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1.
Biomolecules ; 14(10)2024 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-39456167

RESUMO

Isorhamnetin (ISO) is an active flavonoid compound mainly isolated from the fruits of Hippophae rhamnoides L. and the leaves of Ginkgo biloba L. Previous studies have revealed the antifibrotic action of ISO in the liver and lungs, although its potential protective effects against renal fibrosis and the underlying mechanisms are still poorly understood. Given that many actions of ISO could be similarly attained by hydrogen sulfide (H2S), we speculated that ISO may work through the induction of endogenous H2S. To test the hypothesis, we established the unilateral ureteral obstruction (UUO) renal fibrosis rat model and transforming growth factor-ß1(TGF-ß1)-induced fibrosis in cultured renal tubular cells. ISO treatment inhibited epithelial-mesenchymal transition (EMT) formation, decreased extracellular matrix (ECM) deposition, and relieved renal fibrosis. Further analysis revealed that ISO stimulated the expression of the H2S-synthesizing enzyme cystathionine lyase (CSE) and cystathionine beta-synthase (CBS), and promoted H2S production in vivo and in vitro. The elevated H2S attenuated oxidative stress and elevated the thiol level. It induced Keap1 sulfhydration, disrupted Keap1-Nrf2 interaction, and promoted the entry of Nrf2 into the nucleus. Finally, we found that circulating H2S mainly derived from the liver, and not the kidney. Collectively, our study revealed that ISO alleviated renal fibrosis by inducing endogenous H2S and regulating Keap1-Nrf2 interaction through sulfhydration of Keap1. Endogenous H2S could be an important mediator underlying the pharmacological actions of ISO. Due to the multifunctional properties of H2S, the H2S-inducing nature of ISO could be exploited to treat various diseases.


Assuntos
Fibrose , Sulfeto de Hidrogênio , Quercetina , Animais , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Quercetina/farmacologia , Quercetina/análogos & derivados , Quercetina/química , Ratos , Fibrose/tratamento farmacológico , Masculino , Oxirredução/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Obstrução Ureteral/metabolismo , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/patologia , Compostos de Sulfidrila/metabolismo , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Nefropatias/patologia , Estresse Oxidativo/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Ratos Sprague-Dawley , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Cistationina beta-Sintase/metabolismo
2.
Nat Commun ; 15(1): 9071, 2024 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-39433776

RESUMO

Excessive oxidative response, unbalanced immunomodulation, and impaired mesenchymal stem cell function in periodontitis in diabetes makes it a great challenge to achieve integrated periodontal tissue regeneration. Here, a polyphenol-mediated redox-active algin/gelatin hydrogel encapsulating a conductive poly(3,4-ethylenedioxythiopene)-assembled polydopamine-mediated silk microfiber network and a hydrogen sulfide sustained-release system utilizing bovine serum albumin nanoparticles is developed. This hydrogel is found to reverse the hyperglycemic inflammatory microenvironment and enhance functional tissue regeneration in diabetic periodontitis. Polydopamine confers the hydrogel with anti-oxidative and anti-inflammatory activity. The slow, sustained release of hydrogen sulfide from the bovine serum albumin nanoparticles recruits mesenchymal stem cells and promotes subsequent angiogenesis and osteogenesis. Moreover, poly(3,4-ethylenedioxythiopene)-assembled polydopamine-mediated silk microfiber confers the hydrogel with good conductivity, which enables it to transmit endogenous bioelectricity, promote cell arrangement, and increase the inflow of calcium ion. In addition, the synergistic effects of hydrogen sulfide gaseous-bioelectric coupling promotes bone formation by amplifying autophagy in periodontal ligament stem cells and modulating macrophage polarization via lipid metabolism regulation. This study provides innovative insights into the synergistic effects of conductivity, reactive oxygen species scavenging, and hydrogen sulfide on the periodontium in a hyperglycemic inflammatory microenvironment, offering a strategy for the design of gaseous-bioelectric biomaterials to promote functional tissue regeneration in immune-related diseases.


Assuntos
Hidrogéis , Sulfeto de Hidrogênio , Oxirredução , Periodontite , Polifenóis , Animais , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Hidrogéis/química , Polifenóis/química , Polifenóis/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Ligamento Periodontal/citologia , Diabetes Mellitus Experimental , Osteogênese/efeitos dos fármacos , Nanopartículas/química , Regeneração Óssea/efeitos dos fármacos , Masculino , Polímeros/química , Indóis/química , Soroalbumina Bovina/química , Humanos , Ratos , Seda/química
3.
Cell Death Dis ; 15(10): 776, 2024 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-39461943

RESUMO

Insufficient cytotrophoblast (CTB) migration and invasion into the maternal myometrium leads to pregnancy related complications like Intra-uterus Growth Restriction (IUGR), and pre-eclampsia (PE). We previously found that hydrogen sulfide (H2S) enhanced CTB migration without knowing the mechanism(s) and the pathophysiological significance. By studying human samples and cell line, we found that H2S levels were lower in PE patients' plasma; H2S synthetic enzyme cystathionine ß-synthetase (CBS) was reduced in PE extravillious invasive trophoblasts. GYY4137 (H2S donor, 1 µM) promoted CBS/H2S translocation onto mitochondria, preserved mitochondria functions, enhanced cell invasion and migration. CBS knockdown hindered the above functions which were rescued by GYY4137, indicating the vital roles of CBS/H2S signal. Disturbance of mitochondria dynamics inhibited cell invasion and migration. The 185 and 504 cysteines of Mitochondrial Rho GTPase 2 (Miro2C185/C504) were highly sulfhydrated by H2S. Knockdown Miro2 or double mutation of Miro2C185/C504 to serine fragmented mitochondria, and inhibited cell invasion and migration which can't be rescued by H2S. The present study showed that human cytotrophoblast receives low dose H2S regulation; CBS/H2S sustained mitochondria functions via Miro2C185/C504 sulfhydration to enhance cytotrophoblast mobility. These findings established a new regulatory pathway for cytotrophoblast functions, and provided new targets for IUGR and PE.


Assuntos
Movimento Celular , Cistationina beta-Sintase , Sulfeto de Hidrogênio , Mitocôndrias , Dinâmica Mitocondrial , Compostos Organotiofosforados , Pré-Eclâmpsia , Trofoblastos , Proteínas rho de Ligação ao GTP , Humanos , Trofoblastos/metabolismo , Trofoblastos/patologia , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Feminino , Gravidez , Cistationina beta-Sintase/metabolismo , Cistationina beta-Sintase/genética , Mitocôndrias/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/genética , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/genética , Compostos Organotiofosforados/farmacologia , Morfolinas/farmacologia , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Transdução de Sinais , Adulto
4.
Int J Mol Sci ; 25(19)2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-39409062

RESUMO

Hydrogen sulfide (H2S), as a key gas signaling molecule, plays an important role in regulating various diseases, with appropriate concentrations providing antioxidative, anti-inflammatory, and anti-apoptotic effects. The specific role of H2S in acute hypoxic injury remains to be clarified. This study focuses on the H2S donor sodium hydrosulfide (NaHS) and explores its protective effects and mechanisms against acute hypoxic lung injury. First, various mouse hypoxia models were established to evaluate H2S's protection in hypoxia tolerance. Next, a rat model of acute lung injury (ALI) induced by hypoxia at 6500 m above sea level for 72 h was created to assess H2S's protective effects and mechanisms. Evaluation metrics included blood gas analysis, blood routine indicators, lung water content, and lung tissue pathology. Additionally, LC-MS/MS and bioinformatic analyses were combined in performing quantitative proteomics on lung tissues from the normoxic control group, the hypoxia model group, and the hypoxia model group with NaHS treatment to preliminarily explore the protective mechanisms of H2S. Further, enzyme-linked immunosorbent assays (ELISA) were used to measure oxidative stress markers and inflammatory factors in rat lung tissues. Lastly, Western blot analysis was performed to detect Nrf2, HO-1, P-NF-κB, NF-κB, HIF-1α, Bcl-2, and Bax proteins in lung tissues. Results showed that H2S exhibited significant anti-hypoxic effects in various hypoxia models, effectively modulating blood gas and blood routine indicators in ALI rats, reducing pulmonary edema, improving lung tissue pathology, and alleviating oxidative stress, inflammatory responses, and apoptosis levels.


Assuntos
Lesão Pulmonar Aguda , Estresse Oxidativo , Sulfetos , Animais , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/prevenção & controle , Sulfetos/farmacologia , Ratos , Estresse Oxidativo/efeitos dos fármacos , Masculino , Camundongos , Hipóxia/metabolismo , Hipóxia/tratamento farmacológico , Ratos Sprague-Dawley , Modelos Animais de Doenças , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia
5.
Int J Mol Sci ; 25(17)2024 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-39273196

RESUMO

Myocardial ischaemia reperfusion injury (IRI) occurring from acute coronary artery disease or cardiac surgical interventions such as bypass surgery can result in myocardial dysfunction, presenting as, myocardial "stunning", arrhythmias, infarction, and adverse cardiac remodelling, and may lead to both a systemic and a localised inflammatory response. This localised cardiac inflammatory response is regulated through the nucleotide-binding oligomerisation domain (NACHT), leucine-rich repeat (LRR)-containing protein family pyrin domain (PYD)-3 (NLRP3) inflammasome, a multimeric structure whose components are present within both cardiomyocytes and in cardiac fibroblasts. The NLRP3 inflammasome is activated via numerous danger signals produced by IRI and is central to the resultant innate immune response. Inhibition of this inherent inflammatory response has been shown to protect the myocardium and stop the occurrence of the systemic inflammatory response syndrome following the re-establishment of cardiac circulation. Therapies to prevent NLRP3 inflammasome formation in the clinic are currently lacking, and therefore, new pharmacotherapies are required. This review will highlight the role of the NLRP3 inflammasome within the myocardium during IRI and will examine the therapeutic value of inflammasome inhibition with particular attention to carbon monoxide, nitric oxide, and hydrogen sulphide as potential pharmacological inhibitors of NLRP3 inflammasome activation.


Assuntos
Monóxido de Carbono , Sulfeto de Hidrogênio , Inflamassomos , Infarto do Miocárdio , Proteína 3 que Contém Domínio de Pirina da Família NLR , Óxido Nítrico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Humanos , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Inflamassomos/metabolismo , Óxido Nítrico/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Animais , Monóxido de Carbono/metabolismo , Gasotransmissores/metabolismo , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/patologia
6.
Nat Commun ; 15(1): 8086, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39278958

RESUMO

We previously reported that normothermic ex vivo kidney  perfusion (NEVKP) is superior in terms of organ protection compared to static cold storage (SCS), which is still the standard method of organ preservation, but the mechanisms are incompletely understood. We used a large animal kidney autotransplant model to evaluate mitochondrial function during organ preservation and after kidney transplantation, utilizing live cells extracted from fresh kidney tissue. Male porcine kidneys stored under normothermic perfusion showed preserved mitochondrial function and higher ATP levels compared to kidneys stored at 4 °C (SCS). Mitochondrial respiration and ATP levels were further enhanced when AP39, a mitochondria-targeted hydrogen sulfide donor, was administered during warm perfusion. Correspondingly, the combination of NEVKP and AP39 was associated with decreased oxidative stress and inflammation, and with improved graft function after transplantation. In conclusion, our findings suggest that the organ-protective effects of normothermic perfusion are mediated by maintenance of mitochondrial function and enhanced by AP39 administration. Activation of mitochondrial function through the combination of AP39 and normothermic perfusion could represent a new therapeutic strategy for long-term renal preservation.


Assuntos
Transplante de Rim , Rim , Mitocôndrias , Preservação de Órgãos , Perfusão , Isquemia Quente , Animais , Mitocôndrias/metabolismo , Rim/metabolismo , Preservação de Órgãos/métodos , Masculino , Suínos , Perfusão/métodos , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Trifosfato de Adenosina/metabolismo , Estresse Oxidativo , Compostos Organofosforados , Tionas
7.
J Alzheimers Dis ; 101(3): 913-921, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39302367

RESUMO

Background: Impairment of synaptic plasticity along with the formation of amyloid-ß (Aß) plaques and tau-protein neurofibrillary tangles have been associated with Alzheimer's disease (AD). Earlier studies with rat and mouse hippocampal slices have revealed the association of AD with the absence of synthesis of memory related proteins leading to impairment in cognitive functions. The role of hydrogen sulfide (H2S), a gaseous neurotransmitter, has been gaining attention as a neuroprotective agent. However, its role in AD-like conditions has not been studied so far. Objective: To study the neuroprotective role of H2S in AD conditions using rat hippocampal slices and the organic molecule GYY4137, a slow releasing H2S donor. Methods: Electrophysiological recordings were carried out in rat hippocampal slices to look into the impairment of LTP, a cellular correlate of memory. The Aß42 peptide was bath-applied to mimic AD-like conditions and checked for both late-LTP and synaptic tagging and capture (STC) mechanisms of the synapses. GYY4137 was applied to look into its neuroprotective role at different stages during the recording of fEPSP. Results: There has been a steady decline in the plasticity properties of the synapses, in the form of late-LTP and STC, after the application of Aß42 peptide in the hippocampal slices. However, application of GYY4137 rescued these conditions in vitro. Conclusions: GYY4137, with its slow release of H2S, could possibly act as a therapeutic agent in cognitive dysfunctions of the brain, mainly AD.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Região CA1 Hipocampal , Sulfeto de Hidrogênio , Morfolinas , Compostos Organotiofosforados , Fragmentos de Peptídeos , Animais , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Masculino , Ratos , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/metabolismo , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Modelos Animais de Doenças , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos Wistar , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Fármacos Neuroprotetores/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia
8.
Front Endocrinol (Lausanne) ; 15: 1427069, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39324123

RESUMO

Hydrogen sulfide (H2S) is an endogenously produced signaling molecule that belongs to the group of gasotransmitters along with nitric oxide (NO) and carbon monoxide (CO). H2S plays a pivotal role in male reproductive processes. It is produced in various tissues and cells of the male reproductive system, including testicular tissue, Leydig and Sertoli cells, epididymis, seminal plasma, prostate, penile tissues, and sperm cells. This review aims to summarize the knowledge about the presence and effects of H2S in male reproductive tissues and outline possible therapeutic strategies in pathological conditions related to male fertility, e. g. spermatogenetic disorders and erectile dysfunction (ED). For instance, H2S supports spermatogenesis by maintaining the integrity of the blood-testicular barrier (BTB), stimulating testosterone production, and providing cytoprotective effects. In spermatozoa, H2S modulates sperm motility, promotes sperm maturation, capacitation, and acrosome reaction, and has significant cytoprotective effects. Given its vasorelaxant effects, it supports the erection of penile tissue. These findings suggest the importance and therapeutic potential of H2S in male reproduction, paving the way for further research and potential clinical applications.


Assuntos
Sulfeto de Hidrogênio , Reprodução , Espermatogênese , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Masculino , Humanos , Animais , Reprodução/efeitos dos fármacos , Reprodução/fisiologia , Espermatogênese/efeitos dos fármacos , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/metabolismo , Genitália Masculina/metabolismo , Genitália Masculina/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Infertilidade Masculina/metabolismo , Infertilidade Masculina/tratamento farmacológico , Testículo/metabolismo , Testículo/efeitos dos fármacos
9.
Int J Mol Sci ; 25(18)2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39337494

RESUMO

This study proposes a novel therapeutic strategy for cancer management by combining the antitumor effects of hydrogen sulfide (H2S) and inhibition of carbonic anhydrases (CAs; EC 4.2.1.1), specifically isoforms IV, IX, and XII. H2S has demonstrated cytotoxicity against various cancers at high concentrations. The inhibition of tumor-associated CAs leads to lethal intracellular alkalinization and acidification of the extracellular tumor microenvironment and restores tumor responsiveness to the immune system, chemotherapy, and radiotherapy. The study proposes H2S donor-CA inhibitor (CAI) hybrids for tumor management. These compounds effectively inhibit the target CAs, release H2S consistently, and exhibit potent antitumor effects against MDA-MB-231, HCT-116, and A549 cancer cell lines. Notably, some compounds display high cytotoxicity across all investigated cell lines. Derivative 30 shows a 2-fold increase in cytotoxicity (0.93 ± 0.02 µM) under chemically induced hypoxia in HCT-116 cells. These compounds also disturb the cell cycle, leading to a reduction in cell populations in G0/G1 and S phases, with a notable increase in G2/M and Sub-G1. This disruption is correlated with induced apoptosis, with fold increases of 37.2, 24.5, and 32.9 against HCT-116 cells and 14.2, 13.1, and 19.9 against A549 cells compared to untreated cells. These findings suggest the potential of H2S releaser-CAI hybrids as effective and versatile tools in cancer treatment.


Assuntos
Apoptose , Inibidores da Anidrase Carbônica , Proliferação de Células , Sulfeto de Hidrogênio , Humanos , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/química , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Anidrases Carbônicas/metabolismo , Ciclo Celular/efeitos dos fármacos , Células HCT116 , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismo , Células A549
10.
Commun Biol ; 7(1): 1160, 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39289465

RESUMO

Hydrogen sulfide (H2S), mainly produced from L-cysteine (Cys), renders bacteria highly resistant to oxidative stress and potentially increases antimicrobial resistance (AMR). CyuR is a Cys-dependent transcription regulator, responsible for the activation of the cyuPA operon and generation of H2S. Despite its potential importance, its regulatory network remains poorly understood. In this study, we investigate the roles of the CyuR regulon in a Cys-dependent AMR mechanism in E. coli strains. We show: (1) Generation of H2S from Cys affects the sensitivities to growth inhibitors; (2) Cys supplementation decreases stress responses; (3) CyuR negatively controls the expression of mdlAB encoding a potential transporter for antibiotics; (4) CyuR binds to a DNA sequence motif 'GAAwAAATTGTxGxxATTTsyCC' in the absence of Cys; and (5) CyuR may regulate 25 additional genes which were not reported previously. Collectively, our findings expand the understanding of the biological roles of CyuR relevant to antibiotic resistance associated with Cys.


Assuntos
Cisteína , Farmacorresistência Bacteriana , Proteínas de Escherichia coli , Escherichia coli , Regulação Bacteriana da Expressão Gênica , Cisteína/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Escherichia coli/efeitos dos fármacos , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Farmacorresistência Bacteriana/genética , Antibacterianos/farmacologia , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Óperon , Regulon
11.
Biophys Chem ; 314: 107317, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39236424

RESUMO

Hydrogen sulfide (H2S) has emerged as a significant signaling molecule involved in various physiological processes, including vasodilation, neurotransmission, and cytoprotection. Its interactions with biomolecules are critical to understand its roles in health and disease. Recent advances in biophysical characterization techniques have shed light on the complex interactions of H2S with proteins, nucleic acids, and lipids. Proteins are primary targets for H2S, which can modify cysteine residues through S-sulfhydration, impacting protein function and signaling pathways. Advanced spectroscopic techniques, such as mass spectrometry and NMR, have enabled the identification of specific sulfhydrated sites and provided insights into the structural and functional consequences of these modifications. Nucleic acids also interact with H2S, although this area is less explored compared to proteins. Recent studies have demonstrated that H2S can induce modifications in nucleic acids, affecting gene expression and stability. Techniques like gel electrophoresis and fluorescence spectroscopy have been utilized to investigate these interactions, revealing that H2S can protect DNA from oxidative damage and modulate RNA stability and function. Lipids, being integral components of cell membranes, interact with H2S, influencing membrane fluidity and signaling. Biophysical techniques such as electron paramagnetic resonance (EPR) and fluorescence microscopy have elucidated the effects of H2S on lipid membranes. These studies have shown that H2S can alter lipid packing and dynamics, which may impact membrane-associated signaling pathways and cellular responses to stress. In the current work we have integrated this with key scientific explainations to provide a comprehensive review.


Assuntos
Sulfeto de Hidrogênio , Transdução de Sinais , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/farmacologia , Humanos , Animais , Proteínas/química , Proteínas/metabolismo , Ácidos Nucleicos/química , Ácidos Nucleicos/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica
12.
J Med Chem ; 67(19): 17657-17675, 2024 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-39268676

RESUMO

Activating SIRT1 or promoting SIRT1 expression are both protective against myocardial ischemia. Combining these approaches would be an effective strategy for treating ischemic heart disease. Herein, we identified lead compounds with SIRT1 activation activity through screening the natural product library, and five series of H2S donating derivatives were designed and synthesized. Among them, compound 17 exerted an effective cardioprotective effect in vitro and in vivo. The addition of H2S scavenger attenuated the protective activity, emphasizing the critical involvement of H2S in the myocardial ischemia process. Interestingly, 17 exhibited stronger direct SIRT1 activative ability and induced higher SIRT1 expression capability compared to the lead. Furthermore, 17 attenuates oxidative stress-induced cardiomyocytes apoptosis by activating the SIRT1-PGC1α signaling pathway. Our study validated the promising potential of activating SIRT1 and promoting SIRT1 expression through H2S to improve cardiomyocytes function, providing novel insights into the protective mechanisms during the progression of ischemic heart disease.


Assuntos
Sulfeto de Hidrogênio , Isquemia Miocárdica , Miócitos Cardíacos , Sirtuína 1 , Sirtuína 1/metabolismo , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/química , Animais , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Apoptose/efeitos dos fármacos , Masculino , Camundongos , Humanos , Estresse Oxidativo/efeitos dos fármacos , Cardiotônicos/farmacologia , Cardiotônicos/síntese química , Cardiotônicos/química , Camundongos Endogâmicos C57BL , Relação Estrutura-Atividade , Ratos , Transdução de Sinais/efeitos dos fármacos , Descoberta de Drogas
13.
New Phytol ; 244(4): 1377-1390, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39279035

RESUMO

Hydrogen sulfide (H2S) is an endogenous gaseous signaling molecule, which has been shown to play an important role in plant growth and development by coupling with various phytohormones. However, the relationship between H2S and cytokinin (CTK) and the mechanisms by which H2S and CTK affect root growth remain poorly understood. Endogenous CTK was analyzed by UHPLC-ESI-MS/MS. Persulfidation of cytokinin oxidase/dehydrogenases (CKXs) was analyzed by mass spectrometry (MS). ckx2/CKX2wild-type (WT), OE CKX2 and ckx2/CKX2Cys(C)62alanine(A) transgenic lines were isolated with the ckx2 background. H2S is linked to CTK content by CKX2, which regulates root system architecture (RSA). Persulfidation at cysteine (Cys)62 residue of CKX2 enhances CKX2 activity, resulting in reduced CTK content. We utilized 35S-LCD/oasa1 transgenic lines to investigate the effect of endogenous H2S on RSA, indicating that H2S reduces the gravitropic set-point angle (GSA), shortens root hairs, and increases the number of lateral roots (LRs). The persulfidation of CKX2Cys62 changes the elongation of cells on the upper and lower flanks of LR elongation zone, confirming that Cys62 of CKX2 is the specificity target of H2S to regulate RSA in vivo. In conclusion, this study demonstrated that H2S negatively regulates CTK content and affects RSA by persulfidation of CKX2Cys62 in Arabidopsis thaliana.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Citocininas , Sulfeto de Hidrogênio , Raízes de Plantas , Arabidopsis/genética , Arabidopsis/metabolismo , Arabidopsis/crescimento & desenvolvimento , Citocininas/metabolismo , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Raízes de Plantas/metabolismo , Raízes de Plantas/crescimento & desenvolvimento , Plantas Geneticamente Modificadas , Oxirredutases/metabolismo , Oxirredutases/genética , Regulação da Expressão Gênica de Plantas
14.
Nitric Oxide ; 152: 11-18, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39271041

RESUMO

To investigate the protective mechanisms of hydrogen sulfide (H2S) in sepsis-induced acute kidney injury (SAKI), we conducted an in vivo study using a SAKI mouse model induced by intraperitoneal lipopolysaccharide (LPS) injection. Following 6 h of LPS injection, levels of tumor necrosis factor-alpha (TNF-α) and blood urea nitrogen (Bun) were significantly elevated in mouse plasma. In the kidneys of SAKI mice, expression of H2S-generating enzymes cysteinyl-tRNA synthetase (CARS), cystathionine γ-lyase (CSE) and cystathionine ß-synthase (CBS) was markedly downregulated, while glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF6), phosphorylated protein kinase R-like endoplasmic reticulum kinase/protein kinase R-like endoplasmic reticulum kinase (p-PERK/PERK), and B-cell lymphoma-2 recombinant protein X/B-cell lymphoma-2 (Bax/Bcl2) expression was significantly upregulated. H2S improved renal function and attenuated renal histopathological changes in SAKI mice, thereby alleviating LPS-induced endoplasmic reticulum stress (ERS). Additionally, it inhibited the expression of p-PERK/PERK and Bax/Bcl2. After inhibiting CSE activity with dl-propargylglycine (PPG i. p.), the renal tissue pathology in LPS-induced AKI mice was further exacerbated, leading to enhanced activation of the PERK/Bax-Bcl2 pathway. Our findings suggest that endogenous H2S influences the pathogenesis of SAKI, while exogenous H2S protects against LPS-induced AKI by inhibiting the PERK/Bax-Bcl2 pathway involved in ERS.


Assuntos
Injúria Renal Aguda , Chaperona BiP do Retículo Endoplasmático , Sulfeto de Hidrogênio , Lipopolissacarídeos , Proteínas Proto-Oncogênicas c-bcl-2 , Sepse , Proteína X Associada a bcl-2 , eIF-2 Quinase , Animais , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/tratamento farmacológico , Sepse/complicações , Sepse/metabolismo , Sepse/tratamento farmacológico , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo , eIF-2 Quinase/metabolismo , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Rim/metabolismo , Rim/patologia
15.
Nitric Oxide ; 152: 78-89, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39305980

RESUMO

BACKGROUND: Under normal circumstances, high-density lipoprotein (HDL) is considered to have cardiovascular protective effects, but the impact of oxidized HDL (ox-HDL) on vascular endothelial function remains poorly understood. Mitochondrial function is closely related to endothelial function, and hydrogen sulfide (H2S) is a gas with endothelial protective properties. The novel hydrogen sulfide donor AP39 can target mitochondria to release H2S, but the combined effects of ox-HDL and AP39 on vascular endothelium are not well studied. METHODS: We established a cell model of ox-HDL-induced endothelial cell damage and mitochondrial dysfunction using human umbilical vein endothelial cells (HUVECs) and conducted AP39 pretreatment. The experiments confirmed the functional damage and mitochondrial dysfunction in HUVECs caused by ox-HDL. Additionally, to further explore the role of SIRT1 in AS, we analyzed SIRT1 expression in AS carotid artery tissue. This included the analysis of differentially expressed genes from AS-related datasets, presented through volcano plots and heatmaps, with enrichment analysis of downregulated genes in KEGG pathways and GO functions. Furthermore, we evaluated the differences in SIRT1 expression in coronary arteries with varying degrees of stenosis and in early and late-stage AS carotid artery tissues, and analyzed data from SIRT1 knockout mouse models. RESULTS: The experimental results indicate that AP39 effectively alleviated ox-HDL-induced endothelial cell damage and mitochondrial dysfunction by upregulating SIRT1 expression. MTT and CCK-8 assays showed that ox-HDL treatment led to decreased cell viability and proliferation in HUVECs, reduced eNOS expression, and significantly increased levels of ICAM-1, IL-6, and TNF-α, along with enhanced monocyte adhesion. These findings reveal the damaging effects of ox-HDL on HUVECs. Transcriptomic data indicated that while SIRT1 expression did not significantly differ in coronary arteries with varying degrees of stenosis, it was notably downregulated in AS carotid artery tissues, especially in late-stage AS tissues. KEGG pathway enrichment analysis revealed that SIRT1 downregulated genes were associated with processes such as vascular smooth muscle contraction, while GO analysis showed that these downregulated genes were involved in muscle system processes and muscle contraction functions, further confirming SIRT1's critical role in AS pathology. In transcriptomic data from the SIRT1 knockout mouse model, elevated levels of inflammation-related proteins IL-6 and TNF-α were observed after SIRT1 knockout, along with decreased expression of the chaperone protein PGC-1α. The expression of mitochondrial-related functional proteins Nrf2 and PGC-1α was positively correlated with SIRT1 expression, while inflammation-related proteins ICAM-1, IL-6, IL-20, and TNF-α were negatively correlated with SIRT1 expression. We further discovered that ox-HDL triggered mitochondrial dysfunction, as evidenced by reduced expression of Mfn2, Nrf2, PGC1-α, UCP-1, and SIRT1, corroborating the results from the previous database analysis. Additionally, mitochondrial dysfunction was characterized by decreased mitochondrial membrane potential (MMP), increased mitochondrial ROS levels, and reduced ATP content, further impacting cellular energy metabolism and respiratory function. Subsequent experimental results showed that the addition of AP39 mitigated these adverse effects, as evidenced by decreased levels of ICAM-1, IL-6, and TNF-α, increased eNOS expression, reduced monocyte adhesion, increased mitochondrial H2S content, and upregulated expression of SIRT1 protein associated with mitochondrial function, reduced ROS levels, and increased ATP content. Furthermore, validation experiments using the SIRT1 inhibitor EX527 confirmed that AP39 alleviated ox-HDL-induced endothelial cell damage and mitochondrial dysfunction by upregulating SIRT1 expression. CONCLUSION: Ox-HDL can induce damage and mitochondrial dysfunction in HUVECs, while AP39 inhibits ox-HDL-induced endothelial cell damage and mitochondrial dysfunction by upregulating SIRT1.


Assuntos
Células Endoteliais da Veia Umbilical Humana , Sulfeto de Hidrogênio , Lipoproteínas HDL , Mitocôndrias , Sirtuína 1 , Regulação para Cima , Animais , Humanos , Camundongos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Lipoproteínas HDL/metabolismo , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Sirtuína 1/metabolismo , Sirtuína 1/genética , Tionas , Regulação para Cima/efeitos dos fármacos
16.
Folia Med Cracov ; 64(1): 39-52, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-39254580

RESUMO

BACKGROUND: Kidney diseases are a major global health problem affecting millions of people. Despite this, there is as yet no effective drug therapy improving outcome in patients with renal disease. The aim of this study was to examine the nephroprotective effect of α-lipoic acid (ALA) in vitro and to examine the effect of ALA administered in vivo on the production of reactive sulfur species (RSS), including hydrogen sulfide (H2S) and compounds containing sulfane sulfur. METHODS: The effect of ALA was studied in vitro by determining the viability of human embryonic kidney cells (HEK293) in normoxic and hypoxic conditions as well as in vivo in two groups of chronic kidney disease (CKD) patients: non-dialyzed (ND) and undergoing continuous ambulatory peritoneal dialysis (PD) after 30 days of ALA supplementation. RESULTS: The results revealed that the viability of HEK293 cells was significantly decreased by hypoxic conditions, while ALA administered during hypoxia increased the viability to the level observed in normoxic conditions. Studies performed in plasma of CKD patients after ALA supplementation suggested that ALA did not affect the parameters of oxidative stress, while significantly increased the level of reactive sulfane sulfur in both ND and PD patients suffering from CKD. The results suggest that ALA can exert nephroprotective effects which are related to sulfane sulfur production.


Assuntos
Insuficiência Renal Crônica , Ácido Tióctico , Humanos , Ácido Tióctico/farmacologia , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Células HEK293 , Masculino , Feminino , Sobrevivência Celular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pessoa de Meia-Idade , Antioxidantes/farmacologia , Sulfeto de Hidrogênio/farmacologia
17.
Eur J Pharmacol ; 982: 176900, 2024 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-39168432

RESUMO

Atrial fibrosis is associated with the occurrence of atrial fibrillation (AF) and regulated by the transforming growth factor-ß1 (TGF-ß1)/Smad2/3 signalling pathway. Unfortunately, the mechanisms of regulation of TGF-ß1/Smad2/3-induced atrial fibrosis and vulnerability to AF remain still unknown. Previous studies have shown that sirtuin3 (SIRT3) sulfhydration has strong anti-fibrotic effects. We hypothesised that SIRT3 sulfhydration inhibits angiotensin II (Ang-II)-induced atrial fibrosis via blocking the TGF-ß1/Smad2/3 signalling pathway. In this study, we found that SIRT3 expression was decreased in the left atrium of patients with AF compared to that in those with sinus rhythm (SR). In vitro, SIRT3 knockdown by small interfering RNA significantly expanded Ang-II-induced atrial fibrosis and TGF-ß1/Smad2/3 signalling pathway activation, whereas supplementation with Sodium Hydrosulfide (NaHS, exogenous hydrogen sulfide donor and sulfhydration agonist) and SIRT3 overexpression using adenovirus ameliorated Ang-II-induced atrial fibrosis. Moreover, we observed suppression of the TGF-ß1/Smad2/3 pathway when Ang-II was combined with NaHS treatment, and the effect of this co-treatment was consistent with that of Ang-II combined with LY3200882 (Smad pathway inhibitor) on reducing atrial fibroblast proliferation and cell migration in vitro. Supplementation with dithiothreitol (DTT, a sulfhydration inhibitor) and adenovirus SIRT3 shRNA blocked the ameliorating effect of NaHS and AngII co-treatment on atrial fibrosis in vitro. Finally, continued treatment with NaHS in rats ameliorated atrial fibrosis and remodelling, and further improved AF vulnerability induced by Ang-II, which was reversed by DTT and adenovirus SIRT3 shRNA, suggesting that SIRT3 sulfhydration might be a potential therapeutic target in atrial fibrosis and AF.


Assuntos
Angiotensina II , Fibrilação Atrial , Fibrose , Átrios do Coração , Sulfeto de Hidrogênio , Transdução de Sinais , Sirtuína 3 , Proteína Smad2 , Proteína Smad3 , Fator de Crescimento Transformador beta1 , Idoso , Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Angiotensina II/farmacologia , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Fibrilação Atrial/prevenção & controle , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sirtuína 3/metabolismo , Sirtuína 3/genética , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
18.
Biomed Pharmacother ; 179: 117290, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39153433

RESUMO

Hydrogen sulfide (H2S) is a gaseous signaling molecule that influences digestive and nervous system functions. Enteric glial cells (EGCs) are integral to the enteric nervous system and play a role in regulating gastrointestinal motility. This study explored the dual effects of exogenous H2S on EGCs and the influence of apoptosis-related pathways and ion channels in EGCs. We also administered honokiol for further interventional studies. The results revealed that low-concentration H2S increased the mitochondrial membrane potential (MMP) of EGCs, decreased the whole-cell membrane potential, downregulated BAX and caspase-3, upregulated Bcl2 expression, reduced apoptosis, and promoted cell proliferation. The Ca2+ concentration, Cx43 mRNA, and protein expression were also increased. A high concentration of H2S had the opposite effect. In addition, GFAP mRNA expression was upregulated in the test-low group, downregulated in the test-high group, and upregulated in the test-high + Hon group. Honokiol treatment increased MMP, reduced whole-cell membrane potential, inhibited BAX and caspase-3 expression, increased Bcl2 expression, decreased cell apoptosis, and increased cell proliferation. The Ca2+ concentration, Cx43 mRNA, and protein expression were also upregulated. In conclusion, our study showed that exogenous H2S can bidirectionally regulate EGC proliferation and apoptosis by affecting MMP and cell membrane potential via the Bcl2/BAX/caspase-3 pathway and modulate Cx43-mediated Ca2+ responses in EGCs to regulate colonic motility bidirectionally. Honokiol can ameliorate the damage to EGCs induced by high H2S concentrations through the Bcl2/BAX/caspase-3 pathway and improve colon motility by increasing Cx43 expression and Ca2+ concentration.


Assuntos
Apoptose , Compostos de Bifenilo , Sinalização do Cálcio , Proliferação de Células , Conexina 43 , Sulfeto de Hidrogênio , Lignanas , Neuroglia , Ratos Sprague-Dawley , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Lignanas/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Ratos , Conexina 43/metabolismo , Conexina 43/genética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Cálcio/metabolismo , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/metabolismo , Células Cultivadas , Compostos Alílicos , Fenóis
19.
J Cachexia Sarcopenia Muscle ; 15(5): 2118-2133, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39189428

RESUMO

BACKGROUND: Hydrogen sulfide (H2S), the third gasotransmitter discovered, regulates a variety of physiological functions. Whether H2S alleviates skeletal muscle ageing by regulating autophagy has not been reported. METHODS: Mice were administered 150 mg/kg/day of D-galactose (D-gal), and C2C12 myotubes were cultured in 20 g/L D-gal to induce ageing. Sodium hydrosulfide (NaHS) was employed as an exogenous donor in the treatment group. The intracellular concentration of H2S was quantified by the 7-azido-4-methylcoumarin fluorescence probe. The proteins involved in the ubiquitin-mediated degradation of AMPKα1 were detected by liquid chromatography tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation (Co-IP). S-sulfhydration of USP5 was tested by a biotin-switch assay. Associated proteins were analysed by western blot. RESULTS: NaHS was found to effectively restore the H2S content in both ageing gastrocnemius (+91.89%, P < 0.001) and C2C12 myotubes (+27.55%, P < 0.001). In comparison to the D-gal group, NaHS was observed to increase the mean cross-sectional area of muscle fibres (+44.91%, P < 0.001), to decrease the collagen volume fraction of gastrocnemius (-81.32%, P = 0.001) and to reduce the ß-galactosidase-positive area of C2C12 myotubes (-28.74%, P < 0.001). NaHS was also found to reverse the expression of muscle atrophy F box protein (MAFbx), muscle-specific RING finger protein 1 (MuRF1), Cyclin D1 and p21 in the ageing gastrocnemius tissue (MAFbx: -31.73%, P = 0.008; MuRF1: -32.37%, P = 0.003; Cyclin D1: +45.34%, P = 0.010; p21: -25.53%, P = 0.022) and C2C12 myotubes (MAFbx: -16.38%, P < 0.001; MuRF1: -16.45%, P = 0.003; Cyclin D1: +40.23%, P < 0.001; p21: -35.85%, P = 0.026). The AMPKα1-ULK1 pathway was activated and autophagy was up-regulated in NaHS-treated gastrocnemius tissue (p-AMPKα1: +61.61%, P = 0.018; AMPKα1: +30.64%, P = 0.010; p-ULK1/ULK1: +85.87%, P = 0.005; p62: -29.07%, P < 0.001; Beclin1: +24.75%, P = 0.007; light chain 3 II/I [LC3 II/I]: +55.78%, P = 0.004) and C2C12 myotubes (p-AMPKα1: +77.49%, P = 0.018; AMPKα1: +26.18%, P = 0.022; p-ULK1/ULK1: +38.34%, P = 0.012; p62: -9.02%, P = 0.014; Beclin1: +13.36%, P < 0.001; LC3 II/I: +79.38%, P = 0.017; autophagy flux: +24.88%, P = 0.034) compared with the D-gal group. The effects of NaHS on autophagy were comparable to those of acadesine and LYN-1604, and chloroquine could reverse its effects on ageing. LC-MS/MS and Co-IP experiments demonstrated that USP5 is a deubiquitinating enzyme of AMPKα1. Following the knockdown of USP5, the activation of AMPKα1 was decreased (p-AMPKα1: -42.10%, P < 0.001; AMPKα1: -43.93%, P < 0.001), autophagy was inhibited (p-ULK1/ULK1: -27.51, P = 0.001; p62: +36.00, P < 0.001; Beclin1: -22.15%, P < 0.001) and NaHS lost its ability to up-regulate autophagy. NaHS was observed to restore the expression (gastrocnemius: +62.17%, P < 0.001; C2C12 myotubes: +37.51%, P = 0.003) and S-sulfhydration (+53.07%, P = 0.009) of USP5 and reduce the ubiquitination of AMPKα1. CONCLUSIONS: H2S promotes the deubiquitination of AMPKα1 by increasing the expression and S-sulfhydration of USP5, thereby up-regulating autophagy and alleviating skeletal muscle ageing.


Assuntos
Proteínas Quinases Ativadas por AMP , Autofagia , Sulfeto de Hidrogênio , Músculo Esquelético , Animais , Masculino , Camundongos , Envelhecimento/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Ubiquitinação/efeitos dos fármacos
20.
ACS Nano ; 18(33): 22257-22274, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39121010

RESUMO

Iron metabolism has emerged as a promising target for cancer therapy; however, the innate metabolic compensatory capacity of cancer cells significantly limits the effectiveness of iron metabolism therapy. Herein, bioactive gallium sulfide nanodots (GaSx), with dual functions of "reprogramming" and "interfering" iron metabolic pathways, were successfully developed for tumor iron metabolism therapy. The constructed GaSx nanodots ingeniously harness hydrogen sulfide (H2S) gas, which is released in response to the tumor microenvironment, to reprogram the inherent transferrin receptor 1 (TfR1)-ferroportin 1 (FPN1) iron metabolism axis in cancer cells. Concurrently, the gallium ions (Ga3+) derived from GaSx act as a biochemical "Trojan horse", mimicking the role of iron and displacing it from essential biomolecular binding sites, thereby influencing the fate of cancer cells. By leveraging the dual mechanisms of Ga3+-mediated iron disruption and H2S-facilitated reprogramming of iron metabolic pathways, GaSx prompted the initiation of a paraptosis-apoptosis hybrid pathway in cancer cells, leading to marked suppression of tumor proliferation. Importantly, the dysregulation of iron metabolism induced by GaSx notably increased tumor cell susceptibility to both chemotherapy and immune checkpoint blockade (ICB) therapy. This study underscores the therapeutic promise of gas-based interventions and metal ion interference strategies for the tumor metabolism treatment.


Assuntos
Apoptose , Gálio , Ferro , Paraptose , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proteínas de Transporte de Cátions , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Gálio/química , Gálio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/farmacologia , Ferro/metabolismo , Ferro/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Paraptose/efeitos dos fármacos , Receptores da Transferrina/metabolismo , Sulfetos/química , Sulfetos/farmacologia , Microambiente Tumoral/efeitos dos fármacos
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