Hepatology International
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2019
·Vol. 14
·期 1
·145-160
·
IF 5.49
Zhao Jing,Han Ming,Zhou Li,Liang Pu,Wang Yun,Feng Shenghu,Lu Hongping,Yuan Xiaoxue,Han Kai,Chen Xiaofan,Liu Shunai,Cheng Jun
Background This study aimed to investigate the roles and mechanisms of tenofovir alafenamide fumarate (TAF)/tenofovir disoproxil fumarate (TDF) in treating liver fibrosis. Methods The effects of TAF/TDF on carbon tetrachloride (CCl 4 )-induced liver fibrosis in C57BL/6 wild-type or nonstructural protein 5A transactivated protein 9 (NS5ATP9) knockout mice were studied. The differentiation, activation, and proliferation of LX-2 cells after TAF/TDF treatment were tested in vitro. The expression of NS5ATP9 and activities of transforming growth factor-β1 (TGFβ1)/Sekelsky mothers against decapentaplegic homolog 3 (Smad3) and NF-κB/NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome signaling pathways were detected in TAF/TDF-treated mice and LX-2 cells. The genes related to extracellular matrix accumulation were detected in vivo and in vitro after NS5ATP9 silencing or knockout. Results TAF/TDF significantly inhibited CCl 4 -induced liver fibrosis in mice, and regulated the differentiation, activation, and proliferation of hepatic stellate cells (HSCs). Furthermore, TAF/TDF suppressed the activities of TGFβ1/Smad3 and NF-κB/NLRP3 inflammasome signaling pathways in vivo and in vitro. NS5ATP9 inhibited liver fibrosis through TGFβ1/Smad3 and NF-κB signaling pathways. TAF/TDF upregulated the expression of NS5ATP9 in vivo and in vitro. Finally, TAF/TDF could only show marginal therapeutic effects when NS5ATP9 was silenced and knocked out in vivo and in vitro. Conclusions TAF/TDF prevented progression and promoted reversion of liver fibrosis through assembling TGFβ1/Smad3 and NF-κB/NLRP3 inflammasome signaling pathways via upregulating the expression of NS5ATP9. TAF/TDF also regulated the differentiation, activation, and proliferation of HSCs. The findings provided strong evidence for the role of TAF/TDF as a new promising therapeutic strategy in liver fibrosis.
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
BIOMEDICINE & PHARMACOTHERAPY
·
2018
·
IF 3.457
YingHui Zhang,Bing Wang,Feng Guo,ZhiZhen Li,GuiJun Qin
Diabetic nephropathy is one of the manifestations of systemic microangiopathy in diabetes. Hesperetin , a natural flavanone glycoside compound in citrus fruits, has been demonstrated to exert hypoglycemic effects and protect kidney in experimental diabetic animals. The current study was aimed to investigate the mechanisms underlying the hypoglycemic effects of hesperetin in high-fat/streptozocin (STZ)–induced diabetic nephropathy. The results showed that mice in whom hesperetin was administered for 4 weeks attenuated the increased fasting blood glucose and impaired glucose tolerance ability that was observed in high-fat/STZ mice. In addition, we found that hesperetin ameliorated the abnormalities of biochemical parameters in serum, liver, and kidney of mice with diabetic nephropathy. Hesperetin also rescued the irregular distortions in glomerular basement membrane and expanded mesangial regions. Moreover, hesperetin repaired the function of podocyte by increasing renal nephrin expression and decreasing renal alpha-smooth muscle actin expression. Furthermore, hesperetin inhibited the expression of transforming growth factor-β1 (TGF-β1) and its downstream effectors integrin-linked kinase (ILK) and Akt. In conclusion, our study implies that hesperetin produced protective effects in diabetic nephropathy possibly by suppressing TGF-β1-ILK-Akt signaling.
研究领域:
药理学
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内分泌学
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肾病学
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DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2022
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IF 6.633
Huiwen Wang,Jian Zhang,Xiaoxun Zhang,Nan Zhao,Zongtao Zhou,Lijian Tao,Lei Fu,Shifang Peng,Jin Chai
Cholestasis is characterized by intrahepatic accumulation of bile acids (BAs), resulting in liver injury, fibrosis, and liver failure. To date, only ursodeoxycholic acid and obeticholic acid have been approved for the treatment of cholestasis. As fluorofenidone (AKF-PD) was previously reported to play significant anti-fibrotic and anti-inflammatory roles in various diseases, we investigated whether AKF-PD ameliorates cholestasis. A mouse model of cholestasis was constructed by administering a 0.1 % 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) diet for 14 days. Male C57BL/6 J mice were treated with either AKF-PD or pirfenidone (PD) orally in addition to the DDC diet. Serum and liver tissues were subsequently collected and analyzed. We found that AKF-PD significantly reduced the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bile salts (TBA), as well as hepatic bile acids (BAs) levels. Hepatic histological analyses demonstrated that AKF-PD markedly attenuated hepatic inflammation and fibrosis. Further mechanistic analyses revealed that AKF-PD markedly inhibited expression of Cyp7a1, an enzyme key to BAs synthesis, by increasing Fxr nuclear translocation, and decreased hepatic inflammation by attenuating Erk/-Egr-1-mediated expression of inflammatory cytokines and chemokines Tnfα, Il-1β, Il-6, Ccl2, Ccl5 and Cxcl10. Moreover, AKF-PD was found to substantially reduce liver fibrosis via inhibition of Tgfβ1/Smad pathway in our mouse model. Here, we found that AKF-PD effectively attenuates cholestasis and hepatic fibrosis in the mouse model of DDC-induced cholestasis. As such, AKF-PD warrants further investigation as a candidate drug for treatment of cholestasis.
研究领域:
肝病学
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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
CELLULAR SIGNALLING
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2025
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IF 3.7
Tingjuan Huang,Ziyi Shang,Lina Nie,Haichao Diao,Qizhi Shuai,Junjie Ren,Jun Xu,Jun Xie
Hepatic stellate cells (HSCs) are the central link of the occurrence and development of hepatic fibrosis, and autophagy promotes HSCs activation. N6-methyladenosine (m6A) RNA modification can also control autophagy by targeting selected autophagy-associated genes. but up to now, little research has been done on the m6A modification autophagy-related genes (ATGs) in hepatic fibrosis. Here, we identify ATG9A as a previously unrecognized m6A modified ATG using m6A-sequencing (m6A-seq). Importantly, ATG9A is upregulated in liver fibrosis mice and primary biliary cirrhosis (PBC) patient liver tissue. Mechanistically, based on the presence of m6A binding sites on ATG9A, ATG9A promotes HSCs autophagy in an m6A dependent manner, thereby enhancing HSCs activation. Noteworthy, FTO is identified as the upstream of ATG9A, and knockdown of ATG9A can prevent FTO-induced HSCs autophagy and activation. In bile duct ligation (BDL) or CCL4-induced liver fibrosis mouse models, lowering ATG9A alleviated liver fibrosis through PI3K/AKT/mTOR pathway and TGFβ1/smad3 pathway. Taken together, our results provided that ATG9A is a potential prognostic biomarker and therapeutic target for patients with liver fibrosis.
研究领域:
分子生物学
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遗传学
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肝病学
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DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2022
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IF 5.999
Anning Chen,Yaoheng Chen,Shixin Liu,Dong Ma,Jie Tang,Hongzheng Zhang
Cochlear implants (CI) are widely used in patients to restore hearing function. Uncontrolled fibrosis in the cochleae induced by excess secretion of TGFβ1 seriously affects the effectiveness of CIs. siRNA is a potential therapeutic strategy to downregulate TGFβ1 specifically. However, treatment with siRNA in cochleae is difficult due to the poor penetration capability and instability of siRNA and the inaccessibility and vulnerability of cochleae. To address these challenges, we developed amino-functionalized mesoporous silica nanoparticle (MSN-NH 2 )-modified electrode arrays to deliver siRNA-TGFβ1 into the inner ear. The shape, diameter, pore diameter, and zeta potential of MSN-NH 2 were investigated. siRNA loading capability and protective effect of MSN-NH 2 were determined by agarose gel electrophoresis assay. The cytotoxicity, cellular uptake assay, and TGFβ1 knockdown efficiency of MSN-NH 2 were studied by CCK-8 assay, flow cytometry , and real-time PCR, respectively. MSN-NH 2 -siTGFβ1 nanoparticles were absorbed into the electrode arrays and worked in the cochleae. MSN-NH 2 -siTGFβ1-modified CI electrode arrays may be an attractive therapeutic clinical intervention strategy to inhibit cochlear implantation fibrosis.
研究领域:
生物医学工程
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药学
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神经科学
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材料科学
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DOI
PubMed
高影响因子
Annals of Translational Medicine
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2022
·Vol. 10
·期 22
·1239
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IF 3.616
Yuan Liu,Fuai Lu,Xiaofen Li,Youguo Yang,Jianqing Yang
Background: Pulmonary fibrosis, which is a frequent manifestation of connective tissue disease (CTD), is a leading cause of morbidity and mortality. However, the role of long non-coding ribonucleic acids (lncRNAs) in CTD-associated pulmonary fibrosis requires clarification. This study sought to examine the effects of lnc-NONHSAT071210 on the phenotypes of transforming growth factor β1 (TGFβ1)-treated lung epithelial cells. Methods: The GeneChip was used to identify differentially expressed lncRNAs in CTD-associated pulmonary fibrosis patients. After lnc-NONHSAT071210 was knocked down in the TGFβ1-challenged lung epithelial cells, cell viability, cell cycle, migration, and invasion were estimated by Cell Counting Kit-8 assays, a flow cytometry analysis, wound-healing assays, and transwell assays, respectively. The expression and levels of the fibrosis-associated factors were examined by enzyme-linked immunosorbent assays, RT-qPCR, and western blots. Results: The expression of the top 7 most significantly upregulated lncRNAs in the CTD-associated pulmonary fibrosis patients was depicted in a heat map and examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The results showed that the expression of lnc-NONHSAT071210 was significantly increased in the tissues of the CTD-associated pulmonary fibrosis patients (P<0.001). The silencing of Lnc-NONHSAT071210 suppressed proliferation, migration, and invasion in the TGFβ1-exposed alveolar epithelial cells (P<0.001). Conclusions: Thus, lnc-NONHSAT071210 expression was increased in the tissues of the CTD-associated pulmonary fibrosis patients and TGFβ1-treated lung epithelial cells, and TGFβ1-induced lung epithelial cell injury was alleviated by impeding the expression of lnc-NONHSAT071210.
研究领域:
分子生物学
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肺病学
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细胞生物学
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病理学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2020
·
IF 3.943
Ruoyu Wang,Dong Zhang,Dan Tang,Kewei Sun,Jianping Peng,Wenfang Zhu,Sihan Yin,Yunan Wu
The activation of hepatic stellate cells (HSCs) has been considered one of the major events in hepatic fibrosis. Amygdalin has been used to treat cancers and alleviate pain; however, its role and mechanism in HSC activation and hepatic fibrosis remain unclear. In the present study, transforming growth factor-beta 1 (TGF-β1) stimulated the activation of HSCs, as indicated by significantly increased alpha-smooth muscle actin (α-SMA), desmin, collagen I, and tissue inhibitor of metalloproteinase-1 (TIMP-1) protein levels. Amygdalin treatment dramatically suppressed TGF-β1-induced HSC proliferation and activation. Moreover, amygdalin treatment also reduced the TGF-β1-induced secretion of cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), platelet-derived growth factor (PDGF), and chemokine (C-C motif) ligand 2 (CCL2), as well as the phosphorylation of Smad2, Smad3, and p65. In the CCl 4 -stimulated liver fibrosis rat model, amygdalin treatment improved liver fibrosis and liver damage by reducing focal necrosis, collagen fiber accumulation, and the protein levels of α-SMA, desmin, collagen I, and TIMP-1 in hepatic tissue samples and reducing serum alanine transaminase (ALT) and aspartate transaminase (AST) levels. In conclusion, we demonstrated the suppressive effects of amygdalin in TGF-β1-induced HSC activation through modulating proliferation, fibrogenesis, and inflammation signaling in vitro and the antifibrotic effects of amygdalin in CCl 4 -stimulated hepatic fibrosis in rats in vivo .
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
JOURNAL OF NANOBIOTECHNOLOGY
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2022
·Vol. 20
·期 1
·1-16
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IF 9.429
Xing Zhen,Xue Jing,Ma Xindian,Han Congwei,Wang Zhenzhen,Luo Shunhuang,Wang Chunming,Dong Lei,Zhang Junfeng
The formation of biomolecular condensates via liquid‒liquid phase separation (LLPS) is an advantageous strategy for cells to organize their subcellular compartments for diverse functions. Recent findings suggest that RNA or RNA-related LLPS techniques have potential for the development of new cellular regulation strategies. However, manipulating RNA LLPS in living cells has great challenges. Herein, we report that cationic polymers (CPs) have strong RNA LLPS-inducing activity. By introducing CPs into living cells or RNA solutions, significant RNA LLPS was verified through confocal imaging, turbidity assays, and fluorescence recovery after photobleaching (FRAP) tests. Among them, turbidity kinetics determinations indicated that the hydrophilic positively charged amino groups on the CPs play essential roles in RNA phase separation. Moreover, the LLPS induced by the cationic polymers dramatically changed the gene expression patterns in the cells. Interestingly, we found that TGFβ1 mRNA was highly encapsulated in the RNA droplets, which lowered the immunosuppressive capability of the tumor cells and triggered marked antitumor reactions in a mouse breast cancer model. Thus, we present here the CP-based modulation of RNA LLPS as a novel transcriptional manipulation method with potential for cancer immunotherapy drug development. Graphical Abstract
研究领域:
生物物理学
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癌症生物学
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分子生物学
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药学
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DOI
PubMed
高影响因子
MATERIALS & DESIGN
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2024
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IF 7.6
Pei Gong,Lulu Ren,Xinghui Gao,Jie Long,Weidong Tian,Min He
Local oxidative stress induced by surgical trauma has been recognized as one of pathogenesis for postsurgical adhesion tissue formation. Herein, tannic acid (TA) based metal-phenolic networks (MPNs) was assembled via chelating with Fe 3+ , and acted as a novel bio-filler for nanofibrous polycaprolactone (PCL) barrier membrane to endow it with reactive oxygen species (ROS) scavenging capacity. By chelating with Fe 3+ , the release of TA could last for more than 20 days, rendering the membrane with continuous ROS scavenging capacity. The modified membrane could effectively inhibit fibroblasts adhesion and proliferation, as well as immune cells recruitment, infiltration, and expression of pro-inflammatory cytokines. Consequently, a complete prevention of peritoneal adhesion formation was obtained in a rat model of sidewall defect-cecum abrasion, far better than commercial Poly lactic acid (PLA) membrane. Systematic biological mechanism investigations revealed that the enhanced anti-adhesion function was mainly ascribed to its robust ROS scavenging capacity, through which the PI3K-Akt signaling pathway was blocked, leading to repress of downstream NF-κB-TGFβ1-SMAD signaling pathway, finally inhibiting the bioactivity of fibroblasts and immune cells. This work provided a new strategy for the design of advanced barrier membrane, demonstrated its efficacy and mechanism on preventing postoperative adhesion, holding great promise for future clinical application.
研究领域:
生物医学工程
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材料科学
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外科手术
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药理学
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产品关联
DOI
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-24
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IF 10.6
Lai Huasheng,Yip Hon-Chi,Gong Yu,Chan Kai-Fung,Leung Kevin Kai-Chung,Chan Melissa Shannon,Xia Xianfeng,Chiu Philip Wai-Yan
Background Endoscopic submucosal dissection (ESD) is the current standard treatment for early-stage esophageal neoplasms. However, the postoperative esophageal stricture after extensive mucosal dissection remains a severe challenge with limited effective treatments available. In this study, we introduced a chitosan/gelatin (ChGel) sponge encapsulating the adipose mesenchymal stem cells (ADMSCs)-derived exosomes (ChGel MSC−Exo ) for the prevention of esophageal stenosis after ESD in a porcine model. Results Pigs were randomly assigned into (1) ChGel MSC−Exo treatment group, (2) ChGel PBS group, and (3) the controls. Exosome treatments were applied immediately on the day after ESD as well as on day 7. Exosome components crucial for wound healing were investigated by liquid chromatography-tandem mass spectrometry (LC–MS/MS) and small RNA sequencing. ChGel MSC−Exo treatment significantly reduced mucosal contraction on day 21, with less fiber accumulation and inflammatory infiltration, and enhanced angiogenesis when compared with the control and ChGel PBS groups. The anti-fibrotic effects following MSC-Exo treatment were further found to be associated with the anti-inflammatory M2 polarization of the resident macrophages, especially within the M2b subset characterized by the reduced TGFβ1 secretion, which sufficiently inhibited inflammation and prevented the activation of myofibroblast with less collagen production at the early stage after ESD. Moreover, the abundant expression of exosomal MFGE8 was identified to be involved in the transition of the M2b-macrophage subset through the activation of MFGE8/STAT3/Arg1 axis. Conclusions Our study demonstrates that exosomal MFGE8 significantly promotes the polarization of the M2b-macrophage subset, consequently reducing collagen deposition. These findings suggest a promising potential for MSC-Exo therapy in preventing the development of esophageal stricture after near-circumferential ESD. Graphical Abstract
研究领域:
胃肠病学
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干细胞研究
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再生医学
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外科手术
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DOI
PubMed
高影响因子
Cancer Medicine
·
2020
·Vol. 9
·期 7
·2564-2578
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IF 3.491
Yubo Guo,Yingyi Fan,Xiaohua Pei
Triple-negative breast cancer (TNBC) is a basal-like cancer which is considered to be more intrusive, have a poorer prognosis and chemoresistance. TNBC is characterized by the presence of epithelial to mesenchymal transition (EMT) that plays a major role in the progression of the cancer. In the present study, we first use a classic prescription of Chinese medicine Fangjihuangqi Decoction to treat TGFβ1-induced MDA-MB-231 cells in vitro. Our data showed that TGFβ1-induced MDA-MB-231 cell morphology change, promoted MDA-MB 231 invasion, increased Vimentin expression, and decreased E-cadherin expression. Further, Fangjihuangqi Decoction-medicated serum (FHS) treated both MDA-MB 231 cells and TGFβ1-induced MDA-MB-231 cells. Results showed that Fangjihuangqi Decoction could inhibit cell proliferation, reduce cell invasion, increase E-cadherin expression, and decrease EMT markers. Secondly, we established a xenograft tumor zebrafish model to assess Fangjihuangqi Decoction inhibition of cancer cell proliferation and invasion. Our results indicated that Fangjihuangqi Decoction could inhibit tumor growth, restrain the sprouts number of tumor neovascularization, and reduce the length of tumor neoplastic lymphatics by increasing E-cadherin expression and decreasing EMT markers in TNBC xenograft tumor zebrafish model. Overall, our studies provide evidences that Fangjihuangqi Decoction could inhibit TNBC, reverse EMT, and contribute to antimetastasis by increasing E-cadherin expression and decreasing EMT markers, which provide an experimental basis for clinical application of Fangjihuangqi Decoction on TNBC treatment.
研究领域:
肿瘤学
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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
Advanced Healthcare Materials
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2024
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IF 10
Wenxiao Shi,Yu Feng,Jincheng Tang,Yichang Xu,Wang Wei,Lichen Zhang,Xinzhao Jiang,Zhouye Ding,Kun Xi,Liang Chen,Yong Gu
The innate immune response is crucial to the inflammation, but how neutrophils and macrophages act in bone repair and tissue engineering treatment strategies await clarification. In this study, we found N2 neutrophils release stronger “eat me” signals to induce macrophage phagocytosis which then polarize into the M2c anti-inflammatory phenotype. This is beneficial for bone repair. Guided by this biological mechanism, we filled a mesoporous bioactive glass scaffold (MBG) with HAMA hydrogel loaded with TGFβ1 adenovirus (Ad@H), constructing a genetically engineered composite scaffold (Ad@H/M). The scaffold not only has good hydrophilicity and biocompatibility, but also provides mechanical stress support for bone repair. Adenovirus infection quickly induces N2 neutrophils, upregulating NF-κB and MAPK signaling pathways through Toll-like receptor 4 (TLR4) to promote the inflammatory response and macrophage phagocytosis. Macrophages perform phagocytosis and polarize towards the M2 phenotype, mediating the inflammatory response by inhibiting the PI3K-AKT-NF-κB pathway, maintaining homeostasis of the osteogenic microenvironment. The role of Ad@H/M scaffold in regulating early inflammation and promoting long-term bone regeneration was further validated in vivo. In brief, this study focuses on the cascade of reactions between neutrophils and macrophage subtypes, and reports a composite scaffold that coordinates the innate immune response to promote bone repair. This article is protected by copyright. All rights reserved
研究领域:
生物医学工程
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免疫学
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组织工程
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骨再生
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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）