BIOMEDICINE & PHARMACOTHERAPY
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2024
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IF 6.9
Yan Xie,Yimin Jin,Jianhui Wen,Guiping Li,Xue Huai,Yueyang Duan,Fuyong Ni,Juan Fu,Ming Li,Liang Li,Ming Yan,Liang Cao,Wei Xiao,Hao Yang,Zhen-zhong Wang
Non-alcoholic fatty liver disease (NAFLD), particularly advanced non-alcoholic steatohepatitis (NASH), leads to irreversible liver damage. This study investigated the therapeutic effects and potential mechanism of a novel extract from traditional Chinese medicine Alisma orientale (Sam.) Juzep (AE) on free fatty acid (FFA)-induced HepG2 cell model and high-fat diet (HFD) + carbon tetrachloride (CCl 4 )-induced mouse model of NASH. C57BL/6 J mice were fed a HFD for 10 weeks. Subsequently, the mice were injected with CCl 4 to induce NASH and simultaneously treated with AE at daily doses of 50, 100, and 200 mg/kg for 4 weeks. At the end of the treatment, animals were fasted for 12 h and then sacrificed. Blood samples and liver tissues were collected for analysis. Lipid profiles, oxidative stress, and histopathology were examined. Additionally, a polymerase chain reaction (PCR) array was used to predict the molecular targets and potential mechanisms involved, which were further validated in vivo and in vitro . The results demonstrated that AE reversed liver damage (plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatocyte ballooning, hepatic steatosis, and NAS score), the accumulation of hepatic lipids (TG and TC), and oxidative stress (MDA and GSH). PCR array analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that AE protects against NASH by regulating the adipocytokine signaling pathway and influencing nuclear receptors such as PPARα. Furthermore, AE increased the expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PPARGC1α) and reversed the decreased expression of PPARα in NASH mice. Moreover, in HepG2 cells, AE reduced FFA-induced lipid accumulation and oxidative stress, which was dependent on PPARα up-regulation. Overall, our findings suggest that AE may serve as a potential therapeutic approach for NASH by inhibiting lipid accumulation and reducing oxidative stress specifically through the PPARα pathway.
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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传统中药
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产品关联
DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
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2016
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IF 1.931
Shengyan Xi,Lifeng Yue,Mengmeng Shi,Ying Peng,Yangxinzi Xu,Xinrong Wang,Qian Li,Zhijun Kang,Hanjing Li,Yanhui Wang
Chronic liver disease is one of the most common diseases that threaten human health. Effective treatment is still lacking in western medicine. Semen Persicae (Taoren) and Flos Carthami (Honghua) are known to relieve acute hepatic injury and inflammation, improve microcirculation, and reduce tissue fiber. The aim of our study is to investigate the potential mechanisms of Taoren-Honghua Herb Pair (THHP) in murine model of chronic liver disease caused by Carbon Tetrachloride (CCl4). Mice were randomly divided into seven groups: (1) blank, (2) model, (3) control (colchicine, 0.1 mg/kg), (4) THHP (5.53, 2.67, and 1.33 g/kg), and (5) Tao Hong Siwu Decoction (THSWD) (8.50 g/kg). Histological change and microvessels density were examined by microscopy. Hepatic function, serum fibrosis related factors, and hepatic vascular endothelial growth factor (VEGF) were measured with ELISA. VEGF, kinase insert domain-containing receptor (KDR), Flt-1, and Akt mRNA expression in hepatic tissue were determined with PCR. Tissues of Akt, pAkt, KDR, and Flt-1 were measured with western blotting. Data from this study showed that THHP improved hepatic function and restrained the hepatic inflammation and fibrosis. Its role in inhibiting pathological angiogenesis and hepatic fibrogenesis may be through affecting the angiogenesis-associated VEGF and its upstream and downstream signaling pathways.
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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病理学
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DOI
PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
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2020
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IF 2.971
Xiaoman Zhang,Jie Feng,Shaofeng Su,Lei Huang
Context Camellia nitidissima Chi (Theaceae) is an evergreen shrub, the leaves of which are used in many medicinal applications.Objective To characterize the chemical composition of a 10% aqueous ethanol extract of C. nitidissima leaves (CNE), and to explore the protective effect of the extract against acute liver injury (ALI) in rats.Materials and methods Male Sprague-Dawley rats were divided into six groups (n = 10): control and negative (0.5% CMC-Na, 5 mL/kg/d), thiopronin (20 mg/kg/d) and CNE (40, 80 and 160 mg/kg/d). All groups were treated for seven consecutive days, and then, except for the control, carbon tetrachloride was administered intraperitoneally. The biochemical parameters, mRNAs, and proteins were analyzed using enzyme-linked immunoassays kits, quantitative polymerase chain reaction and western blot. Chemical components were identified using mass spectroscopy, and the phenol and flavonoid content determined by ultraviolet spectrophotometry.Results Pre-treatment with CNE (160 mg/kg) attenuated the pathological changes in liver tissues and decreased alanine transaminase (62 and 60%), aspartate transaminase (49 and 53%) and malondialdehyde (35 and 42%) levels in serum and liver tissues. Moreover, CNE reduced the concentrations of reactive oxygen species (55%), tumour necrosis factor-α (26%), interleukin-1β (19%) and IL-6 (19%) and blocked the nuclear translocation of p65. Pre-treatment with CNE increased anti-heme oxygenase-1 (40%), superoxide dismutase (108%) and glutathione (97%) levels through upregulating nuclear factor erythroid-2-related factor 2. Twelve compounds were detected; the content of phenols and flavonoids was determined as 34.474 ± 1.026 and 15.228 ± 0.422 mg/g crude drug in CNE, respectively.Discussion and conclusions These results suggested that CNE is a promising agent for functional food and hepatoprotective drug against ALI.
研究领域:
药理学
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毒理学
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分子生物学
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药物化学
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产品关联
DOI
PubMed
高影响因子
Journal of Inflammation Research
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2021
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IF 6.922
Yongqing Cai,Bin Li,Dan Peng,Xianfeng Wang,Pan Li,Mingchun Huang,Haiyan Xing,Jianhong Chen
Background Nrf2-Bach1 antioxidant signaling pathway is considered as one of the most important mechanisms of cellular resistance to oxidative injury. The effect of hyperoside (Hyp) on the expression and distribution of Bach1, the relationship of Hyp’s antioxidative effect and the influence of Bach1 remains unclear. Purpose The aim of this study was to investigate the role and mechanisms of Bach1 in the protective effect of Hyp on oxidative liver injury. Methods The protective effect of Hyp on oxidative stress injury was observed in vivo and in vitro. Next, the influence of Hyp on Bach1 expression and distribution, and competitive combination of Nrf2-Bach1 with ARE in H 2 O 2 -induced L02 cell was studied by Western blot, RT-PCR, immunofluorescence and CHIP assay. Finally, the expressions of Crm1, ERK and p38 and their roles on Hyp mediated nuclear export of Bach1 were investigated by Western blot. Results Hyp ameliorated the pathological damage, reduced the liver index, AST, ALT and MDA activities, and increased SOD and GSH levels in the CCl 4 -induced acute liver injury mouse model. Hyp attenuated H 2 O 2 -induced oxidative stress injury in L02 cells. Hyp promoted the early rapid redistribution of Bach1 from nucleus to cytoplasm. CHIP analyses demonstrated that Hyp enhanced the levels of Nrf2-ARE complex, and weakened the levels of Bach1-ARE complex within three hours. In addition, Hyp enhanced transport protein Crm1 expression and ERK1/2 activity. And LMB, a Crm1 inhibitor, attenuated the effect of Hyp on Bach1 nuclear export and anti-oxidation. U0126, an ERK1/2 inhibitor, reduced the effect of Hyp on Crm1 expression and the Bach1 redistribution. Conclusion The hepatoprotective mechanism of Hyp was related to improve Bach1 nuclear export depending on ERK1/2-Crm1 to upregulate the level of Nrf2 binding to ARE.
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
Chinese Herbal Medicines
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2024
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IF 4.7
Xin Wu,Cuiwei Chen,Hongyan Zhang,Keda Lu,Gang Cao
Objective This study is mainly to elucidate the characteristic components, hepatoprotective effect, and the underlying anti-hepatic fibrosis molecular mechanism of the total flavonoids of Tetrastigma hemsleyanum Diels & Gilg (SYQTF). Methods The components of SYQTF were confirmed based on global natural products social molecular networking (GNPS) as well as the hepatoprotective effect on CCl 4 -induced acute liver injury. Cell toxicity and viability, cell cycle, and apoptosis analyses were then performed to determine the effects of SYQTF in transforming growth factor-β1 (TGF-β1) (10 ng/mL)-induced HSC-T6 hepatic fibrosis cell model. Finally, the lentiviral particles to package recombinant Ras-related C3 botulinum toxin substrate 1 (Rac1) over-expression and Rac1 knockdown plasmids were transfected into TGF-β1-induced HSC-T6 cells to elucidate the mechanism of anti-hepatic fibrosis of SYQTF targeting Rac1, respectively. Results Our findings demonstrated that 86 components in SYQTF were identified in MS E and FastDDA mode with the aid of GNPS. Moreover, S 15 -ZJ, the genuine functional food and medicinal materials of T. hemsleyanum , was significantly different from other regions by multivariate statistical methods based on progenesis QI. Remarkably, kaempferol-3- O -furananose7- O -rhamnosyl-glucoside, the highest response intensity in S 15 -ZJ, may act as the potential Q-marker of genuine functional food and medicinal materials of T. hemsleyanum in Zhejiang Province distinguished from other areas. In addition, the in vivo experiments revealed that SYQTF greatly alleviated CCl 4 -induced acute liver injury. Furthermore, SYQTF can reversible the activation and proliferation of HSC-T6 cells, block the cell cycle in the G 0 /G 1 phase, and promote cell apoptosis. Remarkably, the study is the first to reveal that SYQTF exhibited the anti-hepatic fibrosis effect through targeting Rac1 in the hedgehog signaling pathway. Conclusion Rac1 is an important signaling molecule for the activation of the hedgehog pathway in HSC-T6. Importantly, SYQTF exerted its anti-hepatic fibrosis effect by inhibiting the Rac1-hedgehog signaling pathway. Furthermore, kaempferol-3- O -furananose7- O -rhamnosyl-glucoside could be a potential Q-marker of T. hemsleyanum in Zhejiang Province distinguished from other areas.
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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天然产物化学
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产品关联
DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6.8
Feng-Yang Wang,Liang-Mei Yang,Xiao-Lin Xiong,Jing Yang,Yan Yang,Jiu-Qin Tang,Lei Gao,Yuan Lu,Yuan Wang,Taotao Zou,Hong Liang,Ke-Bin Huang
Metal-based chemoimmunotherapy has recently garnered significant attention for its capacity to stimulate tumor-specific immunity beyond direct cytotoxic effects. Such effects are usually caused by ICD via the activation of DAMP signals. However, metal complexes that can elicit antitumor immune responses other than ICD have not yet been described. Herein, we report that a rhodium complex (Rh-1) triggers potent antitumor immune responses by downregulating Wnt/β-catenin signaling with subsequent activation of T lymphocyte infiltration to the tumor site. The results of mechanistic experiments suggest that ROS accumulation following Rh-1 treatment is a critical trigger of a decrease in β-catenin and enhanced secretion of CCL4, a key mediator of T cell infiltration. Through these properties, Rh-1 exerts a synergistic effect in combination with PD-1 inhibitors against tumor growth in vivo. Taken together, our work describes a promising metal-based antitumor agent with a noncanonical mode of action to sensitize tumor tissues to ICB therapy.
研究领域:
肿瘤学
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免疫学
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化学
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药理学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2023
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IF 5.6
Sujuan Wang,Wenqing Li,Wenxiu Liu,Lei Yu,Fu Peng,Junyuan Qin,Lin Pu,Yunli Tang,Xiaofang Xie,Cheng Peng
Background: Penthorum chinense Pursh (PCP) is widely utilized in China to treat a variety of liver diseases. It has been shown that flavonoids inhibit inflammation and have the potential to attenuate tissue damage and fibrosis. However, the mechanisms underlying how total flavonoids isolated from PCP (TFPCP) exert their anti-fibrotic effects remain unclear. Methods: The chemical composition of TFPCP was determined using UHPLC–Q-Orbitrap HRMS. Subsequently, rats were randomly assigned to a control group (Control), a carbon tetrachloride (CCl 4 )-induced hepatic fibrosis model group (Model), a positive control group [0.2 mg/(kg∙day)] of Colchicine), and three TFPCP treatment groups [50, 100, and 150 mg/(kg∙day)]. All substances were administered by gavage and treatments lasted for 9 weeks. Simultaneously, rats were intraperitoneally injected with 10%–20% CCl 4 for 9 weeks to induce liver fibrosis. At the end of the experiment, the liver ultrasound, liver histomorphological, biochemical indicators, and inflammatory cytokine levels were tested respectively. The underlying mechanisms were assessed using Western blot, immunohistochemistry, immunofluorescence, RT-qPCR, and metabolomics. Results: Fourteen flavonoids were identified in TFPCP. Compared with control animals, CCl 4 -treated rats demonstrated obvious liver injury and fibrosis, manifested as increases in gray values, distal diameter of portal vein (DDPV) and a decrease in blood flow velocity (VPV) in the ultrasound analysis; increased biochemical index values (serum levels of ALT, AST, TBIL, and ALP); marked increases in the contents of fibrotic markers (PC III, COL4, LN, HA) and inflammatory factors (serum TNF-α, IL-6, and IL-1β); and significant pathological changes. However, compared with the Model group, the ultrasound parameters were significantly improved and the serum levels of inflammatory cytokines were reduced in the TFPCP group. In contrast, the expression of TGF-β 1 , TLR4, and MyD88, as well as the p-P65/P65 and p-IκBα/IκBα ratios, were considerably reduced following TFPCP treatment. In addition, we identified 32 metabolites exhibiting differential abundance in the Model group. Interestingly, TFPCP treatment resulted in the restoration of the levels of 20 of these metabolites. Conclusion: Our findings indicated that TFPCP can ameliorate hepatic fibrosis by improving liver function and morphology via the inactivation of the TLR4/MyD88-mediated NF-κB pathway and the regulation of liver metabolism.
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产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
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2021
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IF 6.419
Jianbo Li,Tiange Feng,Weijing Yang,Yaru Xu,Shuaishuai Wang,Huijie Cai,Zhilei Liu,Hong Qiang,Jinjie Zhang
Although Fraxinellone (Frax) isolated from Dictamnus albus L. possessed excellent anti-hepatic fibrosis activity, oral administration of Frax suffered from the inefficient therapeutic outcome in vivo due to negligible oral absorption. At present, the oral formulation of Frax is rarely exploited. For rational formulation design, we evaluated preabsorption risks of Frax and found that Frax was rather stable while poorly dissolved in the gastrointestinal tract (78.88 μg/mL), which predominantly limited its oral absorption. Further solubility test revealed the outstanding capacity of cyclodextrin derivatives (CDs) to solubilize Frax (6.8–12.8 mg/mL). This led us to study the inclusion complexes of Frax with a series of CDs and holistically explore their drug delivery performance. Characterization techniques involving 1H-NMR, FT-IR, DSC, PXRD, and molecular docking confirmed the most stable binding interactions when Frax complexed with 6-O-α-D-maltosyl-β-cyclodextrin (G2-β-CD-Frax). Notably, G2-β-CD-Frax exhibited the highest solubilizing capacity, fast dissolution rate, and superior Caco-2 cell internalization with no obvious toxicity. Pharmacokinetic studies demonstrated markedly higher oral bioavailability of G2-β-CD-Frax (5.8-fold that of free drug) than other Frax-CDs. Further, long-term administration of G2-β-CD-Frax (5 mg/kg) efficiently inhibited CCl4-induced hepatic fibrosis in the mouse without inducing any toxicity. Our results will inspire the continued advancement of optimal oral Frax formulations for anti-fibrotic therapy.
研究领域:
药学
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药理学
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药物递送系统
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药物化学
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DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
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2024
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IF 18.5
Tiantian Xue,Hongyan Wei,Fenfang Li,Yixin Zhang,Yuanyuan Jin,Yanteng Xu,Hon Fai Chan,Yingying Xu,Yin-Xiong Li,Mingqiang Li,Yu Tao
Acute liver failure (ALF) involves extensive necrosis of liver cells and severe impairment of liver function. Hepatocyte transplantation holds promise for treating ALF by swiftly supporting liver functions and promoting liver regeneration. However, the scarcity of suitable cell sources requires strategies to obtain enough functional hepatocyte-like cells (HLCs) and optimize their in vivo transplantation efficiency. A DNA hexahedral nanostructure (DHN) is developed loaded with microRNA-122 to efficiently induce hepatic differentiation of human adipose-derived mesenchymal stem cells into HLCs. These HLCs can serve as alternative hepatocyte sources, as confirmed by expression of liver-specific genes and proteins, and the restoration of liver functions. To enhance in vivo survival efficiency of HLCs, a versatile scaffold is also created by 3D printing the calcium-cross-linked mixture bioink composed of sodium alginate, gelatin, and silk fibroin with excellent ROS scavenging capabilities. The scaffold is infused with chitosan-DHN hydrogel containing HLCs for tissue engineering orthotopic transplantation in CCl 4 -induced ALF mice. The transplanted composite scaffold-HLCs successfully repair tissue necrosis in the liver injury area of mice and regulate expressions of genes and proteins associated with inflammation, oxidative stress, and hepatocyte function. Collectively, this study offers a novel approach and strategy for identifying alternative hepatocyte sources and treating ALF.
研究领域:
生物医学工程
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组织工程
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干细胞生物学
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分子生物学
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纳米技术
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再生医学
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DOI
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Yifu Lyu,Xiuyi Yang,Lei Yang,Jinyu Dai,Huanyu Qin,Yunuo Zhou,Yunan Huang,Yanmei Wang,Di Wu,Qindai Shuai,Qilong Li,Xiaofei Xin,Lifang Yin
Lipid nanoparticle-mediated co-delivery of siRNA and small molecule holds a great potential to treat metabolic dysfunction-associated steatotic liver disease (MASLD). However, targeted delivery of therapeutics to hepatocytes remains challenging. Taking the advantage of rising low density lipoprotein receptor/very-low density lipoprotein receptor (LDLR/VLDR) levels in MASLD, the biological fate of dinonylamine-ethylene glycol chlorophosphate-1-nonanol (DNNA-COP-NA) based lipid nanoparticles (LNPs) was oriented to liver tissues via apolipoprotein E (ApoE)-LDLR/VLDLR pathway. We then adopted a three-round screening strategy to optimize the formulation with both high potency and selectivity to deliver siRNA-HIF-1α (siHIF1α) and silibinin (SLB) payloads to hepatocytes. The optimized SLB/siHIF1α-LNPs mediates great siRNA delivery and transfection of hepatocytes. In high fat diet (HFD)- and carbon tetrachloride (CCl 4 )-induced mouse models of MASLD, SLB/siHIF1α-LNPs enabled the silencing of hypoxia inducible factor-1α (HIF-1α), a therapeutic target primarily expressed by hepatocytes, leading to significantly reduced inflammation and liver fibrosis synergized with SLB. Moreover, it is demonstrated the hepatocyte-targeting delivery of SLB/siHIF1α-LNPs has the potential to restore the immune homeostasis by modulating the population of Tregs and cytotoxic T cells in spleen. This proof-of-concept study enable siRNA and small molecule co-delivery to hepatocytes through intrinsic variation of targeting receptors for MASLD therapy.
研究领域:
药学
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分子生物学
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肝病学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
eLife
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2022
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IF 8.713
Chen Yang,Hailin Zhang,Mengnuo Chen,Siying Wang,Ruolan Qian,Linmeng Zhang,Xiaowen Huang,Jun Wang,Zhicheng Liu,Wenxin Qin,Cun Wang,Hualian Hang,Hui Wang
Pharmacologic perturbation projects, such as Connectivity Map (CMap) and Library of Integrated Network-based Cellular Signatures (LINCS), have produced many perturbed expression data, providing enormous opportunities for computational therapeutic discovery. However, there is no consensus on which methodologies and parameters are the most optimal to conduct such analysis. Aiming to fill this gap, new benchmarking standards were developed to quantitatively evaluate drug retrieval performance. Investigations of potential factors influencing drug retrieval were conducted based on these standards. As a result, we determined an optimal approach for LINCS data-based therapeutic discovery. With this approach, homoharringtonine (HHT) was identified to be a candidate agent with potential therapeutic and preventive effects on liver cancer. The antitumor and antifibrotic activity of HHT was validated experimentally using subcutaneous xenograft tumor model and carbon tetrachloride (CCL4)-induced liver fibrosis model, demonstrating the reliability of the prediction results. In summary, our findings will not only impact the future applications of LINCS data but also offer new opportunities for therapeutic intervention of liver cancer.
研究领域:
药理学
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计算生物学
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肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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