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BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a critical stage in the progression of non-alcoholic fatty liver disease (NAFLD), characterized by obvious inflammation and fibrosis. Because of its high incidence rate and serious consequences, NASH is becoming a global health problem. The influence of endotoxin translocation on NASH is receiving attention. As a traditional Chinese herb that effectively improves hepatic inflammation, Fructus Aurantii (Quzhou origin, FAQ) is widely used in the clinical treatment of NASH. However, the intervention mechanism of FAQ on reg3g and related endotoxin translocation remains unclear. AIM: To study the mechanism of the impact by which ileal regenerating family member 3 gamma (reg3g) deficiency and subsequent endotoxin translocation impact the progression of NASH; To elucidate the efficacy and mechanism of FAQ in the treatment of NASH. METHODS: Clinical serum, ileal tissue, and dynamic NASH model-related analyses collectively confirmed that reg3g is a pivotal gene associated with NASH. Reg3g-/- mice were used to assess the impact of reg3g on liver injury, inflammation, and fibrosis, as well as the underlying mechanism involved. In vitro studies elucidated the regulatory effects of FAQ on reg3g, intestinal barrier function, and intestinal permeability. Subsequently, the efficacy of FAQ was investigated in NASH mouse models. Pathological examinations combined with Western blotting (WB), immunohistochemistry (IHC), and multiplex immunohistochemical (mIHC) analyses were used to evaluate the effects of FAQ on mucosal repair and barrier function. Transepithelial electrical resistance (TEER), fluorescein isothiocyanate-dextran 4 (FD-4) experiments, coupled with enzyme linked immunosorbent assay (ELISA) and chromogenic LAL endotoxin assay were used to confirm intestinal permeability and endotoxin translocation. The results of WB and mIHC reflected the levels of endotoxin recruitment and M1 macrophage polarization in the liver. Parameters such as body weight, transaminases, and cholesterol were utilized to assess the metabolic effects of FAQ. RESULTS: Decreased expression of reg3g was associated with the progression of NASH. Ileal deficiency in reg3g resulted in damage to the intestinal barrier and permeability, leading to the recruitment of endotoxins via the 'gut-liver' axis to the liver, causing the polarization of M1 macrophages, release of inflammatory factors, excessive inflammation, and activation of hepatic stellate cells (HSCs), leading to fibrosis. FAQ significantly upregulated ileal reg3g expression and the expression of intestinal barrier-related proteins tight junction protein 1 (ZO-1) and occludin (OLCN) in mice (p < 0.05), thereby improving intestinal barrier function and permeability. Reduced intestinal permeability led to decreases in endotoxins entering the bloodstream and accumulating in the liver (p < 0.05). The expression of CD68 suggested reduced polarization of M1 macrophages. Expression levels of actin alpha 2, smooth muscle actin (α-SMA) and extracellular matrix (ECM)-related proteins also decreased, indicating improved liver fibrosis. CONCLUSION: FAQ ameliorates NASH by upregulating the expression of reg3g. The upregulation of reg3g contributes to the repair of the intestinal barrier and permeability, reducing the recruitment of endotoxins and subsequent polarization of M1 macrophages, excessive inflammation, and fibrosis.
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Medicamentos de Ervas Chinesas , Íleo , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Proteínas Associadas a Pancreatite , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Camundongos , Masculino , Humanos , Íleo/efeitos dos fármacos , Íleo/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Modelos Animais de Doenças , Camundongos Knockout , Fígado/efeitos dos fármacos , Fígado/metabolismo , EndotoxinasRESUMO
BACKGROUND: Due to its high incidence and elevated mortality, hepatocellular carcinoma (HCC) has emerged as a formidable global healthcare challenge. The intricate interplay between gender-specific disparities in both incidence and clinical outcomes has prompted a progressive recognition of the substantial influence exerted by estrogen and its corresponding receptors (ERs) upon HCC pathogenesis. Estrogen replacement therapy (ERT) emerged for the treatment of HCC by administering exogenous estrogen. However, the powerful side effects of estrogen, including the promotion of breast cancer and infertility, hinder the further application of ERT. Identifying effective therapeutic targets for estrogen and screening bioactive ingredients without E2-like side effects is of great significance for optimizing HCC ERT. METHODS: In this study, we employed an integrative approach, harnessing data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, clinical paraffin sections, adenoviral constructs as well as in vivo studies, to unveil the association between estrogen, estrogen receptor α (ESR1) and HCC. Leveraging methodologies encompassing molecular dynamics simulation and cellular thermal shift assay (CETSA) were used to confirm whether ESR1 is a molecular target of DHT. Multiple in vitro and in vivo experiments were used to identify whether i) ESR1 is a crucial gene that promotes DNA double-strand breaks (DSBs) and proliferation inhibition in HCC, ii) Dihydrotanshinone I (DHT), a quinonoid monomeric constituent derived from Salvia miltiorrhiza (Dan shen) exerts anti-HCC effects by regulating ESR1 and subsequent DSBs, iii) DHT has the potential to replace E2. RESULTS: DHT could target ESR1 and upregulate its expression in a concentration-dependent manner. This, in turn, leads to the downregulation of breast cancer type 1 susceptibility protein (BRCA1), a pivotal protein involved in the homologous recombination repair (HRR) process. The consequence of this downregulation is manifested through the induction of DSBs in HCC, subsequently precipitating a cascade of downstream events, including apoptosis and cell cycle arrest. Of particular significance is the comparative assessment of DHT and isodose estradiol treatments, which underscores DHT's excellent HCC-suppressive efficacy without concomitant perturbation of endogenous sex hormone homeostasis. CONCLUSION: Our findings not only confirm ESR1 as a therapeutic target in HCC management but also underscores DHT's role in upregulating ESR1 expression, thereby impeding the proliferation and invasive tendencies of HCC. In addition, we preliminarily identified DHT has the potential to emerge as an agent in optimizing HCC ERT through the substitution of E2.
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Carcinoma Hepatocelular , Proliferação de Células , Quebras de DNA de Cadeia Dupla , Receptor alfa de Estrogênio , Neoplasias Hepáticas , Fenantrenos , Carcinoma Hepatocelular/tratamento farmacológico , Receptor alfa de Estrogênio/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Humanos , Proliferação de Células/efeitos dos fármacos , Fenantrenos/farmacologia , Animais , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Linhagem Celular Tumoral , Camundongos Nus , Masculino , Apoptose/efeitos dos fármacos , Camundongos , Células Hep G2 , Furanos , QuinonasRESUMO
The aging process significantly impacts the gastrointestinal tract and various bodily systems, exacerbating age-related diseases. Research suggests a correlation between an imbalance in intestinal flora and gut aging, yet the precise mechanism remains incompletely elucidated. Epigenetic modifications, particularly m6A methylation, play a pivotal role in driving aging and are closely associated with gut aging. Maintaining a healthy balance of intestinal microbes is contingent upon m6A methylation, which is believed to be crucial in the vicious cycle of gut aging and intestinal flora. This article highlights the importance of m6A methylation in the nexus between gut aging and flora. It proposes the potential for targeted m6A methylation to break the vicious cycle of gut aging and flora imbalance, offering novel perspectives on attenuating or reversing gut aging.
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Envelhecimento , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/fisiologia , Envelhecimento/genética , Envelhecimento/fisiologia , Envelhecimento/metabolismo , Animais , Metilação , Epigênese Genética , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologiaRESUMO
Colorectal cancer (CRC) has become a severe global health concern, with the thirdhigh incidence and secondhigh mortality rate of all cancers. The burden of CRC is expected to surge to 60% by 2030. Fortunately, effective early evidencebased screening could significantly reduce the incidence and mortality of CRC. Colonoscopy is the core screening method for CRC with high popularity and accuracy. Yet, the accuracy of colonoscopy in CRC screening is related to the experience and state of operating physicians. It is challenging to maintain the high CRC diagnostic rate of colonoscopy. Artificial intelligence (AI)assisted colonoscopy will compensate for the above shortcomings and improve the accuracy, efficiency, and quality of colonoscopy screening. The unique advantages of AI, such as the continuous advancement of highperformance computing capabilities and innovative deeplearning architectures, which hugely impact the control of colorectal cancer morbidity and mortality expectancy, highlight its role in colonoscopy screening.
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Inteligência Artificial , Neoplasias Colorretais , Humanos , Detecção Precoce de Câncer , Colonoscopia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , IncidênciaRESUMO
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has become a global health issue owing to its large disease population and high morbidity. We previously reported that the improvement in oxidative stress (OS) using pure total flavonoids from citrus (PTFC), flavonoids isolated from the peel of Citrus changshan-huyou Y.B. Chan, is a crucial strategy for NAFLD treatment. However, OS-associated intervention pathways in NAFLD remain unclear. METHODS: In this study, we used microRNA (miR)- and mRNA-sequencing to identify the pathway by which PTFC improve OS in NAFLD. Clinical data, mimic/inhibitor assays, and a dual-luciferase reporter assay were selected to verify the regulatory relationships of this pathway. Moreover, in vivo and in vitro experiments were used to confime the regulatory effect of PTFC on this pathway. RESULTS: miR-seq, mRNA-seq, and bioinformatics analyses revealed that the miR-137-3p/neutrophil cytosolic factor 2 (NCF2, also known as NOXA2)/cytochrome b-245 beta chain (CYBB, also known as NOX2) pathway may be a target pathway for PTFC to improve OS and NAFLD. Additionally, bivariate logistic regression analysis combining the serum and clinical data of patients revealed NOX2 and NOXA2 as risk factors and total antioxidant capacity (indicator of OS level) as a protective factor for NAFLD. miR-137-3p mimic/inhibitor assays revealed that the upregulation of miR-137-3p is vital for improving cellular steatosis, OS, and inflammation. Dual-luciferase reporter assay confirmed that NOXA2 acts as an miR-137-3p sponge. These results co-determined that miR-137-3p/NOXA2/NOX2 is an essential pathway involved in NAFLD pathogenesis, including lipid accumulation, OS, and inflammation. In vivo and in vitro experiments further confirmed that the miR-137-3p/NOXA2/NOX2 pathway is regulated by PTFC. CONCLUSION: PTFC alleviates OS and inflammation in NAFLD by regulating the miR-137-3p/NOXA2/NOX2 pathway.
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Citrus , MicroRNAs , Hepatopatia Gordurosa não Alcoólica , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Flavonoides/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Estresse Oxidativo , RNA Mensageiro/metabolismoRESUMO
Greying population is becoming an increasingly critical issue for social development. In advanced aging context, organismal multiple tissues and organs experience a progressive deterioration, initially presenting with functional decline, followed by structural disruption and eventually organ failure. The aging of the gut is one of the key links. Decreased gut function leads to reduced nutrient absorption and can perturb systemic metabolic rates. The degeneration of the intestinal structure causes the migration of harmful components such as pathogens and toxins, inducing pathophysiological changes in other organs through the "brain-gut axis" and "liver-gut axis". There is no accepted singular underlying mechanism of aged gut. While the inflamm-aging theory was first proposed in 2000, the mutual promotion of chronic inflammation and aging has attracted much attention. Numerous studies have established that gut microbiome composition, gut immune function, and gut barrier integrity are involved in the formation of inflammaging in the aging gut. Remarkably, inflammaging additionally drives the development of aging-like phenotypes, such as microbiota dysbiosis and impaired intestinal barrier, via a broad array of inflammatory mediators. Here we demonstrate the mechanisms of inflammaging in the gut and explore whether aging-like phenotypes in the gut can be negated by improving gut inflammaging.
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Microbioma Gastrointestinal , Microbiota , Humanos , Inflamação/metabolismo , Microbioma Gastrointestinal/fisiologia , FenótipoRESUMO
San-Huang-Chai-Zhu formula (SHCZF), originates from Da-Huang-Xiao-Shi decoction (DHXSD) for the treatment of jaundice as recorded in the Chinese traditional Chinese medicine book Jin Gui Yao Lue. In the clinic, SHCZF has been used to treat cholestasis-related liver disease by improving intrahepatic cholestasis, but the treatment mechanism has not been elucidated. In this study, 24 Sprague-Dawley (SD) rats were randomly assigned to the normal, acute intrahepatic cholestasis (AIC), SHCZF, and ursodeoxycholic acid (UDCA) groups. In addition, 36 SD rats were divided into dynamic groups, namely, normal 24 h, AIC 24 h, normal 48 h, AIC 48 h, normal 72 h, and AIC 72 h groups. Alpha-naphthylisothiocyanate (ANIT) was used to induce an AIC rat model. Serum biochemical indices and hepatic pathology were detected. Part of the hepatic tissues was used for sequencing, and others were used for subsequent experiments. Sequencing data combined with bioinformatics analysis were used to screen target genes and identify the mechanisms of SHCZF in treating AIC rats. Quantitative real-time PCR (qRT-PCR) and Western blotting (WB) were used to detect the RNA/Protein expression levels of screened genes. Rats in the dynamic group were used to determine the sequence of cholestasis and liver injury. High-performance liquid chromatography (HPLC) was used to determine the representative bioingredients of SHCZF. Sequencing and bioinformatics analysis suggested that IDI1 and SREBP2 are hub target genes of SHCZF to ameliorate ANTI-induced intrahepatic cholestasis in rats. The treatment mechanism is associated with the regulation of lipoprotein receptor (LDLr) to reduce cholesterol intake and 3-Hydroxy-3-Methylglutaryl-CoA reductase (HMGCR), and 3-Hydroxy-3-Methylglutaryl-CoA synthase 1 (HMGCS1) to decrease cholesterol synthesis. Animal experiments showed that SHCZF significantly reduced the expression levels of the above genes and proinflammatory cytokine lipocalin 2 (LCN2), inflammatory cytokines interleukin 1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α), thereby improving intrahepatic cholestasis and inflammation and liver injury.
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Shenqi pill (SQP), a famous traditional Chinese medicine (TCM) herbal formula derived from Jinguiyaolue (Synopsis of Prescriptions of the Golden Chamber), has long been used to treat kidney yang deficiency syndrome. According to the TCM treatment principle that the liver and kidney are homologies, the clinical use of SQP in the treatment of nonalcoholic steatohepatitis (NASH) has achieved a good effect. However, the active targeted genes and underlying mechanism remain unclear. In this study, we aimed to explore the treatment mechanism of SQP in NASH rats, which may further contribute to the in-depth exploration of SQP in clinical applications. Network pharmacology analysis was used to screen the target genes of SQP for NASH treatment based on public databases. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and protein-protein interaction (PPI) analysis were used to search for crucial target genes and mechanisms. UPLC-MS/MS was used to verify the active compounds of the SQP screened. The hepatic pathology and biochemical indicators of rats were used to judge the modeling results and the curative effect of SQP. Western blotting and qRT-PCR were used to verify the expression of crucial target genes at the protein and RNA levels, respectively. Network pharmacology analysis and bioinformatics analysis showed that PTGS2, JUN, MYC, and CDKN1A might be crucial target genes in the primary mechanism of SQP in treating NASH and improving the inflammatory response. The UPLC-MS/MS results confirmed that the hub active compound, quercetin, screened out through the TCMSP database, is indeed present in SQP. Hepatic injury and lipid metabolism indicators of NASH rats were significantly improved after SQP treatment. The results of WB and qRT-PCR showed that the expression of PTGS2, JUN, MYC, and CDKN1A was higher in NASH rats than in normal rats and decreased after SQP treatment. The expression of inflammatory cytokines (IL-1ß, IL-6, TNF-α) was reduced after SQP treatment, which confirmed that SQP could improve hepatic inflammation in rats. These results suggested that SQP could ameliorate NASH in rats, and that quercetin may be the critical active compound that exerts the therapeutic effect.
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Medicamentos de Ervas Chinesas , Hepatopatia Gordurosa não Alcoólica , Animais , Cromatografia Líquida , Ciclo-Oxigenase 2 , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Farmacologia em Rede , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Quercetina , Ratos , Espectrometria de Massas em TandemRESUMO
Background: The prevalence of NAFLD is increasing annually. The early diagnosis and control are crucial for the disease. Currently, metabolic indicators are always used clinically as an auxiliary diagnosis of NAFLD. However, the prevalence of NAFLD is not only increased in obese/metabolic-disordered populations. NAFLD patients with thin body are also increasing. Only using metabolic indicators to assist in the diagnosis of NAFLD may have some deficiencies. Continue to develop more clinical auxiliary diagnostic indicators is pressing. Methods: Machine learning methods are applied to capture risk factors for NAFLD in 365 adults from Zhejiang Province. Predictive models are constructed for NAFLD using fibrinolytic indicators and metabolic indicators as predictors respectively. Then the predictive effects are compared; ELISA kits were used to detect the blood indicators of non-NAFLD and NAFLD patients and compare the differences. Results: The prediction accuracy for NAFLD based on fibrinolytic indicators [Tissue Plasminogen Activator (TPA), Plasminogen Activator Inhibitor-1 (PAI-1)] is higher than that based on metabolic indicators. TPA and PAI-1 are more suitable than metabolic indicators to be selected to predict NAFLD. Conclusions: The fibrinolytic indicators have a stronger association with NAFLD than metabolic indicators. We should attach more importance to TPA and PAI-1, in addition to TC, HDL-C, LDL-C, and ALT/AST, when conducting blood tests to assess NAFLD.
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Aim: To investigate the treating effect of Yiqi-Bushen-Tiaozhi (YBT) recipe on nonalcoholic steatohepatitis (NASH) mice, determine whether the outcome was associated with gut microbiota, and clarify the regulating mechanism. Methods: NASH mice were induced by high-fat and high-fructose diets (HFFD). In the fifth week, mice in the YBT group were orally administrated YBT (22.12g·kg-1·d-1) daily for 12 weeks. Fresh stool of mice was collected at the 16th week for fecal 16S rDNA analysis. Hepatic pathology and biochemical indicators were used to reflect the improvement of YBT on hepatic inflammation and lipid metabolism in NASH mice. Quantitative real-time PCR (qRT-PCR) was used to verify the results of PICRUSt analysis. Results: Results of the pathological and biochemical index showed that YBT could improve NASH mice. Compared with improving inflammation and hepatocyte damage, YBT may be more focused on enhancing metabolic disorders in mice, such as increasing HDL-c level. The diversity and richness of the gut microbiota of NASH mice induced by HFFD are significantly different from the normal control (NC) group. After YBT treatment, the diversity and richness of the mice microbiota will be increased to similar NC mice. Intestinimonas, Acetatifactor, Alistipes, Intestinimonas, Acetatifactor, and Alistipes have the most significant changes in the class level. PICRUSt analysis was performed to predict genomic functions based on the 16S rDNA results and reference sequencing. The efficacy of YBT in the treatment of NASH can be achieved by regulating the diversity and richness of gut microbiota. PICRUSt analysis results showed that the most relevant function of the microbiota construction variations is α- Linolenic acid (ALA) metabolism. Results of qRT-PCR showed significant differences between groups in the expression of Fatty acid desaturase 1 (FADS1), Fatty acid desaturase 2 (FADS2), Acyl-CoA Oxidase 1 (ACOX1), and Acyl-CoA Oxidase 2 (ACOX2) related to ALA metabolism. The expression of the above genes will be inhibited in the liver and small intestine of the HFFD group mice, and the expression can be restored after YBT treatment. Conclusion: YBT could treat NASH mice by improving the diversity and richness of gut microbiota and further the improvement of ALA metabolism.
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Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Acil-CoA Oxidase/metabolismo , Animais , DNA Ribossômico , Dieta Hiperlipídica/efeitos adversos , Medicamentos de Ervas Chinesas/farmacologia , Ácidos Graxos Dessaturases , Frutose/efeitos adversos , Microbioma Gastrointestinal/fisiologia , Inflamação/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismoRESUMO
BACKGROUND The incidence of breast cancer is increasing annually. Obesity and metabolism are considered risk factors for breast cancer. Discovery of obesity- and metabolism-related breast cancer prognostic genes is imminent. MATERIAL AND METHODS We screened metabolism-related genes (MRG) from KEGG and downloaded the obese female dataset GSE151839 from GEO, which screened differentially-expressed genes (DEGs), seen as female obesity-related genes. The intersection of MRGs and DEGs was obesity-related metabolic genes (OMGs), verified by enrichment analysis. After downloading breast cancer data from TCGA, univariate Cox regression and log-rank P analyses were used to screen hub OMGs related to breast cancer prognosis. ROC curve and Kaplan-Meier (KM) plotter, GEPIA, and GENT2 databases were used to verify the hub OMGs at the RNA level. CPTAC and HLA databases were used to verify the hub OMGs at the protein level. RESULTS We screened 33 OMGs. The results of univariate Cox regression and log-rank P analysis showed 3 of 33 OMGs (ABCA1, LPIN1, HSD17B8) were associated with the prognosis of breast cancer patients. After verification with ROC, KM-plotter, and GEPIA, only HSD17B8 was related to breast cancer prognosis (overall/disease-free survival). Results of GENT2 showed the RNA expression of HSD17B8 in breast cancer subtypes with poor prognosis is significantly lower than that with good prognosis. Results of CPTAC and HLA databases showed that the protein expression level of HSD17B8 in breast cancer tissues was significantly lower than that in adjacent normal tissues. CONCLUSIONS HSD17B8 is a protective gene against breast cancer. The higher the expression of HSD17B8, the better the prognosis of breast cancer patients.
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Neoplasias da Mama/genética , Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica , Obesidade/genética , Oxirredutases/genética , Mapas de Interação de Proteínas/genética , Proteínas/genética , Transcriptoma/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/complicações , Neoplasias da Mama/metabolismo , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica/métodos , Genes MHC Classe I , Humanos , Obesidade/complicações , Obesidade/metabolismo , Oxirredutases/biossíntese , Prognóstico , Proteômica , Curva ROCRESUMO
Nonalcoholic fatty liver disease (NAFLD) develops rapidly in high-fat diet (HFD) fed Mongolian gerbil (Meriones unguiculatus). Here, we aim to explore the gene expression characteristics of Mongolian gerbil to better understand the underlying mechanism in this animal model. Mongolian gerbils were fed with normal diet or HFD for different periods. High-throughput sequencing was carried out on the hepatic mRNA and bioinformatics analysis was further performed. Eight hub genes Cd44, App, Cdc42, Cd68, Cxcr4, Csf1r, Adgre1, and Fermt3, which were involved in inflammation, fibrosis, and HCC were obtained. Four significant independent poor prognostic factors for HCC (GPC1, ARPC1B, DAB2, and CFL1) were screened out. qRT-PCR result showed that the above genes expressed high levels in different periods of modeling process. The findings of this study provide useful information for further studies on Mongolian gerbil NAFLD model.
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Hepatopatia Gordurosa não Alcoólica/etiologia , Transcriptoma , Animais , Carcinoma Hepatocelular/genética , Biologia Computacional/métodos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Gerbillinae , Cirrose Hepática/genética , Cirrose Hepática/patologia , Neoplasias Hepáticas/genética , Masculino , Hepatopatia Gordurosa não Alcoólica/patologia , Prognóstico , Mapas de Interação de Proteínas/genéticaRESUMO
BACKGROUND: In China, the prevalence and mortality of colorectal cancer (CRC) have always been high, and more than 95% of CRC cases have evolved from colorectal polyps (CPs), especially adenoma. Early detection and treatment of CPs through colonoscopy is essential to reduce the incidence of CRC. Helicobacter pylori (Hp) is regarded as a risk factor for gastritis and gastric cancer and may also be a risk factor for CPs and CRC. However, few studies based on vast clinical cases exist in China to clarify whether Hp is a risk factor for CPs and CRC, and whether Hp-positive patients need to undergo colonoscopy checks earlier. This article attempts to make up for that deficiency. METHOD: This cross-sectional study was conducted based on 13,037 patients without a treatment history of Hp who underwent their first gastroscopy and colonoscopy simultaneously at The First Affiliated Hospital of Zhejiang Chinese Medical University from January 2018 to December 2019. Pearson χ2 test and logistic regression were used to determine whether Hp is a risk factor for CPs and CRC. Multifactor analysis of variance was used to define the impact of Hp on CPs prevalence with different ages, sexes. RESULTS: For Chinese individuals, Hp is a risk factor for CPs and CRC. The odds ratio (OR) value are 1.228 (95% CI, 1.130 to 1.336) and 1.862 (95% CI 1.240-2.796), respectively. Hp-positive patients have a higher probability of multiple or large intestinal polyps. However, Hp infection does not increase the incidence of adenomas, nor does it affect the pathological type of adenomas. The OR of Hp on the risk of CPs was 1.432 (95%CI 1.275-1.608) for males but increased to 1.937 (95%CI 1.334-2.815) for those aged 35 to 40. For females, the results were similar. CONCLUSIONS: For the Chinese, Hp is a risk factor for CPs and CRC (OR>1); the infection of Hp increased CPs risk in Chinese of all ages, especially aged 35-40, suggesting that Hp-positive patients should undergo colonoscopy frequently.
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BACKGROUND: San-Huang-Chai-Zhu formula (SHCZF) has been used to improve cholestasis for many years. This study aims to predict the possible gene targets of SHCZF in treating acute intrahepatic cholestasis (AIC) in rats. MATERIALS AND METHODS: Eighteen SD rats were randomly assigned to the normal group, ANIT group, and ANIT + SHCZF group. Alpha-naphthylisothiocyanate (ANIT) was used to induce AIC. Serum biochemical indexes were detected in each group. After treatment, the livers were collected and used to extract RNA. The library was constructed by TruSeq RNA, sequenced by Illumina, and analyzed by various bioinformatics methods. qRT-PCR was used to verify the target genes related to the efficacy of SHCZF. RESULTS: Serum ALT, AST, ALP, and TBIL were significantly higher in the ANIT group than in the normal group. Serum ALT and AST levels in the ANIT + SHCZF group were substantially lower than those in the ANIT group. A total of 354 intersected genes were screened by expression level correlation and PCA analysis, GO and KEGG pathway enrichment analysis, and WGCNA and STEM analysis. Then, 4 overlapping genes were found by pathway/BP/gene network construction. SHCZF reversed the downregulation of expression of CYP4A1 and HACL1 and the upregulation of expression of DBI and F11R induced by ANIT. In addition, the qRT-PCR result showed that mRNA expression of CYP4A1, HACL1, and F11R genes in the liver was consistent with the prediction result of bioinformatics analysis. CONCLUSION: CYP4A1, HACL1, and F11R are genes related to the occurrence of ANIT-induced AIC in rats and may be considered as targets of SHCZF for the treatment of AIC.
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Gut microbiota (GM) dysbiosis and bile acid (BA) metabolism disorder play an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Probiotics had a beneficial effect on NAFLD, but further study is needed to explore probiotics as a potential therapeutic agent to NAFLD. The aim of this study was to investigate the regulatory effect of probiotics on gut microbiota in NAFLD rats and to explore the possible mechanism of probiotics regulating the bile acid receptor farnesoid X receptor/growth factor 15 (FXR/FGF15) signaling pathway in rats. We established a rat model of NAFLD fed with a high-fat diet (HFD) for 14 weeks, which was given different interventions (312 mg/kg/day probiotics or 10 mg/kg/day atorvastatin) from the 7th week. Serum lipids and total bile acids (TBA) were biochemically determined; hepatic steatosis and lipid accumulation were evaluated with HE staining. The expression levels of FXR, FGF15 mRNA, and protein in rat liver were detected. 16S rDNA was used to detect the changes of gut microbiota in rats. Compared with the HFD group, probiotics and atorvastatin significantly reduced serum lipids and TBA levels. And probiotics increased dramatically the expression of FXR, FGF15 mRNA, and protein in the liver. But there were no significant changes in the atorvastatin group. Probiotics and atorvastatin can upregulate the diversity of gut microbiota and downregulate the abundance of pathogenic bacteria in NAFLD model rats. In summary, probiotics alleviated NAFLD in HFD rats via the gut microbiota/FXR/FGF15 signaling pathway.
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Microbioma Gastrointestinal/imunologia , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Probióticos/administração & dosagem , Animais , Ácidos e Sais Biliares/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Fígado/imunologia , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ratos , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/imunologiaRESUMO
Excessive alcohol intake is a direct cause of alcoholic liver disease (ALD). ALD usually manifests as fatty liver in the initial stage and then develops into alcoholic hepatitis (ASH), fibrosis and cirrhosis. Severe alcoholism induces extensive hepatocyte death, liver failure, and even hepatocellular carcinoma (HCC). Currently, there are few effective clinical means to treat ALD, except for abstinence. Natural compounds are a class of compounds extracted from herbs with an explicit chemical structure. Several natural compounds, such as silymarin, quercetin, hesperidin, and berberine, have been shown to have curative effects on ALD without side effects. In this review, we pay particular attention to natural compounds and developing clinical drugs based on natural compounds for ALD, with the aim of providing a potential treatment for ALD.
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With the continuous improvement of living standards but the lack of exercise, aging-associated metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD) are becoming a lingering dark cloud over society. Studies have found that metabolic disorders are near related to glucose, lipid metabolism, and cellular aging. Fibroblast growth factor 21 (FGF21), a member of the FGFs family, efficiently regulates the homeostasis of metabolism and cellular aging. By activating autophagy genes and improving inflammation, FGF21 indirectly delays cellular aging and directly exerts anti-aging effects by regulating aging genes. FGF21 can also regulate glucose and lipid metabolism by controlling metabolism-related genes, such as adipose triglyceride lipase (ATGL) and acetyl-CoA carboxylase (ACC1). Because FGF21 can regulate metabolism and cellular aging simultaneously, FGF21 analogs and FGF21 receptor agonists are gradually being valued and could become a treatment approach for aging-associated metabolic diseases. However, the mechanism by which FGF21 achieves curative effects is still not known. This review aims to interpret the interactive influence between FGF21, aging, and metabolic diseases and delineate the pharmacology of FGF21, providing theoretical support for further research on FGF21.
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BACKGROUND: Apoptosis-related genes(Args)play an essential role in the occurrence and progression of hepatocellular carcinoma(HCC). However, few studies have focused on the prognostic significance of Args in HCC. In the study, we aim to explore an efficient prognostic model of Asian HCC patients based on the Args. METHODS: We downloaded mRNA expression profiles and corresponding clinical data of Asian HCC patients from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. The Args were collected from Deathbase, a database related to cell death, combined with the research results of GeneCardsãNational Center for Biotechnology Information (NCBI) databases and a lot of literature. We used Wilcoxon-test and univariate Cox analysis to screen the differential expressed genes (DEGs) and the prognostic related genes (PRGs) of HCC. The intersection genes of DEGs and PGGs were seen as crucial Args of HCC. The prognostic model of Asian HCC patients was constructed by least absolute shrinkage and selection operator (lasso)- proportional hazards model (Cox) regression analysis. Kaplan-Meier curve, Principal Component Analysis (PCA) analysis, t-distributed Stochastic Neighbor Embedding (t-SNE) analysis, risk score curve, receiver operating characteristic (ROC) curve, and the HCC data of ICGC database and the data of Asian HCC patients of Kaplan-Meier plotter database were used to verify the model. RESULTS: A total of 20 of 56 Args were differentially expressed between HCC and adjacent normal tissues (p < 0.05). Univariate Cox regression analysis showed that 10 of 56 Args were associated with survival time and survival status of HCC patients (p < 0.05). There are seven overlapping genes of these 20 and 10 genes, including BAK1, BAX, BNIP3, CRADD, CSE1L, FAS, and SH3GLB1. Through Lasso-Cox analysis, an HCC prognostic model composed of BAK1, BNIP3, CSE1L, and FAS was constructed. Kaplan-Meier curve, PCA, t-SNE analysis, risk score curve, ROC curve, and secondary verification of ICGC database and Kaplan-Meier plotter database all support the reliability of the model. CONCLUSIONS: Lasso-Cox regression analysis identified a 4-gene prognostic model, which integrates clinical and gene expression and has a good effect. The expression of Args is related to the prognosis of HCC patients, but the specific mechanism remains to be further verified.
Assuntos
Proteínas Reguladoras de Apoptose/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Povo Asiático/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Proteína de Suscetibilidade a Apoptose Celular/genética , Proteína de Suscetibilidade a Apoptose Celular/metabolismo , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Receptor fas/genética , Receptor fas/metabolismoRESUMO
BACKGROUND: Our previous studies found that Pure total flavnoids from citrus (PTFC) can effectively improve non-alcoholic steatohepatitis (NASH) in mice. Here, we discuss on the mechanism of PTFC in treating NASH with focus on the regulation of the gut microbiota and bile acid metabolism. METHODS: C57BL/6 J mice were randomly divided into three groups: normal diet group (Normal), high-fat diet group (HFD) and high-fat + PTFC treatment group (PTFC). Mice in the Normal group were fed chow diet, while the other groups were fed high fat diet (HFD) for 16 weeks. In the 5th week, the mice in the PTFC group were treated with 50 mg/kg/day PTFC for an additional twelve weeks. After sacrifice, histopathology of the liver was assessed, and the gut microbial composition was analyzed by 16S rDNA gene sequencing. Bile Acid profiles in serum were determined by ultraperformance liquid chromatography (UPLC-MS/MS). RESULTS: PTFC intervention significantly attenuated HFD-induced NASH symptoms compared with the HFD group in mice. 16S rDNA sequencing showed that PTFC treatment increased the phylogenetic diversity of the HFD-induced microbiota dysbiosis. PTFC intervention significantly increased the relative abundances of Bacteroidaceae and Christensenellaceae. Furthermore, PTFC reduced the content of toxic bile acids, such as TDCA, DCA, TCA, CA and increased the ratio of secondary to primary bile acids. FXR and TGR5 deficiency were significantly alleviated. CONCLUSION: PTFC can improve NASH via the the gut microbiota and bile acid metabolism.