RESUMO
Cichoric acid (CA), a widely utilized polyphenolic compound in medicine, has garnered significant attention due to its potential health benefits. Sepsis-induced acute kidney disease (AKI) is related with an elevated risk of end-stage kidney disease (ESKD). However, it remains unclear whether CA provides protection against septic AKI. The aim of this study is to investigated the protective effect and possible mechanisms of CA against LPS-induced septic AKI. Sepsis-induced AKI was induced in mice through intraperitoneal injection of lipopolysaccharide (LPS), and RAW264.7 macrophages were incubated with LPS. LPS exposure significantly increased the levels of M1 macrophage biomarkers while reducing the levels of M2 macrophage indicators. This was accompanied by the release of inflammatory factors, superoxide anion production, mitochondrial dysfunction, activation of succinate dehydrogenase (SDH), and subsequent succinate formation. Conversely, pretreatment with CA mitigated these abnormalities. CA attenuated hypoxia-inducible factor-1α (HIF-1α)-induced glycolysis by lifting the NAD+/NADH ratio in macrophages. Additionally, CA disrupted the K (lysine) acetyltransferase 2A (KAT2A)/α-tubulin complex, thereby reducing α-tubulin acetylation and subsequently inactivating the NLRP3 inflammasome. Importantly, administration of CA ameliorated LPS-induced renal pathological damage, apoptosis, inflammation, oxidative stress, and disturbances in mitochondrial function in mice. Overall, CA restrained HIF-1α-mediated glycolysis via inactivation of SDH, leading to NLRP3 inflammasome inactivation and the amelioration of sepsis-induced AKI.
Assuntos
Injúria Renal Aguda , Ácidos Cafeicos , Lipopolissacarídeos , Macrófagos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sepse , Succinatos , Animais , Sepse/complicações , Sepse/tratamento farmacológico , Camundongos , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Masculino , Succinatos/farmacologia , Succinatos/uso terapêutico , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Células RAW 264.7 , Estresse Oxidativo/efeitos dos fármacos , Inflamassomos/metabolismo , Camundongos Endogâmicos C57BL , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Glicólise/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Rim/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ativação de Macrófagos/efeitos dos fármacosRESUMO
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
BACKGROUND: Skin pruritus is a common complication in patients with uremia. When the hemodialysis time of patients is extended, and the probability of skin pruritus is greater. Patients often have the symptoms of skin pruritus intolerable, affecting the normal sleep and normal life of patients. The patients with uremic pruritus often constant scratching and pruritus skin, resulting in broken skin, and further symptoms such as infection, and subsequent skin shedding, prurigo nodularis, and other adverse complications, aggravating the patient's condition. Some patients will experience symptoms such as depression and insomnia due to skin pruritus, and simply scratching the skin lead to infection. Severely affected patients may even show suicidal tendency, endangering the physical and mental health of patients, and it is needed to give the effective treatment to patients. Hemodialysis is a common treatment for uremic pruritus, which can effectively relieve the pruritus symptoms of patients. The drugs can also relieve the symptoms and improve the degree of pruritus in patients. And some studies show that traditional Chinese medicine UCG combined with HFH in the treatment of uremic pruritus has a very good effect, Therefore, this study will systematically evaluate the clinical efficacy and safety of UCG combined with HFH and HFH alone in the treatment of uremic pruritus. METHODS: Use computer to search English and Chinese databases, English databases include: PubMed, Web of Science, EMbase, The Cochrane Library. Chinese databases include: CNKI, CBM, WanFang Data and VIP databases, collecting the RCT on the clinical effectiveness and safety of UCG combined with HFH and HFH alone in the treatment of uremic pruritus. The retrieval time is from the beginning of each database to May 1, 2021. In order to improve the retrieval rate of the literature, the references cited in the included research are also collected and screened. Set Chinese and English as the search language. Two members of the research group independently collected, included and excluded the literatures. In case of disagreement, consulting the third party to assist in the judgment. For the literature with missing data, the original author should be contacted as far as possible to obtain complete data. Two evaluators evaluate the bias risk of included studies according to the Cochrane Handbook bias risk assessment tool for RCT. RevMan 5.3 software is used for statistical analysis and the forest plot is drawn to show the outcome indicators and funnel plot is drawn to show the publication bias. RESULTS: This study evaluates the advantages and disadvantages of traditional Chinese medicine UCG combined with HFH and HFH alone in the treatment of uremic pruritus through the clinical effectiveness and safety-related indicators. CONCLUSION: This study will give a positive conclusion on the efficacy and safety of uremic clearance granule in the treatment of uremic pruritus, and the research results will be published in professional journals in the form of academic papers, thus benefiting more patients. ETHICS AND DISSEMINATION: This study belongs to meta-analysis and all data comes from academic papers published publicly in formal academic journals, so there are no ethical issues involved in this study and no ethical review or approval is required. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/W8P5G.
Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Falência Renal Crônica/terapia , Prurido/terapia , Diálise Renal/efeitos adversos , Uremia/terapia , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Falência Renal Crônica/complicações , Metanálise como Assunto , Prurido/diagnóstico , Prurido/etiologia , Prurido/psicologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Revisões Sistemáticas como Assunto , Resultado do Tratamento , Uremia/diagnóstico , Uremia/etiologiaRESUMO
Chemical forms of Cr, Cu, Mn, Ni, Pb and Zn in the surface sediments of Nansihu Lake and its main inflow rivers are determined by the BCR sequential extraction method. The chemical fractionation composition characteristics, pollution state and potential ecological effects of the heavy metals are discussed. Cr, Cu, Ni and Zn in the sediments of Sihe River, Jinghang Canal, Zhuzhaoxin River, Guangfu River, south area of the Upper Lakes, and Down Lakes mainly exist in residual fraction, which account for 80% - 90% of their content, mainly reflecting the natural characteristics of the heavy metals; but for the sediment of Old Canal, Guangfu River estuary, Baima River, nearly 80% of Cr, Cu, Ni and Zn exist in extractable fractions due to human pollution, especially with high oxidizable and acid extractable fractions content. Pb and Mn mainly exist in residual fraction and oxidizable fraction in the sediment of Nansihu Lake and its main inflow rivers, which account for 95% and 70% of the content of Pb and Mn, similar to other unpolluted sediments. With the mineralization and decomposition of organic matter and change of environment condition of the surface sediment, the extractable fractions of Cr, Cu, Ni, Zn in the polluted sediment can be reactivated, bringing on ecological harm to the water ecological system.