LIVER INTERNATIONAL
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2025
·Vol. 45
·期 3
·e70024
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IF 5.2
Guqing Luo,Zhenghao Wu,Qiang Fan,Chihao Zhang,Jiayun Lin,Hongjie Li,Jinbo Zhao,Haizhong Huo,Xiaoliang Qi,Guangbo Wu,Min Chen,Jiwei Yu,Lei Zheng,Meng Luo
Background and Aims Lymphangiogenesis is enhanced during the development of liver cirrhosis and portal hypertension (PHT). However, hepatic lymphatic vascular system is understudied in liver cirrhosis and PHT. Hydrogen sulfide (H 2 S) and related compounds have potential prolymphangiogenic effects besides its previously reported vascular-protective effects. Therefore, we aimed to investigate the effects of endogenous H 2 S donor S-allyl-cysteine (SAC) on bile duct ligation (BDL)-induced liver cirrhosis and PHT. Methods BDL rats with cholestatic liver cirrhosis and PHT were orally administrated with SAC at 100 or 200 mg/kg/day, as well as DL-propargylglycine (PAG) or MAZ-51 injections. Hemodynamic parameters were determined, and subsequent evaluations of liver fibrosis, intrahepatic vascular resistance (IHVR) and lymphangiogensis were performed. Human lymphatic endothelial cells (hLECs) were used for in vitro verification of prolymphangiogenic effects of SAC. Results SAC treatment significantly decreased PP and promoted endogenous H 2 S production. Liver fibrosis and IHVR were also ameliorated. Hepatic and mesenteric lymphangiogenesis were enhanced in BDL rats and further promoted by SAC despite a significant downregulation of hepatic VEGF-C. Inhibition of H 2 S production by PAG significantly reduced lymphatic vessels, while inhibition of lymphangiogensis by MAZ-51 reversed the protective effects of SAC against PHT. SAC enhanced lymphangiogenic functions in vitro by promoting cellular H 2 S production and activating Akt phosphorylation without altering VEGF-C/D, which were reversed by PAG and MAZ-51. Conclusions SAC significantly alleviated BDL-induced liver cirrhosis and PHT. Meanwhile, elevated H 2 S induced by SAC facilitated lymphangiogenesis via a VEGF-C-independent manner, which contributed to the alleviation of PHT.
研究领域:
医学
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药理学
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肝脏病学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2025
·
IF 5.9
Zhenghao Wu,Guqing Luo,Hongjie Li,Min Chen,Guangbo Wu,Qiang Fan,Chihao Zhang,Jiwei Yu,Jiayun Lin,Jinbo Zhao,Xiaoliang Qi,Haizhong Huo,Meng Luo,Lei Zheng
Introduction: Formononetin regulates intrahepatic fibrogenesis and macrophage polarization to improve portal pressure and liver function in rats with cirrhotic PHT through SMAD3, STAT1, STAT3 and GSK-3β signaling pathways, and modulates lymphangiogenesis through direct action and macrophage polarization-mediated indirect effects. Formononetin has the potential function of treating cirrhotic PHT.Background and aims: Formononetin (FN) has been reported to have anti-fibrotic effects in the kidneys and anti-M1 polarization effects on macrophages. Lymphangiogenesis is closely associated with macrophages, but its role in cirrhosis and portal hypertension (PHT) remains unclear. This study aims to explore the effects of FN on cirrhotic PHT and the disease-related intrahepatic lymphangiogenesis.Methods: In vivo experiments, bile duct ligation (BDL) induced PHT models were conducted in rats, followed by a 4-week FN treatment (50 mg/kg/day) administered via gavage. Hemodynamics, liver fibrosis, infiltration and polarization of intrahepatic macrophages, as well as intrahepatic lymphangiogenesis, were observed. For in vitro experiments, hepatic stellate cells, macrophages and lymphatic endothelial cells were used to observe the multiple effects of FN.Results: FN significantly ameliorated portal pressure in cirrhosis-induced PHT, improved liver function, and reduced liver fibrosis and hepatic stellate cell activation with decreased SMAD3 protein expression. The intrahepatic macrophage infiltration were markedly decreased, and M1-type macrophage polarization was suppressed by FN, accompanied by inhibition of STAT1, STAT3 and GSK-3β signaling pathways. In PHT models, FN reduced VEGF-C and VEGF-D levels in both the liver and blood, inhibiting intrahepatic lymphangiogenesis in portal area. In vitro, high-dose FN significantly inhibited lymphatic endothelial cell proliferation, while the pro-lymphangiogenic effect of conditioned medium from FN-treated M1 macrophages was diminished.Conclusions: FN significantly ameliorates cirrhotic PHT while reducing fibrosis, suppressing macrophage M1 polarization and inhibiting lymphangiogenesis. This may result from its modulation of multiple signaling pathways (SMAD3, STAT1, STAT3 and GSK-3β).
研究领域:
肝病学
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药理学
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细胞生物学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2025
·
IF 4.7
Ming Luo,Yawei Du,Xuanchen Liu,Shuwen Zhang,Wenwen Zhu,Kaipeng Liu,Xiubao Ren,Ningning Zhang
Background Portal hypertension (PHT) is a severe complication of liver cirrhosis, with limited therapeutic options. Despite emerging evidence linking gut microbiota dysbiosis to PHT progression, the mechanisms by which microbial metabolites modulate liver sinusoidal endothelial cells (LSECs) dysfunction and the therapeutic efficacy of fecal microbiota transplantation (FMT) remain poorly understood. This study investigated the potential of FMT to alleviate PHT in cirrhotic rats, exploring the underlying mechanisms involving butyrate-mediated HDAC3 inhibition and PI3K/Akt/eNOS signaling regulation in LSECs. Methods Cirrhosis with PHT was induced in Sprague-Dawley rats via intraperitoneal carbon tetrachloride injection, followed by FMT or butyrate supplementation via oral gavage. Analyses included portal hemodynamic measurements, gut microbiota sequencing, serum SCFA metabolomics profiling, HDAC3 activity assays, NO level quantification, and assessments of liver fibrosis, liver function, and LSEC ultrastructure. LSECs were isolated for PI3K/Akt/eNOS signaling analysis via qRT-PCR, Western blotting, and immunofluorescence staining. Results A two-week FMT intervention in cirrhotic rats with PHT enriched butyrate-producing bacteria and increased serum butyrate levels, which were associated with reduced portal pressure and intrahepatic vascular resistance, without affecting liver fibrosis, function, or LSEC ultrastructure. FMT reduced HDAC3 activity by 2.17-fold and increased Akt and eNOS phosphorylation in primary LSECs by 1.69-fold and 1.25-fold, respectively, elevating plasma NO levels by 1.66-fold compared to untreated controls. In vitro experiments with primary LSECs confirmed these butyrate-mediated effects. Conclusion FMT alleviates cirrhotic PHT through butyrate-mediated HDAC3 inhibition and subsequent PI3K/Akt/eNOS signaling activation in LSECs, highlighting the therapeutic potential of targeting the gut-liver axis via microbial metabolites for PHT management.
研究领域:
医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2024
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IF 9.4
Shun Xing,Haifeng Zhang,Zhenhao Hou,Feng Peng,Lidan Liu,Donghui Wang,Naijian Ge,Xuanyong Liu
Portal vein tumor thrombus (PVTT) formed by cancer cell invasion is a major cause of high mortality in hepatocellular carcinoma (HCC), and the formation of thrombus will be accelerated by bacterial colonization on the surface of the implant after surgery. In this work, Polypyrrole-coated arsenic-loaded layered double hydroxide films were in situ constructed on the nickel-titanium alloy for the efficient killing of tumour cells by thermo-therapeutic synergistic chemotherapy. The good near-infrared photothermal conversion ability of polypyrrole enables the sample surface temperature to be raised to about 51 °C at a low photothermal power (0.5 w/cm 2 ), while the elevated temperature could further accelerate the release of drug arsenic. In addition, when NIR light is not applied, the polypyrrole coating also cleverly acts as a “barrier layer” to reduce the natural release of arsenic in normal tissues to avoid toxicity issues. In vivo and in vitro experiments have demonstrated that the platform exhibits excellent antitumor and antibacterial abilities. In contrast to the systemic toxicity issues associated with systemic circulation of nanotherapeutic drugs, this in situ functional film is expected to be used in localised interventions for precise drug delivery, and is also more suitable for surgical treatment scenarios in PVTT surgeries.
研究领域:
肿瘤学
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生物材料学
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医学工程
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产品关联
DOI
PubMed
高影响因子
Theranostics
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2023
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IF 12.4
Wei-Hang Zhu,Jie Chen,Run-Kai Huang,Yuan Zhang,Ze-Xuan Huang,Xiu-Qing Pang,Bo Hu,Yang Yang,Xing Li
Rationale : Hepatocellular carcinoma (HCC) is primarily characterized by a high incidence of vascular invasion. However, the specific mechanism underlying portal vein tumor thrombus (PVTT) in HCC remains unclear. As a consequence of myeloid cell developmental arrest, CD71 + erythroid progenitor cells (EPCs) and myeloid-derived suppressor cells play important roles in HCC; however, their roles in PVTT remain unclear. Methods: The role of CD71 + EPCs in the HCC tumor microenvironment (TME) was evaluated via morphological, RNA-sequencing, enzyme-linked immunosorbent assay, and flow cytometric analyses. Co-culture techniques were employed to assess the CD45 + EPCs and their vascular compromising effect. Additionally, the PVTT-promoting function of CD45 + EPCs was explored in vivo in a murine model. Results: The CD45 + EPCs in HCC tissues exhibited increased myeloid cell features, including morphology, surface markers, transforming growth factor (TGF)-β generation, and gene expression, compared with those in circulation. Hence, a large proportion of CD45 + EPCs, particularly those in TMEs, comprise erythroid-transdifferentiated myeloid cells (EDMCs). Additionally, the expression of C-C chemokine receptor type 2 (CCR2) mRNA was upregulated in CD45 + EPCs within the TME. Tumor macrophages from HCC tissues induced substantial migration of CD45 + EPCs in a dose-dependent manner. Meanwhile, results from immunofluorescence analyses revealed that these two cell types are positively associated in the TME and circulation. That is, EDMCs are chemoattracted by HCC macrophages mainly via CCR2 from CD45 + EPCs in the circulation. Additionally, the expressions of FX, FVII, FGB, C4b, CFB, and CFH were elevated in CD45 + EPCs within the TME compared with those in the spleen. The CD45 + EPCs from the HCC TME promoted vessel endothelial cell migration and compromised tube formation through TGF-β and FGB, respectively. Additionally, CD45 + EPCs from the TME induced HCC cell migration. HCC macrophage-induced CD45 + EPCs to exhibit higher levels of FX, FVII, FGB, and TGF-β. Meanwhile, upregulation of CCAAT/enhancer binding protein beta expression induced FGB and TGF-β generation in CD45 + EPCs in the TME. WTAP, a major RNA m 6 A writer, stabilized FX and FVII mRNA and enhanced their nuclear export in CD45 + EPCs from the TME. CD45 + EPCs from the TME were positively associated with PVTT and poor prognosis. Splenectomy reduced the level of CD45 + EPCs in the circulation and TME, as well as the incidence of microvascular invasion. The incidence of microvascular invasion increased following the transfer of HCC tissue CD45 + EPCs to splenectomized HCC-bearing mice. Conclusions: The CD45 + EPCs enriched in the HCC microenvironment are EDMCs, which are induced by HCC macrophages to migrate from the circulation to the TME. Subsequently, EDMCs promote PVTT by compromising the blood vessel endothelium, aggravating coagulation, and promoting HCC cell migration.
研究领域:
肿瘤学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Advances
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2022
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IF 0
Xueqing Yang,Shizhen Wang,Xiang Zhang,Changqing Ye,Shige Wang,Xiao An
The development of tissue adhesive embolization microspheres with imaging ability is one of the important methods to improve the efficacy of interventional embolization. This study reported the synthesis of iodine (I)-polyvinyl alcohol (PVA)@polydopamine (PDA) microspheres to achieve the computed tomography image, drug loading and controlled release, and the enhanced embolization of liver portal vein. The [email protected] microspheres with a diameter of 147.9 μm showed an excellent computed tomography imaging ability. Moreover, the introduction of PDA endowed the [email protected] microspheres with tissue adhesive ability and therefore the in vivo embolization effect was improved. The in vivo embolization results showed that focal necrosis of hepatocytes with necrotic cell fragments and inflammatory cell infiltration was observed in the liver tissue, proving that the [email protected] microspheres have an enhanced embolization effect than PVA particles. The [email protected] microspheres were further used to deliver and release of chemotherapeutic drugs (5-fluorouracil), which displayed an initial fast release (release amount: 29.74%) in the first 24 h and then a sustained release of 34.48% within 72 h. Moreover, as a universal platform, the [email protected] microspheres could combine with other imaging agents like Bi 2 S 3 , thus holding a great potential in the interventional treatment of different diseases.
研究领域:
医学影像
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药学
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介入放射学
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生物材料
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产品关联
DOI
PubMed
EUROPEAN JOURNAL OF PHARMACOLOGY
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2022
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IF 5.195
Xin Zhao,Lingyu Li,Shuang Li,Jinyu Liu,Hongya Wang,Yulin Lin,Dayong Cai
Portal hypertension (PHT) is a complication of liver diseases. Increased intrahepatic vascular resistance is attributed to reduced bioavailability of vasodilator substances . The macrophage activation and superoxide dismutase 3 (SOD3) involve in the pathogenesis of PHT. Diammonium glycyrrhizinate (DG) is the salt form of glycyrrhizin derived from Radix glycyrrhizae , exerting anti-oxidant activities and be beneficial for liver injury. Here, we aimed to investigate effects of DG on PHT and explore its underlying mechanisms on regulation of macrophages and SOD3. The carbon tetrachloride induced PHT rats received administration of liposome-encapsulated clodronate for hepatic macrophage depletion, or PBS liposomes for matched control. DG (25 mg/kg) or vehicle was gavaged. Portal pressure in vivo, and serum biomarkers of macrophage activation were measured. The nitric oxide (NO) and prostacyclin (PGI 2 ) bioavailability was evaluated in the isolated portal perfused rat livers. Liver tissues were collected to evaluate cirrhosis , macrophage oxidation, and SOD3 activity. Depletion of hepatic macrophages decreased portal pressure, increased bioavailability of NO and PGI 2 , and restored SOD3 activity. DG effectively decreased portal pressure, relieved cirrhosis, inhibited macrophage activation. DG increased bioavailability of NO and PGI 2 to relax portal veins. DG relieved portal macrophage oxidation through decreasing nicotinamide adenine dinucleotide phosphate oxidase 2 and inducible NO synthase expressions, elevated SOD3 activities and increased SOD3 expressions at portal triads. These findings indicated that DG restored SOD3 activity, against portal macrophage oxidation, protected bioavailability of NO and PGI 2 , thereby reduced portal pressure. It suggested a potential use of DG for PHT treatment.
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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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2023
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IF 5.1
Yue Gao,Shicheng Fan,Pengfei Zhao,Huilin Li,Chenghui Cai,Xuan Li,Yanying Zhou,Min Huang,Huichang Bi
Liver fibrosis can be characterized by the over-deposition of extracellular matrix (ECM). It has been reported that β-catenin/TCF4 interaction was enhanced in bile duct ligation (BDL) model, which implicated the critical role of β-catenin/TCF4 interaction during the progression of fibrosis . However, whether inhibiting β-catenin/TCF4 signaling attenuates liver fibrosis remains unknown. In the current study, we used ICG-001, an inhibitor that disrupts the interaction between CREB binding protein (CBP) and β-catenin, to inhibit β-catenin/TCF4 transcriptional activity. We also used LF3, a small molecule antagonist, to inhibit β-catenin/TCF4 interaction. The antifibrotic effect of ICG-001 and LF3 was assessed on BDL-induced liver fibrosis model. The results indicated both ICG-001 and LF3 significantly reduced the positive staining area of Sirius Red and α-SMA. The protein expression levels of α-SMA, Collagen Ⅰ and CD31 were also significantly downregulated in BDL + ICG-001 and BDL + LF3 groups. Besides, ICG-001 and LF3 promoted portal angiogenesis and inhibited sinusoids capillarization in fibrotic livers. For mechanistic study, we measured the level of leukocyte cell-derived chemotaxin 2 (LECT2), a direct target of β-catenin/TCF4, which was recently reported to participate in hepatic fibrosis by regulating angiogenesis. The results showed that both ICG-001 and LF3 reduced LECT2 expression in BDL mice. LF3 also downregulated pSer 675 β-catenin and nuclear β-catenin. In conclusion, this study demonstrated that inhibiting β-catenin/TCF4 signaling by ICG-001 or LF3 mitigated liver fibrosis by downregulating LECT2, promoting portal angiogenesis and inhibiting sinusoids capillarization, which provided new evidence that β-catenin/TCF4 signaling might be a target for the treatment of liver fibrosis.
研究领域:
肝病学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2022
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IF 5.168
Jianing Tian,Ruimin Wang,Xiao Yang,Jie Yang,Yifei Zhang,Xuan Li,Hangfei Liang,Shicheng Fan,Yue Gao,Simin Zhang,Xiangyang Qu,Min Huang,Huichang Bi
Nuclear receptor pregnane X receptor (PXR) can induce significant liver enlargement through hepatocyte hypertrophy and proliferation. A previous report showed that during the process of PXR-induced liver enlargement, hepatocyte hypertrophy occurs around the central vein (CV) area while hepatocyte proliferation occurs around the portal vein (PV) area. However, the features of this spatial change remain unclear. Therefore, this study aims to explore the features of the spatial changes in hepatocytes in PXR-induced liver enlargement. PXR-induced spatial changes in hepatocyte hypertrophy and proliferation were confirmed in C57BL/6 mice. The liver was perfused with digitonin to destroy the hepatocytes around the CV or PV areas, and then the regional expression of proteins related to hepatocyte hypertrophy and proliferation was further measured. The results showed that the expression of PXR downstream proteins, such as cytochrome P450 (CYP) 3A11, CYP2B10, P-glycoprotein (P-gp) and organ anion transporting polypeptide 4 (OATP4) was upregulated around the CV area, while the expression of proliferation-related proteins such as cyclin B1 (CCNB1), cyclin D1 (CCND1) and serine/threonine NIMA-related kinase 2 (NEK2) was upregulated around the PV area. At the same time, the expression of cyclin-dependent kinase inhibitors such as retinoblastoma-like protein 2 (RBL2), cyclin-dependent kinase inhibitor 1B (CDKN1B) and CDKN1A was downregulated around the PV area. This study demonstrated that the spatial change in PXR-induced hepatocyte hypertrophy and proliferation is associated with the regional expression of PXR downstream targets and proliferation-related proteins and the regional distribution of triglycerides (TGs). These findings provide new insight into the understanding of PXR-induced hepatomegaly.
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
危险品化学品经营许可证（带存储）