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liver regeneration as treatment target for severe alcoholic hepatitis

World Journal of Gastroenterology 2022年第32期28卷 4557-4573页

作者： Lucija Virovic-Jukic Dominik Ljubas Sanja Stojsavljevic-Shapeski Neven Ljubičić Tajana Filipec Kanizaj Ivana Mikolasevic Ivica Grgurevic Department of Gastroenterology and Hepatology Sisters of Charity University Hospital CenterZagreb 10000Croatia Department of Internal Medicine University of Zagreb School of MedicineZagreb 10000Croatia Department of Internal Medicine University of Zagreb School of Dental MedicineZagreb 10000Croatia Department of Gastroenterology Merkur University HospitalZagreb 10000Croatia Department of Gastroenterology Rijeka University Hospital CenterRijeka 51000Croatia Department of Internal Medicine University of Rijeka School of MedicineRijeka 10000Croatia Department of Gastroenterology Hepatology and Clinical NutritionDubrava University HospitalZagreb 10000Croatia

Severe alcoholic hepatitis(AH)is a distinct entity in the spectrum of alcoholrelated liver disease,with limited treatment options and high *** medical care with corticosteroids in selected patients is the only currently available treatment option,often with poor *** on the insights into the pathogenetic mechanisms of AH,which are mostly obtained from animal studies,several new treatment options are being *** have implicated impaired and deranged liver regeneration processes as one of the culprit mechanisms and a potential therapeutic *** evidence for the beneficial effects of granulocyte colony-stimulating factor(G-CSF)on liver regeneration and immunomodulation in animal models,several human studies investigated its role in the treatment of advanced alcohol-related liver disease and *** to the previously published studies suggesting benefits of G-CSF in the outcomes of patients with severe AH,these effects were not confirmed by a recently published multicenter randomized trial,suggesting that other options should rather be *** cell transplantation represents another option for improving liver regeneration,but evidence for its efficacy in patients with severe AH and advanced alcohol-related liver disease is still very scarce and unconvincing,with established lack of efficacy in patients with compensated *** this review,we summarize the current knowledge on the pathogenesis and experimental therapies targeting liver *** lack of high-quality studies and evidence is a major obstacle in further treatment *** insights into the pathogenesis of not only liver injury,but also liver regeneration processes are mandatory for the development of new treatment options.A reliable experimental model of the pathogenesis of AH and processes involved in liver recovery is still missing,and data obtained from animal studies are essential for future research.

关键词： Severe alcoholic hepatitis Alcohol-related liver disease Treatment liver regeneration Granulocyte colony-stimulating factor Stem cell transplantation

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liver regeneration after split liver transplantation

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Hepatobiliary & Pancreatic Diseases International 2005年第4期4卷 519-523页

作者： Hui-Xing Chen, Guang-Wen Zhou,Lu Yin,Cheng-Hong Peng and Hong-Wei Li Shanghai, China Department of Surgery and Center of Organ Transplantation, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025,China Center of Organ Transplantation Ruijin Hospital Shanghai Second Medical University Shanghai 200025 China. huixingchen@***

BACKGROUND: The number of split liver transplantations (SLT) has increased in the last 5 years. regeneration after the loss of hepatic tissue is a fundamental response to liver injury. Because partial-liver grafts may not be an optimal size for recipients, the purpose of this study was to investigate the regeneration of graft liver after SLT. METHODS: Four recipients have undergone SLT at our hospital since 2002. The graft liver volume (GLV) in the postoperative day ( POD) was measured by computed tomography (CT) and the serum levels of aspartate amino-transferase (AST) , alanine aminotransferase (ALT) , total bilirubin ( TB ), prealbumin ( PA ) and albumin ( ALB ) were monitored. The GLV at different postoperative times was compared to the recipient' s standard liver volume ( SLV) and the liver volume regeneration ratio ( LVRR) was calculated. In order to compare SLV in recipient 2, we measured the total liver volume including the graft and the residual native liver as the GLV. RESULTS: The GLV/SLV at POD120 and POD360 of recipient 1 was measured 114% (1159.32 cm3 71016.95 cm3) , 97% (986.44 cm371016.95 cm3 ) with the LVRR being -11.0%, -24.3%, respectively. For recipient 2, it was measured 96% (927.32 cm3 7965.96 cm3) and 100% (968. 98 cm37965. 96 cm3 ) , with the LVRR being 24. 4% , 30. 0% , respectively. The initial graft volume of segment Ⅱ ,Ⅲ was 265.36 cm3 and increased to 335.24 cm3 and 360.56 cm3 at POD120 and POD360, respectively, with the LVRR being 26.3% and 35.9%, respectively. The GLV/SLV at POD60 of recipient 3 was 86% (893. 04 cm3/ 1038. 42 cm3 ) and the LVRR was 12. 0%. For recipient 4, it was 90% (567. 48 cm3/630. 54 cm3 ) whereas the LVRR was 20. 0%. The serum levels of ALT, AST and TB in all recipients declined gradually and returned to normal while the serum levels of PA and ALB increased to normal. The serum levels of ALT and AST peaked within 3 days after SLT. The neurological symptoms of Wilson 's disease in recipient 2 were improved markedly

关键词： liver transplantation liver regeneration computed tomography

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Changes in growth factor and cytokine expression in biliary obstructed rat liver and their relationship with delayed liver regeneration after partial hepatectomy

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World Journal of Gastroenterology 2006年第13期12卷 2053-2059页

作者： Hironobu Makino Hiroaki Shimizu Hiroshi Ito Fumio Kimura Satoshi Ambiru Akira Togawa Masayuki Ohtsuka Hiroyuki Yoshidome Atsushi Kato Hideyuki Yoshitomi Shigeaki Sawada Masaru Miyazaki Department of General Surgery Graduate School of Medicine Chiba UniversityChibaJapan

AIM： To study the effects of obstructive jaundice on liver regeneration after partial hepatectomy. METHODS： Hepatocyte growth factor （HGF）, its receptor, c-Met, vascular endothelial growth factor （VEGF） and transforming growth factor-β1 （TGF-β1） mRNA expression in both liver tissue and isolated liver cells were investigated after biliary obstruction （BO） by quantitative reverse-transcription polymerase chain reaction （RT-PCR） using a LightCycler. Immunohistochemical staining for desmin and e-smooth muscle actin （α-SNA） was also studied. Regenerating liver weight and proliferating cell nuclear antigen （PCNA） labeling index, and growth factor expression were then evaluated after 70% hepatectomy with concomitant internal bUiary drainage in BO rats or sham-operated rats. RESULTS： Hepatic TGF-β1 mRNA levels increased significantly 14 days after BO, and further increased with duration of cholestasis. Meanwhile, HGF and VEGF tended to increase, but was not significant. In cell isolates, TGF-β1 mRNA was found mainly in the hepatic stellate cell （HSC） fraction. Immunohistochemical studies revealed an increased number of HSCs （desmin-positive cells） and activated HSCs （α-SMA-positive cells） in portal areas after BO. In a hepatectomy model, liver regeneration was delayed in BO rats, as compared to sham-operated rats. TGF-β1 mRNA was significantly up-regulated up to 48 h after hepatectomy, and the earlier HGF mRNA peak was lost in BO rats. CONCLUSION： BO induces HSCs proliferation and activation, leading to up-regulation of TGF-β1 mRNA and suppression of HGF mRNA in livers. These altered expression patterns may be strongly involved in delayed liver regeneration after hepatectomy with obstructive jaundice.

关键词： Biliary obstruction liver regeneration Hepatocyte growth factor Transforming growth factor-β Hepatic stellate cells Hepatectomy

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The “Traditional Chinese medicine regulating liver regeneration” treatment plan for reducing mortality of patients with hepatitis B-related liver failure based on real-world clinical data

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Frontiers of Medicine 2021年第3期15卷 495-505页

作者： Ling Dai Xiang Gao Zhihua Ye Hanmin Li Xin Yao Dingbo Lu Na Wu Institute of liver Diseases Hubei Provincial Hospital of Traditional Chinese MedicineWuhan 430061China Institute of Basic Theory of Chinese Medicine Hubei Province Academy of Traditional Chinese MedicineWuhan 430074China Theory and Application Research of liver and Kidney in Traditional Chinese Medicine Hubei Provincial Key LaboratoryWuhan 430074China Key Laboratory of Treating Chronic liver Diseases from liver and Kidney State Administration of Traditional Chinese MedicineWuhan 430061China

On the basis of real-world clinical data,the study aimed to explore the effect and mechanisms of the treatment plan of“traditional Chinese medicine(TCM)regulating liver regeneration.”A total of 457 patients with HBV-related liver failure were retrospectively *** patients were divided into three groups:the modern medicine control group(MMC group),patients treated with routine medical treatment;the control group combining traditional Chinese and Western medicine(CTW),patients treated with routine medical treatment plus the common TCM formula;and the treatment group of“TCM regulating liver regeneration”(RLR),patients treated with both routine medical treatment and the special TCM formula of *** 8 weeks of treatment,the mortality of patients in the RLR group(12.31%)was significantly lower than those in the MMC(50%)and CTW(29.11%)*** bilirubin level significantly decreased and albumin increased in the RLR group when compared with the MMC and CTW groups(Pliver regeneration in the RLR group compared with the MMC *** treatment can decrease jaundice,improve liver function,and significantly reduce the mortality in patients with HBV-related liver *** mechanism may be related to the role of RLR treatment in influencing cytokines related to liver regeneration.

关键词： hepatitis B virus-related liver failure traditional Chinese medicine liver regeneration liver regeneration microenvironment cytokines

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Signal molecule-mediated hepatic cell communication during liver regeneration

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World Journal of Gastroenterology 2009年第46期15卷 5776-5783页

作者： Zhen-Yu Zheng Shun-Yan Weng Yan Yu School of Agricultureand Biology Shanghai Jiao Tong University Shanghai 200240China

liver regeneration is a complex and well-orchestrated process,during which hepatic cells are activated to produce large signal molecules in response to liver injury or mass *** signal molecules,in turn,set up the connections and cross-talk among liver cells to promote hepatic *** this review,we endeavor to summarize the network of signal molecules that mediates hepatic cell communication in the regulation of liver regeneration.

关键词： Signal molecule Hepatic cells Cellular cross-talk Signal communication liver regeneration

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Constitutive androstane receptor induced-hepatomegaly and liver regeneration is partially via yes-associated protein activation

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Acta Pharmaceutica Sinica B 2021年第3期11卷 727-737页

作者： Yue Gao Shicheng Fan Hua Li Yiming Jiang Xinpeng Yao Shuguang Zhu Xiao Yang Ruimin Wang Jianing Tian Frank JGonzalez Min Huang Huichang Bi Guangdong Provincial Key Laboratory of New Drug Design and Evaluation School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China Department of Hepatic Surgery the Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510006China Laboratory of Metabolism Center for Cancer ResearchNational Cancer InstituteNIHBethesdaMD 20892USA

The constitutive androstane receptor(CAR, NR3 I1) belongs to nuclear receptor *** was reported that CAR agonist TCPOBOP induces hepatomegaly but the underlying mechanism remains largely unknown. Yes-associated protein(YAP) is a potent regulator of organ size. The aim of this study is to explore the role of YAP in CAR activation-induced hepatomegaly and liver ***-induced CAR activation on hepatomegaly and liver regeneration was evaluated in wildtype(WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy(PHx) mice. The results demonstrate that TCPOBOP can increase the liver-to-body weight ratio in wild-type mice and PHx *** enlargement around central vein(CV) area was observed, meanwhile hepatocytesproliferation was promoted as evidenced by the increased number of KI67+cells around portal vein(PV)area. The protein levels of YAP and its downstream targets were upregulated in TCPOBOP-treated mice and YAP translocation can be induced by CAR activation. Co-immunoprecipitation results suggested a potential proteineprotein interaction of CAR and YAP. However, CAR activation-induced hepatomegaly can still be observed in liver-specific YAP-deficient(Yape/e) mice. In summary, CAR activation promotes hepatomegaly and liver regeneration partially by inducing YAP translocation and interaction with YAP signaling pathway, which provides new insights to further understand the physiological functions of CAR.

关键词： Constitutive androstane receptor Nuclear receptors Hepatomegaly liver enlargement liver regeneration Yes-associated protein Proteineprotein interaction Partial hepatectomy

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Fenofibrate-promoted hepatomegaly and liver regeneration are PPARα-dependent and partially related to the YAP pathway

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Acta Pharmaceutica Sinica B 2024年第7期14卷 2992-3008页

作者： Shicheng Fan Yue Gao Pengfei Zhao Guomin Xie Yanying Zhou Xiao Yang Xuan Li Shuaishuai Zhang Frank JGonzalez Aijuan Qu Min Huangb Huichang Bi NMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug Screening&Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Guangdong Provincial Key Laboratory of New Drug Design and Evaluation School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China Department of Physiology and Pathophysiology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China Laboratory of Metabolism Center for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA The State Key Laboratory of Chemical Oncogenomics School of Chemical Biology and BiotechnologyShenzhen Graduate School of Peking UniversityShenzhen 518055China

Fenofibrate,a peroxisome proliferator-activated receptor α(PPARα)agonist,is widely prescribed for hyperlipidemia *** studies also showed that it has therapeutic potential in various liver ***,its effects on hepatomegaly and liver regeneration and the involved mechanisms remain ***,the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice,which was dependent on hepatocyteexpressed PPARα.Yes-associated protein(YAP)is pivotal in manipulating liver growth and *** 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 *** inhibition of YAP-TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced *** factors,such as MYC,KRT23,RAS,and RHOA,might also participate in fenofibrate-promoted hepatomegaly and liver *** studies demonstrate that fenofibratepromoted liver enlargement and regeneration are PPARα-dependent and partially through activating the YAP signaling,with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.

关键词： Fenofibrate PPARa Hepatomegaly Partial hepatectomy liver regeneration YAP TEAD Ubiquitination

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Augmenter of liver regeneration promotes hepatocyte proliferation induced by Kupffer cells

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World Journal of Gastroenterology 2006年第30期12卷 4859-4865页

作者： Chun-Ping Wang Lin Zhou Shu-Hui Su Yan Chen Yin-Ying Lu Fei Wang Hong-Jun Jia Yong-Yi Feng Yong-Ping Yang Department of Gastroenterology 302 Hospital of Chinese PLA Beijing 100039 China

AIM： To observe the effects of augmenter of liver regeneration （ALR） on Kupffer cells and to determine whether ALR promotes hepatocyte proliferation induced by Kupffer cells. METHODS： Kupffer cells and hepatocytes were cultured in vitro and various concentrations of recombinant rat ALR （rrALR） were added. ^3H-thymidine, BrdU and ^3H-leucine incorporation was determined in cultured Kupffer cells and hepatocytes, in hepatocytes conditioned by Kupffer cells, and in associated medium, rrALR was labeled by iodination and used to determine its binding activity by Scatchard analysis in Kupffer cells and primarily cultured rat hepatocytes. RESULTS： rrALR stimulated DNA replication in Kupffer cells and protein synthesis both in cells and in medium in a non-concentration-dependent manner. The effect was significant at the concentration of 1μg/L ALR. However, rrALR had no effect on primarily cultured hepatocytes, when hepatocytes were cultured with the Kupffer cell medium conditioned by ALR, DNA replication and protein synthesis in hepatocytes increased significantly at the concentration of 1μg/L ALR. When the ALR concentration was increased, its effect on hepatocyte proliferation decreased to the basal level. Scatchard analysis indicated the presence of a single class of high affinity receptors with a dissociation constant （Kd） of 0.883 nmol/L and a maximum binding capacity （Bmax） of 126.1 pmol/g protein in the rat Kupffer cells. CONCLUSION： ALR can promote hepatocyte proliferation induced by Kupffer cells, which is associated with the concentration of ALR, suggesting that Kupffer cells play a dual role in liver regeneration.

关键词： liver regeneration Augmenter of liver regeneration Kupffer cell

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Phosphatidic acid-enabled MKL1 contributes to liver regeneration:Translational implication in liver failure

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Acta Pharmaceutica Sinica B 2024年第1期14卷 256-272页

作者： Jiawen Zhou Xinyue Sun Xuelian Chen Huimin Liu Xiulian Miao Yan Guo Zhiwen Fan Jie Li Yong Xu Zilong Li State Key Laboratory of Natural Medicines Department of PharmacologyChina Pharmaceutical UniversityNanjing 211198China Institute of Biomedical Research Liaocheng UniversityLiaocheng 252200China Department of Pathology Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210008China Department of Infectious Diseases Nanjing Drum Tower Hospital Affiliated with Nanjing University Medical SchoolNanjing 210008China Institute of Viruses and Infectious Diseases Nanjing UniversityNanjing 210008China

liver regeneration following injury aids the restoration of liver mass and the recovery of liver *** the present study we investigated the contribution of megakaryocytic leukemia 1(MKL1),a transcriptional modulator,to liver *** report that both MKL1 expression and its nuclear translocation correlated with hepatocyte proliferation in cell and animal models of liver regeneration and in liver failure *** with MKL1 deletion exhibited defective regenerative response in the *** analysis revealed that MKL1 interacted with E2F1 to program pro-regenerative ***2 mediated phosphorylation primed MKL1 for its interaction with *** interest,phospholipase d2 promoted MKL1 nuclear accumulation and liver regeneration by catalyzing production of phosphatidic acid(PA).PA administration stimulated hepatocyte proliferation and enhanced survival in a MKL1-dependent manner in a pre-clinical model of liver ***,PA levels was detected to be positively correlated with expression of pro-regenerative genes and inversely correlated with liver injury in liver failure *** conclusion,our data reveal a novel mechanism whereby MKL1 contributes to liver *** for small-molecule compounds boosting MKL1 activity may be considered as a reasonable approach to treat acute liver failure.

关键词： liver failure liver regeneration Transcription regulation Transcription factor Hepatocytes Phosphatidic acid Phospholipase d2 Translational medicine

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Protective effect of some vitamins against the toxic action of ethanol on liver regeneration induced by partial hepatectomy in rats

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World Journal of Gastroenterology 2008年第6期14卷 899-907页

作者： Carlett Ramírez-Farías Eduardo Madrigal-Santillán José Gutiérrez-Salinas Nidia Rodríguez-Sánchez Maricela Martínez-Cruz Ilse Valle-Jones Ingrid Gramlich-Martínez Alejandra Hernández-Ceruelos José A Morales-González Unidad de Genética de la Nutrición Instituto Nacional de Pediatría México Instituto de Ciencias de la Salud Universidad Autónoma del Estado de Hidalgo México Laboratorio de Bioquímica y Medicina Experimental Unidad de Investigación Biomédica División de Investigación Centro Médico Nacional "20 de Noviembre" ISSSTE México Gatorade Sports Science Institute Mexico City México Escuela de Dietética y Nutrición ISSSTE México University of Ryerson Toronto

AIM: To investigate the effects of vitamins (A, C and E) on liver injury induced by ethanol administration during liver regeneration in rats. METHODS: Male Wistar rats subjected to 70% partial hepatectomy were divided into five groups (groups 1-5). During the experiment, animals of Group 1 drank only water. The other four groups (2-5) drank 30 mL of ethanol/L of water. Group 3 additionally received vitamin A, those of group 4 vitamin C and those of group 5 received vitamin E. Subsequently serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin and bilirubin were measured colorimetrically. Lipid peroxidation (thiobarbituric-acid reactive substances, TBARS) both in plasma and liver was measured, as well as liver mass gain assessment and total DNA. RESULTS: Compared with sham group, serum AST and ALT increased significantly under ethanol treatment (43% and 93%, respectively, with P liver regeneration vitamins C and E significantly ameliorated liver injury for ethanol administration in hepatic lipid peroxidation (4.92 nmol/mg and 4.25 nmol/mg vs 14.78 nmol/mg, respectively, with P liver injury and dysfunction, attenuate lipid peroxidation, and thus appear to be significantly more effective than vitamin A against ethanol-mediated toxic effects during liver regeneration.

关键词： Lipid peroxidation Antioxidant vitamins Alcohol-induced liver injury liver regeneration

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