Pharmaceutics
·
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
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DOI
PubMed
高影响因子
Toxicology Research
·
2015
·Vol. 5
·期 1
·160-167
·
IF 3.983
Liye Zhu,Tao Yu,Xiaozhe Qi,Bo Yang,Lei Shi,Haoshu Luo,Xiaoyun He,Kunlun Huang,Wentao Xu
OTA can induce hepatotoxicity. Our previous research has shown that miRNAs play important roles in the OTA-induced hepatotoxicity. And miR-122 is the most abundant miRNA in the liver and is involved in diverse biological processes. This study was performed to clarify the role of miR-122 in OTA-induced hepatotoxicity. The expression levels of miR-122 and the target genes were quantified by real-time PCR. The OTA-induced apoptosis of hepatocyte and HepG2 cells was evaluated using a TUNEL kit, a CCK-8 kit, a flow cytometer and Hoechst 33342. miR-122 was inhibited in HepG2 cells. The results revealed that OTA affected rat hepatocyte apoptosis. miR-122 decreased at 4 weeks but increased at 13 weeks in the OTA-treated livers, and increased in the OTA-treated HepG2 cells; and the mRNA levels of CCNG1 and Bcl-w increased at 4 weeks and decreased at 13 weeks in the high-dose OTA-treatment groups and decreased in HepG2 cells. The apoptosis of HepG2 cells displayed a dose-related increase with OTA. However, the inhibition of miR-122 greatly reduced OTA-induced apoptosis. p53 decreased in vivo and in vitro. miR-122 is a primary effector of OTA-induced hepatocyte apoptosis through the CCNG1/p53 pathway and Bcl-w/caspase-3 pathway in vivo and in vitro. And miR-122 plays an important role in OTA-induced hepatotoxicity.
研究领域:
分子生物学
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毒理学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2021
·Vol. 25
·期 24
·11113-11127
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IF 5.31
Ting Liu,Shujia Chen,Xiaoli Xie,Hongqun Liu,Yongjuan Wang,Shengbin Qi,Linping Shi,Xue Zhou,Jiuna Zhang,Shuling Wang,Yijun Wang,Shengxiong Chen,Shiying Dou,Xiaoyu Jiang,Ruolin Cui,Huiqing Jiang
Triggering receptor expressed on myeloid cells-1 (TREM-1) exists in two forms: a transmembrane form and a soluble form (sTREM-1). The levels of sTREM-1 are elevated in supernatants of activated HSCs. However, the role of sTREM-1 in HSC activation and liver fibrosis remains undefined. Previous studies have primarily focused on the transmembrane form of TREM-1; we innovatively observed the function of sTREM-1 as a ligand in liver fibrosis and screened its receptor. Here, recombinant sTREM-1 was used as a stimulator which induced HSC activation and further aggravated liver fibrosis. Then, screening for sTREM-1 interacting membrane receptors was performed using pull-down assay followed by mass spectrometry, and the membrane receptor roundabout guidance receptor 2 (Robo2) was identified as a candidate receptor for sTREM-1. The interaction between sTREM-1 and Robo2 was verified by pull-down and immunofluorescence. The role of Robo2 on sTREM-1-induced HSC activation and its downstream signal pathways was assessed by knockdown of Robo2 in LX-2 cells. Furthermore, HSC-specific knockdown of Robo2 was achieved in a mouse model of liver fibrosis by using a recombinant adeno-associated virus (AAV) vector to confirm the role of the receptor, and we proved that Robo2 knockdown inhibited the activation of HSC and liver fibrosis, which also led to the inactivation of Smad2/3 and PI3K/Akt pathways in sTREM-1-induced HSC activation and liver fibrosis. In conclusion, sTREM-1 acts as a new ligand of Robo2; the binding of sTREM-1 to Robo2 initiates the activation of the downstream Smad2/3 and PI3K/Akt signalling pathways, thereby promoting HSC activation and liver fibrosis.
研究领域:
免疫学
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肝病学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Biomaterials Science
·
2019
·Vol. 7
·期 4
·1507-1515
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IF 5.251
Yongjing Li,Jiaxun Wan,Fang Wang,Jia Guo,Changchun Wang
The clinical applications of particulate drug delivery systems have demonstrated limited treatment outcomes, which is largely attributable to the elimination of such systems by the immune system, especially in the liver. Inspired by the mechanism of nanomaterial clearance by the liver, we designed a new anticancer auxiliary delivery system by introducing norepinephrine loaded poly(acrylic acid) nanogels as angiotonics. The auxilliary system effectively decreased the liver uptake of nanodrugs by increasing the liver blood flow rate. With administration of the as-prepared norepinephrine-loaded poly(acrylic acid) nanogels, the blood perfusion amount increased significantly by 177.0% (i.e. 2.77 times) as observed directly by ultrasonic imaging, indicating an increased blood flow rate in the liver. Since the blood flow rate plays a key role in nanomaterial clearance in the liver, nanodrug clearance should be changed by modulation of the blood flow. Our in vivo experimental results clearly showed the enhancement of nanodrug efficiency with this two-step treatment, with a 52% improvement in plasma drug concentration, obvious drug accumulation in the tumor, and significant antitumor effects. These results indicate that a pre-conditioning strategy involving norepinephrine-loaded poly(acrylic acid) nanogels can serve as an ideal route for reducing nanodrug clearance by the liver.
研究领域:
药学
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肿瘤学
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生物医学工程
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DOI
PubMed
高影响因子
JOURNAL OF HEPATOLOGY
·
2019
·
IF 18.946
Shaoping She,Xiaoning Wu,Danfeng Zheng,Xiaolei Pei,Jing Ma,Yameng Sun,Jialing Zhou,Lin Nong,Changyuan Guo,Ping Lv,Quansheng Song,Can Zheng,Weiwei Liang,Shiyang Huang,Qingqing Li,Zhongtian Liu,Zhanming Song,Yuzi Li,Yu Zhang,Wei Kong,Hong You,Jianzhong Xi,Ying Wang
Background & Aims C-C motif chemokine receptor 2 (CCR2) has been recognized as a promising target for the treatment of liver fibrosis. PC3-secreted microprotein (PSMP)/microseminoprotein (MSMP) is a novel chemotactic cytokine and its receptor is CCR2. In the present study we investigated the expression and role of PSMP in liver fibrosis/cirrhosis. Methods PSMP expression was studied in patients with fibrosis/cirrhosis and in 3 murine models of liver fibrosis, including mice treated with carbon tetrachloride (CCl 4 ), bile-duct ligation, or a 5-diethoxycarbonyl-1,4-dihydrocollidine diet. The role of PSMP was evaluated in Psmp -/- mice and after treatment with a PSMP antibody in wild-type mice. The direct effects of PSMP on macrophages and hepatic stellate cells were studied in vitro . Results In this study, we found that PSMP was highly expressed in fibrotic/cirrhotic tissues from patients with different etiologies of liver disease and in the 3 experimental mouse models of fibrosis. Damage-associated molecular pattern molecules HMGB-1 and IL-33 induced hepatocytes to produce PSMP. PSMP deficiency resulted in a marked amelioration of hepatic injury and fibrosis. In CCl 4 -induced hepatic injury, the infiltration of macrophages and CCR2 + monocytes into the liver was significantly decreased in Psmp -/- mice. Consistent with the decreased levels of intrahepatic macrophages, proinflammatory cytokines were significantly reduced. Moreover, adeno-associated virus-8 vectors successfully overexpressing human PSMP in Psmp -/- mouse livers could reverse the attenuation of liver injury and fibrosis induced by CCl 4 in a CCR2-dependent manner. Treatment with a specific PSMP-neutralizing antibody, 3D5, prevented liver injury and fibrosis induced by CCl 4 in mice. At the cellular level, PSMP directly promoted M1 polarization of macrophages and activation of LX-2 cells. Conclusion PSMP enhances liver fibrosis through its receptor, CCR2. PSMP is a potentially attractive therapeutic target for the treatment of patients with liver fibrosis. Lay summary Our present study identifies the essential role of the protein PSMP for the development and progression of liver fibrosis in humans and mice. PSMP promotes liver fibrosis through inflammatory macrophage infiltration, polarization and production of proinflammatory cytokines, as well as direct activation of hepatic stellate cells via its receptor CCR2. A PSMP antibody can significantly reduce liver fibrosis development in vivo . These findings indicate that PSMP is a potential therapeutic target and its antibody is a potential therapeutic agent for the treatment of liver fibrosis.
研究领域:
肝病学
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免疫学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Marine Drugs
·
2022
·Vol. 20
·期 11
·719
·
IF 6.085
Qian Wang,Fu-Jun Liu,Xin-Miao Wang,Guan-Hua Zhao,Dong Cai,Jing-Han Yu,Fa-Wen Yin,Da-Yong Zhou
Low molecular weight (<5 kDa) peptides from mussels (Mytilus edulis) (MPs) and the peptides from clams (Ruditapes philippinarum) (CPs) were prepared through enzymatic hydrolysis by proteases (dispase, pepsin, trypsin, alcalase and papain). Both the MPs and the CPs showed excellent in vitro scavenging ability of free radicals including OH, DPPH and ABTS in the concentration range of 0.625–10.000 mg/mL. By contrast, the MPs hydrolyzed by alcalase (MPs-A) and the CPs hydrolyzed by dispase (CPs-D) had the highest antioxidant activities. Furthermore, MPs-A and CPs-D exhibited protective capabilities against oxidative damage induced by H2O2in HepG2 cells in the concentration range of 25–800 μg/mL. Meanwhile, compared with the corresponding indicators of the negative control (alcohol-fed) mice, lower contents of hepatic MDA and serums ALT and AST, as well as higher activities of hepatic SOD and GSH-PX were observed in experiment mice treated with MPs-A and CPs-D. The present results clearly indicated thatMytilus edulisandRuditapes philippinarumare good sources of hepatoprotective peptides.Keywords:Mytilus edulis;Ruditapes philippinarum;hepatoprotective peptide;H2O2-induced oxidative damage;mice;acute liver injury
研究领域:
生物化学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2022
·
IF 6.656
Simeng Chu,Yujie Lu,Wenjuan Liu,Xiaoyao Ma,Jiamin Peng,Xiaoying Wang,Min Jiang,Gang Bai
Background Tetrandrine (TET), a bisbenzylisoquinoline alkaloid isolated from Stephania tetrandra S. Moore, is the only approved medicine in China for silicosis. However, TET-induced hepatotoxicity has raised safety concerns. The underlying toxic targets and mechanism induced by TET remain unclear; there are no targeted detoxification strategies developed for TET-induced hepatotoxicity. Ursolic acid (UA), a pentacyclic triterpene with liver protective effects, may have detoxification effects on TET-induced hepatotoxicity. Purpose This study aims to explore toxic targets and mechanism of TET and present UA as a potential targeted therapy for alleviating TET-induced hepatotoxicity. Methods A TET-induced liver-injury model was established to evaluate TET toxicity and the potential UA detoxification effect. Alkenyl-modified TET and UA probes were designed to identify potential liver targets. Pharmacological and molecular biology methods were used to explore the underlying toxicity/detoxification mechanism. Results TET induced liver injury by covalently binding to the substrate-binding pocket (H-site) of glutathione S-transferases (GSTs) and inhibiting GST activity. The covalent binding led to toxic metabolite accumulation and caused redox imbalance and liver injury. UA protected the liver from TET-induced damage by competitively binding to the GST H-site. Conclusion The mechanism of TET-induced hepatotoxicity is related to irreversible binding with the GST H-site and GST-activity inhibition. UA, a natural antidote, competed with TET on H-site binding and reversed the redox imbalance. This study revealed the hepatotoxic mechanism of TET and provided a targeted detoxifying agent, UA, to alleviate hepatotoxicity caused by GST inhibition.
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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DOI
PubMed
高影响因子
LIVER INTERNATIONAL
·
2023
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IF 6.7
Qiuyuan Yang,Yue Wu,Wei Liu,Xiaojuan Ou,Wei Zhang,Jianning Wang,Yanzhong Chang,Fudi Wang,Ming Gao,Sijin Liu
Background and Aims Disorders in liver lipid metabolism have been implicated in a range of metabolic conditions, including fatty liver and liver cancer. Altered lipid distribution within the liver, shifting from the pericentral to the periportal zone under pathological circumstances, has been observed; however, the underlying mechanism remains elusive. Iron, an essential metal, exhibits a zonal distribution in the liver similar to that of lipids. Nevertheless, the precise relationship between iron and lipid distribution, especially in the pericentral and periportal zones, remains poorly understood. Methods We conducted comprehensive in vitro and in vivo experiments, combining with in situ analysis and RNA sequencing, aiming for a detailed exploration of the causal relationship between iron accumulation and lipid metabolism. Results Our research suggests that iron overload can disrupt the normal distribution of lipids within the liver, particularly in the periportal zone. Through meticulous gene expression profiling in both the pericentral and periportal zones, we identified pyruvate carboxylase (PC) as a pivotal regulator in iron overload-induced lipid accumulation. Additionally, we revealed that the activation of cyclic adenosine monophosphate response element binding protein (CREB) was indispensable for Pc gene expression when in response to iron overload. Conclusions In summary, our investigation unveils the crucial involvement of iron overload in fostering hepatic lipid accumulation in the periportal zone, at least partly mediated by the modulation of Pc expression. These insights offer new perspectives for understanding the pathogenesis of fatty liver diseases and their progression.
研究领域:
肝病学
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代谢学
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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
TOXICOLOGY LETTERS
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2022
·
IF 4.271
Mingyang Chen,Mengru Bai,Yaodong Yi,Shuanghui Lu,Jun Luo,Ping Li,Hengbin Zhang,Huidi Jiang,Hui Zhou
Glucocorticoids such as dexamethasone (DEX) are widely prescribed to treat numerous conditions and diseases. However, glucocorticoid-induced liver lipid metabolism disorder, even nonalcoholic fatty liver disease , has caused extensive attention. Since fatty acid transporters such as CD36 and FATP play crucial roles in hepatic fatty acid uptake, this work examined their potential involvement in DEX-induced liver lipid accumulation. Chronic DEX administration (1–5 mg/kg/day over 28 days) induced hepatic lipid accumulation in mice. Fatty acid uptake in HepG2 cells and mouse primary hepatocytes was also stimulated after incubation with 0.5–2 μM DEX. Meanwhile, qPCR and western blotting demonstrated dose-dependent upregulation of CD36 expression by DEX in the mouse liver and in cultured hepatocytes. Glucocorticoid receptor (GR) inhibition with mifepristone (RU486) and siRNA-mediated GR knockdown attenuated lipid accumulation in hepatocytes by inhibiting DEX-induced CD36 upregulation, and direct binding of GR to the CD36 promoter was demonstrated by luciferase reporter and chromatin immunoprecipitation assays. These results indicate that DEX promotes free fatty acid uptake leading to hepatic steatosis by upregulating CD36 expression via activation of GR. Thus, strategies aimed at inhibiting GR/CD36 expression or activity might help prevent or reduce the onset and progression of hepatic lipid metabolism disorders induced by glucocorticoid drugs.
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
PHYTOMEDICINE
·
2025
·
IF 8.3
Chunyu Wang,Kunjing Liu,Jing Ji,Wenyuan Ma,Haojia Zhang,Kai Wang,Yukun Lin,Chongyang Ma,Xueqian Wang,Fafeng Cheng
Background Metabolic dysfunction-associated fatty liver disease (MAFLD) is a major global chronic liver disorder, with metabolic dysfunction-associated steatohepatitis (MASH) representing its severe subtype. Liu-Jun-Zi Decoction (LJZD), a classical traditional Chinese medicine (TCM) formula, has shown clinical efficacy against MASH, however, its underlying mechanisms remain unclear. Purpose To investigate the molecular mechanism through which LJZD alleviates hepatic steatosis in MASH mice by restoring irisin secretion in skeletal muscle. Methods A MASH mouse model was established using a methionine and choline deficient (MCD) diet, followed by LJZD treatment. First, major chemical components of LJZD were identified via UHPLC-QE-MS. Subsequently, histopathological and biochemical analyses were performed to evaluate the effects of LJZD on MASH and skeletal muscle atrophy. Finally, the secretion of irisin in skeletal muscle was assessed, and bioinformatics analysis was used to screen downstream targets of irisin. Results LJZD significantly alleviated hepatic steatosis, injury, inflammation, and fibrosis in MASH mice while improving concomitant skeletal muscle atrophy. Furthermore, LJZD enhanced irisin secretion from skeletal muscle. Integrated transcriptomic analysis identified carboxylesterase 2A (CES2A) as a key hepatic downstream effector of irisin. Conclusion LJZD ameliorates MASH by promoting skeletal muscle irisin secretion, which upregulates hepatic CES2A to enhance lipid catabolism. In summary, current data extend the research scope on LJZD's pharmacological effects and suggest new approaches for clinical MASH treatment. LJZD alleviates hepatic steatosis by targeting skeletal muscle, indicating its potential as a therapeutic candidate for MASH.
研究领域:
中医药学
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药理学
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肝病学
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分子生物学
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代谢疾病
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生物信息学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2024
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IF 6.6
Xiangdong Gongye,Peng Xia,Tianyin Ma,Yibo Chai,Zhang Chen,Yimin Zhu,Chengming Qu,Jie Liu,Wing Wa Guo,Minghe Zhang,Yingyi Liu,Ming Tian,Yufeng Yuan
Background The liver’s regenerative capacity allows it to repair itself after injury. Extracellular vesicles and particles (EVPs) in the liver’s interstitial space are crucial for signal transduction, metabolism, and immune regulation. Understanding the role and mechanism of liver-derived EVPs in regeneration is significant, particularly after partial hepatectomy, where the mechanisms remain unclear.Methods A 70% hepatectomy model was established in mice, and EVPs were isolated and characterized using electron microscopy, nanocharacterization, and Western blot analysis. Combined metabolomic and transcriptomic analyses revealed β-sitosterol enrichment in EVPs and activation of the Hedgehog signaling pathway during regeneration. The role of β-sitosterol in EVPs on the Hedgehog pathway and its targets were identified using qRT-PCR, Western blot analysis. The regulation of carnitine synthesis by this pathway was determined using a dual luciferase assay. The effect of a β-sitosterol diet on liver regeneration was verified in mice.Results After 70% hepatectomy, the liver successfully regenerated without liver failure or death. At 24 hours post-surgery, tissue staining showed transient regeneration-associated steatosis (TRAS), with increased Ki67 positivity at 48 hours. EVPs displayed a spherical lipid bilayer structure with particle sizes of 70–130 nm. CD9, CD63, and CD81 in liver-derived EVPs were confirmed. Transcriptomic and metabolomic analyses showed EVPs supplementation significantly promoted carnitine synthesis and fatty acid oxidation. Tissue staining confirmed accelerated TRAS resolution and enhanced liver regeneration with EVP supplementation. Mass spectrometry identified β-sitosterol in EVPs, which binds to Smo protein, activating the Hedgehog pathway. This led to the nuclear transport of Gli3, stimulating Setd5 transcription and inducing carnitine synthesis, thereby accelerating fatty acid oxidation. Mice with increased β-sitosterol intake showed faster TRAS resolution and liver regeneration compared to controls.Conclusion Liver-derived EVPs promote regeneration after partial hepatectomy. β-sitosterol from EVPs accelerates fatty acid oxidation and promotes liver regeneration by activating Hedgehog signaling pathway.
研究领域:
肝病学
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分子生物学
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再生医学
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代谢组学
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转录组学
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产品关联
DOI
PubMed
高影响因子
Cell Metabolism
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2025
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IF 30.9
Jie Jiang,Yuqing Gao,Jiang Wang,Yan Huang,Rong Yang,Yongxin Zhang,Yuandi Ma,Yingquan Wen,Gongkai Luo,Shurui Zhang,Yutang Cao,Minjun Yu,Qinxue Wang,Shulei Hu,Kanglong Wang,Xiaozhen Guo,Frank J. Gonzalez,Yameng Liu,Hong Liu,Qing Xie,Cen Xie
Metabolic-dysfunction-associated steatohepatitis (MASH) remains a major health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption or pharmacological inhibition of SMPD3 alleviates MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. Although healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses sirtuin 1 (SIRT1), triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes disease progression by enhancing caveolae-dependent lipid uptake and extracellular vesicle secretion from steatotic hepatocytes to exacerbate inflammation and fibrosis. Consequently, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid metabolism and holds great promise for developing novel MASH therapies.
研究领域:
生物化学
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肝脏病学
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代谢医学
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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）