RESUMO
Cardiometabolic diseases (CMDs) are major contributors to global mortality, emphasizing the critical need for novel therapeutic interventions. Hydrogen sulfide (H2S) has garnered enormous attention as a significant gasotransmitter with various physiological, pathophysiological, and pharmacological impacts within mammalian cardiometabolic systems. In addition to its roles in attenuating oxidative stress and inflammatory response, burgeoning research emphasizes the significance of H2S in regulating proteins via persulfidation, a well known modification intricately associated with the pathogenesis of CMDs. This review seeks to investigate recent updates on the physiological actions of endogenous H2S and the pharmacological roles of various H2S donors in addressing diverse aspects of CMDs across cellular, animal, and clinical studies. Of note, advanced methodologies, including multiomics, intestinal microflora analysis, organoid, and single-cell sequencing techniques, are gaining traction due to their ability to offer comprehensive insights into biomedical research. These emerging approaches hold promise in characterizing the pharmacological roles of H2S in health and diseases. We will critically assess the current literature to clarify the roles of H2S in diseases while also delineating the opportunities and challenges they present in H2S-based pharmacotherapy for CMDs. SIGNIFICANCE STATEMENT: This comprehensive review covers recent developments in H2S biology and pharmacology in cardiometabolic diseases CMDs. Endogenous H2S and its donors show great promise for the management of CMDs by regulating numerous proteins and signaling pathways. The emergence of new technologies will considerably advance the pharmacological research and clinical translation of H2S.
Assuntos
Doenças Cardiovasculares , Sulfeto de Hidrogênio , Sulfeto de Hidrogênio/metabolismo , Humanos , Animais , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Gasotransmissores/metabolismoRESUMO
BACKGROUND: Neutral cholesterol ester hydrolase 1 (NCEH1) plays a critical role in the regulation of cholesterol ester metabolism. Deficiency of NCHE1 accelerated atherosclerotic lesion formation in mice. Nonetheless, the role of NCEH1 in endothelial dysfunction associated with diabetes has not been explored. The present study sought to investigate whether NCEH1 improved endothelial function in diabetes, and the underlying mechanisms were explored. METHODS: The expression and activity of NCEH1 were determined in obese mice with high-fat diet (HFD) feeding, high glucose (HG)-induced mouse aortae or primary endothelial cells (ECs). Endothelium-dependent relaxation (EDR) in aortae response to acetylcholine (Ach) was measured. RESULTS: Results showed that the expression and activity of NCEH1 were lower in HFD-induced mouse aortae, HG-exposed mouse aortae ex vivo, and HG-incubated primary ECs. HG exposure reduced EDR in mouse aortae, which was exaggerated by endothelial-specific deficiency of NCEH1, whereas NCEH1 overexpression restored the impaired EDR. Similar results were observed in HFD mice. Mechanically, NCEH1 ameliorated the disrupted EDR by dissociating endothelial nitric oxide synthase (eNOS) from caveolin-1 (Cav-1), leading to eNOS activation and nitric oxide (NO) release. Moreover, interaction of NCEH1 with the E3 ubiquitin-protein ligase ZNRF1 led to the degradation of Cav-1 through the ubiquitination pathway. Silencing Cav-1 and upregulating ZNRF1 were sufficient to improve EDR of diabetic aortas, while overexpression of Cav-1 and downregulation of ZNRF1 abolished the effects of NCEH1 on endothelial function in diabetes. Thus, NCEH1 preserves endothelial function through increasing NO bioavailability secondary to the disruption of the Cav-1/eNOS complex in the endothelium of diabetic mice, depending on ZNRF1-induced ubiquitination of Cav-1. CONCLUSIONS: NCEH1 may be a promising candidate for the prevention and treatment of vascular complications of diabetes.
Assuntos
Caveolina 1 , Dieta Hiperlipídica , Células Endoteliais , Endotélio Vascular , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo III , Vasodilatação , Animais , Masculino , Camundongos , Aorta/enzimologia , Aorta/fisiopatologia , Aorta/metabolismo , Aorta/efeitos dos fármacos , Aorta/patologia , Caveolina 1/metabolismo , Caveolina 1/deficiência , Caveolina 1/genética , Células Cultivadas , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/fisiopatologia , Células Endoteliais/enzimologia , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Endotélio Vascular/metabolismo , Endotélio Vascular/enzimologia , Endotélio Vascular/efeitos dos fármacos , Camundongos Knockout , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade/enzimologia , Obesidade/fisiopatologia , Obesidade/metabolismo , Transdução de Sinais , Esterol Esterase/metabolismo , Esterol Esterase/genética , Ubiquitinação , Vasodilatação/efeitos dos fármacosRESUMO
Chordin like-1 (CHRDL1) is an antagonist of bone morphogenetic proteins (BMPs) that acts through binding BMPs and blocking their interaction with BMP receptors. CHRDL1 plays a role in osteoblast differentiation but controversial effects were reported. On the other hand, the role of CHRDL1 in adipogenesis is unknown. In the present study, we investigated the function of CHRDL1 in regulating differentiation of osteoblasts and adipocytes and elucidated the underlying mechanism. CHRDL1 expression was downregulated during osteogenesis while it was upregulated during adipogenesis in primary cultured and established mesenchymal progenitor cell lines. Functional experiments revealed that CHRDL1 suppressed osteoblast differentiation and promoted adipocyte differentiation. Mechanistic explorations revealed that CHRDL1 is directly bound to insulin-like growth factor binding protein 3 (IGFBP3) and attenuated the degradation of the latter. Furthermore, CHRDL1 and IGFBP3 suppressed the activity of insulin receptor substrate 1 (IRS1)/AKT serine/threonine kinase (AKT)/mechanistic target of rapamycin kinase complex 1 (mTORC1) signaling in progenitor cells undergoing osteogenic differentiation. By contrast, they activated AKT/mTORC1 signaling independently of IRS1 during adipogenic differentiation. CHRDL1 enhanced the interaction of nuclear IGFBP3 and retinoid X receptor α (RXRα) during adipogenesis, and inhibition of RXR inactivated AKT and attenuated the stimulation of adipogenic differentiation by CHRDL1. Overexpression of IGFBP3 relieved the perturbation of osteogenic and adipogenic differentiation of progenitor cells induced by CHRDL1 silencing. Finally, CHRDL1 and IGFBP3 were upregulated in the trabecular bone of aged mice. Our study provides evidence that CHRDL1 reciprocally regulates osteoblast and adipocyte differentiation through stabilizing IGFBP3 and differentially modulating AKT/mTORC1 signaling.
Assuntos
Osteogênese , Proteínas Proto-Oncogênicas c-akt , Animais , Camundongos , Adipócitos/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular/fisiologia , Proteínas do Olho/metabolismo , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Osteoblastos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Acute kidney injury (AKI) remains a global public health problem with high incidence, high mortality rates, expensive medical costs, and limited treatment options. AKI can further progress to chronic kidney disease (CKD) and eventually end-stage renal disease (ESRD). Previous studies have shown that trauma, adverse drug reactions, surgery, and other factors are closely associated with AKI. With further in-depth exploration, the role of gut microbiota in AKI is gradually revealed. After AKI occurs, there are changes in the composition of gut microbiota, leading to disruption of the intestinal barrier, intestinal immune response, and bacterial translocation. Meanwhile, metabolites of gut microbiota can exacerbate the progression of AKI. Therefore, elucidating the specific mechanisms by which gut microbiota is involved in the occurrence and development of AKI can provide new insights from the perspective of intestinal microbiota for the prevention and treatment of AKI.
Assuntos
Injúria Renal Aguda , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/fisiologia , Injúria Renal Aguda/microbiologia , Injúria Renal Aguda/etiologia , Animais , Translocação Bacteriana , Insuficiência Renal Crônica/microbiologia , Progressão da DoençaRESUMO
OBJECTIVE: Gut microbiota dysbiosis is closely linked to the pathogenesis of rheumatoid arthritis (RA). We aimed to identify potential probiotic gut microbes that can ameliorate the development of RA. DESIGN: Microbiota profiling in patients with RA and healthy individuals was investigated via 16S rDNA bacterial gene sequencing and shotgun metagenomics. Collagen-induced arthritic mice and TNF-α transgenic mice were used to evaluate the roles of the gut commensal Parabacteroides distasonis in RA. The effects of P. distasonis-derived microbial metabolites on the differentiation of CD4+ T cells and macrophage polarisation were also investigated. RESULTS: The relative abundance of P. distasonis in new-onset patients with RA and patients with RA with history of the disease was downregulated and this decrease was negatively correlated with Disease Activity Score-28 (DAS28). Oral treatment of arthritic mice with live P. distasonis (LPD) considerably ameliorated RA pathogenesis. LPD-derived lithocholic acid (LCA), deoxycholic acid (DCA), isolithocholic acid (isoLCA) and 3-oxolithocholic acid (3-oxoLCA) had similar and synergistic effects on the treatment of RA. In addition to directly inhibiting the differentiation of Th17 cells, 3-oxoLCA and isoLCA were identified as TGR5 agonists that promoted the M2 polarisation of macrophages. A specific synthetic inhibitor of bile salt hydrolase attenuated the antiarthritic effects of LPD by reducing the production of these four bile acids. The natural product ginsenoside Rg2 exhibited its anti-RA effects by promoting the growth of P. distasonis. CONCLUSIONS: P. distasonis and ginsenoside Rg2 might represent probiotic and prebiotic agents in the treatment of RA.
Assuntos
Artrite Reumatoide , Camundongos , Animais , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Bacteroidetes , BactériasRESUMO
Hydrogen sulfide (H2S) is previously described as a potentially lethal toxic gas. However, this gasotransmitter is also endogenously generated by the actions of cystathionine-ß-synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) in mammalian systems, thus belonging to the family of gasotransmitters after nitric oxide (NO) and carbon monoxide (CO). The physiological or pathological significance of H2S has been extensively expanded for decades. Growing evidence has revealed that H2S exerts cytoprotective functions in the cardiovascular, nervous, and gastrointestinal systems by modulating numerous signaling pathways. With the continuous advancement of microarray and next-generation sequencing technologies, noncoding RNAs (ncRNAs) have gained recognition as key players in human health and diseases due to their considerable potential as predictive biomarkers and therapeutic targets. Coincidentally, H2S and ncRNAs are not independent regulators but interact with each other during the development and progression of human diseases. Specifically, ncRNAs might serve as downstream mediators of H2S or act on H2S-generating enzymes to govern endogenous H2S production. The purpose of this review is to summarize the interactive regulatory roles of H2S and ncRNAs in the initiation and development of various diseases and explore their potential health and therapeutic benefits. This review will also highlight the importance of cross talk between H2S and ncRNAs in disease therapy.
Assuntos
Gasotransmissores , Sulfeto de Hidrogênio , Animais , Humanos , Sulfeto de Hidrogênio/metabolismo , Cistationina , Transdução de Sinais , Óxido Nítrico , Cistationina gama-Liase , Mamíferos/metabolismoRESUMO
BACKGROUND: Periostin is an extracellular matrix protein that plays a critical role in cell fate determination and tissue remodeling, but the underlying role and mechanism of periostin in diabetic cardiomyopathy (DCM) are far from clear. Thus, we aimed to clarify the mechanistic participation of periostin in DCM. METHODS: The expression of periostin was examined in DCM patients, diabetic mice and high glucose (HG)-exposed cardiac fibroblasts (CF). Gain- and loss-of-function experiments assessed the potential role of periostin in DCM pathogenesis. RNA sequencing was used to investigate the underlying mechanisms of periostin in DCM. RESULTS: A mouse cytokine antibody array showed that the protein expression of periostin was most significantly upregulated in diabetic mouse heart, and this increase was also observed in patients with DCM or HG-incubated CF. Periostin-deficient mice were protected from diabetes-induced cardiac dysfunction and myocardial damage, while overexpression of periostin held the opposite effects. Hyperglycemia stimulated the expression of periostin in a TGF-ß/Smad-dependent manner. RNA sequencing results showed that periostin upregulated the expression of nucleosome assembly protein 1-like 2 (NAP1L2) which recruited SIRT3 to deacetylate H3K27ac on the promoters of the branched-chain amino acid (BCAA) catabolism-related enzymes BCAT2 and PP2Cm, resulting in BCAA catabolism impairment. Additionally, CF-derived periostin induced hypertrophy, oxidative injury and inflammation in primary cardiomyocytes. Finally, we identified that glucosyringic acid (GA) specifically targeted and inhibited periostin to ameliorate DCM. CONCLUSION: Overall, manipulating periostin expression may function as a promising strategy in the treatment of DCM.
Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Sirtuína 3 , Humanos , Camundongos , Animais , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/metabolismo , Sirtuína 3/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Miócitos Cardíacos/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Aminoácidos de Cadeia Ramificada/farmacologia , Fibroblastos/metabolismoRESUMO
Hypertension, a chronic and progressive disease, is an outstanding public health issue that affects nearly 40% of the adults worldwide. The increasing prevalence of hypertension is one of the leading causes of cardiovascular morbidity and mortality. Despite of the available treatment medications, an increasing number of hypertensive individuals continues to have uncontrolled blood pressure. In the vasculature, endothelial cells, vascular smooth muscle cells (VSMCs), and adventitial fibroblasts play a fundamental role in vascular homeostasis. The aberrant interactions between vascular cells might lead to hypertension and vascular remodeling. Identification of the precise mechanisms of vascular remodeling may be highly required to develop effective therapeutic approaches for hypertension. Recently, extracellular vesicle-mediated transfer of proteins or noncoding RNAs (ncRNAs) between vascular cells holds promise for the treatment of hypertension. Especially, extracellular vesicle-packaging ncRNAs have gained enormous attention of basic and clinical scientists because of their tremendous potential to act as novel clinical biomarkers and therapeutic targets of hypertension. Here we will discuss the current findings focusing on the emerging roles of extracellular vesicle-carrying ncRNAs in the pathologies of hypertension and its associated vascular remodeling. Furthermore, we will highlight the potential of extracellular vesicles and ncRNAs as biomarkers and therapeutic targets for hypertension. The future research directions on the challenges and perspectives of extracellular vesicles and ncRNAs in hypertensive vascular remodeling are also proposed.
Assuntos
Vesículas Extracelulares/metabolismo , Hipertensão/terapia , RNA não Traduzido/genética , Animais , Comunicação Celular/fisiologia , Células Endoteliais/metabolismo , Fibroblastos/metabolismo , Humanos , Hipertensão/genética , Hipertensão/fisiopatologia , Miócitos de Músculo Liso/citologia , Remodelação Vascular/fisiologiaRESUMO
Due to their high prevalence and incidence, diabetes and atherosclerosis are increasingly becoming global public health concerns. Atherosclerosis is one of the leading causes of morbidity and disability in type 1 and/or type 2 diabetes patients. Atherosclerosis risk in diabetic patients is obviously higher than that of non-diabetic individuals. Diabetes-related glycolipid metabolism disorder has been shown to play a central role in atherosclerosis development and progression. Hyperglycemia and dyslipidemia increase the risks for atherosclerosis and plaque necrosis through multiple signaling pathways, such as a prolonged increase in reactive oxygen species (ROS) and inflammatory factors in cardiovascular cells. Notwithstanding the great advances in the understanding of the pathologies of diabetes-accelerated atherosclerosis, the current medical treatments for diabetic atherosclerosis hold undesirable side effects. Therefore, there is an urgent demand to identify novel therapeutic targets or alternative strategies to prevent or treat diabetic atherosclerosis. Burgeoning evidence suggests that plant and herbal medicines are closely linked with healthy benefits for diabetic complications, including diabetic atherosclerosis. In this review, we will overview the utilization of plant and herbal medicines for the treatment of diabetes-accelerated atherosclerosis. Furthermore, the underlying mechanisms of the ethnopharmacological therapeutic potentials against diabetic atherosclerosis are gathered and reviewed. It is foreseeable that the natural constituents from medicinal plants might be a new hope for the treatment of diabetes-accelerated atherosclerosis.
Assuntos
Aterosclerose , Diabetes Mellitus Tipo 2 , Dislipidemias , Plantas Medicinais , Aterosclerose/tratamento farmacológico , Aterosclerose/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/diagnóstico , Dislipidemias/tratamento farmacológico , Dislipidemias/epidemiologia , HumanosRESUMO
Glucose and lipids are essential elements for maintaining the body's homeostasis, and their dysfunction may participate in the pathologies of various diseases, particularly diabetes, obesity, metabolic syndrome, cardiovascular ailments, and cancers. Among numerous endogenous mediators, the gasotransmitter hydrogen sulfide (H2S) plays a central role in the maintenance of glucose and lipid homeostasis. Current evidence from both pharmacological studies and transgenic animal models suggest a complex relationship between H2S and metabolic dysregulation, especially in diabetes and obesity. This notion is achieved through tissue-specific expressions and actions of H2S on target metabolic and hormone organs including the pancreas, skeletal muscle, livers, and adipose. In this chapter, we will summarize the roles and mechanisms of H2S in several metabolic organs/tissues that are necessary for glucose and lipid metabolic homeostasis. In addition, future research directions and valuable therapeutic avenues around the pharmacological regulation of H2S in glycolipid metabolism disorder will be also discussed.
Assuntos
Gasotransmissores , Sulfeto de Hidrogênio , Animais , Glucose , Metabolismo dos Lipídeos , LipídeosRESUMO
Recently diverged taxa with contrasting phenotypes offer opportunities for unravelling the genetic basis of phenotypic variation in nature. Horseshoe bats are a speciose group that exhibit a derived form of high-duty cycle echolocation in which the inner ear is finely tuned to echoes of the narrowband call frequency. Here, by focusing on three recently diverged subspecies of the intermediate horseshoe bat (Rhinolophus affinis) that display divergent echolocation call frequencies, we aim to identify candidate loci putatively involved in hearing frequency variation. We used de novo transcriptome sequencing of two mainland taxa (himalayanus and macrurus) and one island taxon (hainanus) to compare expression profiles of thousands of genes. By comparing taxa with divergent call frequencies (around 15 kHz difference), we identified 252 differentially expressed genes, of which six have been shown to be involved in hearing or deafness in human/mouse. To obtain further validation of these results, we applied quantitative reverse transcription-PCR to the candidate gene FBXL15 and found a broad association between the level of expression and call frequency across taxa. The genes identified here represent strong candidate loci associated with hearing frequency variation in bats.
Assuntos
Quirópteros/genética , Ecolocação/fisiologia , Transcriptoma , Animais , Fluxo Gênico , Audição , FilogeniaRESUMO
BACKGROUND: The gut is the major organ for nutrient absorption and immune response in the body of animals. Although effects of fasting on the gut functions have been extensively studied in model animals (e.g. mice), little is known about the response of the gut to fasting in a natural condition (e.g. hibernation). During hibernation, animals endure the long term of fasting and hypothermia. RESULTS: Here we generated the first gut transcriptome in a wild hibernating bat (Rhinolophus ferrumequinum). We identified 1614 differentially expressed genes (DEGs) during four physiological states (Torpor, Arousal, Winter Active and Summer Active). Gene co-expression network analysis assigns 926 DEGs into six modules associated with Torpor and Arousal. Our results reveal that in response to the stress of luminal nutrient deficiency during hibernation, the gut helps to reduce food intake by overexpressing genes (e.g. CCK and GPR17) that regulate the sensitivity to insulin and leptin. At the same time, the gut contributes energy supply by overexpressing genes that increase capacity for ketogenesis (HMGCS2) and selective autophagy (TEX264). Furthermore, we identified separate sets of multiple DEGs upregulated in Torpor and Arousal whose functions are involved in innate immunity. CONCLUSION: This is the first gut transcriptome of a hibernating mammal. Our study identified candidate genes associated with regulation of food intake and enhance of innate immunity in the gut during hibernation. By comparing with previous studies, we found that two DEGs (CPE and HSPA8) were also significantly elevated during torpor in liver and brain of R. ferrumequinum and several DEGs (e.g. TXNIP and PDK1/4) were commonly upregulated during torpor in multiple tissues of different mammals. Our results support that shared expression changes may underlie the hibernation phenotype by most mammals.
RESUMO
Cardiovascular diseases are recognized to be a major cause of people morbidity and mortality. A host of stress signals contribute to the pathogenesis of cardiovascular disorders. Deficiency of hydrogen sulfide (H2S) or nitric oxide (NO) coordinately plays essential roles in the development of cardiovascular diseases. Recent studies have shown that interaction between the two gaseostransmitters, H2S and NO, may give rise to nitroxyl (HNO), one-electron-reduced product of NO. HNO is found to exhibit a variety of biological and pharmacological properties including positive inotropy and cardiovascular protective effects, etc. In this review, recent progresses regarding HNO generation, detection, biochemical and pharmacological functions are discussed.
Assuntos
Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Sistema Cardiovascular/efeitos dos fármacos , Óxidos de Nitrogênio/uso terapêutico , Animais , Fármacos Cardiovasculares/efeitos adversos , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Humanos , Sulfeto de Hidrogênio/metabolismo , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/uso terapêutico , Óxidos de Nitrogênio/efeitos adversos , Óxidos de Nitrogênio/metabolismoRESUMO
Endothelial cells are major constituents in the vasculature, and they act as important players in vascular homeostasis via secretion/release of vasodilators and vasoconstrictors. In healthy arteries, endothelial cells play a key role in the regulation of vascular tone, cellular adhesion, and angiogenesis. A shift in the functions of the blood vessels toward vasoconstriction, proinflammatory state, oxidative stress and deficiency of nitric oxide (NO) might lead to endothelial dysfunction, a key event implicated in the pathophysiology of cardiovascular metabolic diseases, including diabetes, atherosclerosis, arterial hypertension and pulmonary arterial hypertension (PAH). Thus, reversibility of endothelial dysfunction may be beneficial for maintaining vascular homeostasis. In recent years, accumulative evidence has documented that noncoding RNAs (ncRNAs) are critically involved in endothelial homeostasis. Specifically, long noncoding RNAs (lncRNAs) and circular RNAs are highly expressed in endothelial cells where they serve as important mediators in normal endothelial functions. Dysregulation of lncRNAs and circular RNAs has been tightly associated with hypertension-related endothelial dysfunction. In this review, we will summarize the current progression and underlying mechanisms of lncRNA and circular RNA in endothelial cell biology under hypertensive conditions. We will also highlight their potential as biomarkers or therapeutic targets for hypertension and its associated endothelial dysfunction.
Assuntos
Células Endoteliais/metabolismo , Hipertensão/genética , RNA Circular/genética , RNA Longo não Codificante/genética , Animais , Artérias/metabolismo , Aterosclerose/genética , Biomarcadores/metabolismo , Doenças Cardiovasculares/genética , Diabetes Mellitus/genética , Células Endoteliais/fisiologia , Homeostase/genética , Homeostase/fisiologia , Humanos , Hipertensão/metabolismo , Hipertensão/patologia , Óxido Nítrico/metabolismo , Estresse Oxidativo , RNA Circular/metabolismo , RNA Longo não Codificante/metabolismoRESUMO
BACKGROUND: BTBD7_hsa_circ_0000563, which is located on chromosome 14, contains conserved binding sites with miR-155/130a and RNA-binding proteins according to bioinformatic prediction. We investigated the association of BTBD7_hsa_circ_0000563 expression in coronary artery segments with atherosclerotic stenosis and identified the proteome-wide BTBD7_hsa_circ_0000563-regulated proteins in human coronary artery. METHODS: The atherosclerotic grade and extent in coronary artery segments were determined by hematoxylin and eosin staining. BTBD7_hsa_circ_0000563 expression in eight coronary artery segments from one patient was quantified by RT-qPCR assay. A proteomic approach was adopted to reveal significant differences in protein expression between among four groups differing in their BTBD7_hsa_circ_0000563 expression levels. RESULTS: The RT-qPCR assay revealed that coronary artery segments with severe atherosclerotic stenosis had significantly low BTBD7_hsa_circ_0000563 levels. The proteomic analysis identified 49 differentially expressed proteins among the segment groups with different BTBD7_hsa_circ_0000563 expression levels, of which 10 were downregulated and 39 were upregulated with increases in the BTBD7_hsa_circ_0000563 level. The 10 downregulated proteins were P61626 (LYSC_HUMAN), P02760 (AMBP_HUMAN), Q02985 (FHR3_HUMAN), P01701 (LV151_HUMAN), P06312(KV401_HUMAN), P01624 (KV315_HUMAN), P13671 (CO6_HUMAN), P01700(LV147_HUMAN), Q9Y287(ITM2B_HUMAN), and A0A075B6I0 (LV861_HUMAN). The top 10 upregulated proteins were Q92552 (RT27_HUMAN), Q9UJY1(HSPB8_HUMAN), Q9Y235(ABEC2_HUMAN), P19022 (CADH2_HUMAN), O43837(IDH3B_HUMAN), Q9H479(FN3K_HUMAN), Q9UM22(EPDR1_HUMAN), P48681(NEST_HUMAN), Q9NRP0(OSTC_HUMAN), and Q15628(TRADD_HUMAN). CONCLUSION: BTBD7_hsa_circ_0000563 is involved in the atherosclerotic changes in human coronary artery segments. Verification, mechanistic, and function studies are needed to confirm whether patients with coronary artery disease would benefit from such personalized medicine in the future.
Assuntos
Vasos Coronários , Proteoma , RNA Circular , Idoso , Vasos Coronários/química , Vasos Coronários/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mapas de Interação de Proteínas/genética , Proteoma/análise , Proteoma/genética , Proteoma/metabolismo , Proteômica , RNA Circular/genética , RNA Circular/metabolismoRESUMO
Cisplatin, a widely used chemotherapy for the treatment of various tumors, is clinically limited due to its extensive nephrotoxicity. Inflammatory response in tubular cells is a driving force for cisplatin-induced nephrotoxicity. The plant-derived agents are widely used to relieve cisplatin-induced renal dysfunction in preclinical studies. Polysulfide and hydrogen sulfide (H2S) are ubiquitously expressed in garlic, and both of them are documented as potential agents for preventing and treating inflammatory disorders. This study was designed to determine whether polysulfide and H2S could attenuate cisplatin nephrotoxicity through suppression of inflammatory factors. In renal proximal tubular cells, we found that sodium tetrasulfide (Na2S4), a polysulfide donor, and sodium hydrosulfide (NaHS) and GYY4137, two H2S donors, ameliorated cisplatin-caused renal toxicity through suppression of the massive production of inflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2). Mechanistically, the anti-inflammatory actions of Na2S4 and H2S may be mediated by persulfidation of signal transducer and activator of transcription 3 (STAT3) and inhibitor kappa B kinase ß (IKKß), followed by decreased phosphorylation of STAT3 and IKKß. Moreover, the nuclear translocation of nuclear transcription factor kappa B (NF-κB), and phosphorylation and degradation of nuclear factor kappa B inhibitor protein alpha (IκBα) induced by cisplatin, were also mitigated by both polysulfide and H2S. In mice, after treatment with polysulfide and H2S donors, cisplatin-associated renal dysfunction was strikingly ameliorated, as evidenced by measurement of serum blood urea nitrogen (BUN) and creatinine levels, renal morphology, and the expression of renal inflammatory factors. Our present work suggests that polysulfide and H2S could afford protection against cisplatin nephrotoxicity, possibly via persulfidating STAT3 and IKKß and inhibiting NF-κB-mediated inflammatory cascade. Our results might shed light on the potential benefits of garlic-derived polysulfide and H2S in chemotherapy-induced renal damage.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Sulfeto de Hidrogênio/farmacologia , Sulfetos/farmacologia , Injúria Renal Aguda/tratamento farmacológico , Animais , Quinase I-kappa B/química , Quinase I-kappa B/metabolismo , Túbulos Renais/citologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Nefrite/induzido quimicamente , Nefrite/tratamento farmacológico , Fator de Transcrição STAT3/química , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Arterial hypertension remains to be a serious problem with considerable morbidity and mortality worldwide in the present age. Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, renal failure, and heart failure. Hypertensive nephropathy is the second leading cause of death in chronic kidney disease (CKD) around the world. Long-time hypertension loading results in renal interstitial fibrosis, which is associated with aberrant activation of renal fibroblasts and excessive generation of extracellular matrix (ECM) proteins. Increasing evidence supported that proteinuria, tubular hypertrophy, oxidative stress, activation of renin-aldosterone-angiotensin system (RAAS), collagen turnover, chronic inflammation, and vasoactive substances synergistically contributed to the pathogenesis of hypertensive renal fibrosis. However, the mechanisms involving the pathogenesis of hypertensive renal fibrosis are complex and not fully understood. Also, the effective clinical therapy to halt or even reverse renal fibrosis in hypertension is still limited. In this chapter, we aimed to provide an overview of the main pathophysiologic and mechanistic features of renal fibrosis under hypertensive state. The completion of the studies in these directions would improve our understanding of renal fibrosis in hypertension and also help us better screen treatment strategies for preventing renal destruction associated with hypertension.
Assuntos
Hipertensão/complicações , Nefropatias/complicações , Fibrose , Humanos , Hipertrofia , Rim/patologia , Estresse Oxidativo , Proteinúria , Sistema Renina-AngiotensinaRESUMO
Cardiovascular complications are a major leading cause of mortality in patients suffering from type 2 diabetes mellitus (T2DM). Vascular endothelial dysfunction is a core pathophysiological event in the early stage of T2DM and eventually leads to cardiovascular disease. Vaccarin (VAC), an active flavonoid glycoside extracted from vaccariae semen, exhibits extensive biological activities including vascular endothelial cell protection effects. However, little is known about whether VAC is involved in endothelial dysfunction regulation under high glucose (HG) or hyperglycemia conditions. Here, in an in vivo study, we found that VAC attenuated increased blood glucose, increased glucose and insulin tolerance, relieved the disorder of lipid metabolism and oxidative stress, and improved endothelium-dependent vasorelaxation in STZ/HFD-induced T2DM mice. Furthermore, in cultured human microvascular endothelial cell-1 (HMEC-1) cells, we showed that pretreatment with VAC dose-dependently increased nitric oxide (NO) generation and the phosphorylation of eNOS under HG conditions. Mechanistically, VAC-treated HMEC-1 cells exhibited higher AMPK phosphorylation, which was attenuated by HG stimulation. Moreover, HG-triggered miRNA-34a upregulation was inhibited by VAC pretreatment, which is in accordance with pretreatment with AMPK inhibitor compound C (CC). In addition, both reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) and VAC abolished HG-evoked dephosphorylation of AMPK and eNOS, increased miRNA-34a expression, and decreased NO production. These results suggest that VAC impedes HG-induced endothelial dysfunction via inhibition of the ROS/AMPK/miRNA-34a/eNOS signaling cascade.
Assuntos
Angiopatias Diabéticas/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Glicosídeos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/patologia , Modelos Animais de Doenças , Glicosídeos/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , MicroRNAs , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Substâncias Protetoras/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
Diabetic kidney disease develops in approximately 40% of diabetic patients and is a major cause of chronic kidney diseases (CKD) and end stage kidney disease (ESKD) worldwide. Hydrogen sulfide (H2S), the third gasotransmitter after nitric oxide (NO) and carbon monoxide (CO), is synthesized in nearly all organs, including the kidney. Though studies on H2S regulation of renal physiology and pathophysiology are still in its infancy, emerging evidence shows that H2S production by renal cells is reduced under disease states and H2S donors ameliorate kidney injury. Specifically, aberrant H2S level is implicated in various renal pathological conditions including diabetic nephropathy. This review presents the roles of H2S in diabetic renal disease and the underlying mechanisms for the protective effects of H2S against diabetic renal damage. H2S may serve as fundamental strategies to treat diabetic kidney disease. These H2S treatment modalities include precursors for H2S synthesis, H2S donors, and natural plant-derived compounds. Despite accumulating evidence from experimental studies suggests the potential role of the H2S signaling pathway in the treatment of diabetic nephropathy, these results need further clinical translation. Expanding understanding of H2S in the kidney may be vital to translate H2S to be a novel therapy for diabetic renal disease.
Assuntos
Sulfeto de Hidrogênio/metabolismo , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Avaliação Pré-Clínica de Medicamentos , Fibrose , Humanos , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/uso terapêutico , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/metabolismo , Podócitos/metabolismo , Podócitos/patologia , Sistema Renina-AngiotensinaRESUMO
Sympathetic overdrive, activation of renin angiotensin systems (RAS), and oxidative stress are vitally involved in the pathogenesis of hypertension and cardiovascular remodeling. We recently identified that vaccarin protected endothelial cell function from oxidative stress or high glucose. In this study, we aimed to investigate whether vaccarin attenuated hypertension and cardiovascular remodeling. Two-kidney one-clip (2K1C) model rats were used, and low dose of vaccarin (10 mg/kg), high dose of vaccarin (30 mg/kg), captopril (30 mg/kg) were intraperitoneally administrated. Herein, we showed that 2K1C rats exhibited higher systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), left ventricular mass/body weight ratio, myocardial hypertrophy or fibrosis, media thickness, and media thickness to lumen diameter, which were obviously alleviated by vaccarin and captopril. In addition, both vaccarin and captopril abrogated the increased plasma renin, angiotensin II (Ang II), norepinephrine (NE), and the basal sympathetic activity. The AT1R protein expressions, NADPH oxidase subunit NOX-2 protein levels and malondialdehyde (MDA) content were significantly increased, whereas superoxide dismutase (SOD) and catalase (CAT) activities were decreased in myocardium, aorta, and mesenteric artery of 2K1C rats, both vaccarin and captopril treatment counteracted these changes in renovascular hypertensive rats. Collectively, we concluded that vaccarin may be a novel complementary therapeutic medicine for the prevention and treatment of hypertension. The mechanisms for antihypertensive effects of vaccarin may be associated with inhibition of sympathetic activity, RAS, and oxidative stress.