarian cancer is the leading cause of gynecologic cancer deaths. Most patients respond initially to platinum-based chemotherapy after surgical debulking, however relapse is very common and ultimately platinum resistance emerges. Understanding the mechanism of tumor growth, metastasis and drug resistant relapse will profoundly impact the therapeutic management of ovarian cancer. Methods/Principal FindingsUsing patient tissue microarray (TMA), in vitro and in vivo studies we report a role of of cystathionine-beta-synthase (CBS), a sulfur metabolism enzyme in ovarian carcinoma. We report here that the expression of cystathionine-beta-synthase (CBS), a sulfur metabolism enzyme, is common in primary serous ovarian carcinoma. The in vitro effects of CBS silencing can be reversed by exogenous supplementation with the GSH and H 2S producing chemical Na 2S. Silencing CBS in a cisplatin resistant orthotopic model in vivo by nanoliposomal delivery of CBS siRNA inhibits tumor growth, reduces nodule formation and sensitizes ovarian cancer cells to cisplatin. The effects were further corroborated by immunohistochemistry that demonstrates a reduction of H&E, Ki-67 and CD31 positive cells in si-RNA treated as compared to scrambled-RNA treated animals. Furthermore, CBS also regulates bioenergetics of ovarian cancer cells by regulating mitochondrial ROS production, oxygen consumption and ATP generation. This study reports an important role of CBS in promoting ovarian tumor growth and maintaining drug resistant phenotype by controlling cellular redox behavior and regulating mitochondrial bioenergetics. ConclusionThe present investigation highlights CBS as a potential therapeutic target in relapsed and platinum resistant ovarian cancer. 相似文献
7.
Hydrogen sulfide (H2S), previously recognized as a toxic gas, has emerged as an important gaseous signaling molecule along with nitric oxide, carbon monoxide and also hydrogen. H2S can be endogenously produced in the mammalian body at a very low level for various pathophysiological processes. Notably, H2S can interact with several essential metals in the body such as iron, copper, nickel, and zinc to carry out specific functions. The interactions of H2S with metal-binding proteins have been shown to aid in its signal transduction and cellular metabolism. In addition, H2S is capable of providing a cytoprotective role against metal toxicity. As the research in the field of H2S signaling in biology and medicine increases, much progresses have been developed for detecting H2S via interaction with metals. In this review, the interaction of H2S with metals, specifically in regard to metal-driven metabolism of H2S, the protection against metal toxicity by H2S and the detection of H2S using metals will be discussed. Discovering the interactions of this gasotransmitter with metals is important for determining the mechanisms underlying the cellular functions of H2S as well as developing novel therapeutic avenues. 相似文献
8.
Androgen receptor (AR) signaling is indispensable for the development of prostate cancer from the initial androgen-dependent state to a later aggressive androgen-resistant state. This study examined the role of hydrogen sulfide (H 2S), a novel gasotransmitter, in the regulation of AR signaling as well as its mediation in androgen-independent cell growth in prostate cancer cells. Here we found that H 2S inhibits cell proliferation of both androgen-dependent (LNCaP) and antiandrogen-resistant prostate cancer cells (LNCaP-B), with more significance on the latter, which was established by long term treatment of parental LNCaP cells with bicalutamide. The expression of cystathionine γ-lyase (CSE), a major H 2S-producing enzyme in prostate tissue, was reduced in both human prostate cancer tissues and LNCaP-B cells. LNCaP-B cells were resistant to bicalutamide-induced cell growth inhibition, and CSE overexpression could rebuild the sensitivity of LNCaP-B cells to bicalutamide. H 2S significantly repressed the expression of prostate-specific antigen ( PSA) and TMPRSS2, two AR-targeted genes. In addition, H 2S inhibited AR binding with PSA promoter and androgen-responsive element (ARE) luciferase activity. We further found that AR is post-translationally modified by H 2S through S-sulfhydration. Mutation of cysteine 611 and cysteine 614 in the second zinc finger module of AR-DNA binding domain diminished the effects of H 2S on AR S-sulfhydration and AR dimerization. These data suggest that reduced CSE/H 2S signaling contributes to antiandrogen-resistant status, and sufficient level of H 2S is able to inhibit AR transactivation and treat castration-resistant prostate cancer. 相似文献
9.
Reactive sulfur species (RSS), such as H 2S, hydrogen polysulfide (H 2S n, n ≥ 2), and hydropersulfides (RSS nH, n ≥ 1), are known to mediate diverse signaling pathways and possess a plethora of exciting therapeutic opportunities. Historically, due to the rapid inter-conversion among those species in vivo, the biological differences of distinct sulfur species were often overlooked. These species were considered to enrich the global sulfur pool in almost an equal fashion. However, advancement in this field has revealed that sulfur species at different oxidation states result in different pharmacological effects including scavenging reactive oxygen species (ROS), activating ion channels, and exhibiting analgesic effects. Here, we summarize recent advances in studying the biological and pharmacological differences of distinct sulfur species; discuss this phenomenon from the view of chemical properties and sulfur signaling pathways; and lay out a roadmap to transforming such new knowledge into general principles in developing sulfur-based therapeutics. 相似文献
10.
Gases, such as nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H 2S), and sulfur dioxide (SO 2) are known toxic pollutants in the air. However, they are now recognized as important signaling molecules synthesized in
animals and humans from arginine, glycine (heme), and cysteine, respectively. At physiological levels, NO, CO, and SO 2 activate guanylyl cyclase to generate cGMP which elicits a variety of responses (including relaxation of vascular smooth
muscle cells, hemodynamics, neurotransmission, and cell metabolism) via cGMP-dependent protein kinases. H 2S is also a crucial regulator of both neurological function and endothelium-dependent relaxation through cGMP-independent
mechanisms involving stimulation of membrane K ATP channels and intracellular cAMP signaling. Additionally, NO, CO, and H 2S confer cytoprotective and immunomodulatory effects. Moreover, NH 3 is a major product of amino acid catabolism and profoundly affects the function of neurons and the vasculature through glutamine-dependent
inhibition of NO synthesis. Emerging evidence shows that amino acids are not only precursors for these endogenous gases, but
are also regulators of their production in a cell-specific manner. Thus, recent advances on gaseous signaling have greatly
expanded our basic knowledge of amino acid biochemistry and nutrition. These exciting discoveries will aid in the design of
new nutritional and pharmacological means to prevent and treat major health problems related to developmental biology and
nutrient metabolism, including intrauterine growth restriction, preterm birth, aging, neurological disorders, cancer, obesity,
diabetes, and cardiovascular disease. 相似文献
11.
In recent years, a vast number of potential cancer therapeutic targets have emerged. However, developing efficient and effective drugs for the targets is of major concern. Hydrogen sulfide (H 2S), one of the three known gasotransmitters, is involved in the regulation of various cellular activities such as autophagy, apoptosis, migration, and proliferation. Low production of H 2S has been identified in numerous cancer types. Treating cancer cells with H 2S donors is the common experimental technique used to improve H 2S levels; however, the outcome depends on the concentration/dose, time, cell type, and sometimes the drug used. Both natural and synthesized donors are available for this purpose, although their effects vary independently ranging from strong cancer suppressors to promoters. Nonetheless, numerous signaling pathways have been reported to be altered following the treatments with H 2S donors which suggest their potential in cancer treatment. This review will analyze the potential of H 2S donors in cancer therapy by summarizing key cellular processes and mechanisms involved. 相似文献
12.
Plants often face a variety of abiotic stresses, which affects them negatively and lead to yield loss. The antioxidant system efficiently removes excessive reactive oxygen species and maintains redox homeostasis in plants. With better understanding of these protective mechanisms, recently the concept of hydrogen sulfide (H 2S) and its role in cell signaling has become the center of attention. H 2S has been recognized as a third gasotransmitter and a potent regulator of growth and development processes such as germination, maturation, senescence and defense mechanism in plants. Because of its gaseous nature, H 2S can diffuse to different part of the cells and balance the antioxidant pools by supplying sulfur to cells. H 2S showed tolerance against a plethora of adverse environmental conditions like drought, salt, high temperature, cold, heavy metals and flood via changing in level of osmolytes, malonaldialdehyde, Na +/K + uptake, activities of H 2S biosynthesis and antioxidative enzymes. It also promotes cross adaptation through persulfidation. H 2S along with calcium, methylglyoxal and nitric oxide, and their cross talk induces the expression of mitogen activated protein kinases as well as other genes in response to stress. Therefore, it is sensible to evaluate and explore the stress responsive genes involved in H 2S regulated homeostasis and stress tolerance. The current article is aimed to summarize the recent updates on H 2S-mediated gene regulation in special reference to abiotic stress tolerance mechanism, and cross adaptation in plants. Moreover, new insights into the H 2S-associated signal transduction pathway have also been explored. 相似文献
13.
Hydrogen sulfide (H 2S), which has been identified as the third gaseous signaling molecule after nitric oxide (NO) and carbon monoxide (CO), plays an important role in maintaining homeostasis in the cardiovascular system. Endogenous H 2S is produced mainly by three endogenous enzymes: cystathionine β-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfur transferase. Numerous studies have shown that H 2S has a significant protective role in myocardial ischemia. The mechanisms by which H 2S affords cardioprotection include the antifibrotic and antiapoptotic effects, regulation of ion channels, protection of mitochondria, reduction of oxidative stress and inflammatory response, regulation of microRNA expression, and promotion of angiogenesis. Amplification of NO- and CO-mediated signaling through crosstalk between H 2S, NO, and CO may also contribute to the cardioprotective effect. Exogenous H 2S donors are expected to become effective drugs for the treatment of cardiovascular diseases. This review article focuses on the protective mechanisms and potential therapeutic applications of H 2S in myocardial ischemia. 相似文献
14.
Plants are exposed to a plethora of abiotic stresses such as drought, salinity, heavy metal and temperature stresses at different stages of their life cycle, from germination to seedling till the reproductive phase. As protective mechanisms, plants release signaling molecules that initiate a cascade of stress-signaling events, leading either to programmed cell death or plant acclimation. Hydrogen sulfide (H 2S) and nitric oxide (NO) are considered as new ‘gasotransmitter’ molecules that play key roles in regulating gene expression, posttranslational modification (PTM), as well as cross-talk with other hormones. Although the exact role of NO in plants remains unclear and is species dependent, various studies have suggested a positive correlation between NO accumulation and environmental stress in plants. These molecules are also involved in a large array of stress responses and act synergistically or antagonistically as signaling components, depending on their respective concentration. This study provides a comprehensive update on the signaling interplay between H 2S and NO in the regulation of various physiological processes under multiple abiotic stresses, modes of action and effects of exogenous application of these two molecules under drought, salt, heat and heavy metal stresses. However, the complete picture of the signaling cascades mediated by H 2S and NO is still elusive. Recent researches indicate that during certain plant processes, such as stomatal closure, H 2S could act upstream of NO signaling or downstream of NO in response to abiotic stresses by improving antioxidant activity in most plant species. In addition, PTMs of antioxidative pathways by these two molecules are also discussed. 相似文献
15.
Hydrogen sulfide (H2S) has emerged as a novel gaseous signal molecule with multifarious effects on seed germination, plant growth, development, and physiological processes. Due to its dominant role in plant stress tolerance and cross-adaptation, it is getting more attention nowadays, although it has been largely referred as toxic and environmental hazardous gas. In this review work, we are highlighting the importance of H2S as an essential gaseous molecule to help in signaling, metabolism, and stress tolerance in plants. Firstly, production of H2S from different natural and artificial sources were discussed with its transformation from sulfur (S) to sulfate (SO42−) and then to sulfite (SO32−). The importance of different kinds of transporters that helps to take SO42− from the soil solution was presented. Mainly, these transporters are SULTRs (H+/SO42− cotransporters) and multigene family encodes them. Furthermore, these SULTRs have LAST (Low affinity transport proteins), HAST (High affinity transport proteins), vacuole transporters, and plastid transporters. Since it is well known that there is strong relationship between SO42− and synthesis of hydrogen sulfide or dihydrogen sulfide or sulfane in plant cells. Thus, cysteine (Cys) metabolism through which H2S could be generated in plant cell with the role of different enzymes has been presented. Furthermore, H2S in interaction with other molecules could help to mitigate biotic and abiotic stress. Based on this review work, it can be concluded that H2S has potential to induce cross-adaptation to biotic and abiotic stress; thus, it is recommended that it should be considered in future studies to answer the questions like what are the receptors of H2S in plant cell, where in plants the physiological concentration of H2S is high in response to multiple stress and how it induces cross-adaptation by interaction with other signal molecules. 相似文献
16.
Bcl-2 family proteins, known for their apoptosis functioning at the mitochondria, have been shown to localize to other cellular compartments to mediate calcium (Ca 2+) signals. Since the proper supply of Ca 2+ in cells serves as an important mechanism for cellular survival and bioenergetics, we propose an integrating role for Bcl-2 family proteins in modulating Ca 2+ signaling. The endoplasmic reticulum (ER) is the main Ca 2+ storage for the cell and Bcl-2 family proteins competitively regulate its Ca 2+ concentration. Bcl-2 family proteins also regulate the flux of Ca 2+ from the ER by physically interacting with inositol 1,4,5-trisphosphate receptors (IP 3Rs) to mediate their opening. Type 1 IP 3Rs reside at the bulk ER to coordinate cytosolic Ca 2+ signals, while type 3 IP 3Rs reside at mitochondria-associated ER membrane (MAM) to facilitate mitochondrial Ca 2+ uptake. In healthy cells, mitochondrial Ca 2+ drives pyruvate into the citric acid (TCA) cycle to facilitate ATP production, while a continuous accumulation of Ca 2+ can trigger the release of cytochrome c, thus initiating apoptosis. Since multiple organelles and Bcl-2 family proteins are involved in Ca 2+ signaling, we aim to clarify the role that Bcl-2 family proteins play in facilitating Ca 2+ signaling and how mitochondrial Ca 2+ is relevant in both bioenergetics and apoptosis. We also explore how these insights could be useful in controlling bioenergetics in apoptosis-resistant cell lines. 相似文献
17.
Although cells often can tolerate oxidative environments, abnormal oxidative stress has been identified in inflammation, cardiovascular and neurodegenerative diseases, and aging. The impact of oxidative stress on the cellular biomechanics is poorly understood, however. In this study, we used C2C12 myoblasts to investigate the effect of oxidative stress, mimicked by hydrogen peroxide (H 2O 2), on the cell elasticity (i.e., Young?s modulus), viability, and production of intracellular reactive oxygen species (ROS). To better understand the mechanisms underlying the impact of H 2O 2, we examined various effectors of the Rho signaling pathway, which has been shown to play a key role in the control of cell mechanics. H 2O 2 decreased the cell stiffness in a dose-dependent manner, caused cell death, and reduced the RhoA expression that was accompanied by down-regulation of α-actin, cytoskeleton-membrane linker proteins (ezrin–radixin–moesion proteins), and focal adhesion. Modulating the Rho signaling by using a Rho activator partially restored the cell stiffness, enhanced the cell viability, and decreased the intracellular ROS level, suggesting a potential intervention strategy to maintain the cellular biomechanical homeostasis and rescue cell damage in the threat of oxidative stresses. 相似文献
18.
Thrombospondin-1 is a potent suppressor of T cell activation via its receptor CD47. However, the precise mechanism for this inhibition remains unclear. Because H 2S is an endogenous potentiator of T cell activation and is necessary for full T cell activation, we hypothesized that thrombospondin-1 signaling through CD47 inhibits T cell activation by antagonizing H 2S signaling. Primary T cells from thrombospondin-1 null mice were more sensitive to H 2S-dependent activation assessed by proliferation and induction of interleukin-2 and CD69 mRNAs. Exogenous thrombospondin-1 inhibited H 2S responses in wild type and thrombospondin-1 null T cells but enhanced the same responses in CD47 null T cells. Fibronectin, which shares integrin and glycosaminoglycan binding properties with thrombospondin-1 but not CD47 binding, did not inhibit H 2S signaling. A CD47-binding peptide derived from thrombospondin-1 inhibited H 2S-induced activation, whereas two other functional sequences from thrombospondin-1 enhanced H 2S signaling. Therefore, engaging CD47 is necessary and sufficient for thrombospondin-1 to inhibit H 2S-dependent T cell activation. H 2S stimulated T cell activation by potentiating MEK-dependent ERK phosphorylation, and thrombospondin-1 inhibited this signaling in a CD47-dependent manner. Thrombospondin-1 also limited activation-dependent T cell expression of the H 2S biosynthetic enzymes cystathionine β-synthase and cystathionine γ-lyase, thereby limiting the autocrine role of H 2S in T cell activation. Thus, thrombospondin-1 signaling through CD47 is the first identified endogenous inhibitor of H 2S signaling and constitutes a novel mechanism that negatively regulates T cell activation. 相似文献
19.
The role of cocaine in modulating the metabolism of sulfur-containing compounds in the peripheral tissues is poorly understood. In the present study we addressed the question about the effects of acute and repeated (5 days) cocaine (10 mg/kg i.p.) administration on the total cysteine (Cys) metabolism and on the oxidative processes in the rat liver and kidney. The whole pool of sulfane sulfur, its bound fraction and hydrogen sulfide (H 2S) were considered as markers of anaerobic Cys metabolism while the sulfate as a measure of its aerobic metabolism. The total-, non-protein- and protein- SH group levels were assayed as indicators of the redox status of thiols. Additionally, the activities of enzymes involved in H 2S formation (cystathionine γ-lyase, CSE; 3-mercaptopyruvate sulfurtransferase, 3-MST) and GSH metabolism (γ-glutamyl transpeptidase, γ-GT; glutathione S-transferase, GST) were determined. Finally, we assayed the concentrations of reactive oxygen species (ROS) and malondialdehyde (MDA) as markers of oxidative stress and lipid peroxidation, respectively. In the liver, acute cocaine treatment, did not change concentrations of the whole pool of sulfane sulfur, its bound fraction, H 2S or sulfate but markedly decreased levels of non-protein SH groups (NPSH), ROS and GST activity while γ-GT was unaffected. In the kidney, acute cocaine significantly increased concentration of the whole pool of sulfane sulfur, reduced the content of its bound fraction but H 2S, sulfate and NPSH levels were unchanged while ROS and activities of GST and γ-GT were reduced. Acute cocaine enhanced activity of the CSE and 3-MST in the liver and kidney, respectively. Repeatedly administered cocaine enhanced the whole pool of sulfane sulfur and reduced H 2S level simultaneously increasing sulfate content both in the liver and kidney. After repeated cocaine, a significant decrease in ROS was still observed in the liver while in the kidney, despite unchanged ROS content, a marked increase in MDA level was visible. The repeated cocaine decreased 3-MST and increased γ-GT activities in both organs but reduced GST in the kidney. Our results show that cocaine administered at a relatively low dose shifts Cys metabolism towards the formation of sulfane sulfur compounds which possess antioxidant and redox regulatory properties and are a source of H 2S which can support mitochondrial bioenergetics. 相似文献
20.
Shewanella oneidensis is a model species for aquatic ecosystems and plays an important role in bioremediation, biofuel cell manufacturing and biogeochemical cycling. S. oneidensis MR-1 is able to generate hydrogen sulfide from various sulfur species; however, its catalytic kinetics have not been determined. In this study, five in-frame deletion mutants of S. oneidensis were constructed and their H 2S-producing activities were analyzed. SirA and PsrA were the two major contributors to H 2S generation under anoxic cultivation, and the optimum SO 32− concentration for sulfite respiration was approximately 0.8 mM, while the optimum S 2O 32− concentration for thiosulfate respiration was approximately 0.4 mM. Sulfite and thiosulfate were observed to interfere with each other during respiration, and a high concentration of sulfite or thiosulfate chelated extracellular free-iron but did not repress the expression of sirA or psrA. Nitrite and nitrate were two preferred electron acceptors during anaerobic respiration; however, under energy-insufficient conditions, S. oneidensis could utilize multiple electron acceptors simultaneously. Elucidiating the stoichiometry of H 2S production in S. oneidensis would be helpful for the application of this species in bioremediation and biofuel cell manufacturing, and would help to characterize the ecophysiology of sulfur cycling. 相似文献
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