CHEMICAL ENGINEERING JOURNAL
·
2022
·
IF 16.744
Jinwei Zhong,Qingfei Zhang,Gaizhen Kuang,Jinglin Xia,Luoran Shang
Tumor recurrence after hepatic resection is a severe challenge of current liver cancer treatment. Here we present novel multicomponent microspheres (MCMs) with co-encapsulation and spatiotemporal drug release capabilities for post-surgical liver cancer treatment and liver regeneration. The MCMs were fabricated via a stepwise microfluidic platform and were composed of a sodium alginate (ALG) shell and gelatin methacrylate (GelMA) cores. Benefitting from the “particle-in-particle” structure, the MCMs provided the possibility of loading doxorubicin (DOX) and augmenter of liver regeneration (ALR) into the shell and the cores, respectively. Besides, the MCMs enabled rapid release of DOX and more sustained release of ALR. Therefore, the dual-drug-loaded MCMs exhibited prominent effects of postsurgical tumor killing and promoting liver regeneration. We anticipate that the present MCMs have remarkable potentials as versatile drug delivery systems for post-surgical cancer therapy.
研究领域:
药学
·
生物医学工程
·
癌症研究
·
再生医学
✓ 已验证
产品关联
DOI
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2025
·
IF 4
Yue Gao,Chenghui Cai,Wanyu Zheng,Shicheng Fan,Yifei Zhang,Yanying Zhou,Huilin Li,Jie Yang,Shaoxing Guan,Huichang Bi
Constitutive androstane receptor (CAR, NR1I3), a nuclear receptor superfamily member, plays a pivotal role in liver size regulation. Murine CAR agonist TCPOBOP was reported to induce hepatomegaly in mice, accompanied by hepatocyte hypertrophy and proliferation. However, whether CAR activation-induced hepatomegaly is reversible and the histological changes during reversal process remain elusive. In the current study, C57BL/6 mice were administered TCPOBOP for 5 days and sacrificed at different time points after drug withdrawal. The results showed that TCPOBOP-induced hepatomegaly required a long time to reverse, as evidenced by the liver-to-body weight ratio in the TCPOBOP group remained significantly higher than that in the Vehicle group even 120 days after withdrawal. CTNNB1 and CCND1 staining indicated a reduction in hepatocyte size and proliferating cells. To investigate the involved mechanisms, we measured proteins associated with hepatomegaly and liver regeneration termination. The results suggested that YAP, C-MYC, CTNNB1, FOXM1 and HNF4α changed significantly after TCPOBOP withdrawal and functioned at different stages during reversal. Furthermore, we established a UPLC-MS/MS method to quantify TCPOBOP concentration. The results indicated a long-term hepatic retention of TCPOBOP, which constantly activated CAR and led to sustained hepatomegaly after TCPOBOP withdrawal. Overall, these findings revealed the reversibility of CAR activation-induced hepatomegaly and provided new insights into the safety of CAR as a drug target. Additionally, the results highlighted the importance of considering long-term TCPOBOP accumulation in the liver to avoid potential adverse effects and experimental biases.
研究领域:
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CURRENT ISSUES IN MOLECULAR BIOLOGY
·
2022
·Vol. 44
·期 2
·470-482
·
IF 2.976
Jiawang Tao,Yan Chen,Yuanqi Zhuang,Ruzhi Wei,Anteneh Getachew,Tingcai Pan,Fan Yang,Yinxiong Li
Liver regeneration is a complicated biological process orchestrated by various liver resident cells. Hepatic cell proliferation and reconstruction of the hepatic architecture involve multiple signaling pathways. It has been reported that the Hh signal is involved in liver regeneration. However, the signal transduction pathways and cell types involved are ill studied. This study aimed to investigate hedgehog signal response cell types and the specific molecular mechanism involved in the process of liver regeneration. Partial hepatectomy (PH) of 70% was performed on ICR (Institute of Cancer Research) mice to study the process of liver regeneration. We found that the hedgehog signal was activated significantly after PH, including hedgehog ligands, receptors and intracellular signaling molecules. Ligand signals were mainly expressed in bile duct cells and non-parenchymal hepatic cells, while receptors were expressed in hepatocytes and some non-parenchymal cells. Inhibition of the hedgehog signal treated with vismodegib reduced the liver regeneration rate after partial hepatectomy, including inhibition of hepatic cell proliferation by decreasing Cyclin D expression and disturbing the cell cycle through the accumulation of Cyclin B. The current study reveals the important role of the hedgehog signal and its participation in the regulation of hepatic cell proliferation and the cell cycle during liver regeneration. It provides new insight into the recovery of the liver after liver resection.Keywords:vismodegib;smoothened;liver regeneration;hedgehog signaling;mitosis
研究领域:
分子生物学
·
细胞生物学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2022
·Vol. 13
·期 9
·1-9
·
IF 9.685
Bi Jianbin,Zhang Jia,Ke Mengyun,Wang Tao,Wang Mengzhou,Liu Wuming,Du Zhaoqing,Ren Yifan,Zhang Shuqun,Wu Zheng,Lv Yi,Wu Rongqian
Heat shock proteins (HSPs) depletion and protein misfolding are important causes of hepatocyte death and liver regeneration disorder in liver injury. HSF2BP, as its name implies, is a binding protein of HSF2, but the specific role of HSF2BP in heat shock response (HSR) remains unknown. The aim of this study is to identify the role of HSF2BP in HSR and acute liver injury. In this study, we found that HSF2BP expression increased significantly within 24 h after APAP administration, and the trend was highly consistent with that of HSP70. hsf2bp - KO and hsf2bp - TG mouse models demonstrated HSF2BP reduced hepatocyte death, ameliorated inflammation, and improved liver function in APAP- or D-GalN/LPS- induced liver injury. Meanwhile, a significant increase of the survival rate was observed in hsf2bp - TG mice after APAP administration. Further studies showed that HSF2BP upregulated the expression of HSF2 and HSP70 and inhibited the activation of Jnk1/2 and P38 MAPK. Additionally, HSP70 siRNA pretreatment abolished the effect of HSF2BP on the MAPK pathway in APAP-treated hepatocytes. The results reveal that HSF2BP is a protective factor in acute liver injury, and the HSF2BP/HSP70/MAPK regulatory axis is crucial for the pathogenesis of liver injury. HSF2BP is a potential therapeutic target for liver injury.
研究领域:
分子生物学
·
医学
·
肝脏研究
✓ 已验证
DOI
高影响因子
Acta Pharmaceutica Sinica B
·
2024
·
IF 14.7
Shicheng Fan,Yue Gao,Pengfei Zhao,Guomin Xie,Yanying Zhou,Xiao Yang,Xuan Li,Shuaishuai Zhang,Frank J. Gonzalez,Aijuan Qu,Min Huang,Huichang Bi
Fenofibrate, a peroxisome proliferator-activated receptor α (PPAR α ) agonist, is widely prescribed for hyperlipidemia management. Recent studies also showed that it has therapeutic potential in various liver diseases. However, its effects on hepatomegaly and liver regeneration and the involved mechanisms remain unclear. Here, the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice, which was dependent on hepatocyte-expressed PPAR α . Yes-associated protein (YAP) is pivotal in manipulating liver growth and regeneration. We further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitination, promoting its K63-linked ubiquitination, and enhancing the interaction and transcriptional activity of the YAP–TEAD complex. Pharmacological inhibition of YAP–TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced hepatomegaly. Other factors, such as MYC, KRT23, RAS, and RHOA, might also participate in fenofibrate-promoted hepatomegaly and liver regeneration. These studies demonstrate that fenofibrate-promoted liver enlargement and regeneration are PPAR α -dependent and partially through activating the YAP signaling, with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.
研究领域:
药理学
·
肝脏生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACTA BIOCHIMICA ET BIOPHYSICA SINICA
·
2024
·Vol. 57
·期 4
·604
·
IF 3.3
Xuewei Li,Jinghui Feng,Haiqin Cheng,Ning Jin,Shanshan Jin,Zhizhen Liu,Jun Xu,Jun Xie
Liver fibrosis is a critical stage in the progression of various chronic liver diseases to cirrhosis and liver cancer. Early inhibition of liver fibrosis is crucial for the treatment of liver disease. Hepatectomy, a common treatment for liver-related diseases, promotes liver regeneration. However, in the context of liver fibrosis, liver regeneration is hindered. Many studies have shown that mesenchymal stem cells (MSCs) can promote liver regeneration after partial hepatectomy (PH). However, there are few reports on the impact of MSC therapy on liver regeneration post-PH in the context of hepatic fibrosis. The objective of this study is to examine the impact of MSCs on liver regeneration following PH in the fibrotic liver and uncover the related molecular mechanisms. This study reveals that MSC therapy significantly enhances liver function and mitigates liver inflammation after PH in the context of hepatic fibrosis. MSCs also significantly promote liver regeneration and alleviate liver fibrosis. In addition, this study identifies the role of MSCs in promoting liver regeneration and alleviating liver fibrosis via the activation of Wnt/β-catenin signaling. The combination of MSCs with hepatectomy may offer a novel approach for the treatment of liver fibrotic diseases.
研究领域:
医学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Genes & Genomics
·
2022
·Vol. 44
·期 8
·1017-1029
·
IF 2.164
Hou Fangxing,Li Xing,Wang Yanfeng,Xiao Xiangzuo
Background Liver regeneration is a highly orchestrated process concerning the modulation of various microRNAs (miRs). miR-183 was recently found to be involved in the process of liver regeneration, that miR-183 was remarkably up-regulated at 2–6 h after partial hepatectomy. Objective This study was aimed to explore the mechanism of miR-183 in on liver regeneration. Methods After partial hepatectomy (PH) or transfection, we measured the changes of miR-183 and programmed cell death protein 6 (PDCD6) levels in rats and the hepatocytes. The histopathology was observed with hematoxylin–eosin staining. The miR-183 mimic and inhibitor plasmids were intravenously injected into rats, and the liver weight/body weight ratio was calculated. The prediction of TargetScan and the validation of luciferase activity assay were employed to confirm the targeting relationship between miR-183 and PDCD6. The viability, apoptosis and cell cycle of transfected rat hepatocyte BRL-3A were determined via MTT and flow cytometry assays. Results MiR-183 expression showed a contrary tendency with that of PDCD6 during liver regeneration. Enhanced miR-183 in rats could notably increase liver/body weight ratio, while its inhibition did conversely. Overexpressed PDCD6, a target of miR-183, repressed the viability and cell cycle in hepatocytes, whereas its silence led to contrary results. Overexpressed miR-183 in BRL-3A cells enhanced cell viability and promoted the cell cycle yet suppressed apoptosis, whereas its inhibition showed contrary results, which were offset by PDCD6. Conclusions Collectively, miR-183 promoted liver regeneration via targeting PDCD6.
研究领域:
分子生物学
·
肝病学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Yanghao Li,Xu Yang,Tiantian Bao,Xiaojuan Sun,Xiang Li,Huilin Zhu,Bo Zhang,Tonghui Ma
Background The therapeutic efficacy of liver injuries heavily relies on the liver's remarkable regenerative capacity, necessitating the maintenance of glycose/lipids homeostasis and oxidative eustasis during the recovery process. Astragali Radix, an herbal tonic widely used in China and many other countries, is believed to have many positive effects, including immune stimulation, nourishing, antioxidant, liver protection, diuresis, anti-diabetes, anti-cancer and expectorant. Astragali Radix is widely integrated into hepatoprotective formulas as it is believed to facilitate liver regeneration. Nevertheless, the precise molecular pharmacological mechanisms underlying this hepatoprotective effect remain elusive. Purpose To investigate the improving effects of Astragali Radix on liver regeneration and the underlying mechanisms. Methods A mouse model of 70% partial hepatectomy (PHx) was employed to investigate the impact of Radix Astragali decoction (HQD) on liver regeneration. HQD was orally administered for 7 days before the PHx procedure and throughout the experiment. N-acetylcysteine (NAC) was used as a positive control for liver regeneration. Liver regeneration was assessed by evaluating the liver-to-body weight ratio (LW/BW) and the expression of representative cell proliferation marker proteins. Oxidative stress and glucose metabolism were analyzed using biochemical assays, Western blotting, dihydroethidium (DHE) fluorescence, and periodic acid-Schiff (PAS) staining methods. To understand the role of AQP9 as a potential molecular target of HQD in promoting liver regeneration, td-Tomato-tagged AQP9 transgenic mice (AQP9-RFP) were employed to determine the expression pattern of AQP9 protein. AQP9 knockout mice (AQP9 −/− ) were used to assess the specific targeting of AQP9 in the promotion of liver regeneration by HQD. Results HQD significantly upregulated hepatic AQP9 expression, alleviated liver injury and promoted liver regeneration in wild-type (AQP9 +/+ ) mice after 70% PHx. However, the beneficial impact of HQD on liver regeneration was absent in AQP9 gene knockout (AQP9 −/− ) mice. Moreover, HQD facilitated the uptake of glycerol by hepatocytes, enhanced gluconeogenesis, and concurrently reduced H 2 O 2 content and oxidative stress levels in AQP9 +/+ but not AQP9 −/− mouse livers. Additionally, main active substance of Radix Astragali, astragaloside IV (AS-IV) and cycloastragenol (CAG), demonstrated substantial upregulation of AQP9 expression and promoted liver regeneration in AQP9 +/+ but not AQP9 −/− mice. Conclusion This study is the first to demonstrate that Radix Astragali and its main active constituents (AS-IV and CAG) improve liver regeneration by upregulating the expression of AQP9 in hepatocytes to increase gluconeogenesis and reduce oxidative stress. The study revealed novel molecular pharmacological mechanisms of Radix Astragali and provided a promising therapeutic target of liver diseases.
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Chinese Journal of Natural Medicines
·
2020
·
IF 2.014
Dong-Shun LI,Quan-Fei HUANG,Li-Huan GUAN,Hui-Zhen ZHANG,Xi LI,Kai-Li FU,Yi-Xin CHEN,Jian-Bo WAN,Min HUANG,Hui-Chang BI
ABSTRACT Cholestasis is caused by the obstacle of bile formation or secretion and can develop into severe liver diseases. We previously reported the ethanol extract of Schisandra sphenanthera (Wuzhi tablet, WZ) can significantly protect against lithocholic acid (LCA)-induced intrahepatic cholestasis in mice, partially due to the activation of PXR pathway and promotion of liver regeneration. However, the effect of WZ on the bile acids profile and gut microbiome in cholestastic mice remain unknown. In this study, the effect of WZ against LCA-induced liver injury was evaluated and its effect on the bile acids metabolome and gut microbiome profiles in cholestastic mice was further investigated. Targeted metabolomics analysis was performed to examine the change of bile acids in the serum, liver, intestine and feces. The change of intestinal flora were detected by the genomics method. Targeted metabolomics analysis revealed that WZ enhanced the excretion of bile acids from serum and liver to intestine and feces. Genomics analysis of gut microbiome showed that WZ can reverse LCA-induced gut microbiome disorder to the normal level. In conclusion, WZ protects against LCA-induced cholestastic liver injury by reversing abnormal bile acids profiles and alteration of gut microbiome.
研究领域:
药理学
·
肝病学
·
微生物学
·
代谢组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
·
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
·
分子生物学
·
再生医学
·
代谢组学
·
转录组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2021
·
IF 5.34
Ying-yuan Zhao,Xin-peng Yao,Ting-ying Jiao,Jia-ning Tian,Yue Gao,Shi-cheng Fan,Pan-pan Chen,Yi-ming Jiang,Yan-ying Zhou,Yi-xin Chen,Xiao Yang,Min Huang,Hui-chang Bi
Background Schisandrol B (SolB) is one of the bioactive components from a traditional Chinese medicine Schisandra chinensis or Schisandra sphenanthera . It has been demonstrated that SolB exerts hepatoprotective effects against drug-induced liver injury and promotes liver regeneration . It was found that SolB can induce hepatomegaly but the involved mechanisms remain unknown. Purpose This study aimed to explore the mechanisms involved in SolB-induced hepatomegaly. Methods Male C57BL/6 mice were injected intraperitoneally with SolB (100 mg/kg) for 5 days. Serum and liver samples were collected for biochemical and histological analyses. The mechanisms of SolB were investigated by qRT-PCR and western blot analyses, luciferase reporter gene assays and immunofluorescence. Results SolB significantly increased hepatocyte size and proliferation, and then promoted liver enlargement without liver injury and inflammation. SolB transactivated human PXR , activated PXR in mice and upregulated hepatic expression of its downstream proteins, such as CYP3A11 , CYP2B10 and UGT1A1. SolB also significantly enhanced nuclear translocation of PXR and YAP in human cell lines. YAP signal pathway was activated by SolB in mice. Conclusion These findings demonstrated that SolB can significantly induce liver enlargement, which is associated with the activation of PXR and YAP pathways.
研究领域:
药理学
·
分子生物学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Shengwei Shen,Wencheng Zhang,Chang Xu,Zhaoxuan Dong,Xicheng Wang,Changcheng Liu,Fengfeng Lu,Yihui Hu,Qinghe Tang,Yu Cheng,Zhiying He
Clinical application of hepatocyte transplantation has been halted due to the low engraftment efficiency and limited proliferation capacity of donor hepatocytes in the host liver. Here, we developed a magneto-plasmonic nanohybrid to spatiotemporally drive the primary hepatocytes into the host liver under the external magnetic field that significantly improves the engraftment efficiency of donor hepatocytes. A magnetic lipid-coated-gold-nanorods/iron-oxide nanocluster (GNR-IO) (LGI) was designed for efficient magneto-actuation and photoacoustic imaging-guided cell tracking during the hepatocyte transplantation. By optimizing the concentration of LGI (100 μg /mL) and the configuration of a magnetic field (260 mT), we were able to increase the engraftment efficiency of primary hepatocytes into the host livers of Fah -/- mice, a model with the genetic deficit of fumarylacetoacetate hydrolase (FAH) resulting in liver injuries, for 3.89-fold of the control by one week of the transplantation. Further assessment of repopulation of hepatocytes in the host liver indicated the LGI (100 μg /mL) + magnetic field (260 mT) group had up to 15 % repopulation of the host liver by three-weeks-post-transplantation and reached full repopulation by 6-weeks-post-transplantation. This was 3 ∼ 5 times more rapid than the Fah -/- mice transplanted with hepatocytes without the LGI and the magnetic field. RNA-sequencing of the hepatocytes incubated with LGI indicated that the loading of LGIs enhanced the migration, survival, and engraftment of hepatocytes by regulating the tumor necrosis factor (TNF)-signaling pathway and reducing the macrophage in host liver. Furthermore, LGI-labeled hepatocytes could be tracked in host livers with photoacoustic imaging for at least one week post transplantation. Most of the LGI were cleared from the host systems via the kidneys by six weeks. The novel strategy established in this study, which utilized nanoparticles combined with the magnetic field to improve the efficiency of primary hepatocyte engraftment and repopulation, can provide a feasible scheme for the clinical application of hepatocyte transplantation in the treatment of liver failure.
研究领域:
移植学
·
纳米技术
·
肝病学
·
生物医学工程
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）