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1.
Sci Total Environ ; 750: 141685, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32862004

RESUMO

Human exposure to bisphenol A (BPA) is unavoidable in daily life. Recently, research has showen that BPA could induce oxidative imbalance, thereby causing reproductive toxicity and liver dysfunction. Accumulated evidence has demonstrated that metformin possesses strong anti-oxidative properties. This study aimed to study the mechanism underlying the hepatic-protective effect of metformin on liver injury induced by BPA in rats via the UPLC-MS/MS metabolomics approach. Forty-two male rats were randomly divided into six groups (n = 7), namely the saline group (control), the corn oil group (vehicle), the metformin group (Met), the bisphenol A group (BPA), the bisphenol A and metformin group (BPA + Met), and the bisphenol A and diammonium glycyrrhizinate (positive control) group (BPA + DG). Serum was collected for biochemical analysis and metabolomics, and liver tissue was collected for histopathology and metabolomics in each group. We found that metformin could significantly reduce the levels of liver function enzymes (ALT, AST and GGT) and ameliorate inflammatory cell infiltration and hepatocyte necrosis induced by BPA. On the other hand, metformin could significantly enhance the total antioxidant capacity in BPA rats. Notably, metabolomics data indicated that the principal altered metabolic pathways based on the 26 differential metabolites in liver tissue, and 21 in serum among vehicle, BPA and BPA + Met groups, respectively, including cysteine and methionine metabolism, glutathione metabolism, and arginine biosynthesis and purine metabolism. Additionally, metformin significantly increased cystathionine ß synthase (CBS) and cystathionine γ lyase (CSE), thus reducing serum levels of homocysteine and increasing hepatic levels of cysteine and glutathione in BPA-treated rats. Overall, this study's results provided new insights into the role and mechanism of metformin in BPA-induced liver injury in rats.


Assuntos
Cistationina gama-Liase , Metformina , Animais , Compostos Benzidrílicos/toxicidade , Cromatografia Líquida , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Humanos , Fígado/metabolismo , Masculino , Metformina/toxicidade , Fenóis , Ratos , Espectrometria de Massas em Tandem , Regulação para Cima
2.
J Environ Pathol Toxicol Oncol ; 39(3): 281-290, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865918

RESUMO

Objective-To investigate cystathionine ß synthase (CBS)/hydrogen sulfide (H2S) signaling in multiple myeloma (MM) patients and to identify its effect on the proliferation of U266 cells. Methods-Bone marrow samples of 19 MM patients and 23 healthy donors were collected. qRT-PCR was performed to measure the mRNA expression levels of H2S synthases, cystathionine ß synthase, and cystathionine γ lyase. ELISA assays quantified the amount of H2S produced by the two enzymes CBS and CSE. CCK-8 experiment was used to investigate the influence of the CBS inhibitor amino oxyacetic acid and the CSE inhibitor propargylglycine on the proliferation of U266 cells. Flow cytometry and western blotting were performed to determine the effects of AOAA, PAG, and NaHS on cell cycle distribution as well as Caspase-3 and Bcl-2 expression. Results-Patients with MM had higher level of CBS compared with healthy donors. AOAA significantly inhibited cell proliferation in both a time and concentration dependent characteristic, whereas PAG does not. After 24 hours of treatment, AOAA significantly elevated the G0/G1 phase proportion of cells, and reduced the cell distribution in both S and G2/M phases, while NaHS accelerated cell cycle progression by reducing the relative number of cells in G0/G1 phase and increasing the proportion of cells in the G2/M phase. Moreover, AOAA abolished the impact of NaHS on cell cycle progression of U266 cells. AOAA treatment also led to a significant decrease in Bcl-2 expression and dramatic increase in Caspase-3 expression, though NaHS reversed these effects. Conclusion-CBS/H2S system might have a certain effect on the proliferation and apoptosis of MM cells.


Assuntos
Apoptose , Proliferação de Células , Cistationina beta-Sintase/metabolismo , Sulfeto de Hidrogênio/metabolismo , Mieloma Múltiplo/metabolismo , Adulto , Idoso , Alquinos/farmacologia , Ácido Amino-Oxiacético/farmacologia , Apoptose/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Estudos de Casos e Controles , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cistationina beta-Sintase/antagonistas & inibidores , Cistationina gama-Liase/antagonistas & inibidores , Cistationina gama-Liase/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Transdução de Sinais
3.
Life Sci ; 261: 118348, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32860803

RESUMO

AIMS: 3,3'-Diindolylmethane (DIM) has limited anti-cancer effects in gastric cancer. Hydrogen sulfide (H2S) plays an important role in the tumor development and therapy, cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE), two key endogenous H2S biosynthesis enzymes, can affect endogenous H2S levels and alter cancer treatment. Our main objective was to investigate whether the aminooxyacetic acid (AOAA) and DL-Propargylglycine (PAG), two specific inhibitors of CBS and CSE, could assist DIM to exert a stronger anti-cancer effects in gastric cancer BGC-823 and SGC-7901 cells. MATERIALS AND METHODS: Cell proliferation was assayed by MTT and cell colony-forming assay. Apoptosis and migration were detected by Hoechst staining and scratch test respectively. Western blot was used to evaluate the expression of proteins related to proliferation, apoptosis and migration. KEY FINDINGS: Combination of AOAA or PAG with DIM synergistically inhibited proliferation and migration, increased apoptosis in gastric cancer cells. The p38-p53 axis was also further activated by the combination of AOAA or PAG with DIM. Exogenous H2S from sodium hydrosulfide, attenuated the efficacy of DIM in cancer cells by reducing the activation level of p38-p53 axis. Taken together, AOAA or PAG inhibited the expression of endogenous H2S biosynthesis enzymes and effectively enhanced susceptibility of gastric cancer to DIM through activating p38-p53 axis. SIGNIFICANCE: The current study highlight more precise requirements for the clinical application of sulfur-containing anti-cancer drugs, and open a new way to enhance the sensitivity of DIM in chemotherapy of gastric cancer.


Assuntos
Anticarcinógenos/farmacologia , Sulfeto de Hidrogênio/antagonistas & inibidores , Indóis/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Alquinos/administração & dosagem , Alquinos/farmacologia , Ácido Amino-Oxiacético/administração & dosagem , Ácido Amino-Oxiacético/farmacologia , Anticarcinógenos/administração & dosagem , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Sinergismo Farmacológico , Glicina/administração & dosagem , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Sulfeto de Hidrogênio/metabolismo , Indóis/administração & dosagem , Neoplasias Gástricas/patologia , Proteína Supressora de Tumor p53/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
4.
Life Sci ; 254: 117699, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32437793

RESUMO

AIMS: Ischemia/reperfusion (I/R) injury largely limits the efficacy of revascularization in acute myocardial infarction. Long noncoding RNA (lncRNA) Oprm1 is protective in cerebral I/R injury. This study aimed to investigate the effect of lncRNA Oprm1 on myocardial I/R injury and its mechanism. MAIN METHODS: We ligated and then released the left anterior descending coronary artery of adult male rats to build the I/R model in vivo. At the same time, an H9c2 cardiomyocytes hypoxia-reoxygenation (H/R) model was also used. Myocardial infarction area, cardiac function, histology, TUNEL staining, cell viability, and vital protein expression was conducted and compared. KEY FINDINGS: LncRNA Oprm1 was significantly down-regulated in the I/R injury model. When administered with the AAV9-Oprm1 vector, the myocardial injury and cardiac function were mitigated and preserved, with apoptosis reduced. The cystathionine-γ-lyase (CSE) expression and hydrogen sulfide (H2S) expression were increased. The dual-luciferase reporter gene revealed the targeted relationship between lncRNA Oprm1 and miR-30b-5p. In H9c2 cardiomyocytes models, the miR-30b-5p blocked the protective effect of lncRNA Oprm1 on H/R injury, when Bcl-2, Bcl-xl was down-regulated, and HIF-1α, Bnip-3, Caspase-3, and Caspase-9 up-regulated. SIGNIFICANCE: LncRNA Oprm1can competitively combines with miR-30b-5p, which down-regulates the expression of CSE. When administered with lncRNA Oprm1, increased endogenous H2S can reduce apoptosis and protect the myocardium from I/R injury via activating PI3K/Akt pathway and inhibiting HIF1-α activity.


Assuntos
Cistationina gama-Liase/metabolismo , Sulfeto de Hidrogênio/metabolismo , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , RNA Longo não Codificante/genética , Receptores Opioides mu/genética , Animais , Modelos Animais de Doenças , Humanos , Ratos , Ratos Sprague-Dawley , Receptores Opioides mu/metabolismo
5.
Biochem Pharmacol ; 176: 113931, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32224139

RESUMO

Nitric oxide (NO) and hydrogen sulfide (H2S) are industrial toxins or pollutants; however, both are produced endogenously and have important biological roles in most mammalian tissues. The recognition that these gasotransmitters have a role in physiological and pathophysiological processes has presented opportunities to harness their intracellular effects either through inhibition of their production; or more commonly, through inducing their levels and or delivering them by various modalities. In this review article, we have focused on an array of NO and H2S donors, their hybrids with other established classes of drugs, and the various engineered delivery platforms such a fibers, polymers, nanoparticles, hydrogels, and others. In each case, we have reviewed the rationale for their development.


Assuntos
Gasotransmissores/metabolismo , Sulfeto de Hidrogênio/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais , Animais , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Cisteína/metabolismo , Humanos , Óxido Nítrico Sintase/metabolismo
6.
Life Sci ; 252: 117661, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32305523

RESUMO

AIMS: Hydrogen sulfide (H2S) as a novel gasotransmitter can be endogenously produced in liver by cystathionine gamma-lyase (CSE). The dysfunctions of CSE/H2S system have been linked to various liver diseases. Acetyl-CoA is the key intermediate from the metabolism of lipid. This study examined the roles of H2S in hepatic acetyl-CoA and lipid metabolism. MATERIALS AND METHODS: Both in vitro cell model and in vivo animal model of lipid accumulation were used in this study. Western blotting and real-time PCR were used for analysis of protein and mRNA expression. Acetyl-CoA was analyzed by a coupled enzyme assay, and lipid accumulation was observed with Oil Red O staining. KEY FINDINGS: Incubation of human liver carcinoma (HepG2) cells with a mixture of free fatty acids (FFAs) or high glucose reduced CSE expression and H2S production, promoted intracellular accumulation of acetyl-CoA and lipid. Supply of exogenous NaHS or cysteine reduced acetyl-CoA contents and lipid accumulation, while blockage of CSE activity promoted intracellular lipid accumulation. Furthermore, H2S blocked FFAs-induced transcriptions of de novo lipogenesis, inflammation, and fibrosis-related genes. In vivo, knockout of CSE gene stimulated more hepatic acetyl-CoA and lipid accumulation in mice induced by high-fat choline-deficient diet. The expressions of lipogenesis, inflammation, and fibrosis-related genes were significantly higher in liver tissues from CSE knockout mice when compared with wild-type mice. SIGNIFICANCE: CSE/H2S system is indispensable for maintaining the homeostasis of acetyl-CoA and lipid accumulation and protecting from the development of inflammation and fibrosis in liver under excessive caloric ingestion.


Assuntos
Acetilcoenzima A/metabolismo , Cistationina gama-Liase/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Sulfeto de Hidrogênio/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Animais , Cistationina gama-Liase/genética , Modelos Animais de Doenças , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
7.
Ecotoxicol Environ Saf ; 195: 110464, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32171946

RESUMO

Nickel compounds are known to be common environmental and occupational carcinogens which also promote the migration of lung cancer cells. However, the molecular mechanism yet remains to be clarified. Hydrogen sulfide (H2S) is involved in cancer biological processes. However, the exact effect and functionality of H2S on nickel, towards the promotion of the migration ability of lung cancer cells, remains to be unknown. In this study, we have found that the nickel chloride (NiCl2) treatment significantly downregulates the protein levels of endogenous H2S enzyme cystathionine ß-synthase (CBS), cystathionine γ-lyase (CSE) and 3-Mercaptopyruvate sulfurtransferase (3-MST). A correlation between NiCl2-induced epithelial-mesenchymal transition (EMT) and the migration ability of lung cancer A549 cells has been observed. Exogenous H2S donor, sodium hydrogen sulfide (NaHS) (100 µmol/L), can reverse NiCl2-induced EMT as well as the migration ability of A549 cells. NiCl2 treatment is able to upregulate the protein level of transforming growth factor-ß1 (TGF-ß1), p-Smad2, p-Smad3, p-JNK, p-ERK and p-P38 in a time-dependent fashion, indicating that both TGF-ß1/Smad2/Smad3 and mitogen-activated protein kinase (MAPK) signaling cascades (a non-Smad pathway) may play essential roles in NiCl2-dependent EMT as well as cell migration of human lung cancer cells. Furthermore, exogenous NaHS alleviates the NiCl2-induced EMT and the migration ability of A549 cells only by regulating TGF-ß1/Smad2/Smad3, rather than the MAPK, signaling pathway. These results indicate that the exogenous administration of NaHS might be a potential therapeutic strategy against nickel-induced lung cancer progression.


Assuntos
Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Níquel/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfetos/farmacologia , Células A549 , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Humanos , Sulfeto de Hidrogênio/química , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Sulfurtransferases/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
8.
Biochem Pharmacol ; 176: 113833, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32027885

RESUMO

RATIONALE: Hydrogen sulfide (H2S) is a physiological mediator that regulates cardiovascular homeostasis. Three major enzymes contribute to the generation of endogenously produced H2S, namely cystathionine γ-lyase (CSE), cystathionine ß-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). Although the biological roles of CSE and CBS have been extensively investigated in the cardiovascular system, very little is known about that of 3-MST. In the present study we determined the importance of 3-MST in the heart and blood vessels, using a genetic model with a global 3-MST deletion. RESULTS: 3-MST is the most abundant transcript in the mouse heart, compared to CSE and CBS. 3-MST was mainly localized in smooth muscle cells and cardiomyocytes, where it was present in both the mitochondria and the cytosol. Levels of serum and cardiac H2S species were not altered in adult young (2-3 months old) 3-MST-/- mice compared to WT animals. No significant changes in the expression of CSE and CBS were observed. Additionally, 3-MST-/- mice had normal left ventricular structure and function, blood pressure and vascular reactivity. Interestingly, genetic ablation of 3-MST protected mice against myocardial ischemia reperfusion injury, and abolished the protection offered by ischemic pre- and post-conditioning. 3-MST-/- mice showed lower expression levels of thiosulfate sulfurtransferase, lower levels of cellular antioxidants and elevated basal levels of cardiac reactive oxygen species. In parallel, 3-MST-/- mice showed no significant alterations in endothelial NO synthase or downstream targets. Finally, in a separate cohort of older 3-MST-/- mice (18 months old), a hypertensive phenotype associated with cardiac hypertrophy and NO insufficiency was observed. CONCLUSIONS: Overall, genetic ablation of 3-MST impacts on the mouse cardiovascular system in an age-dependent manner. Loss of 3-MST exerts a cardioprotective role in young adult mice, while with aging it predisposes them to hypertension and cardiac hypertrophy.


Assuntos
Sistema Cardiovascular/metabolismo , Sulfeto de Hidrogênio/metabolismo , Miócitos Cardíacos/metabolismo , Sulfurtransferases/metabolismo , Animais , Antioxidantes/metabolismo , Sistema Cardiovascular/enzimologia , Cistationina beta-Sintase/genética , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Regulação Enzimológica da Expressão Gênica , Sulfeto de Hidrogênio/sangue , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/enzimologia , Óxido Nítrico/metabolismo , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Sulfurtransferases/genética , Vasodilatação/efeitos dos fármacos
9.
Oxid Med Cell Longev ; 2020: 4309605, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32082478

RESUMO

We recently showed that blunt chest trauma reduced the expression of the myocardial oxytocin receptor (Oxtr), which was further aggravated by genetic deletion of the H2S-producing enzyme cystathionine γ-lyase (CSE). Exogenous H2S supplementation restored myocardial Oxtr expression under these conditions. Early life stress (ELS) is a risk factor for cardiovascular disease by affecting vascular and heart structures. Therefore, we tested the hypotheses that (i) ELS affects cardiac Oxtr and CSE expressions and (ii) Oxtr and CSE expression patterns depend on the duration of stress exposure. Thus, two stress paradigms were compared: long- and short-term separation stress (LTSS and STSS, respectively). Cardiac Oxtr expression was differentially affected by the two stress paradigms with a significant reduction after LTSS and a significant increase after STSS. CSE expression, which was significantly reduced in Oxtr-/- knockout hearts, was downregulated and directly related to Oxtr expression in LTSS hearts (r = 0.657, p = 0.012). In contrast, CSE expression was not related to Oxtr upregulation in STSS. Plasma Oxt levels were not affected by either ELS paradigm. The coincidence of LTSS-induced reduction of cardiac Oxtr and reduced CSE expression may suggest a novel pathophysiological link between early life adversities and increased risk for the development of cardiovascular disorders in adulthood.


Assuntos
Cistationina gama-Liase/metabolismo , Ocitocina/sangue , Receptores de Ocitocina/metabolismo , Animais , Feminino , Heterozigoto , Homozigoto , Masculino , Privação Materna , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Ocitocina/metabolismo , Regulação para Cima
10.
Comp Biochem Physiol B Biochem Mol Biol ; 243-244: 110430, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32105700

RESUMO

To lend insight into the potential role of the gasotransmitter hydrogen sulfide (H2S) in facilitating anoxia survival of anoxia-tolerant vertebrates, we quantified the gene expression of the primary H2S-synthesizing enzymes, 3-mercaptopyruvate sulfurtransferase (3MST), cystathionine γ-lyase (CSE) and cystathionine ß-synthase (CBS), in ventricle and brain of normoxic, anoxic and reoxygenated 21 °C- and 5 °C-acclimated freshwater turtles (Trachemys scripta) and 10 °C-acclimated crucian carp (Carassius carassius). Semi-quantitative Western blotting analysis was also conducted to assess 3MST and CBS protein abundance in ventricle and brain of 5 °C turtles and 10 °C crucian carp subjected to normoxia, anoxia and reoxygenation. We hypothesized that if H2S was advantageous for anoxia survival, expression levels would remain unchanged or be upregulated with anoxia and/or reoxygenation. Indeed, for both species, gene and protein expression were largely maintained with anoxia exposure (24 h, 21 °C; 5 d, 10 °C; 14 d, 5 °C). With reoxygenation, 3MST expression was increased in turtle and crucian carp brain at the protein and gene level, respectively. Additionally, the effect of cold acclimation on gene expression was assessed in several tissues of the turtle. Expression levels were maintained in most tissues, but decreased in others. The maintenance of gene and protein expression of the H2S-producing enzymes with anoxia exposure and the up-regulation of 3MST with reoxygenation suggests that H2S may facilitate anoxic survival of the two champions of vertebrate anoxia survival. The differential effects of cold acclimation on H2S enzyme expression may influence blood flow to different tissues during winter anoxia.


Assuntos
Aclimatação/genética , Encéfalo/metabolismo , Carpas/metabolismo , Sulfeto de Hidrogênio/metabolismo , Hipóxia/metabolismo , Tartarugas/metabolismo , Animais , Carpas/genética , Temperatura Baixa , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Hipóxia/enzimologia , Sulfurtransferases/metabolismo , Tartarugas/genética
11.
Int J Mol Sci ; 21(2)2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952233

RESUMO

Molecular responses mediated by sensor proteins are important for biological defense against electrophilic stresses, such as xenobiotic electrophile exposure. NF-E2-related factor 2 (Nrf2) has an essential function as a master regulator of such cytoprotective molecular responses along with sensor protein Kelch-like ECH-associated protein 1. This review focuses on Nrf2 activation and its involvement with the protective defense systems under electrophilic stresses integrated with our recent findings that reactive sulfur species (RSS) mediate detoxification of electrophiles. The Nrf2 pathway does not function redundantly with the RSS-generating cystathionine γ-lyase pathway, and vice versa.


Assuntos
Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Enxofre/química , Animais , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Citoproteção/genética , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/genética , Transdução de Sinais/genética , Enxofre/metabolismo , Ativação Transcricional
12.
Nat Commun ; 11(1): 446, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974383

RESUMO

Afterglow luminescent probes with high signal-to-background ratio show promise for in vivo imaging; however, such probes that can be selectively delivered into target sites and switch on afterglow luminescence remain limited. We optimize an organic electrochromic material and integrate it into near-infrared (NIR) photosensitizer (silicon 2,3-naphthalocyanine bis(trihexylsilyloxide) and (poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene]) containing nanoparticles, developing an H2S-activatable NIR afterglow probe (F12+-ANP). F12+-ANP displays a fast reaction rate (1563 ± 141 M-1 s-1) and large afterglow turn-on ratio (~122-fold) toward H2S, enabling high-sensitivity and -specificity measurement of H2S concentration in bloods from healthy persons, hepatic or colorectal cancer patients. We further construct a hepatic-tumor-targeting and H2S-activatable afterglow probe (F12+-ANP-Gal) for noninvasive, real-time imaging of tiny subcutaneous HepG2 tumors (<3 mm in diameter) and orthotopic liver tumors in mice. Strikingly, F12+-ANP-Gal accurately delineates tumor margins in excised hepatic cancer specimens, which may facilitate intraoperative guidance of hepatic cancer surgery.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Sulfeto de Hidrogênio/análise , Neoplasias Hepáticas/diagnóstico por imagem , Substâncias Luminescentes/química , Imagem Molecular/métodos , Animais , Neoplasias Colorretais/sangue , Cistationina beta-Sintase/análise , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/análise , Cistationina gama-Liase/metabolismo , Células Hep G2 , Humanos , Sulfeto de Hidrogênio/sangue , Sulfeto de Hidrogênio/química , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Substâncias Luminescentes/síntese química , Camundongos Endogâmicos BALB C , Nanopartículas/química , Fármacos Fotossensibilizantes/química , Polímeros/química , Compostos de Vinila/química , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Int Immunopharmacol ; 80: 106136, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31991372

RESUMO

Garlic (Allium sativum) - derived organosulfur compound diallyl disulfide (DADS) possesses antioxidant, anti-inflammatory and anti-cancer effects. This study was aimed to investigate the anti-inflammatory role and the underlying molecular mechanisms of DADS in cerulein-induced acute pancreatitis (AP) and associated lung injury. Administration of DADS significantly attenuated the severity of pancreatic and pulmonary inflammation by inhibiting cerulein induced serum amylase, myeloperoxidase activity (MPO) and histological changes in pancreas and lung. Furthermore, the anti-inflammatory effect of DADS was associated with the decrease in tumor necrosis factor (TNF)-α,cystathionine-γ-lyase (CSE), preprotachykinin A (PPTA), neurokinin-1-receptor (NK1R) expression and hydrogen sulfide (H2S) production in both pancreas and lung. In addition, DADS reduced caerulein-induced I-κB degradation and subsequent translocation of NF-κB in the pancreas and lung. These results show for the first time that in AP, DADS exhibits an anti-inflammatory effect by inhibiting CSE/H2S and SP/NK1R signaling and NF-кB pathway.


Assuntos
Compostos Alílicos/farmacologia , Anti-Inflamatórios/farmacologia , Dissulfetos/farmacologia , Lesão Pulmonar/tratamento farmacológico , Pancreatite/tratamento farmacológico , Compostos Alílicos/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Ceruletídeo/toxicidade , Cistationina gama-Liase/metabolismo , Modelos Animais de Doenças , Dissulfetos/uso terapêutico , Humanos , Sulfeto de Hidrogênio/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Lesão Pulmonar/imunologia , Masculino , Camundongos , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/complicações , Pancreatite/imunologia , Receptores da Neurocinina-1/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Substância P/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
14.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 64-71, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31889183

RESUMO

Previous studies have shown that during severe acute pancreatitis (SAP) attacks, hydrogen sulfide (H2S) is released in the colon. However, the roles played by H2S in regulating enteric nerves remain unclear. In this study, we examined the association between SAP-induced H2S release and loss of intestinal motility, and also explored the relevant mechanism in enteric nerve cells. A rat SAP model was constructed and enteric nerve cells were prepared. Intestinal mobility was evaluated by measuring the number of bowel movements at indicated time points and by performing intestinal propulsion tests. The production of inflammatory cytokines during a SAP attack was quantified by ELISA, and the levels of cystathionine-γ-lyase (CSE) and cystathionine-ß-synthase (CBS) were examined by immunohistochemistry and western blot analysis. In vivo studies showed that PI3K/Akt/Sp1 signaling in enteric nerve cells was blocked, confirming the mechanism of endogenous H2S formation by western blot analysis and immunofluorescence. Our results also showed that rats with SAP symptoms had reduced intestinal motility. Furthermore, PI3K/Akt/Sp1 signaling was triggered and CSE expression was up-regulated, and these changes were associated with H2S formation in the colon. In addition, propargylglycine reduced the levels of inflammatory cytokines and suppressed the release of H2S. Enteric nerve cells that were incubated with LY294002 and transfected with a Sp1-knockdown vector displayed decreased levels of CSE production, which led to a decrease in H2S production. These results suggest that SAP symptoms suppressed the intestinal motility of rats via the release of H2S in enteric nerve cells, which was dependent on the inflammation-induced PI3K/Akt/Sp1 signaling pathway.


Assuntos
Movimento Celular , Sistema Nervoso Entérico/patologia , Sulfeto de Hidrogênio/metabolismo , Neurônios/metabolismo , Pancreatite/metabolismo , Animais , Cromonas/farmacologia , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Citocinas/metabolismo , Motilidade Gastrointestinal , Técnicas de Silenciamento de Genes , Inflamação/metabolismo , Masculino , Morfolinas/farmacologia , Pancreatite/induzido quimicamente , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Ácido Taurocólico/efeitos adversos , Ácido Taurocólico/farmacologia , Transfecção
15.
Planta ; 251(2): 42, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907619

RESUMO

Main conclusion: Jasmonic acid (JA) negatively regulates stomatal development by promoting LCD expression and hydrogen sulfide (H2S) biosynthesis. H2S inhibits the initiation of stomata formation and acts upstream of SPEECHLESS. Abstract: Stomatal development is strictly regulated by endogenous signals and environmental cues. We recently revealed that jasmonic acid (JA) negatively regulates stomatal development in Arabidopsis thaliana cotyledons (Han et al., Plant Physiol 176:2871-2885, 2018), but the underlying molecular mechanism remains largely unknown. Here, we uncovered a role for H2S in regulating stomatal development. The H2S scavenger hypotaurine reversed the JA-induced repression of stomatal development in the epidermis of wild-type Arabidopsis. The H2S-deficient mutant lcd displayed increased stomatal density and stomatal index values, which were rescued by treatment with sodium hydrosulfide (NaHS; an H2S donor) but not JA, suggesting that JA-mediated repression of stomatal development is dependent on H2S biosynthesis. The high stomatal density of JA-deficient mutants was rescued by exogenous NaHS treatment. Further analysis indicated that JA positively regulates LCD expression, L-cysteine desulfhydrases (L-CDes) activity, and endogenous H2S content. Furthermore, H2S represses the expression of stomate-associated genes and functions downstream of stomate-related signaling pathway components TOO MANY MOUTHS (TMM) and STOMATAL DENSITY AND DISTRIBUTION1 (SDD1) and upstream of SPEECHLESS (SPCH). Therefore, H2S acts downstream of JA signaling to regulate stomatal development in Arabidopsis cotyledons.


Assuntos
Arabidopsis/efeitos dos fármacos , Arabidopsis/metabolismo , Ciclopentanos/farmacologia , Sulfeto de Hidrogênio/farmacologia , Oxilipinas/farmacologia , Estômatos de Plantas/efeitos dos fármacos , Estômatos de Plantas/metabolismo , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/genética
16.
Biochem Biophys Res Commun ; 521(3): 786-790, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31706571

RESUMO

Hydrogen sulfide (H2S) is a novel adipokine mediating glucose uptake, lipid storage and mobilization, thus contributing to the genesis of obesity and associated diseases. Our previous work demonstrated that H2S inhibited isoproterenol-stimulated lipolysis by reducing the phosphorylation of perilipin 1 (plin-1), a lipid-droplet protein blocking lipase access. How H2S modulates plin-1 phosphorylation is still unclear. Our present study found that an H2S donor slightly increased adipose tissue weight and reduced lipolysis in mice; by contrast, deleting the key H2S generation enzyme cystathionine gamma lyase (CSE) in adipocytes lowered adipose accumulation and enhanced lipolysis. Intriguingly, an H2S donor induced sulfhydration of plin-1 but not hormone-sensitive lipase, and CSE deletion abolished the post-translational modification of plin-1. During isoproterenol-stimulated lipolysis, plin-1 sulfhydration was associated with reduced phosphorylation, and removing sulfhydration by dithiothreitol recovered the phosphorylation. Finally, plin-1 knockout abolished the effect of H2S on lipolysis, which indicates that plin-1 sulfhydration is a major direct target of H2S in lipolysis. We have identified a new post-translation modification, sulfhydration (direct action by H2S) of plin-1, causing reduced phosphorylation then decreased lipolysis. This finding also highlights a novel molecular regulatory mechanism of lipolysis.


Assuntos
Adipócitos/metabolismo , Cistationina gama-Liase/metabolismo , Sulfeto de Hidrogênio/metabolismo , Lipólise , Perilipina-1/metabolismo , Animais , Células Cultivadas , Masculino , Camundongos Endogâmicos C57BL , Fosforilação , Processamento de Proteína Pós-Traducional , Ratos Sprague-Dawley
17.
Redox Biol ; 28: 101379, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31759247

RESUMO

Cystathionine γ lyase (CSE) is the major source of hydrogen sulfide-derived species (H2Sn) in endothelial cells and plays an important role in protecting against atherosclerosis. Here we investigated the molecular mechanisms underlying the regulation of CSE expression in endothelial cells by fluid shear stress/flow. Fluid shear stress decreased CSE expression in human and murine endothelial cells and was negatively correlated with the transcription factor Krüppel-like factor (KLF) 2. CSE was identified as a direct target of the KLF2-regulated microRNA, miR-27b and high expression of CSE in native human plaque-derived endothelial cells, was also inversely correlated with KLF2 and miR-27b levels. One consequence of decreased CSE expression was the loss of Prx6 sulfhydration (on Cys47), which resulted in Prx6 hyperoxidation, decamerization and inhibition, as well as a concomitant increase in endothelial cell reactive oxygen species and lipid membrane peroxidation. H2Sn supplementation in vitro was able to reverse the redox state of Prx6. Statin therapy, which is known to activate KLF2, also decreased CSE expression but increased CSE activity by preventing its phosphorylation on Ser377. As a result, the sulfhydration of Prx6 was partially restored in samples from plaque containing arteries from statin-treated donors. Taken together, the regulation of CSE expression by shear stress/disturbed flow is dependent on KLF2 and miR-27b. Moreover, in murine and human arteries CSE acts to maintain endothelial redox balance at least partly by targeting Prx6 to prevent its decamerization and inhibition of its peroxidase activity.


Assuntos
Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Peroxidação de Lipídeos , Placa Aterosclerótica/metabolismo , Animais , Células Endoteliais , Regulação da Expressão Gênica , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Sulfeto de Hidrogênio/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Camundongos , MicroRNAs/genética , Oxirredução , Peroxirredoxina VI/metabolismo , Estresse Mecânico
18.
Oxid Med Cell Longev ; 2019: 7629673, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885816

RESUMO

While the role of hyperhomocysteinemia in cardiovascular pathogenesis continuously draws attention, deficiency of hydrogen sulfide (H2S) has been growingly implicated in cardiovascular diseases. Generation of H2S is closely associated with the metabolism of homocysteine via key enzymes such as cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE). The level of homocysteine and H2S is regulated by each other. Metabolic switch in the activity of CBS and CSE may occur with a resultant operating preference change of these enzymes in homocysteine and H2S metabolism. This paper presented an overview regarding (1) linkage between the metabolism of homocysteine and H2S, (2) mutual regulation of homocysteine and H2S, (3) imbalance of homocysteine and H2S in cardiovascular disorders, (4) mechanisms underlying the protective effect of H2S against homocysteine-induced vascular injury, and (5) the current status of homocysteine-lowering and H2S-based therapies for cardiovascular disease. The metabolic imbalance of homocysteine and H2S renders H2S/homocysteine ratio a potentially reliable biomarker for cardiovascular disease and development of drugs or interventions targeting the interplay between homocysteine and H2S to maintain the endogenous balance of these two molecules may hold an even bigger promise for management of vascular disorders than targeting homocysteine or H2S alone.


Assuntos
Vasos Sanguíneos/patologia , Homocisteína/metabolismo , Sulfeto de Hidrogênio/metabolismo , Hiper-Homocisteinemia/metabolismo , Lesões do Sistema Vascular/metabolismo , Animais , Vasos Sanguíneos/metabolismo , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Humanos , Sulfeto de Hidrogênio/uso terapêutico , Hiper-Homocisteinemia/terapia , Transdução de Sinais , Lesões do Sistema Vascular/terapia
19.
Am J Physiol Heart Circ Physiol ; 317(5): H1157-H1165, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31625777

RESUMO

Hydrogen sulfide (H2S) dilates isolated arteries, and knockout of the H2S-synthesizing enzyme cystathionine γ-lyase (CSE) increases blood pressure. However, the contributions of endogenously produced H2S to blood flow regulation in specific vascular beds are unknown. Published studies in isolated arteries show that CSE production of H2S influences vascular tone more in small mesenteric arteries than in renal arteries or the aorta. Therefore, the goal of this study was to evaluate H2S regulation of blood pressure, vascular resistance, and regional blood flows using chronically instrumented rats. We hypothesized that during whole animal CSE inhibition, vascular resistance would increase more in the mesenteric than the renal circulation. Under anesthesia, CSE inhibition [ß-cyanoalanine (BCA), 30 mg/kg bolus + 5 mg·kg-1·min-1 for 20 min iv) rapidly increased mean arterial pressure (MAP) more than saline administration (%Δ: saline -1.4 ± 0.75 vs. BCA 7.1 ± 1.69, P < 0.05) but did not change resistance (MAP/flow) in either the mesenteric or renal circulation. In conscious rats, BCA infusion similarly increased MAP (%Δ: saline -0.8 ± 1.18 vs. BCA 8.2 ± 2.6, P < 0.05, n = 7) and significantly increased mesenteric resistance (saline 0.9 ± 3.1 vs. BCA 15.6 ± 6.5, P < 0.05, n = 12). The H2S donor Na2S (50 mg/kg) decreased blood pressure and mesenteric resistance ,but the fall in resistance was not significant. Inhibiting CSE for multiple days with dl-proparglycine (PAG, 50 mg·kg-1·min-1 iv bolus for 5 days) significantly increased vascular resistance in both mesenteric (ratio of day 1: saline 0.86 ± 0.033 vs. PAG 1.79 ± 0.38) and renal circulations (ratio of day 1: saline 1.26 ± 0.22 vs. 1.98 ± 0.14 PAG). These results support our hypothesis that CSE-derived H2S is an important regulator of blood pressure and vascular resistance in both mesenteric and renal circulations. Furthermore, inhalation anesthesia diminishes the effect of CSE inhibition on vascular tone.NEW & NOTEWORTHY These results suggest that CSE-derived H2S has a prominent role in regulating blood pressure and blood flow under physiological conditions, which may have been underestimated in prior studies in anesthetized subjects. Therefore, enhancing substrate availability or enzyme activity or dosing with H2S donors could be a novel therapeutic approach to treat cardiovascular diseases.


Assuntos
Sulfeto de Hidrogênio/metabolismo , Artérias Mesentéricas/metabolismo , Artéria Renal/metabolismo , Circulação Renal , Circulação Esplâncnica , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Pressão Arterial , Velocidade do Fluxo Sanguíneo , Cistationina gama-Liase/antagonistas & inibidores , Cistationina gama-Liase/metabolismo , Inibidores Enzimáticos/farmacologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Ratos Sprague-Dawley , Artéria Renal/efeitos dos fármacos , Circulação Renal/efeitos dos fármacos , Circulação Esplâncnica/efeitos dos fármacos , Sulfetos/farmacologia , Resistência Vascular
20.
FASEB J ; 33(12): 13098-13125, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31648556

RESUMO

Hydrogen sulfide can signal through 3 distinct mechanisms: 1) reduction and/or direct binding of metalloprotein heme centers, 2) serving as a potent antioxidant through reactive oxygen species/reactive nitrogen species scavenging, or 3) post-translational modification of proteins by addition of a thiol (-SH) group onto reactive cysteine residues: a process known as persulfidation. Below toxic levels, hydrogen sulfide promotes mitochondrial biogenesis and function, thereby conferring protection against cellular stress. For these reasons, increases in hydrogen sulfide and hydrogen sulfide-producing enzymes have been implicated in several human disease states. This review will first summarize our current understanding of hydrogen sulfide production and metabolism, as well as its signaling mechanisms; second, this work will detail the known mechanisms of hydrogen sulfide in the mitochondria and the implications of its mitochondrial-specific impacts in several pathologic conditions.-Murphy, B., Bhattacharya, R., Mukherjee, P. Hydrogen sulfide signaling in mitochondria and disease.


Assuntos
Sulfeto de Hidrogênio/metabolismo , Mitocôndrias/metabolismo , Animais , Cistationina gama-Liase/metabolismo , Doença , Humanos , Transdução de Sinais , Sulfurtransferases/metabolismo
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