CHEMICO-BIOLOGICAL INTERACTIONS
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2024
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IF 4.7
Shaofei Song,Hong Peng,Yuan Li,Tingting Zhao,Renjie Cao,Lei Zheng,Min Huang,Yiming Jiang
Liver regeneration after liver tumor resection or liver transplantation is crucial, the remaining liver frequently fails to regenerate in some patients. Oleanolic acid (OA), a pentacyclic triterpenoid compound which has been shown to protect against various liver diseases. However, the effect of OA on liver regeneration after partial hepatectomy (PHx) is still unclear. In this study, the results showed that OA (50 mg/kg, twice daily) treatment induced liver mass restoration and increased the liver-to-body weight ratio of mice following PHx. Meanwhile, OA promoted hepatocyte proliferation and increased the number of BrdU-, Ki67-and PCNA-positive cells. Furthermore, OA increased the nuclear accumulation of PXR and induced the expression of PXR downstream proteins such as CYP3A11, UGT1A1 and GSTM2 in mice, as well as in AML12 and HepRG cells. Luciferase reporter assay and nuclear localization of PXR further demonstrated the effect of OA on PXR activation in vitro . Molecular docking simulation showed that OA could interact with the PXR active sites. Moreover, OA inhibited the expression of FOXO1, RBL2 and CDKN1B, and increased the expression of PCNA, CCND1 and CCNE1 in vivo and in vitro . Silencing of Pxr further confirmed that OA-mediated upregulation of proliferation-related proteins depended on PXR. The current study illustrated that OA exhibited a significant promoting effect on liver regeneration following PHx, potentially through regulation of the PXR signaling pathway to accelerate liver recovery.
研究领域:
药理学
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肝脏病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Cell Reports
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2023
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IF 8.8
Pengcheng Cai,Rui Ni,Mengzhu Lv,Huijuan Liu,Jieqiong Zhao,Jianbo He,Lingfei Luo
Summary Biliary epithelial cells (BECs) are a potential source to repair the damaged liver when hepatocyte proliferation is compromised. Promotion of BEC-to-hepatocyte transdifferentiation could be beneficial to the clinical therapeutics of patients with end-stage liver diseases. However, mechanisms underlying the initiation of BEC transdifferentiation remain largely unknown. Here, we show that upon extreme hepatocyte injury, vegfaa and vegfr2/kdrl are notably induced in hepatic stellate cells and BECs, respectively. Pharmacological and genetic inactivation of vascular endothelial growth factor (VEGF) signaling would disrupt BEC dedifferentiation and proliferation, thus restraining hepatocyte regeneration. Mechanically, VEGF signaling regulates the activation of the PI3K-mammalian target of rapamycin complex 1 (mTORC1) axis, which is essential for BEC-to-hepatocyte transdifferentiation. In mice, VEGF signaling exerts conserved roles in oval cell activation and BEC-to-hepatocyte differentiation. Taken together, this study shows VEGF signaling as an initiator of biliary-mediated liver regeneration through activating the PI3K-mTORC1 axis. Modulation of VEGF signaling in BECs could be a therapeutic approach for patients with end-stage liver diseases.
研究领域:
分子生物学
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肝脏病学
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再生医学
✓ 已验证
DOI
高影响因子
CARBOHYDRATE POLYMERS
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2025
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IF 12.5
Qiuxia Zheng,Jia Yao,Zongbin Sun,Rui Li,Yue Zhang,Pan Jiang,Ye Xie,Xiaojing Song,Hongfa Sun,Dan Zhu,Haixu Ni,Xun Li
Hepatectomy is the primary therapeutic intervention for liver disorders. Nonetheless, an increased risk of liver failure and postoperative mortality exists due to the rapid reduction in liver size after surgery. Human umbilical cord mesenchymal stem cell (hucMSC) exosomes (Exos) have been recognized in the promotion of liver regeneration. However, intravenous administration of Exos faces several challenges including poor targeting and rapid clearance. Herein, we employed CMCS/OHA/LA-loaded hucMSCs derived Exos (hydrogel-Exos) to address liver regeneration after hepatectomy. Release and uptake studies showed hydrogel-Exos enables localized release of Exos, prolonging their presence and concentration in liver tissue. Meanwhile, the hydrogel-Exos exhibited good characteristics in injectability, self-healing, biocompatibility, liver adhesion, swelling performance, postoperative hemostasis and minimization of peritoneal adhesions post-resection. Moreover, proliferation and scratch wound healing assays demonstrated the ability of hydrogel-Exos to promote liver cell proliferation and migration. During in vivo studies, the Exos-containing hydrogel was injected into the resected surface of a 70 % hepatectomy rat model. The result indicated Exos was released into the liver tissue through the hydrogel to promote angiogenesis and liver regeneration. Bioinformatics analysis revealed liver regeneration mechanisms involve cell cycle-related pathways. As such, hydrogel-encapsulated Exos appeared promising to be employed following hepatectomy.
研究领域:
医学
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生物材料学
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再生医学
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产品关联
DOI
PubMed
高影响因子
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
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2024
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IF 2.7
Guofang Bi,Fengting Liang,Ting Wu,Peng Wang,Xiaowen Jiang,Shuang Hu,Chenghua Wu,Wenhong Zhou,Jiayin Guo,Xiao Yang,Jian-hong Fang,Wenying Chen,Huichang Bi
Human pregnane X receptor (PXR) is critical for regulating the expression of key drug-metabolizing enzymes such as CYP3A and CYP2C. Our recent study revealed that treatment with rodent-specific PXR agonist pregnenolone-16α-carbonitrile (PCN) significantly induced hepatomegaly and promoted liver regeneration after two-thirds partial hepatectomy (PHx) in mice. However, it remains unclear whether PXR activation induces hepatomegaly and liver regeneration and simultaneously promotes metabolic function of the liver. Here, we investigated the metabolism activity of CYP1A2, CYP3A1/2 and CYP2C6/11 during PXR activation-induced liver enlargement and regeneration in rats after cocktail dosing of CYP probe drugs. For PCN-induced hepatomegaly, a notable increase in the metabolic activity of CYP3A1/2 and CYP2C6/11, as evidenced by the plasma exposure of probe substrates and the AUC ratios of the characteristic metabolites to its corresponding probe substrates. The metabolic activity of CYP1A2, CYP3A1/2 and CYP2C6/11 decreased significantly after PHx. However, PCN treatment obviously enhanced the metabolic activity of CYP2C6/11 and CYP3A1/2 in PHx rats. Furthermore, the protein expression levels of CYP3A1/2 and CYP2C6/11 in liver were up-regulated. Taken together, this study demonstrates that PXR activation not only induces hepatomegaly and liver regeneration in rats, but also promotes the protein expression and metabolic activity of the PXR downstream metabolizing enzymes such as CYP3A1/2 and CYP2C6/11 in the body.
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
ACS Nano
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2023
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IF 17.1
Fenfang Li,Hongyan Wei,Yuanyuan Jin,Tiantian Xue,Yanteng Xu,Haixia Wang,Enguo Ju,Yu Tao,Mingqiang Li
Acute liver failure (ALF) is a critical life-threatening disease that occurs due to a rapid loss in hepatocyte functions. Hepatocyte transplantation holds great potential for ALF treatment, as it rapidly supports liver biofunctions and enhances liver regeneration. However, hepatocyte transplantation is still limited by renewable and ongoing cell sources. In addition, intravenously injected hepatocytes are primarily trapped in the lungs and have limited efficacy because of the rapid clearance in vivo. Here, we designed a Y-shaped DNA nanostructure to deliver microRNA-122 (Y-miR122), which could induce the hepatic differentiation and maturation of human mesenchymal stem cells. mRNA sequencing analysis revealed that the Y-miR122 promoted important hepatic biofunctions of the induced hepatocyte-like cells including fat and lipid metabolism, drug metabolism, and liver development. To further improve hepatocyte transplantation efficiency and therapeutic effects in ALF treatment, we fabricated protective microgels for the delivery of Y-miR122-induced hepatocyte-like cells based on droplet microfluidic technology. When cocultured with human umbilical vein endothelial cells in microgels, the hepatocyte-like cells exhibited an increase in hepatocyte-associated functions, including albumin secretion and cytochrome P450 activity. Notably, upon transplantation into the ALF mouse model, the multiple cell-laden microgels effectively induced the restoration of liver function and enhanced liver regeneration. Overall, this study presents an efficient approach from the generation of hepatocyte-like cells to hepatocyte transplantation in ALF therapy.
研究领域:
生物医学工程
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组织工程
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分子生物学
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再生医学
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产品关联
DOI
PubMed
高影响因子
STEM CELLS
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2021
·Vol. 39
·期 11
·1546-1562
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IF 6.277
Dong Yuan,Kong Weining,An Wei
Cell-based therapeutic approaches have been proven to be effective strategies for the treatment of acute liver injury (ALI). However, widespread application of these procedures is limited by several key issues, including rapid loss of stemness in vitro, aberrant differentiation into undesirable cell types, and low engraftment in vivo. In this study, liver epithelial progenitor cells (LEPCs) were characterized and transfected with augmenter of liver regeneration (ALR). The results revealed that in ALI mice with CCl4, the transplantation of ALR-bearing LEPCs into the liver markedly protected mice against ALI by decreasing the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), thus relieving hepatic tissue injury and attenuating inflammatory infiltration. Mechanistically, the knockdown of ALR in LEPCs activated the phosphorylation of dynamin-related protein 1 (Drp1) at the S616 site and thereby enhanced mitochondrial fission. In contrast, the transfection of ALR into LEPCs significantly inhibited Drp1 phosphorylation, thereby favoring the maintenance of mitochondrial integrity and the preservation of adenosine triphosphate contents in LEPCs. Consequently, the ALR-bearing LEPCs transplanted into ALI mice exhibited substantially greater homing ability to the injured liver via the SDF-1/CXCR4 axis than that of LEPCs-lacking ALR. In conclusion, we demonstrated that the transplantation of ALR-transfected LEPCs protected mice against CCl4-induced ALI, thus offering immense curative potential in the clinic.
研究领域:
肝病学
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干细胞生物学
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分子生物学
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细胞治疗
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2023
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IF 14
Jiabin Zhang,Yanteng Xu,Chenya Zhuo,Run Shi,Haixia Wang,Zuquan Hu,Hon Fai Chan,Hae-Won Kim,Yu Tao,Mingqiang Li
Engineering hepatocytes as multicellular cell spheroids can improve their viability after implantation in vivo for effective rescue of the devastating acute liver failure (ALF). However, there is still a lack of straightforward methods for efficient generation of functional hepatocyte spheroids. In this study, a magnetic system, consisting of magnetic microwell arrays and magnet blocks, is developed to realize magnetically controlled 3D cell capture and spatial confinement-mediated cell aggregation. The cell spheroids with smaller size show superior hepatic functions than the larger-sized counterparts. Notably, the intrinsic magnetism of magnetic microwell arrays can regulate superoxide anions in hepatocyte spheroids and herein promote various biological processes , including antioxidation, hepatocyte-related functions, and pro-angiogenic potential. Ectopic implantation of the functional cell spheroids in ALF-challenged mice significantly prolongs the animal survival, ameliorates inflammation, and promotes liver regeneration . Hence, application of the magnetic system for generation of functionally enhanced hepatocyte spheroids holds great potential for clinical translation in the future.
研究领域:
组织工程
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再生医学
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生物医学工程
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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