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To determine their involvement in the onset of the disease, we investigated the changing levels of liver fibrosis-related proteins, namely, type-I collagen, α-smooth muscle actin (α-SMA), and transforming growth factor ß1 and ß3 (TGF-ß1, ß3). The four groups of Sprague-Dawley (SD) rats were involved in the study, namely, (i) normal control group, (ii) high-fat diet group (HFD), (iii) carbon tetrachloride (CCl4) group, and (iv) NAFLD group (animal model) which were chosen at random. The NAFLD model received HFD combined with subcutaneous injection of small doses of CCl4. Histopathological examination confirmed extent of liver fibrosis, while other immunological and molecular methods were used to evaluate expression and distribution of α-SMA, type I collagen TGF-ß1 and TGF-ß3, at both m-RNA and protein levels. In contrast to the normal control group, the NAFLD group showed moderately elevated expressions of TGF-ß1, α-SMA, and type I collagen, which was proportional on temporal scale of NAFLD persistence in the model (P < 0.05). In the early phage of NAFLD, enhancement in the mRNA transcripts and, henceforth, protein expression of TGF-ß3 was observed. However, these were found to be downregulated in case of liver fibrosis (P < 0.05). This NAFLD rat model shows the histopathologic changes of human NAFLD and is suitable for the study of NAFLD pathogenesis. These findings suggest that type I collagen and the liver fibrosis-related factors TGF- ß1, TGF- ß3, and α-SMA may be significant contributors to NAFLD. Although NAFLD model is previously demonstrated by other researchers, our study is novel in terms of exploration of involvement of fibrosis-related factors and in particular aforementioned proteins at the early stage of NAFLD vis-à-vis dynamics of type-I collagen distribution.
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Bone morphogenetic protein (BMP)-9, a member of the TGFß-family of cytokines, is believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly diagnosed diabetic patients and BMP-9 overexpression ameliorated steatosis in the high fat diet-induced obesity mouse model. Furthermore, injection of BMP-9 in mice enhanced expression of fibroblast growth factor (FGF)21. However, whether BMP-9 also regulates the expression of the related FGF19 is not clear. Because both FGF21 and 19 were described to protect the liver from steatosis, we have further investigated the role of BMP-9 in this context. We first analyzed BMP-9 levels in the serum of streptozotocin (STZ)-induced diabetic rats (a model of type I diabetes) and confirmed that BMP-9 serum levels decrease during diabetes. Microarray analyses of RNA samples from hepatic and intestinal tissue from BMP-9 KO- and wild-type mice (C57/Bl6 background) pointed to basal expression of BMP-9 in both organs and revealed a down-regulation of hepatic Fgf21 and intestinal Fgf19 in the KO mice. Next, we analyzed BMP-9 levels in a cohort of obese patients with or without diabetes. Serum BMP-9 levels did not correlate with diabetes, but hepatic BMP-9 mRNA expression negatively correlated with steatosis in those patients that did not yet develop diabetes. Likewise, hepatic BMP-9 expression also negatively correlated with serum LPS levels. In situ hybridization analyses confirmed intestinal BMP-9 expression. Intestinal (but not hepatic) BMP-9 mRNA levels were decreased with diabetes and positively correlated with intestinal E-Cadherin expression. In vitro studies using organoids demonstrated that BMP-9 directly induces FGF19 in gut but not hepatocyte organoids, whereas no evidence of a direct induction of hepatic FGF21 by BMP-9 was found. Consistent with the in vitro data, a correlation between intestinal BMP-9 and FGF19 mRNA expression was seen in the patients' samples. In summary, our data confirm that BMP-9 is involved in diabetes development in humans and in the control of the FGF-axis. More importantly, our data imply that not only hepatic but also intestinal BMP-9 associates with diabetes and steatosis development and controls FGF19 expression. The data support the conclusion that increased levels of BMP-9 would most likely be beneficial under pre-steatotic conditions, making supplementation of BMP-9 an interesting new approach for future therapies aiming at prevention of the development of a metabolic syndrome and liver steatosis.
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Diabetes Mellitus Experimental , Fígado Gorduroso , Humanos , Ratos , Camundongos , Animais , Fator 2 de Diferenciação de Crescimento/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Fígado/metabolismo , Fígado Gorduroso/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: There is significant heterogeneity between gastroesophageal varices (GOV2) and isolated gastric varices (IGV1). The data on the difference between GOV2 and IGV1 are limited. AIM: To determine the etiology, clinical profiles, endoscopic findings, imaging signs, portosystemic collaterals in patients with GOV2 and IGV1. METHODS: Medical records of 252 patients with gastric fundal varices were retrospectively collected, and computed tomography images were analyzed. RESULTS: Significant differences in routine blood examination, Child-Pugh classification and MELD scores were found between GOV2 and IGV1. The incidence of peptic ulcers in patients with IGV1 (26.55%) was higher than that of GOV2 (11.01%), while portal hypertensive gastropathy was more commonly found in patients with GOV2 (22.02%) than in those with IGV1 (3.54%). Typical radiological signs of cirrhotic liver were more commonly observed in patients with GOV2 than in those with IGV1. In patients with GOV2, the main afferent vessels were via the left gastric vein (LGV) (97.94%) and short gastric vein (SGV) (39.18%). In patients with IGV1, the main afferent vessels were via the LGV (75.61%), SGV (63.41%) and posterior gastric vein (PGV) (43.90%). In IGV1 patients with pancreatic diseases, spleno-gastromental-superior mesenteric shunt (48.15%) was a major collateral vessel. In patients with fundic varices, the sizes of gastric/esophageal varices were positively correlated with afferent vessels (LGVs and PGVs) and efferent vessels (gastrorenal shunts). The size of the esophageal varices was negatively correlated with gastrorenal shunts in GOV2 patients. CONCLUSION: Significant heterogeneity in the etiology and vascular changes between GOV2 and IGV1 is useful in making therapeutic decisions.
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Lipotoxicity and unresolved oxidative stress are key drivers of metabolic inflammation in nonalcoholic steatohepatitis (NASH). cAMP-response element binding protein H(CREBH) is a liver-specific transcription factor and regulates the glucose and lipid metabolism of NASH. However, its role in mitochondrial oxidative stress and its association with sirtuin 3 (SIRT3), a master regulator of deacetylation for mitochondrial proteins, remains elusive. In this study, AML-12 cells were treated with palmitic acid to imitate the pathological changes of NASH in vitro and 8-week-old male C57BL/6J mice were fed with a high-fat (HF) diet or a methionine-choline-deficient (MCD) diet to build the widely accepted in vivo model of NASH. We found that lipid overload induced mitochondrial oxidative stress and stimulated the expression of CREBH and SIRT3. CREBH overexpression alleviated the mitochondrial oxidative stress. Moreover, CREBH promoted SIRT3 expression, which regulated the deacetylation of manganese superoxide dismutase (MnSOD) and inhibited NOD-Like Receptor Pyrin Domain Containing 3 (Nlrp3) inflammasome activation whereas suppression of SIRT3 damaged the protecting ability of CREBH in mitochondrial oxidative stress. CREBH knockout mice were highly susceptible to HF and MCD diet-induced NASH with more severe oxidative stress. Collectively, our results firstly provided the support that CREBH could serve as a protective factor in the progression of NASH by regulating the acetylation of MnSOD and the activation of Nlrp3 inflammasome through SIRT3. These results suggest that CREBH might be a valuable therapeutic candidate for NASH.
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Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hepatopatia Gordurosa não Alcoólica , Sirtuína 3 , Animais , Inflamassomos/genética , Inflamassomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo , Sirtuína 3/genética , Sirtuína 3/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismoRESUMO
INTRODUCTION AND OBJECTIVES: We performed a systematic review and meta-analysis to evaluate the prevalence of concomitant Sjögren's syndrome (SS) with primary biliary cholangitis (PBC) in adults and quantify the impact of SS on PBC. METHODS: PubMed, Web of Science and Cochrane library were searched using subject terms and predefined inclusion and exclusion criteria. RESULTS: Seventeen articles were included. The prevalence of SS in PBC patients ranged from 3.5 to 73% (35% pooled) (95% CI: 28-41%; p < 0.01). Seven studies included various biochemical indicators, including alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyltransferase (γ-GT), total bilirubin (TBiL), albumin (ALB) and platelet (PLT), and immunological indexes including IgG, IgM, antinuclear antibody (ANA), anti-mitochondrial antibody (AMA), AMA-M2 and anti-Ro/Sjögren's syndrome antigen A (SSA) antibodies. Meta-analysis showed that there were no significant differences in ALT, AST, ALP, γ-GT, TBiL and IgM levels between PBS and PBC with SS. Pooled analysis showed that ALB (MD=0.82; 95% CI: 0.08-1.56) and PLT (MD=30.41; 95% CI: 10.16-50.66) levels were lower, IgG levels (MD=-1.55; 95% CI: -2.39 to -0.72) were higher, and the positive ratios of ANA (RR=0.92; 95% CI: 0.87-0.98), AMA (RR=0.94; 95% CI: 0.89-0.98), AMA-M2 (RR=0.77; 95% CI: 0.70-0.85) and anti-Ro/SSA antibodies (RR=0.29; 95% CI: 0.08-1.01) were significantly higher in PBC patients with SS than in PBC patients. CONCLUSIONS: Our study confirms that SS is common in PBC. Comorbid SS appears to influence the clinical phenotype of PBC and may therefore influence the management of PBC.
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Cirrose Hepática Biliar , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/epidemiologia , Síndrome de Sjogren/complicações , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/epidemiologia , Autoanticorpos , Prevalência , Anticorpos Antinucleares , gama-Glutamiltransferase , Fosfatase Alcalina , Alanina Transaminase , Imunoglobulina M , Imunoglobulina GRESUMO
OBJECTIVE: To explore the anti-inflammatory effect of the traditional Chinese medicine Zhikang capsule (ZKC) on lipopolysaccharide (LPS)-induced RAW264.7 cells. METHODS: Safe concentrations of ZKC (0.175, 0.35, and 0.7 mg/mL) were used after the half-maximal inhibitory concentration (IC50) of RAW264.7 cells was calculated through the CCK-8 assay. In addition, the optimal intervention duration of ZKC (0.7 mg/mL) on RAW264.7 cells was determined to be 6 h, since all proinflammatory mediators [tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), inteleukin-6 (IL-6), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and monocyte chemotactic protein-1 (MCP-1)] had a decreasing tendency and relatively down-regulated mRNA expression levels as compared with other durations (4, 8, and 12 h). RAW264.7 cells were pretreated with ZKC at various concentrations (0.175, 0.35 and 0.7 mg/mL) for 6 h and then stimulated with LPS (1 µg/mL) for an additional 12 h. RESULTS: In terms of inflammation, ZKC could reverse LPS-induced upregulation of TNF-α, IL-1ß, IL-6, COX-2, iNOS, and MCP-1 at both the mRNA and protein levels in RAW264.7 cells in a dose-dependent manner. In terms of the NF-κB signaling pathway, ZKC could reduce phosphorylated p65 and promote M2 polarization of RAW264.7 cells under LPS stimulation in a dose-dependent manner. Moreover, ZKC exhibited a protective effect on macrophages from apoptosis. CONCLUSION: ZKC exhibited obvious antiinflammatory and anti-apoptotic effects on LPS-induced RAW264.7 cells at the cellular level, and a weakened NF-κB signaling pathway may be a potential significant target.
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Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Animais , Interleucina-1beta/metabolismo , Camundongos , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Background: Hepatocellular carcinoma (HCC) is the world's second most deadly cancer, and metabolic reprogramming is its distinguishing feature. Among metabolite profiling, variation in amino acid metabolism supports tumor proliferation and metastasis to the most extent, yet a systematic study on the role of amino acid metabolism-related genes in HCC is still lacking. An effective amino acid metabolism-related prediction signature is urgently needed to assess the prognosis of HCC patients for individualized treatment. Materials and Methods: RNA-seq data of HCC from the TCGA-LIHC and GSE14520 (GPL3921) datasets were defined as the training set and validation set, respectively. Amino acid metabolic genes were extracted from the Molecular Signature Database. Univariate Cox and LASSO regression analyses were performed to build a predictive risk signature. K-M curves, ROC curves, and univariate and multivariate Cox regression were conducted to evaluate the predictive value of this risk signature. Functional enrichment was analyzed by GSEA and CIBERSORTx software. Results: A nine-gene amino acid metabolism-related risk signature including B3GAT3, B4GALT2, CYB5R3, GNPDA1, GOT2, HEXB, HMGCS2, PLOD2, and SEPHS1 was constructed to predict the overall survival (OS) of HCC patients. Patients were separated into high-risk and low-risk groups based on risk scores and low-risk patients had lower risk scores and longer survival time. Univariate and multivariate Cox regression verified that this signature was an independent risk factor for HCC. ROC curves showed that this risk signature can effectively predict the 1-, 2-, 3- and 5-year survival times of patients with HCC. Additionally, prognostic nomograms were established based on the training set and validation set. These genes were closely correlated with the immune regulation. Conclusion: Our study identified a nine-gene amino acid metabolism-related risk signature and built predictive nomograms for OS in HCC. These findings will help us to personalize the treatment of liver cancer patients.
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Bone morphogenetic protein 9 (BMP9) is a recently discovered cytokine mainly secreted by the liver and is a member of the transforming growth factor ß (TGF-ß) superfamily. In recent years, an increasing number of studies have shown that BMP9 is associated with liver diseases, including nonalcoholic fatty liver disease (NAFLD), liver fibrosis and hepatocellular carcinoma (HCC), and BMP9 signaling may play dual roles in liver diseases. In this review, we mainly summarized and discussed the roles and potential mechanisms of BMP9 signaling in NAFLD, liver fibrosis and HCC. Specifically, this article will provide a better understanding of BMP9 signaling and new clues for the treatment of liver diseases.
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Fator 2 de Diferenciação de Crescimento/metabolismo , Hepatopatias/metabolismo , Transdução de Sinais , Animais , Humanos , Hepatopatias/patologia , Hepatopatias/terapiaRESUMO
Our previous study confirmed that bone morphogenetic protein 9 (BMP9) participated in the development of nonalcoholic steatohepatitis (NASH) by affecting macrophage polarization. The focus of this study was to further confirm the role of macrophages in BMP9-mediated NASH and to analyze the underlying mechanism. In vivo, mice that were administered adeno-associated viral (AAV) vectors containing a null transgene (AAV-null) or the BMP9 transgene (AAV-BMP9) were divided into methionine- and choline-deficient (MCD) and control diet (CD) groups, and they were administered either control liposomes or clodronate liposomes via tail vein injection, the latter to deplete macrophages. The mice were sacrificed after 4 weeks of MCD diet feeding. In vitro, RAW264.7 cells were pretreated with or without BAY11-7085 (an NF-κB inhibitor) and stimulated with recombinant human BMP9 (rh-BMP9). To explore the underlying mechanism of action of BMP9, primary human monocyte-derived macrophages were additionally investigated and immunohistochemistry, biochemical assays, qRT-PCR, and Western blotting were used. The characteristics of NASH-related inflammation were assessed by hepatic histological analysis. Serum AST and ALT and hepatic triglyceride were examined by biochemical assays. We found that the expression of M1 macrophage genes (including CD86, IL1ß, IL6, MCP-1 and TNFα) and the number of M1 macrophages (iNOS+ macrophages) in the liver were significantly elevated after BMP9 overexpression and BMP9 directly upregulated TLR4 expression in MCD-induced NASH. These effects were eliminated by macrophage depletion. In vitro, we discovered that BMP9 enhanced the nuclear translocation of NF-κB to induce macrophage M1 polarization in RAW264.7 cells and it promoted LPS-mediated activation of the NF-κB pathway in primary human macrophages. Taken together, this study demonstrates that BMP9 promotes NASH development by directly acting on macrophages.
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Fator 2 de Diferenciação de Crescimento/metabolismo , Macrófagos/imunologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Adenoviridae/genética , Animais , Diferenciação Celular , Colina/metabolismo , Citocinas/metabolismo , Dieta , Modelos Animais de Doenças , Regulação da Expressão Gênica , Vetores Genéticos/genética , Fator 2 de Diferenciação de Crescimento/genética , Humanos , Masculino , Metionina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica/imunologia , Células RAW 264.7 , Células Th1/imunologiaRESUMO
Resolvin D1 (RvD1) was previously reported to relieve inflammation and liver damage in several liver diseases, but its potential role in liver fibrosis remains elusive. The aim of our study was to investigate the effects and underlying mechanisms of RvD1 in hepatic autophagy in liver fibrosis. In vivo, male C57BL/6 mice were intraperitoneally injected with 20% carbon tetrachloride (CCl4, 5 ml/kg) twice weekly for 6 weeks to establish liver fibrosis model. RvD1 (100 ng or 300 ng/mouse) was added daily in the last 2 weeks of the modeling period. In vitro, lipopolysaccharide (LPS)-activated LX-2 cells were co-treated with increasing concentrations (2.5-10 nM) of RvD1. The degree of liver injury was measured by detecting serum AST and ALT contents and H&E staining. Hepatic fibrosis was assessed by masson's trichrome staining and metavir scoring. The qRT-PCR, western blot, immunohistochemistry, and immunofluorescence were applied to liver tissues or LPS-activated LX-2 cells to explore the protective effects of RvD1 in liver fibrosis. Our findings reported that RvD1 significantly attenuated CCl4 induced liver injury and fibrosis by decreasing plasma AST and ALT levels, reducing collagen I and α-SMA accumulation and other pro-fibrotic genes (CTGF, TIMP-1 and Vimentin) expressions in mouse liver, restoring damaged histological architecture and improving hepatic fibrosis scores. In vitro, RvD1 also repressed the LPS induced LX-2 cells activation and proliferation. These significant improvements mainly attributed to the inhibiting effect of RvD1 on autophagy in the process of hepatic stellate cell (HSC) activation, as demonstrated by decreased ratio of LC3-II/I and elevated p62 after RvD1 treatment. In addition, using AZD5363 (an AKT inhibitor that activates autophagy) and AZD8055 (an mTOR inhibitor, another autophagy activator), we further verified that RvD1 suppressed autophagy-mediated HSC activation and alleviated CCl4 induced liver fibrosis partly through AKT/mTOR pathway. Overall, these results demonstrate that RvD1 treatment is expected to become a novel therapeutic strategy against liver fibrosis.
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AIMS: Resolvin D1 (RvD1), a potent endogenous lipid mediator converted from docosahexaenoic acid (DHA), has exert anti-inflammatory and antioxidant effects in many preclinical disease models, but its potential role in non-alcoholic steatohepatitis (NASH) remains elusive. This study was performed to investigate the protective effects and mechanisms of RvD1 in NASH. MAIN METHODS: In vivo, male C57BL/6 mice were fed an MCD diet for 4 weeks to induce NASH. RvD1 was added in the last 2 weeks of the feeding period. In vitro, lipopolysaccharide (LPS)-activated RAW264.7 macrophages were pretreated with increasing concentrations of RvD1. Serum liver functional markers and hepatic oxidative stress indicators were measured biochemically. Mouse liver tissue sections were stained with hematoxylin-eosin, oil red O, and Masson's trichrome to assess the severity of steatohepatitis, steatosis and fibrosis. The qRT-PCR, immunohistochemistry and Western blotting assays were applied to analyse mechanisms underlying RvD1 protection in NASH. KEY FINDINGS: In vivo, RvD1 significantly attenuates steatohepatitis in MCD diet-fed mice by modulating key events, including steatosis, inflammation, oxidative stress and fibrosis in the progression of NASH. In vitro, RvD1 also represses LPS-induced inflammation in RAW264.7 cells. These effects may be mainly attributed to RvD1 markedly suppressing excessive inflammatory responses via the inhibition of the TLR4-MyD88-mediated NF-κB and MAPK signalling pathways as well as enhancing antioxidation capacity via the activation of the Nrf2 pathway. SIGNIFICANCE: These results demonstrate that RvD1 is a promising hepatoprotective agent for the therapy of NASH.
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Anti-Inflamatórios/uso terapêutico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/imunologia , NF-kappa B/imunologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Células RAW 264.7 , Receptor 3 Toll-Like/imunologiaRESUMO
INTRODUCTION: Cyclic adenosine monophosphate (AMP)-responsive element-binding protein H (CREBH), an endoplasmic reticulum-anchored transcription factor essential for lipid metabolism and inflammation in nonalcoholic fatty liver disease (NAFLD), is covalently modified by N-acetylglucosamine. Glycosylation is a ubiquitous type of protein involved in posttranslational modifications, and plays a critical role in various biological processes. However, the mechanism of glycosylated CREBH remains poorly understood in NAFLD. METHODS: CREBH glycosylation mutants were obtained by site-mutation methods. After transfection with plasmids, AML-12, LO2, or HepG2 cells were treated with palmitic acid (PA) proteolysis, tunicamycin (Tm), or their combination. Glycosyltransferase V (GnT-V) was used induce hyperglycosylation to further understand the effect of CREBH. In addition, glycosylation mutant mice and hyperglycosylated mice were generated by lentivirus injection to construct two kinds of NAFLD animal models. The expression of NAFLD-related factors was detected to further verify the role of N-linked glycosylation of CREBH in lipid and sterol metabolism, inflammation, and lipotoxicity. RESULTS: N-glycosylation enhanced the ability of CREBH to activate transcription and modulated the production of peroxisome proliferator-activated receptor alpha (PPARα) and stearoyl-CoA desaturase-1 (SCD-1) activity by affecting their promoter-driven transcription activity and protein interactions, leading to reduce lipid deposition and attenuate lipotoxicity. Deglycosylation of CREBH induced by Tm could inhibit the proteolysis of CREBH induced by PA. The addition of unglycosylated CREBH to cells upregulates gene and protein expression of lipogenesis, lipotoxicity, and inflammation, and aggravates liver damage by preventing glycosylation in cells, as well as in mouse models of NAFLD. Furthermore, increased N-glycosylation of CREBH, as achieved by overexpressing GnT-V could significantly improve liver lesion caused by unglycosylation of CREBH. CONCLUSION: These findings have important implications for the role of CREBH N-glycosylation in proteolytic activation, and they provide the first link between N-glycosylation of CREBH, lipid metabolism, and lipotoxicity processes in the liver by modulating PPARα and SCD-1. These results provide novel insights into the N-glycosylation of CREBH as a therapeutic target for NAFLD.
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Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação da Expressão Gênica , Lipídeos/toxicidade , Lipogênese , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , PPAR alfa/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/química , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Modelos Animais de Doenças , Glicosilação , Células HEK293 , Humanos , Metabolismo dos Lipídeos , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/genética , Estearoil-CoA Dessaturase/genéticaRESUMO
The homeostasis of mitochondrial functional state is intimately in relation with SIRT3 (sirtuin3). SIRT3, the deacetylase mainly anchored in mitochondria, acts as a modulator of metabolic regulation via manipulating the activity and function of downstream targets at post-translational modification levels. The features of energy sensing and ADP-ribose transference of SIRT3 have also been reported. Recently, accumulating SIRT3-focusing evidences have suggested its complicated role in a series of adverse events such as metabolic disorders, aging-related diseases, coupled with tumors, in which SIRT3 regulates the progress of corresponding biochemical reactions by targeting key mediators. By systematically summarizing the downstream deacetylated proteins of the SIRT3 axis, this review aims to give a comprehensive introduction to the main metabolic pathways and diseases of the molecules involved in acetylation modification, which is expected to provide a direction for further exploration of the pathogenesis and therapeutic targets of the above diseases.
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Mitocôndrias/genética , Mitocôndrias/metabolismo , Sirtuína 3/genética , Sirtuína 3/metabolismo , Acetilação , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Humanos , Metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/metabolismoRESUMO
OBJECTIVE: To investigate the overall performance of carbon nanoparticles (CNs) for detecting lymph nodes (LNs) and node metastasis during colorectal cancer surgery. METHODS: The English and Chinese literature was searched until 29 April 2020. Studies were included if they were randomized controlled trials (RCTs) for colorectal resection and LN dissection that compared the use of CNs with a blank control in colorectal cancer surgery. Quality assessment and data extraction were performed, and a meta-analysis was conducted using ReviewManager 5.3 and Stata 15.1 software. RESULTS: A total of 17 RCTs comprising 1241 patients were included for analysis. Compared with the outcomes of the blank controls, the use of CNs resulted in an average of 5.21 more LNs per patient (weighted mean differenceâ¯=â¯5.21, 95% confidence interval [CI]â¯=â¯4.14-6.29, p < 0.001) and a 68% higher detection rate of micro LNs (relative risk [RR]â¯=â¯1.68, 95% CIâ¯=â¯1.38-2.04, p < 0.001). In addition, more metastatic LNs were identified in stained nodes (RRâ¯=â¯1.56, 95% CIâ¯=â¯1.40-1.75, p < 0.001), but the total detection rate of metastatic nodes did not differ between the groups. CONCLUSION: CN is an effective lymphatic tracer in colorectal cancer surgeries. Further studies with larger sample sizes are needed to validate these findings.
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Neoplasias Colorretais/diagnóstico , Linfonodos/patologia , Metástase Linfática/diagnóstico , Nanopartículas/administração & dosagem , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Humanos , Período Intraoperatório , Excisão de Linfonodo/métodos , Metástase Linfática/patologia , Nanopartículas/química , Nanotubos de Carbono/química , Ensaios Clínicos Controlados Aleatórios como AssuntoAssuntos
COVID-19/diagnóstico , Gastroenteropatias/microbiologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , SARS-CoV-2RESUMO
Objective Recently, there have been several studies on the clinical characteristics of patients with coronavirus disease 2019 (COVID-19); however, these studies have mainly been concentrated in Wuhan, China; the sample sizes of each article were different; and the reported clinical characteristics, especially blood biochemical indices, were quite different. This study aimed to summarize the blood biochemistry characteristics of COVID-19 patients by performing a systemic review and meta-analysis of published studies. Methods Comprehensive studies were screened from PubMed, Embase, and Cochrane Library through March 11, 2020. The inclusion criteria included studies investigating the biochemical indexes of patients with COVID-19. The statistical software R3.6.3 was used for meta-analysis. Results Ten studies including 1745 COVID-19 patients met the inclusion criteria for our meta-analysis. Meta-analysis showed that 16% and 20% of patients with COVID-19 had alanine transaminase (ALT) and aspartate aminotransferase (AST) levels higher than the normal range, respectively. Thirty-four percent of patients showed albumin (ALB) levels lower than the normal range, and 6% of patients showed abnormal total bilirubin (TBil) levels. The levels of creatinine (CRE) were increased in 8% of patients. The creatine kinase (CK) level of 13% of patients exceeded the normal range, and 52% of patients had elevated lactate dehydrogenase (LDH) levels. In addition, six studies met the inclusion criteria for the systemic review evaluating the relevance between LDH levels and the severity of COVID-19, and all six studies showed a positive association between these two factors. Conclusions Some patients with COVID-19 had different degrees of blood biochemical abnormalities, which might indicate multiple organ dysfunction. Some biochemical indexes, such as abnormal ALB and LDH, could reflect the severity of the disease to a certain extent. These blood biochemical indicators should be considered in the clinical management of the disease.
Assuntos
Betacoronavirus , Análise Química do Sangue/estatística & dados numéricos , Técnicas de Laboratório Clínico/estatística & dados numéricos , Infecções por Coronavirus/sangue , Pneumonia Viral/sangue , COVID-19 , Teste para COVID-19 , Infecções por Coronavirus/diagnóstico , Humanos , L-Lactato Desidrogenase/sangue , Pandemias , Análise de Regressão , SARS-CoV-2 , Albumina Sérica Humana/análiseRESUMO
AIMS: The primary focus of this study was to explore the effects of cyclic AMP response element-binding protein H (CREBH) on the development of nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: CREBH knockout (KO) and wildtype (WT) mice were averagely divided into a methionine and choline-deficient (MCD) or high fat (HF) diet group and respective chow diet (CD) groups. Mice were sacrificed after 4-week treatment for MCD model and 24-week treatment for HF model. KEY FINDINGS: Characteristics of nonalcoholic steatohepatitis-related liver fibrosis in KO-MCD/HF group were verified by hepatic histological analyses. Compared with WT-MCD/HF group, levels of plasma ALT and hepatic hydroxyproline increased in KO-MCD/HF group. Significantly higher levels of MCP-1, αSMA, Desmin, COL-1, TIMP-1, TGF-ß1, TGF-ß2 were found while MMP-9 and FGF21 mRNA levels decreased in KO-MCD/HF group. There was also a distinct difference of mRNA levels of TNFα, CTGF and CCND1 in KO-HF group compared with controls. Protein levels of MCP-1, BAX, αSMA, COL-1, TGF-ß1 and SMAD2/3 significantly increased in KO-MCD/HF group and CCND1 was also upregulated in KO-HF group compared to their counterparts. SIGNIFICANCE: CREBH knockout may primarily regulate the TGF-ß1 signaling pathway via TGF-ß2 and FGF21 resulting in more severe inflammation and fibrosis in NAFLD.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Cirrose Hepática/genética , Hepatopatia Gordurosa não Alcoólica/genética , Fator de Crescimento Transformador beta/metabolismo , Alanina Transaminase/sangue , Animais , Deficiência de Colina , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/deficiência , Dieta Hiperlipídica , Fatores de Crescimento de Fibroblastos/biossíntese , Hidroxiprolina/metabolismo , Lipídeos/sangue , Cirrose Hepática/sangue , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Metionina/deficiência , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais/genéticaRESUMO
BACKGROUND AND AIMS: Scoparone has been shown to ameliorate many forms of liver disease, and several underlying molecular mechanisms involved have been previously revealed. However, the potential role of scoparone in autophagy, which is dysregulated in nonalcoholic fatty liver disease-nonalcoholic steatohepatitis (NAFLD-NASH), has not been evaluated. In the current study, we investigated the effect and potential mechanisms of scoparone in hepatic autophagy in mice with NASH. METHODS: In vivo, mice were fed a methionine-choline deficient (MCD) diet to establish a NASH model and then subjected to treatment with or without scoparone for 4 weeks. In vitro, scoparone was applied in a hepatocellular lipid overload model in AML12 cells challenged with palmitic acid (PA) and in lipopolysaccharide (LPS)-induced RAW264.7 cells. RESULTS: Scoparone improved impaired autophagy and several key features of NASH in mice fed an MCD diet. In vitro, scoparone had an effect on the autophagy of macrophages but not hepatocytes. In RAW264.7 cells, scoparone reduced the LPS-induced accumulation of autophagosomes and autophagy substrates, the production of reactive oxygen species (ROS) and the inflammatory response. Scoparone inhibited the upregulation of p62 transcription, which is mediated by the ROS/P38/Nrf2 axis. Chloroquine (CQ), an inhibitor of autophagic flux, significantly inhibited scoparone-mediated protection against inï¬ammation. In addition, scoparone suppressed activation of the PI3K/AKT/mTOR pathway, and MHY1485 (an mTOR activator that inhibits autophagy) inhibited the anti-inflammatory effect of scoparone. CONCLUSIONS: In LPS-induced macrophages, scoparone regulates autophagy and further suppresses inflammation by inhibiting the ROS/P38/Nrf2 axis and PI3K/AKT/mTOR pathway and enhancing autophagic flux. Scoparone may improve hepatic autophagy and NASH partly through enhancing autophagy in macrophages but not hepatocytes. Scoparone is expected to become a novel therapeutic drug for NASH or diseases associated with dysregulated autophagy in macrophages.
Assuntos
Autofagia/fisiologia , Cumarínicos/uso terapêutico , Fígado/metabolismo , Macrófagos/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Autofagia/efeitos dos fármacos , Colagogos e Coleréticos/farmacologia , Colagogos e Coleréticos/uso terapêutico , Cumarínicos/farmacologia , Relação Dose-Resposta a Droga , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fígado/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células RAW 264.7 , Espécies Reativas de Oxigênio/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND AND AIMS: Diagnostic performance of ascitic fluid total protein (AFTP) concentration remained unsettled. Our aim was to determine diagnostic value of AFTP in differential diagnosis of causes of ascites. METHODS: Seven hundred four consecutive patients with new-onset ascites were prospectively enrolled in this study. RESULTS: In the training cohort, diagnostic performance of quantitative AFTP assay was superior to that of Rivalta test in differential diagnosis of ascites. At the predetermined cut-off value of 25 g/L, quantitative AFTP assay was more useful in the differentiation of non-portal hypertensive ascites from portal hypertensive ascites compared with the exudate-transudate classification, area under curve of receiver operating characteristic curve was 0.958. Quantitative AFTP assay was superior to serum-ascites albumin gradient in the detection of non-portal hypertensive ascites, especially malignant ascites and tuberculous peritonitis. In mixed ascites, AFTP was useful in identifying peritoneal lesions. CONCLUSIONS: Ascitic fluid total protein is a useful marker in non-portal hypertensive ascites; thus, it should be determined in diagnostic work-up of the patients with ascites.
Assuntos
Ascite/diagnóstico , Ascite/etiologia , Líquido Ascítico/química , Proteínas/análise , Biomarcadores/análise , Diagnóstico Diferencial , Humanos , Hipertensão/complicaçõesRESUMO
BACKGROUND: MicroRNAs (miRNAs) are small noncoding single-stranded RNAs with a length of â¼21 nucleotides. Single nucleotide polymorphisms (SNPs) may affect the function of miRNAs, resulting in a variety of disorders in vivo. Recently, diabetes mellitus (DM) has become a global healthcare problem, and several studies have reported that 2 common polymorphisms (miRNA 146a rs2910164 and miRNA 27a rs895819) are related to susceptibility to diabetes. Given that no consensus had been reached regarding the association of the 2 polymorphisms with diabetes, we conducted this meta-analysis. METHODS: Four databases (PubMed, EMBASE, Cochrane, and Web of Science) were searched up to January 9, 2019. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the association strength. Subgroup and sensitivity analyses were also performed. RESULTS: Six studies involving 2585 cases and 2435 controls for miR146a rs2910164 and 5 studies involving 2922 cases and 2781 controls for miR27a rs895819 were ultimately analyzed in our meta-analysis. Based on pooled results, no statistical significance in association between rs2910164 and diabetes in Caucasians, Asians, or type 2 diabetes was observed in any genetic models. Nevertheless, we found a significant correlation between miRNA27a rs895819 and diabetes in the homozygote model (CC vs TT: ORâ=â0.58, 95%CI [0.35,0.98]) and recessive model (CC vs CTâ+âTT: ORâ=â0.59, 95%CI [0.36,0.97]). By performing subgroup analysis, we also observed that C allele conveyed a significant protective effect against diabetes development in Caucasians (C vs T: ORâ=â0.67, 95%CI [0.52,0.85]). CONCLUSION: In conclusion, this meta-analysis indicated that miRNA27a rs895819 might play a protective role in diabetes, and miRNA146a rs2910164 likely had no association with diabetes.