PLANTA MEDICA
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2020
·Vol. 86
·期 04
·255-266
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IF 2.687
Nan Xu,Xue Wu,Hui-Juan Luo,Fang-Fang Xu,Qiong-Hui Huang,Jia-Zhen Wu,Yu-Xuan Gan,Min-Yao Li,Zheng-Quan Lai,Hui-Ran Lin,Jian-Nan Chen,Zi-Ren Su,Wei-Peng Ai,Yu-Hong Liu
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. Nevertheless, no first-line therapy exists. Hepatic steatosis is the earliest stage of NAFLD, which is characterized by an accumulation of hepatic lipids. Patchouli oil (PO), which is isolated from the well-known Chinese herb named Pogostemon cablin (Blanco) Benth. (Lamiaceae), inhibits hepatic lipid accumulation effectively. However, its potential ability for the treatment of NAFLD had not been reported before. Thus, the objective of this study was to investigate the effectiveness of PO against hepatic steatosis and its underlying mechanisms. We used a high fat diet (HFD)-induced hepatic steatosis model of rats to estimate the effect of PO against NAFLD. Hematoxylin-eosin and oil red O staining were used to analyze the hepatic histopathological changes. ELISA, RT-qPCR, and Western blotting analysis were applied to evaluate the parameters for hepatic steatosis. Our results showed that PO significantly attenuated the lipid profiles and the serum enzymes, evidenced by quantitative and histopathological analyses. It also markedly down-regulated the expression of sterol regulatory element-binding protein 1 (SREPB-1c) with its downstream factors in de novo lipogenesis. And, likewise, in lipid export by very low-density lipoproteins (VLDL), related molecules were dramatically improved. Furthermore, PO observably normalized the aberrant peroxisome proliferator-activated receptor α (PPAR-α) signal in fatty acids oxidation. In conclusion, PO exerted a preventing effect against HFD-induced steatosis and might be due to decrease de novo lipogenesis, promote export of lipids, as well as owing to improve fatty acids oxidation.
研究领域:
药理学
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肝病学
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代谢性疾病
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2018
·
IF 3.457
Qingqing Yu,Yayun Liu,Yufei Wu,Yong Chen
Aims Curcumin is a polyphenol compound with many pharmacological activities including antioxidant, lipid-loweing and liver protective. Dihydrocurcumin (DHC) is one of the major metabolites of curcumin. So far, the pharmacological activity of DHC has not been reported. Here, we evaluate the effects of DHC on oleic acid (OA)-induced lipid accumulation, oxidative stress and insulin resistance and the underlying mechanism in L02 and HepG2 cells. Main methods OA-induced L02 and HepG2 cells were used as the in vitro model of nonalcoholic fatty liver disease (NAFLD). Lipid accumulation, oxidative stress, glucose uptake and cell inflammation were evaluated by cellular biochemical assay, respectively. Signaling pathways involved in lipid metabolism including peroxisome proliferator activated receptor-α (PPARα), the sterol regulatory element binding protein-1C (SREBP-1C) and patatin-like phospholipase domain containing 3 (PNPLA3), glucose uptake including phosphatidylinositol 3-kinase (PI3K) and phosphorylated serine-threonine protein kinase (pAKT), and oxidative stress including nuclear factor E2-related factor 2 (Nrf2), cytochrome P450 4A (CYP4A) and 2E1 (CYP2E1) were investigated by western blotting and RT-qPCR, respectively. Key findings DHC decreased the levels of cellular triglycerides (TG) by regulating the mRNA and protein expression levels of SREBP-1C , PNPLA3 and PPARα . At the same time, DHC improved the hepatocellular glucose uptake by increasing the protein expression levels of pAKT and PI3K. Furthermore, DHC reduced the levels of cellular NO and ROS via Nrf2 signaling pathways. Significance The present study firstly revealed that DHC ameliorated OA-induced steatosis through regulating the lipid metabolism, oxidative stress and insulin resistance in HepG2 and L02 cells.
研究领域:
药理学
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细胞生物学
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代谢
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肝脏疾病
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2021
·
IF 5.811
Hanqing Chen,Shuang Zhou,Meilin Zhu,Bing Wang,Wei Chen,Lingna Zheng,Meng Wang,Weiyue Feng
Gold nanoparticles (GNPs) have been used as a potential bioactive platform for drug delivery due to their unique optical and thermal characteristics. Liver is the main organ in orchestrating physiological homeostasis through metabolization of drugs and detoxification of exogenous substances. Therefore, it is crucial to deeply understand the mechanism of nanoparticle–liver interaction and the potential hepatic effects of GNPs in vivo . In this study, we studied the hepatic impacts of the intravenously injected polyethyleneimine (PEI)-modified GNPs (PEI-GNPs) on the expression of hepatic drug-metabolic enzymes and sterol responsive element binding protein 1c (SREBP-1c)-mediated de novo lipogenesis in mice for 24 h and 1 week. PEI-GNP accumulation in the liver is associated with increased liver inflammation, as evidenced by the gene expression of pro-inflammatory cytokines. Moreover, the GNP-induced hepatotoxicity in mice is partly due to liver inflammation–triggered disruption in the function of drug-metabolic enzymes, including hepatic uptake and efflux transporters, cytochrome P450 (CYP450), and UDP-glucuronosyltransferases (UGTs). The study provides evidence that it is necessary to consider the nanomaterial–liver interaction and manipulate the surface chemistry of GNPs prior to biomedical application of nanoparticles.
研究领域:
纳米技术
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药理学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2022
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IF 5.195
Fangfang Xu,Jun Wang,Pan Wang,Tao Hou,Han Zhou,Yaopeng Zhao,Jixia Wang,Yanfang Liu,Xinmiao Liang
Ursodeoxycholic acid (UDCA) is a safe bile acid effective in reducing hepatic steatosis in non-alcoholic fatty liver disease (NAFLD). However, the mechanism of action linked to this effect is poorly defined. In the present study, we identified that UDCA acted as a free fatty acid receptor 4 (FFA4) agonist with EC 50 of 10.4 ± 0.7 μM, and its activity was determined by dynamic mass redistribution, fluorometric imaging plate reader, inositol monophosphate and bioluminescence resonance energy transfer assays. Moreover, UDCA showed FFA4 selectivity over eleven other G protein-coupled receptors. Real-Time PCR and immunocytochemistry analyses showed that FFA4 was abundantly expressed in human hepatocytes HuH-7 cells. In an in vitro model of NAFLD induced by oleic acid (OA), UDCA downregulated lipid accumulation in HuH-7 cells and suppressed sterol-regulatory element binding protein-1c (SREBP-1c) mRNA expression. This suppression of SREBP-1c was restored when FFA4 expression was knocked down in siRNA assay. In a mouse model of hepatic steatosis, db/db mice were exposed to a high-fat diet (HFD), and treatment of UDCA or docosahexaenoic acid (DHA, an endogenous FFA4 agonist) effectively prevented body weight gain and hepatic fat deposition and reduced triglyceride (TG) levels in serum and liver. This study not only identified a new skeleton of FFA4 agonists, but also demonstrated that FFA4 signal was accounting for the protective effects of UDCA in the NAFLD treatment.
研究领域:
药理学
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肝病学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
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2019
·
IF 3.061
Jianying Bai,Zhen He,Yaofu Li,Xuexia Jiang,Hongmei Yu,Qing Tan
Mono-2-ethylhexyl phthalate (MEHP) is a major bioactive metabolite in the widely used industrial plasticizer diethylhexyl phthalate (DEHP) that has been found to be toxic to the liver. The aim of this study is to determine whether MEHP exposure can change the expression of fatty acid metabolism-related genes in HepG2 cells, which might be related to non-alcoholic fatty liver disease (NAFLD). The results revealed that exposure to MEHP promoted lipid accumulation in HepG2 cells. The levels of intracellular triglycerides in the hepatocytes increased after exposure to 0.8–100 μM MEHP for 24 h and 48 h. The genetic expressions of SREBP-1c, ChREBP, ACC1, FASN, and SCD significantly increased at 6 h after exposure to MEHP. At 24 h, the expression of the SREBP-1c and ChREBP genes remained increased, while the expression of the FASN and SCD genes decreased. At 48 h, the expression of SREBP-1c, ChREBP, ACC1, FASN, and SCD decreased. Furthermore, the levels of proteins including ACC1, FASN, SCD, and ChREBP (except SREBP-1c) increased at 24 h. These findings suggest that MEHP exposure can promote fatty acid synthesis in hepatocytes by regulating the expression of relevant genes and proteins, contributing to NAFLD.
研究领域:
毒理学
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细胞生物学
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分子生物学
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肝病学
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产品关联
DOI
PubMed
高影响因子
Food Science and Human Wellness
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2022
·
IF 8.022
Peng Ma,Rongrong Huang,Yu Ou
Soy glycinin derived octapeptide (SGP8) is a peptide obtained from degradation of the soy glycinin, whose amino acid sequence is IAVPGEVA. To determine the effect of SGP8 on non-alcoholic fatty liver disease (NAFLD), steatosis HepG2 cells were induced by 1 mmol/L free fatty acid (FFA) and C57BL/6J mice were fed with methionine-choline deficient (MCD) diet for 3 weeks to establish NAFLD model. The results of oil red O staining and total cholesterol (TC)/triglyceride (TG) contents showed that SGP8 could significantly reduce the lipid content of steatosis HepG2 cells. In vivo , SGP8 lowered plasma alanine aminotransferase (ALT) and low density lipoprotein (LDL) content, normalized hepatic superoxide dismutase (SOD) and malondialdehyde (MDA) production, and reduced the severity of liver inflammation. The results of Western blotting showed that SGP8 increased expression of Sirtuin-1 (SIRT1) and phosphorylation level of AMP activated protein kinase (AMPK) in hepatocytes. Through activation of SIRT1/AMPK pathway, SGP8 downregulated the expression of sterol regulatory element binding protein 1c (SREBP-1c) and its target genes ACC and FAS expression levels, and increased the phosphorylation level of acetyl CoA carboxylase (ACC). Furthermore, SGP8 also upregulated the expression of transcription factor peroxisome proliferator activated receptor α (PPARα), which was regulated by SIRT1/AMPK pathway, and its target gene CPT1 level. In conclusion, SGP8 might improve NAFLD by activating the SIRT1/AMPK pathway. Our data suggest that SGP8 may act as a novel and potent therapeutic agent against NAFLD.
研究领域:
药理学
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分子生物学
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肝病学
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DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2021
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IF 5.279
Ruiqian Duan,Xiao Guan,Kai Huang,Yu Zhang,Sen Li,Ji’an Xia,Meng Shen
A high-fat diet (HFD) causes hyperlipidemia, which worsens disturbances in bile acid (BA) metabolism and gut microbiota. This study aimed to investigate the regulation of flavonoids from whole-grain oat (FO) on BA metabolism and gut microbiota in HFD-induced hyperlipidemic mice. The experiment results showed that FO improved serum lipid profiles and decreased body weight and lipid deposition in HFD-fed mice. Through real-time qualitative polymerase chain reaction (RT-qPCR) and Western blot assays, by up-regulating the expression of PPARα, CPT-1, CYP7A1, FXR, TGR5, NTCP, and BSTP, and down-regulating those of SREBP-1c, FAS, and ASBT, FO suppressed lipogenesis, promoted lipolysis and BA synthesis, and efflux to faeces via the FXR pathway. 16s rRNA sequencing revealed that FO significantly increased Akkermansia and significantly decreased Lachnoclostridium, Blautia, Colidextribacter, and Desulfovibrio. Spearman’s correlation analysis showed that these bacteria were strongly correlated with hyperlipidemia-related parameters. Therefore, our results indicated that FO possessed an antihyperlipidemic effect via regulating the gut–liver axis, i.e., BA metabolism and gut microbiota.
研究领域:
营养学
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生物化学
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微生物学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
LIFE SCIENCES
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2019
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IF 3.448
Sijing Dong,Jianbo Ji,Lingyun Hu,Haina Wang
Aims We previously reported that Hovenia dulcis Thunb. extract, a traditional Chinese medicine rich in dihydromyricetin (DHM), exhibited a significant hepatoprotective effect against acetaminophen (APAP)-induced liver injury. However, whether DHM plays a protective role in APAP hepatotoxicity and what mechanisms are involved remain unclear. In this study, we evaluated the hepatoprotective effects of DHM against APAP-induced liver injury. Main methods Male C57BL/6 mice were used for the experiment. LC-MS, q-PCR, immunochemistry and western blot analysis were employed to mechanism analysis. Key findings DHM exhibited a protective effect against APAP-induced liver injury. Further mechanistic investigations revealed that the protective effect of DHM against APAP hepatotoxicity had multi-target and multi-pathway characteristics involving APAP metabolism, lipid regulation, and hepatocyte death and regeneration. DHM pretreatment resulted in cytochrome P450 2E1 inhibition and UDP-glucuronosyltransferase 1A1 activation, affecting APAP biotransformation. Moreover, DHM pretreatment significantly ameliorated lipid dysregulation via peroxisome proliferator-activated receptor and sterol regulatory element-binding protein-1c (SREBP-1c) signalling pathways. Furthermore, DHM regulated the expression of cell death- and liver regeneration-associated proteins. Significance These results suggested that DHM alleviated APAP-induced liver injury in mice by inhibiting hepatocyte death, promoting p53-related regeneration, and regulating lipid homeostatic imbalance and APAP transformation. Based on these findings, DHM provides a potential and novel approach for preventing and treating APAP-induced liver damage, and SREBP-1c signalling might be a new therapeutic target for APAP hepatotoxicity.
研究领域:
药理学
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毒理学
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肝病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Food & Function
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2017
·Vol. 8
·期 12
·4496-4507
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IF 3.247
Daorui Pang,Lijun You,Lin Zhou,Tong Li,Bisheng Zheng,Rui Hai Liu
The objective of the present study is to investigate the hepatic steatosis relieving effect of Averrhoa carambola free phenolic extract (ACF) on leptin receptor-deficient (db/db) mice and elucidate the modulation hepatic lipogenesis mechanisms. The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) assays, accompanying hematoxylin and eosin (H&E) staining, were applied to identify the alleviation of liver histopathological changes. Serum and hepatic lipid assays, combined with oil red O staining, were used to investigate the amelioration of lipid accumulation. Further assessments by quantitative real-time PCR and western blot assays were used to elucidate the suppression of the fatty acid and triglyceride (TG) synthesis mechanisms underlying ACF protection. These results indicated that ACF treatment significantly reduced the liver TG of db/db mice (p < 0.05). The mechanisms are partly through phosphorylation of AMPK α and down-regulation of SREBP-1c expression, and further down-regulation of FAS and SCD1 (p < 0.05). In addition, the expression levels of mircoRNA-34a and mircoRNA-33, which modulate this signaling pathway, were significantly down-regulated by ACF treatment (p < 0.05). Collectively, these results revealed that ACF exhibited a potent hepatic steatosis relieving effect partly by inhibiting the signal transduction of hepatic lipogenesis.
研究领域:
药理学
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分子生物学
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肝病学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2019
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IF 4.784
Jixu Wu,Huarong Shao,Jinhua Zhang,Yong Ying,Yanling Cheng,Dan Zhao,Xixi Dou,Huimin Lv,Shuaiguang Li,Fei Liu,Peixue Ling
We isolated and characterized a Mussel polysaccharide, α -D-glucan (MP-A), from Mytilus coruscus earlier. In this work, the pharmacological activity and mechanisms of MP-A as an oral supplement for non-alcoholic fatty liver disease (NAFLD) were explored. High fat diet (HFD) was utilized to induce NAFLD in Sprague Dawley male rats and MP-A (0.6 g/kg) was supplemented for 4 weeks. The results showed that MP-A supplementation reduced blood lipid levels, intrahepatic lipid accumulation and NAFLD activity score in HFD-fed rats. Additionally, the analysis of 16S rDNA sequencing on gut microbiota samples revealed that HFD could induce microbial dysbiosis. However, MP-A supplementation could remodel gut microbiota structure, inhibit LPS-TLR4-NF- κ B pathway activation, and restrain subsequent inflammation factors secretion. Furthermore, MP-A regulated the lipid metabolism by promoting the production of short chain fatty acids and suppressing PPAR γ and SREBP-1c expression. Our results support that MP-A can prevent against NAFLD and act as an oral supplementation for hepatoprotection via modulating gut microbiota and related gut-liver axis signaling pathways.
研究领域:
药理学
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胃肠病学
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微生物学
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代谢学
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产品关联
DOI
PubMed
高影响因子
Chinese Journal of Natural Medicines
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2016
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IF 1.382
Zhi-Shen XIE,Ling-Jun ZHONG,Xiao-Meng WAN,Meng-Ning LI,Hua YANG,Ping LI,Xiao-Jun XU
As a culinary and medicinal herb, rosemary is widely used. The present work aimed to investigate the effects of rosemary extracts on metabolic diseases and the underlying mechanisms of action. Liver cells stably expressing SREBP reporter were used to evaluate the inhibitory effects of different fractions of rosemary extracts on SREBP activity. The obese mice induced by Western-type diet were orally administered with rosemary extracts or vehicle for 7 weeks, the plasma and tissue lipids were analyzed. SREBPs and their target genes were measured by quantitative RT-PCR. We demonstrated that the petroleum ether sub-fraction of rosemary extracts (PER) exhibited the best activity in regulating lipid metabolism by inhibiting SREBPs, while water and n -BuOH sub-fraction showed the SREBPs agonist-effect. After PER treatment, there was a significant reduction of total SREBPs in liver cells. PER not only decreased SREBPs nuclear abundance, but also inhibited their activity, resulting in decreased expression of SREBP-1c and SREBP-2 target genes in vitro and in vivo . Inhibiting SREBPs by PER decreased the total triglycerides and cholesterol contents of the liver cells. In the mice fed with Western-type diet, PER treatment decreased TG, TC, ALT, glucose, and insulin in blood, and improved glucose tolerance and insulin sensitivity. Furthermore, PER treatment also decreased lipid contents in liver, brown adipose tissue, and white adipose tissue. Our results from the present study suggested that petroleum ether fraction of rosemary extracts exhibited the best potential of improving lipid metabolism by inhibiting SREBPs activity.
研究领域:
药理学
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代谢学
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营养学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2024
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IF 5.3
Yufeng Dai,Jinxiang Chen,Jialong Fang,Shuxiao Liang,Hao Zhang,Haitao Li,Wei Chen
Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses a broad spectrum of hepatic disorders, including hyperglycemia, hepatic steatosis, and insulin resistance. Piperlongumine (PL), a natural amide alkaloid extracted from the fruits of Piper longum L., exhibited hepatoprotective effects in zebrafish and liver injury mice. This study aimed to investigate the therapeutic potential of PL on MAFLD and its underlying mechanisms. The findings demonstrate that PL effectively combats MAFLD induced by a high-fat diet (HFD) and improves metabolic characteristics in mice. Additionally, our results suggest that the anti-MAFLD effect of PL is attributed to the suppression of excessive hepatic gluconeogenesis, inhibition of de novo lipogenesis, and alleviation of insulin resistance. Importantly, the results indicate that, on the one hand, the hypoglycemic effect of PL is closely associated with CREB-regulated transcriptional coactivators (CRTC2)-dependent cyclic AMP response element binding protein (CREB) phosphorylation; on the other hand, the lipid-lowering effect of PL is attributed to reducing the nuclear localization of sterol regulatory element-binding proteins 1c (Srebp-1c). Mechanistically, PL could alleviate insulin resistance induced by endoplasmic reticulum stress by antagonizing the thromboxane A 2 receptor (TP)/Ca 2+ signaling, and the TP receptor serves as the potential target for PL in the treatment of MAFLD. Therefore, our results suggested PL effectively improved the major hallmarks of MAFLD induced by HFD, highlighting a potential therapeutic strategy for MAFLD.
研究领域:
药理学
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肝病学
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代谢学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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