PHYTOMEDICINE
·
2023
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IF 7.9
Yanghao Li,Xu Yang,Tiantian Bao,Xiaojuan Sun,Xiang Li,Huilin Zhu,Bo Zhang,Tonghui Ma
Background The therapeutic efficacy of liver injuries heavily relies on the liver's remarkable regenerative capacity, necessitating the maintenance of glycose/lipids homeostasis and oxidative eustasis during the recovery process. Astragali Radix, an herbal tonic widely used in China and many other countries, is believed to have many positive effects, including immune stimulation, nourishing, antioxidant, liver protection, diuresis, anti-diabetes, anti-cancer and expectorant. Astragali Radix is widely integrated into hepatoprotective formulas as it is believed to facilitate liver regeneration. Nevertheless, the precise molecular pharmacological mechanisms underlying this hepatoprotective effect remain elusive. Purpose To investigate the improving effects of Astragali Radix on liver regeneration and the underlying mechanisms. Methods A mouse model of 70% partial hepatectomy (PHx) was employed to investigate the impact of Radix Astragali decoction (HQD) on liver regeneration. HQD was orally administered for 7 days before the PHx procedure and throughout the experiment. N-acetylcysteine (NAC) was used as a positive control for liver regeneration. Liver regeneration was assessed by evaluating the liver-to-body weight ratio (LW/BW) and the expression of representative cell proliferation marker proteins. Oxidative stress and glucose metabolism were analyzed using biochemical assays, Western blotting, dihydroethidium (DHE) fluorescence, and periodic acid-Schiff (PAS) staining methods. To understand the role of AQP9 as a potential molecular target of HQD in promoting liver regeneration, td-Tomato-tagged AQP9 transgenic mice (AQP9-RFP) were employed to determine the expression pattern of AQP9 protein. AQP9 knockout mice (AQP9 −/− ) were used to assess the specific targeting of AQP9 in the promotion of liver regeneration by HQD. Results HQD significantly upregulated hepatic AQP9 expression, alleviated liver injury and promoted liver regeneration in wild-type (AQP9 +/+ ) mice after 70% PHx. However, the beneficial impact of HQD on liver regeneration was absent in AQP9 gene knockout (AQP9 −/− ) mice. Moreover, HQD facilitated the uptake of glycerol by hepatocytes, enhanced gluconeogenesis, and concurrently reduced H 2 O 2 content and oxidative stress levels in AQP9 +/+ but not AQP9 −/− mouse livers. Additionally, main active substance of Radix Astragali, astragaloside IV (AS-IV) and cycloastragenol (CAG), demonstrated substantial upregulation of AQP9 expression and promoted liver regeneration in AQP9 +/+ but not AQP9 −/− mice. Conclusion This study is the first to demonstrate that Radix Astragali and its main active constituents (AS-IV and CAG) improve liver regeneration by upregulating the expression of AQP9 in hepatocytes to increase gluconeogenesis and reduce oxidative stress. The study revealed novel molecular pharmacological mechanisms of Radix Astragali and provided a promising therapeutic target of liver diseases.
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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DOI
PubMed
高影响因子
Molecular Metabolism
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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
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Yuan Yuan,Xiaoxuan Yin,Lu Li,Ziyue Wang,Haiyang Yan
ABSTRACT Glycidol (CAS: 556-52-5), a known carcinogen and genotoxicant, is often found in refined vegetable oils. Human exposure predominantly occurs through consumption of these oils and their byproducts, which contain glycidyl esters (GEs). Upon ingestion, GEs are metabolized to release glycidol, posing substantial health hazards. Historical studies have reported the tumorigenic properties of glycidol across various organs in mice models, encompassing the stomach, liver, lungs, brain, mammary gland, and skin. In this study, we employed a Balb/c mice model to investigate the hepatotoxic effects of glycidol following exposure to escalating doses (0, 25, 50, and 100 mg/kg bw/day). The hepatotoxicity was evidenced by a significant elevation in liver enzymes (ALT, AST), indicative of liver cell damage. Furthermore, biochemical analysis revealed heightened levels of oxidative stress indicators (SOD, MDA, GSH) and the upregulation of endoplasmic reticulum stress proteins, underscoring the cellular stress response. The induction of hepatocyte apoptosis served as a direct marker of liver damage caused by glycidol exposure. Additionally, glycidol altered the composition of intestinal microbiota and short-chain fatty acids (SCFAs), which unbalanced homeostasis. Gut barrier integrity markers (ZO-1, Claudin-1, Occludin, TLR4, LPS) indicated increased permeability of harmful substances to the liver via the gut-liver axis, which exacerbated hepatic injury. These findings highlight glycidol's disruption of gut homeostasis and its hepatotoxic potential.
研究领域:
毒理学
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肝病学
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微生物学
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分子生物学
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产品关联
DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
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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
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肝病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2023
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IF 5.4
Yating Guo,Qiushuang Sun,Shijiao Wang,Mengdi Zhang,Yuanyuan Lei,Jiejie Wu,Xinhong Wang,Wenjun Hu,Haitao Meng,Zhiyu Li,Luzhou Xu,Fang Huang,Zhixia Qiu
Ethnopharmacological relevance Along with the gradually increasing incidence, nonalcoholic fatty liver disease (NAFLD) has already been influencing the health of more and more people in the world. Corydalis saxicola Bunting (CSB), a valuable folk medicine, is the dried whole grass of a perennial herb, Yanhuanglian ( Papaveraceae ), which has significant effects on various hepatitis, liver fibrosis , cirrhosis and other liver diseases. Corydalis saxicola Bunting total alkaloids (CSBTA), a mixture of alkaloids extracted from CSB, exhibit widely-accepted hepatoprotective effects. Aim of the study This study aimed to explore the therapeutic potential of CSBTA on NAFLD and the underlying mechanism. Materials and methods A mice model was established by high fat and high cholesterol diet (HFHCD) to study the benefits of CSBTA on the progression of NAFLD. The efficacy of CSBTA on NAFLD was revealed systematically via RNA-sequencing analysis. Further efficacy and molecular mechanism study were explored in mouse primary hepatocytes and HepG2 cells stimulated with high energy with or without pharmacological inhibition or gene silencing. Results CSBTA effectively improved the major hallmarks of NAFLD including liver lipid accumulation, liver injury, inflammation and fibrosis in HFHCD-fed mice. RNA sequencing and targeted qPCR analysis jointly evidenced CSBTA significantly suppressed the expression of Srebf1 , Acc1 and Fasn which are the genes responsible for fatty acid biosynthesis. Moreover, stable isotope tracer test denoted CSBTA reduced lipid accumulation via interrupting fatty acid biosynthesis in hepatocytes or the liver. Mechanistically, CSBTA could impede SREBP1 maturation via AMPK activation, thereby reducing DNL-derived lipid accumulation in hepatocytes. Conclusions CSBTA protected against hepatic steatosis and other hallmarks of NAFLD induced by HFHCD via suppressing DNL, through modulating the AMPK-SREBP1 axis. CSBTA may therefore have a therapeutic potential for 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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产品关联
DOI
PubMed
高影响因子
Nature Communications
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2025
·Vol. 16
·期 1
·1-15
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IF 15.7
Liu Wenjia,Liu Yuting,Zhang Liqiang,Li Liya,Yang Wenguang,Li Jia,He Wangxiao
Liver sinusoidal endothelial cells (LSECs) lose their characteristic fenestrations and become capillarized during the progression of liver fibrosis. Mesenchymal stem cell (MSC) transplantation can reverse this capillarization and reduce fibrosis, but MSC therapy has practical limitations that hinder its clinical use. Here, with the help of artificial intelligence (AI), we show that MSCs secrete a microRNA (miR-325-3p) that helps restore LSEC fenestrations (tiny pores) by modulating their cytoskeleton, effectively reversing capillarization. We further develop a spherical nucleic acid (SNA) nanoparticle carrying miR-325-3p as an alternative to MSC therapy. This SNA specifically enters fibrotic LSECs via the scavenger receptor A (Scara). In three mouse models of liver fibrosis, the SNA treatment restores LSEC fenestrations, reverses capillarization, and significantly reduces fibrosis without adverse effects. Our findings highlight the potential of SNA-based therapy for liver fibrosis, paving the way for targeted nucleic acid treatments directed at LSECs and offering hope for patients.
研究领域:
分子生物学
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肝脏病学
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纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmaceutics
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2025
·Vol. 17
·期 3
·351
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IF 5.5
Xunzhi Liu,Changlong Fang,Hongling Yu,Lu Huang,Jiaxing Feng,Shiqin Luo,Li Song,Mengying Wu,Yulu Tan,Jianxia Dong,Tao Gong,Peihong Xiao
Background: Activated hepatic stellate cells (aHSCs) play a significant role during the onset of hepatic fibrosis, ultimately leading to excessive deposition of extracellular matrix (ECM) and other typical pathological features, and thus have become a popular target for the treatment of hepatic fibrosis. However, current aHSC-centric therapy strategies achieve unsatisfactory results, mainly due to the lack of approved anti-fibrosis drugs and sufficiently efficient aHSC-targeted delivery systems. In this study, our aim was to develop an Imatinib-loaded nanoparticle delivery system based on a chondroitin sulfate derivative to enhance aHSC targeting efficiency, improve the therapeutic effect for hepatic fibrosis, and investigate the underlying mechanism.Methods: The carboxyl group of chondroitin sulfate and the amino group of 1-hexadecylamine were linked by an amide bond in this study to produce the amphiphilic carrier CS-HDA. Then, the Imatinib-loaded nanoparticles (IM-CS NPs) were designed to efficiently target aHSCs through CD44-mediated endocytosis and effectively inhibit HSC overactivation via PDGF and TGF-β signaling pathways.Results: Both in vitro cellular uptake experiments and in vivo distribution experiments demonstrated that CS-HDA-modified nanoparticles (IM-CS NPs) exhibited a better targeting ability for aHSCs, which were subsequently utilized to treat carbon tetrachloride-induced hepatic fibrosis mouse models. Finally, significant fibrosis resolution was observed in the carbon tetrachloride-induced hepatic fibrosis mouse models after tail vein injection of the IM-CS NPs, along with their outstanding biocompatibility and biological safety.Conclusions: IM-loaded NPs based on an amphiphilic CS derivative have remarkable antifibrotic effects, providing a promising avenue for the clinical treatment of advanced hepatic fibrosis.
研究领域:
药学
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肝脏病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Today
·
2025
·
IF 10.9
Peng Yang,Weijing Liu,Zhuang Chen,Deshang Duan,Jiamin Xu,Xian An,Anna Xie,Zhiping Rao,Yuqiong Xia,Ruili Zhang,Pengbo Ning,Chaoqiang Qiao,Xianghan Zhang,Zhongliang Wang
Therapeutic-induced hepatocyte pyroptosis is often overlooked and leads to the release of inflammatory mediators, creating a vicious self-injury of the activated hepatic stellate cells (aHSCs) and fibrosis progression. Additionally, the dense extracellular matrix (ECM) serves as a barrier, significantly limiting the accessibility of therapeutics to aHSCs, presenting a challenge for effective anti-liver fibrosis therapies. Herein, we introduce an innovative dual-faceted strategy that focuses on regulating glutamine metabolism to disrupt the vicious cycle of inflammation, while leveraging ultrasound to improve drug accessibility to aHSCs. Porous coordination network nanoparticles (PCN-NPs) used as sonosensitizers were shown to soften and remodel the ECM through the rapid collapse of bubbles and the generation of shock waves and high pressure under ultrasound irradiation, facilitating increased accessibility of therapeutics to aHSCs. Furthermore, the glutamine metabolism inhibitor V-9302, delivered via PCN-NPs, induced apoptosis of aHSCs in a non-inflammatory manner, thereby breaking the pro-inflammatory vicious cycle. Hyaluronic acid-modified nanoparticles specifically targeted aHSCs by recognizing overexpressed CD44 receptors, resulting in significant amelioration of fibrosis in CCl 4 -induced fibrotic mice. This study underscores the critical role of regulating glutamine metabolism in terminating the vicious crosstalk between hepatocytes and hepatic stellate cells and presents a promising avenue for the development of antifibrotic therapies.
研究领域:
医学
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生物工程
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药理学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Ranyi Luo,Yinhao Zhang,Hong Wang,Bing Xu,Jiaorong Qu,Shuwen Duan,Runping Liu,Jia Liu,Shuo Li,Xiaojiaoyang Li
Ethnopharmacological relevance Hepatic ischemia/reperfusion injury (HIRI) is a common occurrence during or after liver surgery, representing a major cause for postoperative complications or increased morbidity and mortality in liver diseases. Rehmanniae Radix Praeparata (RRP) is a traditional Chinese medicine frequently used and has garnered extensive attention for its therapeutic potential treating cardiovascular and hepatic ailments. Recent studies have indicated the possibility of RRP in regulating lipid accumulation and apoptosis in hepatocytes. Aim of the study This study aimed to investigate the specific mechanisms by which RRP may impede the progression of HIRI through the regulation of lipid metabolism. Materials and methods High-performance liquid chromatography (HPLC) was used to identify the major components of RRP water extract. C57BL/6J mice were orally given RRP at doses of 2.5 g/kg, 5 g/kg, and 10 g/kg for a duration of 7 days before undergoing HIRI surgery. Furthermore, we established a lipid-loaded in vitro model by exposing hepatocytes to oleic acid and palmitic acid (OAPA). The anti-HIRI effect of RRP was determined through transcriptomics and various molecular biology experiments. Results After identifying active ingredients in RRP, we observed that RRP exerted lipid-lowering and hepatoprotective effects on HIRI mice and OAPA-treated hepatocytes. RRP activated AMP-activated protein kinase (AMPK) and inhibited mammalian target of rapamycin (mTOR), which further on the one hand, inhibited the cleavage and activation of sterol regulatory element binding protein 2 (SREBP2) by limiting the movement of SREBPs cleavage-activating protein (SCAP)-SREBP2 complex with the help of endoplasmic reticulum lipid raft-associated protein 1 (ERLIN1) and insulin-induced gene 1 (INSIG1), and on the other hand, promoted liver X receptor α (LXRα) nuclear transportation and subsequent cholesterol efflux. Meanwhile, the anti-lipotoxic effect of RRP can be partly reversed by an LXRα inhibitor but largely blocked by the application of compound C, an AMPK inhibitor. Conclusion Our study elucidated that RRP served as a potential AMPK activator to alleviate HIRI by blocking SREBP2 activation and cholesterol synthesis, while also activating LXRα to facilitate cholesterol efflux. These findings shed new light on the potential therapeutic use of RRP for improving HIRI.
研究领域:
药理学
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肝病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Ying Liang,Zi Wang,Deyang Huo,Jun-nan Hu,Lingjie Song,Xiaochi Ma,Shuang Jiang,Wei Li
In recent years, there has been a growing concern regarding health issues arising from exposure to nanoplastics (Nps) in the natural environment. The Nps bioaccumulate within the body via the circulatory system and accumulate in the liver, resulting in damage. Previous studies have demonstrated that maltol, derived from red ginseng (Panax ginseng C.A. Meyer) as a Maillard product, exhibits hepatoprotective effects by alleviating liver damage caused by carbon tetrachloride or cisplatin. In order to explore the specific mechanism of maltol in improving hepatotoxicity induced by Nps, mice exposed to 100 mg/kg Nps were given maltol at doses of 50 and 100 mg/kg, respectively. The results showed that Nps induced an increase in the levels of liver apoptotic factors BAX and cytochrome c, a decrease in the levels of the autophagy key gene LC3 II/I, and an increase in P62. It also caused oxidative stress by affecting the Nrf2/HO-1 pathway, and a decrease in GPX4 protein expression suggested the occurrence of ferroptosis. However, treatment with maltol significantly improved these changes. In addition, maltol (2, 4, and 8 μM) also protected human normal liver L02 cells from Np (400 μg/mL)-induced damage. Our data suggest that maltol could ameliorate Np-induced L02 cytotoxicity by reducing autophagy-dependent oxidative stress, exhibiting similar protective effects in vitro as in vivo. This study helps shed light on the specific molecular mechanism of Np-induced hepatotoxicity. For the first time, we studied the protective effect of maltol on Np-induced liver injury from multiple perspectives, expanding the possibility of treatment for diseases caused by environmental pollutants.
研究领域:
毒理学
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药理学
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环境科学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2024
·
IF 4.3
Fei Yu,Zongyu Liu,Jie Feng,Yuhong Man,Huan Zhang,Jingying Shi,Xiang Pang,Yang Yu,Ye Bi
Rationale Transforming growth factor-beta1 (TGF-β1) plays a pivotal role in promoting hepatic fibrosis, pirfenidone (PFD) could inhibit TGF-β1 signaling pathway to alleviate hepatic stellate cells (HSC) activation mediated hepatic fibrosis. The targeting delivery strategy of PFD to hepatic stellate cells is a challenge. Extracellular vesicles (EVs), cell-derived membranous particles are intraluminal nano-vesicles that play a vital role in intercellular communication, they also be considered as an ideal nano-carrier. Methods In this study, we developed a target strategy to deliver PFD to HSC with CD44 over-expression by EVs, hyaluronic acid (HA) modified DSPE-PEG 2000 endows the active targeting ability of activated HSCs to PFD-loaded EVs. Results In both rat hepatic stellate cell line HSC-T6 and rat hepatocyte cell line BRL, HA@EVs-PFD demonstrated the capacity to down-regulate the expression of collagen-synthesis-related proteins and showed superior inhibition efficacy of HSC-T6 activation compared to free PFD. In hepatic fibrosis model, 4 weeks of HA@EVs-PFD treatment resulted in a reduction in liver collagen fibers, significant improvement in hepatic cell morphology, and amelioration of hepatic fibrosis. Conclusions HA@EVs-PFD, as a drug delivery system that effectively targets and inhibits activated HSCs to treat hepatic fibrosis, holds promise as a potential therapeutic agent against hepatic fibrosis.
研究领域:
医学
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药学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2021
·
IF 7.963
Limei Sun,Ming Gao,Qiuhui Qian,Ziyi Guo,Peng Zhu,Xuedong Wang,Huili Wang
Chronic exposure of triclosan (TCS) to zebrafish triggers high incidence of fatty liver and hepatitis; however, the underlying molecular mechanisms remain unclear. Herein, we identified miR-30b as a sensitive biomarker to TCS stress, reflecting in that its decreased expression caused metabolic toxicity, abnormal development and behavior, and lipid-metabolism disorder. By microinjecting the inhibitor and mimic experiments, miR-30b was proved to regulate lipid metabolism by its main target gene fto . Over-expression of FTO resulted in fat accumulation, elevation of the TG and TC levels and up-regulation of the PPARγ and CEBPα, as well as decrease of the global m 6 A level in larvae. On the contrary, the knock-down of FTO using MO caused the anti-lipogenic effect, decrease of the TG and T-CHO levels, and abnormal changes of cebpɑ , acsl 5, fasn , ppap 2c and ppar γ etc. Further fortification tests of cycloleucine and betaine evidenced that the toxic effect was strongly dependent on regulation of the m 6 A level. The toxicity effects in the treatments of methylated donors and receptors were consistent with the changes in physiological functions of FTO knockdown and overexpression. The effects of cycloleucine on m 6 A level and lipid metabolism generally consisted with those of FTO, but this was not the case for betaine, reflecting in increased m 6 A level and lipid accumulation in larval liver. Consequently, we posit that TCS exposure caused zebrafish lipid-metabolism disorder by decreasing miR-30b expression to regulate fto-mediated m 6 A methylation level. These findings contribute to our deep understanding of the underlying molecular mechanisms regarding contaminant-originating fatty liver and hepatocellular carcinoma, and also have practical significance in pollution warning and target therapy for related diseases.
研究领域:
毒理学
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分子生物学
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环境科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）