Journal of Clinical and Translational Hepatology
·
2023
·
IF 3.6
Fulin Nian,Longyun Wu,Qiaoyun Xia,Peiying Tian,Chunmei Ding,Xiaolan Lu
Background and aims Non-alcoholic fatty liver disease (NAFLD) is closely associated with gut microbiota and has become the most common chronic liver disease worldwide, but the relationship between specific strains and NAFLD has not been fully elucidated. We aimed to investigate whether Akkermansia muciniphila and Bifidobacterium bifidum could prevent NAFLD, the effects of their action alone or in combination, possible mechanisms, and modulation of the gut microbiota. Methods Mice were fed with high-fat diets (HFD) for 20 weeks, in which experimental groups were pretreated with quadruple antibiotics and then given the corresponding bacterial solution or PBS. The expression of the glycolipid metabolism indicators, liver, and intestinal farnesol X receptors (FXR), and intestinal mucosal tight junction proteins were detected. We also analyzed the alterations of inflammatory and immune status and the gut microbiota of mice. Results Both strains were able to attenuate mass gain ( p <0.001), insulin resistance ( p <0.001), and liver lipid deposition ( p <0.001). They also reduced the levels of the pro-inflammatory factors ( p <0.05) and the proportion of Th17 ( p <0.001), while elevating the proportion of Treg ( p <0.01). Both strains activated hepatic FXR while suppressing intestinal FXR ( p <0.05), and elevating tight junction protein expression ( p <0.05). We also perceived changes in the gut microbiota and found both strains were able to synergize beneficial microbiota to function. Conclusions Administration of A. muciniphila or B. bifidum alone or in combination was protective against HFD-induced NAFLD formation and could be used as alternative treatment strategy for NAFLD after further exploration.
研究领域:
微生物学
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肝病学
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营养学
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免疫学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2024
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IF 5.2
Kai Yang,Xiaoxiao Yu,Zihao Guo,Zhihao Fang,Hongyu Zhang,Wanyangchuan Zhang,Changxu Liu,Yanchao Ji,Zhichao Dong,Qiang Gu,Jiahao Yao,Chang Liu
Aims Non-alcoholic fatty liver disease (NAFLD) has risen as a significant global public health issue, for which vertical sleeve gastrectomy (VSG) has become an effective treatment method. The study sought to elucidate the processes through which PIM1 mitigates the advancement of NAFLD. The Pro-viral integration site for Moloney murine leukemia virus 1 (PIM1) functions as a serine/threonine kinase. Bioinformatics analysis revealed that reduced PIM1 expression in NAFLD. Methods To further prove the role of PIM1 in NAFLD, an in-depth in vivo experiment was performed, in which male C57BL/6 mice were randomly grouped to receive a normal or high-fat diet for 19 weeks. They were operated or delivered the loaded adeno-associated virus which the PIM1 was overexpressed (AAV-PIM1). In an in vitro experiment, AML12 cells were treated with palmitic acid to induce hepatic steatosis. Key findings The results revealed that the VSG surgery and virus delivery of mice alleviated oxidative stress, and apoptosis in vivo. For AML12 cells, the levels of oxidative stress, apoptosis, and lipid metabolism were reduced via PIM1 upregulation. Moreover, ML385 treatment resulted in the downregulation of the NRF2/HO-1/NQO1 signaling cascade, indicating that PIM1 mitigates NAFLD by targeting this pathway. Significance PIM1 alleviated mice liver oxidative stress and NAFLD induced by High-fat diet by regulating the NRF2/HO-1/NQO1 signaling Pathway.
研究领域:
肝病学
·
分子生物学
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病理学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF FOOD BIOCHEMISTRY
·
2023
·
IF 4
Qiao Tong,Jianjun Xi,Yu Cao,Ruoyu He,Yanmei Zhao,Yidan Shao,Xuwang Pan,Jinsong Huang,Yongping Chen,Rangxiao Zhuang
Chronic fructose consumption is becoming one leading risk factor for NAFLD due to its hazard on cellular lipid metabolism, which plays an essential role in the pathogenesis of NAFLD. Morroniside, an iridoid glycoside from Cornus officinalis, has been suggested to have potent in regulating cellular glucolipid metabolism. However, the effect and mechanism of morroniside on improving fructose-induced hepatic steatosis and retarding NAFLD progression remain ambiguous. In this study, we illustrate the efficacy of morroniside in alleviating fructose-triggered hepatic steatosis in mice. Mechanically, morroniside suppressed de novo lipogenesis and promoted β-oxidation by inhibiting the activation of PGC1β. Additionally, morroniside was found to work in attenuating hepatic inflammation in response to long-term fructose intake. Taken together, the current study reveals that morroniside is a promising food and medicinal therapy for NAFLD treatment and is effective in delaying the progression of NAFLD to NASH, especially in subtypes caused by excessive carbohydrate intake.
研究领域:
药理学
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肝病学
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营养学
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代谢紊乱
✓ 已验证
产品关联
DOI
高影响因子
Molecular Metabolism
·
2024
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IF 7
Junyong Wang,Yaping Guo,Yunduan He,Yifan Qin,Xiuling Li,Ling Yang,Kangdong Liu,Li Xiao
Objective Nonalcoholic fatty liver disease (NAFLD) is an emerging public health threat as the most common chronic liver disease worldwide. However, there remains no effective medication to improve NAFLD. G protein-coupled receptors (GPCRs) are the most frequently investigated drug targets family. The Regulator of G protein signaling proteins 14 (RGS14), as an essential negative modulator of GPCR signaling, play important regulatory roles in liver damage and inflammatory responses. However, the role of RGS14 in NAFLD remains largely unclear. Methods and Results In this study, we found that RGS14 was decreased in hepatocytes in NAFLD individuals in a public database. We employed genetic engineering technique to explore the function of RGS14 in NAFLD. We demonstrated that RGS14 overexpression ameliorated lipid accumulation, inflammatory response and liver fibrosis in hepatocytes in vivo and in vitro . Whereas, hepatocyte specific Rgs14 -knockout ( Rgs14 -HKO) exacerbated high fat high cholesterol diet (HFHC) induced NASH. Further molecular experiments demonstrated that RGS14 depended on GDI activity to attenuate HFHC-feeding NASH. More importantly, RGS14 interacted with Guanine nucleotide-binding protein (Gi) alpha 1 and 3 (Giα1/3, gene named GNAI1/3 ), promoting the generation of cAMP and then activating the subsequent AMPK pathways. GNAI1/3 knockdown abolished the protective role of RGS14, indicating that RGS14 binding to Giα1/3 was required for prevention against hepatic steatosis. Conclusions RGS14 plays a protective role in the progression of NAFLD. RGS14-Giα1/3 interaction accelerated the production of cAMP and then activated cAMP-AMPK signaling. Targeting RGS14 or modulating the RGS14-Giα1/3 interaction may be a potential strategy for the treatment of NAFLD in the future.
研究领域:
分子生物学
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药理学
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肝病学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD RESEARCH INTERNATIONAL
·
2021
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IF 6.475
Chuang Zhu,Qi Guan,Chenwei Song,Lingyue Zhong,Xinwen Ding,Hui Zeng,Pan Nie,Lihua Song
Gut microbiota dysbiosis and oxidative stress may play important roles in the progression of nonalcoholic fatty liver disease (NAFLD). Fermented foods contain probiotics and other bioactive components that may improve gastrointestinal health and provide other health benefits. Here, we investigated the effect of Lactobacillus -fermented black barley on NAFLD rats. Adult Sprague Dawley rats were randomized into four groups: normal chow diet (NC), high-fat diet (HF), HF + fermented black barley treatment (HB) and HF + Lactobacillus treatment (HL). The rats in the HB and HL groups were continuously administered fermented black barley or Lactobacillus , respectively, for 12 weeks (1 mL/100 g·BW, containing 1 × 10 8 CFU/mL Lactobacillus ). Compared with the HF treatment, HB treatment effectively inhibited the increase in body weight, liver and abdominal fat indexes and hepatic lipids ( p < 0.01), increased hepatic SOD activity ( p < 0.05), decreased thiobarbituric acid reactive substances (TBARSs) ( p < 0.01) and improved liver function. Moreover, Lactobacillus -fermented black barley exhibited regulatory effect on high-fat diet-induced intestinal microbiota dysbiosis by increasing the relative microbiota abundance and diversity, increasing the relative abundance of Bacteroidetes , decreasing the Firmicutes/Bacteroidetes ratio, increasing the abundances of some intestinal probiotics (such as Akkermansia and Lactococcus ), and influencing some of the fecal metabolites related to hormones and lipid metabolism. The supplementation of fermented cereal food might be a new effective and safe preventive dietary strategy against NAFLD.
研究领域:
胃肠病学
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营养学
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微生物学
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肝病学
✓ 已验证
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
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2023
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IF 7.31
Yanan Qiao,Huifang Deng,Lihua Liu,Shuran Liu,Luyao Ren,Chuandao Shi,Xi Chen,Lixia Guan,Weiran Liu,Zehua Li,Yunlan Li
Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions with no pharmacological treatment approved. Several highly accessible computational tools were employed to predict the activities of twelve novel compounds prior to actual chemical synthesis. We began our work by designing two or three hydroxyl groups appended to the phenyl ketone core, followed by prediction of drug-likeness and targets. Most predicted targets for each compound overlapped with NAFLD targets (≥80%). Enrichment analysis showed that these compounds might regulate oxidoreductase activity. Then, these compounds were synthesized and confirmed by IR, MS, 1H, and 13C NMR. Their cell viability demonstrated that twelve compounds exhibited appreciable potencies against NAFLD (). Furthermore, the most potent compound 5f effectively prevented NAFLD progression as evidenced by the change in histological features. 5f significantly reduced total cholesterol and triglyceride levels in vitro/in vivo, and the effects of 5f were significantly stronger than those of the control drug. The proteomic data showed that oxidoreductase activity was the most significantly enriched, and this finding was consistent with docking results. In summary, this validated presynthesis prediction approach was cost-saving and worthy of popularization. The novel synthetic phenyl ketone derivative 5f holds great therapeutic potential by modulating oxidoreductase activity to counter NAFLD.
研究领域:
药理学
·
药物化学
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分子生物学
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生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Fanghua Guo,Dongying Chen,Rong Tsao,Fereidoon Shahidi,Hua Xiong,Hua Zhang,Li Jiang,Yong Sun
Lentil hulls, a by-product of lentil processing, are rich in polyphenols and dietary fiber. In this study, a mouse model of nonalcoholic fatty liver disease (NAFLD) induced by dextran sulfate sodium (DSS) and high-fat diet (HFD) was used to investigate the intervention effect of green lentil hulls (GLH) from the perspective of intestinal and hepatic metabolism. Results suggest that DSS-induced gut inflammation and barrier disruption aggravate NAFLD; GLH intervention lowered body weight, liver weight gain and lipid deposition. It also inhibited liver fat accumulation and inflammation as well as intestinal inflammation. In addition, it enhanced liver antioxidant capacity, glucose tolerance and intestinal barrier integrity. Analysis of intestinal flora indicated that GLH advanced the abundance of Akkermansia-muciniphila and Verrucomicrobiaceae , which led to increased content of short-chain fatty acids (SCFAs) and inhibited the Firmicutes and Proteobacteria . Moreover, GLH intervention regulated taurine and hypotaurine metabolism, as well as the biosynthesis of unsaturated and saturated fatty acids in the liver. The relief by GLH on NAFLD may be a comprehensive effect of its rich dietary fiber and polyphenols on intestinal and hepatic metabolism via the gut-liver axis. This research also suggests that the low-value lentil hulls can serve as a valuable food supplement for enhanced gut health and reduced risk of NAFLD.
研究领域:
营养学
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胃肠病学
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肝病学
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微生物学
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代谢学
✓ 已验证
产品关联
DOI
高影响因子
LIFE SCIENCES
·
2020
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IF 3.647
Yaoxiang Zhu,Ruijue Liu,Zhenglin Shen,Guoqiang Cai
Aim Luteolin and lycopene are common natural products, widely existing in nature, and both of which were reported to have various biological functions including anti-inflammatory, anti-obesity and anti-NAFLD. In the present study, we aimed to evaluate the therapeutic efficacy of luteolin and lycopene in combination and its latent molecular mechanisms in vitro and in vivo models of NAFLD. Main methods Sodium palmitate (PA)-induced steatotic HepG2 cells and primary hepatocytes, and high-fat diet-induced C57BL/6J obese mice were treated with luteolin, lycopene and their combination. Metabolic parameters were measured. Key findings We found that luteolin (20 μM) + lycopene (10 μM) was the best therapeutic combination in PA-induced HepG2 cells, and significantly improve cell viability and lipid accumulation in PA-induced HepG2 cells and primary hepatocytes. In addition, luteolin (20 mg/kg) + lycopene (20 mg/kg) could ameliorate increased body weight and hepatocyte steatosis; regulate serum triglycerides, serum total cholesterol, hepatic triglycerides and hepatic total cholesterol; decrease serum alanine transaminase and aspartate transaminase. Furthermore, in vivo and in vitro, luteolin, lycopene and their combination had no effect on Sirt1 expression, but all of them could upregulate the expression of NAMPT, which could increase the level of NAD+, the co-substrate of Sirt1, indirectly activating Sirt1/AMPK pathway, and then inhibited lipogenesis and increased β-oxidation, defensing the “first hit”; they also inactivated nuclear factor-κB (NF-κB) and decreased the levels of IL-6, IL-1β and TNF-α, defensing the “second hit”. Significance Thus, luteolin and lycopene in combination can effectively ameliorate “two-hit” in NAFLD through activation of the Sirt1/AMPK pathway.
研究领域:
药理学
·
分子生物学
·
细胞生物学
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代谢
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营养学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2019
·
IF 4.868
Qiang Chu,Shuang Zhang,Meng Chen,Wen Han,Ruoyi Jia,Wen Chen,Xiaodong Zheng
Nonalcoholic fatty liver disease (NAFLD) is a common chronic disease that threatens human health, and present therapies remain limited due to the lack of effective drugs. Lipid metabolic disturbance and oxidative stress have strong links to the development of NAFLD, while autophagy was generally accepted as a key regulatory mechanism on these steps. Our previous studies indicated that cherry anthocyanins (CACN) protected against high fat diet-induced obesity and NALFD in C57BL/6 mice, while the underlying molecule mechanism is still unclear. Thus, in this study, we show that CACN protect against oleic acid- (OA-) induced oxidative stress and attenuate lipid droplet accumulation in NAFLD cell models. According to the results of a transmission electron microscope (TEM), western blot, immunofluorescence (IF), and adenovirus transfection (Ad-mCherry-GFP-LC3B), autophagy is in accordance with the lipid-lowering effect induced by CACN. Further studies illustrate that CACN may activate autophagy via mTOR pathways. In addition, an autophagy inhibitor, 3-methyladenine (3-MA), was applied and the result suggested that autophagy indeed participates in the lipid clearance process in OA-induced lipid accumulation. All these results indicate that the positive effects of CACN on OA-induced hepatic lipid accumulation are mediated via activating autophagy, showing a potential target for the therapeutic strategy of NAFLD.
研究领域:
药理学
·
肝病学
·
细胞生物学
·
营养学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Mingming Qi,Hui Zhong,Zhaoyan Cheng,Shujie Chen,Han Xiao,Jing Shang,Li Chen,Jianbo Sun
Activating Nrf2 through inhibiting Keap1 has been proven to alleviate oxidative stress and related diseases, including nonalcoholic fatty liver disease (NAFLD). Traditional Keap1 inhibitors could not avoid the “off-target” effects, but using proteolysis targeting chimera (PROTAC) technology to induce Keap1 degradation might be an effective strategy to find potential NAFLD improving agents. Thus, several PROTACs were designed and synthesized by harnessing CDDO as the Keap1 ligand in this study. PROTAC I-d exhibited optimal Keap1 degradation activity, which could increase the Nrf2 level and alleviate oxidative stress in free fatty acid-induced AML12 cells and the liver of mice fed with a methionine-choline-deficient diet. Moreover, compared with CDDO, PROTAC I-d displayed significant advantages in inhibiting hepatic steatosis, steatohepatitis, and fibrosis in the in vivo and in vitro models of NAFLD. In addition, PROTAC I-d also showed lower in vivo toxicity than CDDO. All these results suggested that PROTAC I-d might be a potential improving agent for NAFLD.
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Qinyu Meng,Mengru Zhong,Jiangrong Zhao,Hong Xu,Wentao Jiang,Chenru Lin,Ghaffar Karishma,Feng Wang,Fang Xu,Yana Li
Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disorder worldwide, characterized by progression from simple steatosis to inflammatory liver injury. Artesunate (AS), an antimalarial agent derived from Artemisia annua, possesses well-documented metabolic regulatory, antioxidant, and anti-inflammatory properties. This study comprehensively evaluated the therapeutic effects of AS on NAFLD pathogenesis and elucidated its underlying molecular mechanisms using integrated experimental approaches. AS administration significantly mitigated NAFLD progression, as reflected by marked reductions in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, substantial attenuation of lobular inflammation, and notable improvement in hepatocellular ballooning, collectively resulting in decreased NAFLD activity scores. Network pharmacology analysis further identified oxidative stress and inflammatory pathways as major molecular targets of AS intervention. Mechanistic investigations revealed that AS-mediated hepatoprotection is primarily driven by strong activation of the Nrf2 antioxidant pathway, evidenced by enhanced nuclear translocation of Nrf2 and consequent upregulation of key downstream antioxidant enzymes, including superoxide dismutase (SOD) and glutathione (GSH). The essential role of Nrf2 signaling was conclusively validated through genetic and pharmacological inhibition studies, which completely abolished the therapeutic effects of AS on hepatic injury and oxidative imbalance. Taken together, these findings provide robust preclinical evidence that AS confers multi-dimensional protection against NAFLD progression through targeted activation of the Nrf2 pathway, offering new mechanistic insight into NAFLD treatment and underscoring the strong translational potential of AS given its established clinical safety profile.
研究领域:
肝脏病学
·
药理学
·
分子生物学
·
氧化应激研究
·
炎症性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF FOOD BIOCHEMISTRY
·
2025
·Vol. 2025
·期 1
·6134296
·
IF 4.2
Ruixi Luo,Jing Zhang,Peng Chen,La Wang,Wenjia Wang,Ping Wang,Xing Zhao,Weiyi Tian
The aim of this study was to construct curcumin-loaded mesenchymal stem cell-derived exosomes (Cur-exos) and explore their effects on nonalcoholic fatty liver disease (NAFLD) models both in vitro and in vivo. Cur-exos were prepared using three common drug-loading techniques—incubation, sonication, and freeze–thaw cycles. Among these, Cur-exos prepared via repeated freeze–thawing demonstrated higher encapsulation efficiency and drug-loading rates than those produced by other methods. In vitro, Cur-exos exhibited enhanced stability, were efficiently taken up by hepatocytes, and mitigated palmitic acid (PA)–induced lipotoxicity in HepG2 cells. Moreover, Cur-exos significantly ameliorated liver damage in NAFLD model mice, reduced inflammation, decreased reactive oxygen species (ROS) levels, and mitigated endoplasmic reticulum (ER) stress. Additionally, Cur-exos effectively regulated lipid metabolism disorders and improved impaired glucose tolerance. Overall, we demonstrate that, compared with free curcumin, Cur-exos significantly improve curcumin stability and offer superior therapeutic effects in NAFLD mouse models. This study provides a novel approach for developing treatments for NAFLD.
研究领域:
药理学
·
肝病学
·
干细胞研究
·
药物递送系统
·
代谢性疾病
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）