BACKGROUND The success of liver resection relies on the ability of the remnant liver to regenerate.Most of the knowledge regarding the pathophysiological basis of liver regeneration comes from rodent studies,and data ...BACKGROUND The success of liver resection relies on the ability of the remnant liver to regenerate.Most of the knowledge regarding the pathophysiological basis of liver regeneration comes from rodent studies,and data on humans are scarce.Additionally,there is limited knowledge about the preoperative factors that influence postoperative regeneration.AIM To quantify postoperative remnant liver volume by the latest volumetric software and investigate perioperative factors that affect posthepatectomy liver regenera-tion.METHODS A total of 268 patients who received partial hepatectomy were enrolled.Patients were grouped into right hepatectomy/trisegmentectomy(RH/Tri),left hepa-tectomy(LH),segmentectomy(Seg),and subsegmentectomy/nonanatomical hepatectomy(Sub/Non)groups.The regeneration index(RI)and late rege-neration rate were defined as(postoperative liver volume)/[total functional liver volume(TFLV)]×100 and(RI at 6-months-RI at 3-months)/RI at 6-months,respectively.The lower 25th percentile of RI and the higher 25th percentile of late regeneration rate in each group were defined as“low regeneration”and“delayed regeneration”.“Restoration to the original size”was defined as regeneration of the liver volume by more than 90%of the TFLV at 12 months postsurgery.RESULTS The numbers of patients in the RH/Tri,LH,Seg,and Sub/Non groups were 41,53,99 and 75,respectively.The RI plateaued at 3 months in the LH,Seg,and Sub/Non groups,whereas the RI increased until 12 months in the RH/Tri group.According to our multivariate analysis,the preoperative albumin-bilirubin(ALBI)score was an independent factor for low regeneration at 3 months[odds ratio(OR)95%CI=2.80(1.17-6.69),P=0.02;per 1.0 up]and 12 months[OR=2.27(1.01-5.09),P=0.04;per 1.0 up].Multivariate analysis revealed that only liver resection percentage[OR=1.03(1.00-1.05),P=0.04]was associated with delayed regeneration.Furthermore,multivariate analysis demonstrated that the preoperative ALBI score[OR=2.63(1.00-1.05),P=0.02;per 1.0 up]and liver resection percentage[OR=1.02(1.00-1.05),P=0.04;per 1.0 up]were found to be independent risk factors associated with volume restoration failure.CONCLUSION Liver regeneration posthepatectomy was determined by the resection percentage and preoperative ALBI score.This knowledge helps surgeons decide the timing and type of rehepatectomy for recurrent cases.展开更多
BACKGROUND The function of prohibitin 1(Phb1)during liver regeneration(LR)remains relatively unexplored.Our previous research identified downregulation of Phb1 in rat liver mitochondria 24 h after 70%partial hepatecto...BACKGROUND The function of prohibitin 1(Phb1)during liver regeneration(LR)remains relatively unexplored.Our previous research identified downregulation of Phb1 in rat liver mitochondria 24 h after 70%partial hepatectomy(PHx),as determined by subcellular proteomic analysis.AIM To investigate the potential role of Phb1 during LR.METHODS We examined changes in Phb1 mRNA and protein levels,subcellular distribution,and abundance in rat liver during LR following 70%PHx.We also evaluated mitochondrial changes and apoptosis using electron microscopy and flow cytometry.RNA-interference-mediated knockdown of Phb1(PHBi)was performed in BRL-3A cells.RESULTS Compared with sham-operation control groups,Phb1 mRNA and protein levels in 70%PHx test groups were downregulated at 24 h,then upregulated at 72 and 168 h.Phb1 was mainly located in mitochondria,showed a reduced abundance at 24 h,significantly increased at 72 h,and almost recovered to normal at 168 h.Phb1 was also present in nuclei,with continuous increase in abundance observed 72 and 168 h after 70%PHx.The altered ultrastructure and reduced mass of mitochondria during LR had almost completely recovered to normal at 168 h.PHBi in BRL-3A cells resulted in increased S-phase entry,a higher number of apoptotic cells,and disruption of mitochondrial membrane potential.CONCLUSION Phb1 may contribute to maintaining mitochondrial stability and could play a role in regulating cell proliferation and apoptosis of rat liver cells during LR.展开更多
BACKGROUND Although the associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)induces more rapid liver regeneration than portal vein embolization,the mechanism remains unclear.AIM To assess...BACKGROUND Although the associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)induces more rapid liver regeneration than portal vein embolization,the mechanism remains unclear.AIM To assess the influence of inflammatory cytokines and endothelial nitric oxide synthase(eNOS)activation on liver regeneration in ALPPS.METHODS The future liver remnant/body weight(FLR/BW)ratio,hepatocyte proliferation,inflammatory cytokine expression,and activation of the Akt-eNOS pathway were evaluated in rat ALPPS and portal vein ligation(PVL)models.Hepatocyte proliferation was assessed based on Ki-67 expression,which was confirmed using immunohistochemistry.The serum concentrations of inflammatory cytokines were measured using enzyme linked immune-solvent assays.The Akt-eNOS pathway was assessed using western blotting.To explore the role of inflammatory cytokines and NO,Kupffer cell inhibitor gadolinium chloride(GdCl3),NOS inhibitor N-nitro-arginine methyl ester(L-NAME),and NO enhancer molsidomine were administered intraperitoneally.RESULTS The ALPPS group showed significant FLR regeneration(FLR/BW:1.60%±0.08%,P<0.05)compared with that observed in the PVL group(1.33%±0.11%)48 h after surgery.In the ALPPS group,serum interleukin-6 expression was suppressed using GdCl3 to the same extent as that in the PVL group.However,the FLR/BW ratio and Ki-67 labeling index were significantly higher in the ALPPS group administered GdCl3(1.72%±0.19%,P<0.05;22.25%±1.30%,P<0.05)than in the PVL group(1.33%±0.11%and 12.78%±1.55%,respectively).Phospho-Akt Ser473 and phospho-eNOS Ser1177 levels were enhanced in the ALPPS group compared with those in the PVL group.There was no difference between the ALPPS group treated with L-NAME and the PVL group in the FLR/BW ratio and Ki-67 labeling index.In the PVL group treated with molsidomine,the FLR/BW ratio and Ki-67 labeling index increased to the same level as in the ALPPS group.CONCLUSION Early induction of inflammatory cytokines may not be pivotal for accelerated FLR regeneration after ALPPS,whereas Akt-eNOS pathway activation may contribute to accelerated regeneration of the FLR.展开更多
Partial hepatectomy(PH)can lead to severe complications,including liver failure,due to the low regenerative capacity of the remaining liver,especially after extensive hepatectomy.Liver sinusoidal endothelial cells(LSE...Partial hepatectomy(PH)can lead to severe complications,including liver failure,due to the low regenerative capacity of the remaining liver,especially after extensive hepatectomy.Liver sinusoidal endothelial cells(LSECs),whose proliferation occurs more slowly and later than hepatocytes after PH,compose the lining of the hepatic sinusoids,which are the smallest blood vessels in the liver.Vascular endothelial growth factor(VEGF),secreted by hepatocytes,promotes LSEC proliferation.Supplementation of exogenous VEGF after hepatectomy also increases the number of LSECs in the remaining liver,thus promoting the reestablishment of the hepatic sinusoids and accelerating liver regeneration.At present,some shortcomings exist in the methods of supplementing exogenous VEGF,such as a low drug concentration in the liver and the reaching of other organs.Moreover,VEGF should be administered multiple times and in large doses because of its short half-life.This review summarized the most recent findings on liver regeneration and new strategies for the localized delivery VEGF in the liver.展开更多
BACKGROUND Rapid regeneration of the residual liver is one of the key determinants of successful partial hepatectomy(PHx).At present,there is a lack of recognized safe,effective,and stable drugs to promote liver regen...BACKGROUND Rapid regeneration of the residual liver is one of the key determinants of successful partial hepatectomy(PHx).At present,there is a lack of recognized safe,effective,and stable drugs to promote liver regeneration.It has been reported that vagus nerve signaling is beneficial to liver regeneration,but the potential mechanism at play here is not fully understood.AIM To explore the effect and mechanism of hepatic vagus nerve in liver regeneration after PHx.METHODS A PHx plus hepatic vagotomy(Hv)mouse model was established.The effect of Hv on liver regeneration after PHx was determined by comparing the liver regeneration levels of the PHx-Hv group and the PHx-sham group mice.In order to further investigate the role of interleukin(IL)-22 in liver regeneration inhibition mediated by Hv,the levels of IL-22 in the PHx-Hv group and the PHx-sham group was measured.The degree of liver injury in the PHx-Hv group and the PHx-sham group mice was detected to determine the role of the hepatic vagus nerve in liver injury after PHx.RESULTS Compared to control-group mice,Hv mice showed severe liver injury and weakened liver regeneration after PHx.Further research found that Hv downregulates the production of IL-22 induced by PHx and blocks activation of the signal transducer and activator of transcription 3(STAT3)pathway then reduces the expression of various mitogenic and anti-apoptotic proteins after PHx.Exogenous IL-22 reverses the inhibition of liver regeneration induced by Hv and alleviates liver injury,while treatment with IL-22 binding protein(an inhibitor of IL-22 signaling)reduce the concentration of IL-22 induced by PHx,inhibits the activation of the STAT3 signaling pathway in the liver after PHx,thereby hindering liver regeneration and aggravating liver injury in PHx-sham mice.CONCLUSION Hv attenuates liver regeneration after hepatectomy,and the mechanism may be related to the fact that Hv downregulates the production of IL-22,then blocks activation of the STAT3 pathway.展开更多
The present study attempted to examine the effects of bile acid pool size on liver regeneration after hepatectomy.The rats were fed on 0.2% cholic acid(CA)or 2% cholestyramine for 7 days to induce a change in the bile...The present study attempted to examine the effects of bile acid pool size on liver regeneration after hepatectomy.The rats were fed on 0.2% cholic acid(CA)or 2% cholestyramine for 7 days to induce a change in the bile acid size,and then a partial hepatectomy(PH)was performed.Rats fed on the normal diet served as the controls.Measurements were made on the rate of liver regeneration,the labeling indices of PCNA,the plasma total bile acids(TBA),and the mRNA expression of cholesterol 7alpha-hydroxylase(CYP7A1),farnesoid X receptor(FXR),and transcription factor c-Jun or c-fos.As compared with the normal and CA groups,the rate of liver regeneration was decreased on the day 3,and 7 after PH;the peak of the labeling indices of PCNA was delayed and the labeling indices were significantly reduced on the day 1;the TBA were also decreased on the day 1;the expression of FXR decreased but that of CYP7A1 increased at any given time;at the 1st,and 3rd h,the expression of c-Jun was declined in the cholestyramine group.The reduction in the bile acid pool size was found to delay the liver regeneration,which may be caused by the down-regulation of FXR and c-Jun expression.展开更多
The liver is an exceptional organ,not only because of its unique anatomical and physiological characteristics,but also because of its unlimited regenerative capacity.Unfolding of the molecular mechanisms that govern l...The liver is an exceptional organ,not only because of its unique anatomical and physiological characteristics,but also because of its unlimited regenerative capacity.Unfolding of the molecular mechanisms that govern liver regeneration has allowed researchers to exploit them to augment liver regeneration.Dramatic progress in the field,however,was made by the introduction of the powerful tool of gene therapy.Transfer of genetic materials,such as hepatocyte growth factor,using both viral and non-viral vectors has proved to be successful in augmenting liver regeneration in various animal models.For future clinical studies,ongoing research aims at eliminating toxicity of viral vectors and increasing transduction efficiency of non-viral vectors,which are the main drawbacks of these systems.Another goal of current research is to develop gene therapy that targets specific liver cells using receptors that are unique to and highly expressed by different liver cell types.The outcome of such investigations will,undoubtedly,pave the way for future successful clinical trials.展开更多
Recent studies indicate that the process of liver regeneration involves multiple signaling pathways and a variety of genes,cytokines and growth factors. Protein-protein interactions(PPIs)play a role in nearly all even...Recent studies indicate that the process of liver regeneration involves multiple signaling pathways and a variety of genes,cytokines and growth factors. Protein-protein interactions(PPIs)play a role in nearly all events that take place within the cell and PPI maps should be helpful in further understanding the process of liver regeneration.In this review,we discuss recent progress in understanding the PPIs that occur during liver regeneration especially those in the transforming growth factorβsignaling pathways.We believe the use of large-scale PPI maps for integrating the information already known about the liver regeneration is a useful approach in understanding liver regeneration from the standpoint of systems biology.展开更多
Background:Toll-like receptor 5(TLR5)-mediated pathways play critical roles in regulating the hepatic immune response and show hepatoprotective effects in mouse models of hepatic diseases.However,the role of TLR5 in e...Background:Toll-like receptor 5(TLR5)-mediated pathways play critical roles in regulating the hepatic immune response and show hepatoprotective effects in mouse models of hepatic diseases.However,the role of TLR5 in experimental models of liver regeneration has not been reported.This study aimed to investigate the role of TLR5 in partial hepatectomy(PHx)-induced liver regeneration.Methods:We performed 2/3 PHx in wild-type(WT)mice,TLR5 knockout mice,or TLR5 agonist CBLB502 treated mice,as a model of liver regeneration.Bacterial flagellin content was measured with ELISA,and hepatic TLR5 expression was determined with quantitative PCR analyses and flow cytometry.To study the effects of TLR5 on hepatocyte proliferation,we analyzed bromodeoxyuridine(BrdU)incorporation and proliferating cell nuclear antigen(PCNA)expression with immunohistochemistry(IHC)staining.The effects of TLR5 during the priming phase of liver regeneration were examined with quantitative PCR analyses of immediate early gene mRNA levels,and with Western blotting analysis of hepatic NF-κB and STAT3 activation.Cytokine and growth factor production after PHx were detected with real-time PCR and cytometric bead array(CBA)assays.Oil Red O staining and hepatic lipid concentrations were analyzed to examine the effect of TLR5 on hepatic lipid accumulation after PHx.Results:The bacterial flagellin content in the serum and liver increased,and the hepatic TLR5 expression was significantly up-regulated in WT mice after PHx.TLR5-deficient mice exhibited diminished numbers of BrdU-and PCNA-positive cells,suppressed immediate early gene expression,and decreased cytokine and growth factor production.Moreover,PHx-induced hepatic NF-κB and STAT3 activation was inhibited in Tlr5–/–mice,as compared with WT mice.Consistently,the administration of CBLB502 significantly promoted PHx-mediated hepatocyte proliferation,which was correlated with enhanced production of proinflammatory cytokines and the recruitment of macrophages and neutrophils in the liver.Furthermore,Tlr5–/–mice displayed significantly lower hepatic lipid concentrations and smaller Oil Red O positive areas than those in control mice after PHx.Conclusions:We reveal that TLR5 activation contributes to the initial events of liver regeneration after PHx.Our findings demonstrate that TLR5 signaling positively regulates liver regeneration and suggest the potential of TLR5 agonist to promote liver regeneration.展开更多
AIM To evaluate the liver regeneration capacity(LRC) after partial hepatectomy(PH) in experimental non-alcoholic steatohepatitis(NASH).METHODS Fifty-four female rats were fed a high-fat, high-cholesterol diet(HFCD, 65...AIM To evaluate the liver regeneration capacity(LRC) after partial hepatectomy(PH) in experimental non-alcoholic steatohepatitis(NASH).METHODS Fifty-four female rats were fed a high-fat, high-cholesterol diet(HFCD, 65% fat, 1% cholesterol) or standard diet(STD) for 16 wk. A 70% PH was performed and the animals were euthanised before PH or 2 or 5 d postPH. LRC was evaluated using: The total number of Ki-67 positive hepatocytes in the caudate lobe, N(Ki-67, lobe) evaluated in a stereology-based design, the regenerated protein ratio(RPR), prothrombin-proconvertin ratio(PP), and m RNA expression of genes related to regeneration.RESULTS The HFCD NASH model showed significant steatosis with ballooning and inflammation, while no fibrosis was present. Mortality was similar in HFCD and STD animals following PH. HFCD groups were compared to respective STD groups and HFCD animals had a significantly elevated alanine transaminase at baseline(P < 0.001), as well as a significantly elevated bilirubin at day 2 after PH(P < 0.05). HFCD animals had a higher N(Ki-67, lobe) at baseline,(P < 0.0001), day 2 after PH(P = 0.06) and day 5 after PH(P < 0.025). We found no significant difference in RPR or PP neither 2 or 5 d post-PH. Expression of liver regeneration genes(e.g., hepatic growth factor) was higher at both day 2 and 5 post-PH in HFCD groups(P < 0.05).CONCLUSION NASH rats had a preserved LRC after hepatectomy when compared to STD rats. The methods and models of NASH are essential in understanding and evaluating LRC.展开更多
The liver has remarkable regenerative potential,with the capacity to regenerate after 75%hepatectomy in humans and up to 90%hepatectomy in some rodent models,enabling it to meet the challenge of diverse injury types,i...The liver has remarkable regenerative potential,with the capacity to regenerate after 75%hepatectomy in humans and up to 90%hepatectomy in some rodent models,enabling it to meet the challenge of diverse injury types,including physical trauma,infection,inflammatory processes,direct toxicity,and immunological insults.Current understanding of liver regeneration is based largely on animal research,historically in large animals,and more recently in rodents and zebrafish,which provide powerful genetic manipulation experimental tools.Whilst immensely valuable,these models have limitations in extrapolation to the human situation.In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids,but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu.The process of liver regeneration is only partially understood and characterized by layers of complexity.Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine,paracrine,and endocrine ways,with much redundancy and cross-talk between biochemical pathways.The regenerative response is variable,involving both hypertrophy and true proliferative hyperplasia,which is itself variable,including both cellular phenotypic fidelity and cellular trans-differentiation,according to the type of injury.Complex interactions occur between parenchymal and non-parenchymal cells,and regeneration is affected by the status of the liver parenchyma,with differences between healthy and diseased liver.Finally,the process of termination of liver regeneration is even less well understood than its triggers.The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration.Moreover,manipulating the fundamental biochemical pathways involved would require cautious assessment,for fear of unintended consequences.Nevertheless,current knowledge provides guiding principles for strategies to optimise liver regeneration potential.展开更多
The liver is a unique parenchymal organ with a regenerative capacity allowing it to restore up to 70%of its volume.Although knowledge of this phenomenon dates back to Greek mythology(the story of Prometheus),many aspe...The liver is a unique parenchymal organ with a regenerative capacity allowing it to restore up to 70%of its volume.Although knowledge of this phenomenon dates back to Greek mythology(the story of Prometheus),many aspects of liver regeneration are still not understood.A variety of different factors,including inflammatory cytokines,growth factors,and bile acids,promote liver regeneration and control the final size of the organ during typical regeneration,which is performed by mature hepatocytes,and during alternative regeneration,which is performed by recently identified resident stem cells called“hepatic progenitor cells”.Hepatic progenitor cells drive liver regeneration when hepatocytes are unable to restore the liver mass,such as in cases of chronic injury or excessive acute injury.In liver maintenance,the body mass ratio is essential for homeostasis because the liver has numerous functions;therefore,a greater understanding of this process will lead to better control of liver injuries,improved transplantation of small grafts and the discovery of new methods for the treatment of liver diseases.The current review sheds light on the key molecular pathways and cells involved in typical and progenitor-dependent liver mass regeneration after various acute or chronic injuries.Subsequent studies and a better understanding of liver regeneration will lead to the development of new therapeutic methods for liver diseases.展开更多
BACKGROUND The phenomenon of liver regeneration after partial hepatectomy(PH)is still a subject of considerable interest due to the increasing frequency of half liver transplantation on the one hand,and on the other h...BACKGROUND The phenomenon of liver regeneration after partial hepatectomy(PH)is still a subject of considerable interest due to the increasing frequency of half liver transplantation on the one hand,and on the other hand,new surgical approaches which allow removal of massive space-occupying hepatic tumors,which earlier was considered as inoperable.Interestingly,the mechanisms of liver regeneration are extensively studied after PH but less attention is paid to the architectonics of the regenerated organ.Because of this,the question“How does the structure of regenerated liver differ from normal,regular liver?”has not been fully answered yet.Furthermore,almost without any attention is left the liver's structural transformation after repeated hepatectomy(of the re-regenereted liver).ATM To compare the architectonics of the lobules and circulatory bed of normal,regenerated and re-regenerated livers.METHODS The livers of 40 adult,male,albino Wistar rats were studied.14 rats were subjected to PH-the 1st study group(SG1);10 rats underwent repeated PH–the 2nd study group(SG2);16 rats were subjected to sham operation-control group(CG);The livers were studied after 9 months from PH,and after 6 months from repeated PH.Cytological(Schiff reaction for the determination of DNA concentration),histological(H&E,Masson trichrome,CK8 Immunohistochemical marker,transparent slides after Indian Ink injection,),morphometrical(hepatocytes areas,perimeters and ploidy)and Electron Microscopical(Scanning Electron Microscopy of corrosion casts)methods were used.RESULTS In the SG1 and SG2,the area of hepatocytes and their perimeter are increased compared to the CG(P<0.05).However,the areas and perimeters of the hepatocytes of the SG1 and SG2 groups reveal a lesser difference.In regenerated(SG1)and re-regenerated(SG2)livers,the hepatocytes form the remodeled lobules,which size(300-1200μm)exceeds the sizes of the lobules from CG(300-600μm).The remodeled lobules(especially the“mega-lobules”with the sizes 1000-1200μm)contain the transformed meshworks of the sinusoids,the part of which is dilated asymmetrically.This meshwork might have originated from the several portal venules(interlobular and/or inlet).The boundaries between the adjacent lobules(including mega-lobules)are widened and filled by connective tissue fibers,which gives the liver parenchyma a nodular look.In SG2 the unevenness of sinusoid diameters,as well as the boundaries between the lobules(including the mega-lobules)are more vividly expressed in comparison with SG1.The liver tissue of both SG1 and SG2 is featured by the slightly expressed ductular reaction.CONCLUSION Regenerated and re-regenerated livers in comparison with normal liver contain hypertrophied hepatocytes with increased ploidy which together with transformed sinusoidal and biliary meshworks form the remodeled lobulli.展开更多
Severe alcoholic hepatitis(AH)is a distinct entity in the spectrum of alcoholrelated liver disease,with limited treatment options and high mortality.Supportive medical care with corticosteroids in selected patients is...Severe alcoholic hepatitis(AH)is a distinct entity in the spectrum of alcoholrelated liver disease,with limited treatment options and high mortality.Supportive medical care with corticosteroids in selected patients is the only currently available treatment option,often with poor outcomes.Based on the insights into the pathogenetic mechanisms of AH,which are mostly obtained from animal studies,several new treatment options are being explored.Studies have implicated impaired and deranged liver regeneration processes as one of the culprit mechanisms and a potential therapeutic target.Acknowledging 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 AH.Contrary 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 pursued.Stem 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 cirrhosis.In this review,we summarize the current knowledge on the pathogenesis and experimental therapies targeting liver regeneration.The lack of high-quality studies and evidence is a major obstacle in further treatment development.New 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.展开更多
BACKGROUND Liver reduction is the main curative treatment for primary liver cancer,but its use remains limited as liver regeneration requires a minimum of 30%functional parenchyma.AIM To study the dynamics of the live...BACKGROUND Liver reduction is the main curative treatment for primary liver cancer,but its use remains limited as liver regeneration requires a minimum of 30%functional parenchyma.AIM To study the dynamics of the liver regeneration process and consequent behavior of cell cycle regulators in rats after extended hepatectomy(90%)and postoperative glucose infusions.METHODS Post-hepatectomy liver failure was triggered in 84 Wistar rats by reducing their liver mass by 90%.The animals received a post-operative glucose infusion and were randomly assigned to two groups:One to investigate the survival rate and the other for biochemical analyses.Animals that underwent laparotomy or 70%hepatectomy were used as controls.Blood and liver samples were collected on postoperative days 1 to 7.Liver morphology,function,and regeneration were studied with histology,immunohistochemistry,and western blotting.RESULTS Postoperative mortality after major resection reached 20%and 55%in the first 24 h and 48 h,respectively,with an overall total of 70%7 d after surgery.No apparent signs of apoptotic cell death were detected in the extended hepatectomy rat livers,but hepatocytes displaying a clear cytoplasm and an accumulation of hyaline material testified to changes affecting their functional activities.Liver regeneration started properly,as early events initiating cell proliferation occurred within the first 3 h,and the G1 to S transition was detected in less than 12 h.However,a rise in p27(Kip1)followed by p21(Waf1/Cip1)cell cycle inhibitor levels led to a delayed S phase progression and mitosis.Overall,liver regeneration in rats with a 90%hepatectomy was delayed by 24 h and associated with a delayed onset and lower peak magnitude of hepatocellular deoxyribonucleic acid synthesis.CONCLUSION This work highlights the critical importance of the cyclin/cyclin-dependent kinase inhibitors of the Cip/Kip family in regulating the liver regeneration timeline following extended hepatectomy.展开更多
Hepatocytes can divide rapidly and proliferate in the absence of inflammation and fibroplasia in the damaged or partial hepatectomy(PHx)of the liver,which is essential for the recovery of related patients.Recent studi...Hepatocytes can divide rapidly and proliferate in the absence of inflammation and fibroplasia in the damaged or partial hepatectomy(PHx)of the liver,which is essential for the recovery of related patients.Recent studies have found that bile acids(BA)play an important role in the process of liver regeneration.In the early stages of PHx,bile acid overload occurs,and liver injury is aggravated by loading.Later bile acids can induce protective and proliferative responses in the liver and promote liver regeneration.In this paper,we summarize the negative effects after bile acid overload and its positive role as a signaling molecule involved in related signaling pathways on liver regeneration,including protection of the liver and promotion of liver regeneration,and its double-edswordged"in Liver regeneration.This provides a theoretical basis for subsequent in-depth study of the mechanism and benefit avoidance in clinical treatment.展开更多
A partial hepatectomy is a surgical procedure performed during the living-donor liver transplantation and sometimes the only option for patients with hepatocarcinoma. However the remnant liver after the hepatectomy is...A partial hepatectomy is a surgical procedure performed during the living-donor liver transplantation and sometimes the only option for patients with hepatocarcinoma. However the remnant liver after the hepatectomy is still a major concern. Therefore, the process of liver regeneration has been a constant theme of study in order to optimize this process. Erythropoietin, a hormone produced by the kidney and involved in protecting organs like heart, liver and kidney itself against injuries can be one of these factors that could accelerate the liver regeneration. This study aims to observe if erythropoietin can accelerate the process of liver regeneration after partial hepatectomy in pigs. Methods: 8 pigs were classified into 2 groups of 4 pigs each: the control group and the test group. The animals in the first group underwent an application of saline solution subcutaneous on the day before the hepatectomy. Instead of saline solution, the test groups received a subcutaneous injection of 200 UI/lg of recombinant erythropoietin also on the day before the surgical procedure. After 7 days since the hepatectomy, in each animal the liver was biopsied in two regions, one next to the hepatectomy section and other far from it. The liver regeneration was analyzed using Ki-67. Results: Pigs from control group presented the following results: Control pig I: 30% of regeneration in the hepatectomy section and 10% in the region far from it;control pig II 24% and 4%;control pig III 27% and 7%. The test group presented no significant liver regeneration since Ki-67 could not identify cell proliferation in neither the biopsied areas. Conclusion: Since the number of pigs was not statistically significant, we could not conclude any further hypothesis. We strong believe that enhancing the number of pigs and testing different doses, we will be able to reach further conclusions.展开更多
AIM: To explore the mechanism of protection against acetaminophen-induced acute liver injury by Liuweiwuling tablets.METHODS: Intraperitoneal injections of acetaminophen(250 mg/kg) were used to induce acute liver inju...AIM: To explore the mechanism of protection against acetaminophen-induced acute liver injury by Liuweiwuling tablets.METHODS: Intraperitoneal injections of acetaminophen(250 mg/kg) were used to induce acute liver injury in male C57BL/6 mice.A total of 24 healthy mice were randomly assigned to two groups: an acute liver injury group(control group) and a Liuweiwuling tablet group.Mice were given Liuweiwuling tablets or a vehicle(PBS) orally prior to the administration of acetaminophen.Serum alanine aminotransferase(ALT) and aspartate aminotransaminase(AST) levels were measured at different time points within one week,and pathological examinations of liver tissues were performed 36 h after induction of acute liver injury.Serum inflammatory cytokines,such as high mobility group box protein B1(HMGB1),tumor necrosis factor(TNF)-α and interleukin IL-1b,were detected using an ELISA method according to the manufacturer's instructions.Hepatic morphological changes at 36 h were assessed by hematoxylin and eosin staining.Expression of proliferating cell nuclear antigen(PCNA) in liver tissue was determined by Western blot analysis.The m RNA levels of hepatocyte proliferation markers(PCNA,Cyclin D1 and p21) were detected by real-time quantitative reverse transcription-polymerase chain reaction.RESULTS: The levels of ALT/AST in the Liuweiwuling tablet group were decreased significantly at 6,12 and 24 h compared to that of the control group(654.38 ± 120.87 vs 1566.17 ± 421.64,1154.18 ± 477.72 vs 4654.84 ± 913.71 and 935.13 ± 252.34 vs 4553.75 ± 727.37,P < 0.01).Serum HMGB1 levels at 6 and 12 h for the Liuweiwuling tablet group were significantly lower than those of the control group(23.49 ± 3.89 vs58.6 ± 3.65,61.62 ± 13.07 vs 27.32 ± 5.97,P < 0.01).Furthermore,serum TNF-α and IL-1b levels at 12 h in the Liuweiwuling tablet group were also significantly lower than those of the control group(299.35 ± 50.61 vs 439.03 ± 63.59,57.42 ± 12.98 vs 160.07 ± 49.87,P < 0.01).Centrilobular necrosis was evident in liver tissue of mice with acetaminophen-induced acute liver injury,but was almost abolished in the Liuweiwuling tablet group.The expression levels of PCNA and Cyclin D1 were up-regulated in liver tissue in the Liuweiwuling tablet group(321.08 ± 32.87 vs 157.91 ± 21.52,196.37 ± 25.39 vs 68.72 ± 11.27,P < 0.01); however,expression of p21 in liver tissue was downregulated compared to that of the control group(40.26 ± 9.97 vs 138.24 ± 13.66,P < 0.01).CONCLUSION: Liuweiwuling tablets can attenuate acute liver injury by decreasing inflammatory cytokine(HMGB1,TNF-α and IL-1b) levels and promoting liver regeneration.展开更多
INTRODUCTIONThe liver is one of the organs,which have potentialregenerative capability in mammalian animal.The study of the canine model indicated that theliver could regenerate to original size after 70%hepatectomy i...INTRODUCTIONThe liver is one of the organs,which have potentialregenerative capability in mammalian animal.The study of the canine model indicated that theliver could regenerate to original size after 70%hepatectomy in only two weeks.So it is a hotresearch topic for the cellular and molecularmechanism of liver regeneration.展开更多
Hepatocellular carcinoma(HCC),which develops from liver cirrhosis,is highly prevalent worldwide and is a malignancy that leads to liver failure and systemic metastasis.While surgery is the preferred treatment for HCC,...Hepatocellular carcinoma(HCC),which develops from liver cirrhosis,is highly prevalent worldwide and is a malignancy that leads to liver failure and systemic metastasis.While surgery is the preferred treatment for HCC,intervention and liver transplantation are also treatment options for end-stage liver disease.However,the success of partial hepatectomy and intervention is hindered by the decompensation of liver function.Conversely,liver transplantation is difficult to carry out due to its high cost and the lack of donor organs.Fortunately,research into bone-marrow stromal cells(BMSCs)has opened a new door in this field.BMSCs are a type of stem cell with powerful proliferative and differential potential that represent an attractive tool for the establishment of successful stem cell-based therapy for liver diseases.A number of different stromal cells contribute to the therapeutic effects exerted by BMSCs because BMSCs can differentiate into functional hepatic cells and can produce a series of growth factors and cytokines capable of suppressing inflammatory responses,reducing hepatocyte apoptosis,reversing liver fibrosis and enhancing hepatocyte functionality.Additionally,it has been shown that BMSCs can increase the apoptosis rate of cancer cells and inhibit tumor metastasis in some microenvironments.This review focuses on BMSCs and their possible applications in liver regeneration and metastasis after hepatectomy.展开更多
文摘BACKGROUND The success of liver resection relies on the ability of the remnant liver to regenerate.Most of the knowledge regarding the pathophysiological basis of liver regeneration comes from rodent studies,and data on humans are scarce.Additionally,there is limited knowledge about the preoperative factors that influence postoperative regeneration.AIM To quantify postoperative remnant liver volume by the latest volumetric software and investigate perioperative factors that affect posthepatectomy liver regenera-tion.METHODS A total of 268 patients who received partial hepatectomy were enrolled.Patients were grouped into right hepatectomy/trisegmentectomy(RH/Tri),left hepa-tectomy(LH),segmentectomy(Seg),and subsegmentectomy/nonanatomical hepatectomy(Sub/Non)groups.The regeneration index(RI)and late rege-neration rate were defined as(postoperative liver volume)/[total functional liver volume(TFLV)]×100 and(RI at 6-months-RI at 3-months)/RI at 6-months,respectively.The lower 25th percentile of RI and the higher 25th percentile of late regeneration rate in each group were defined as“low regeneration”and“delayed regeneration”.“Restoration to the original size”was defined as regeneration of the liver volume by more than 90%of the TFLV at 12 months postsurgery.RESULTS The numbers of patients in the RH/Tri,LH,Seg,and Sub/Non groups were 41,53,99 and 75,respectively.The RI plateaued at 3 months in the LH,Seg,and Sub/Non groups,whereas the RI increased until 12 months in the RH/Tri group.According to our multivariate analysis,the preoperative albumin-bilirubin(ALBI)score was an independent factor for low regeneration at 3 months[odds ratio(OR)95%CI=2.80(1.17-6.69),P=0.02;per 1.0 up]and 12 months[OR=2.27(1.01-5.09),P=0.04;per 1.0 up].Multivariate analysis revealed that only liver resection percentage[OR=1.03(1.00-1.05),P=0.04]was associated with delayed regeneration.Furthermore,multivariate analysis demonstrated that the preoperative ALBI score[OR=2.63(1.00-1.05),P=0.02;per 1.0 up]and liver resection percentage[OR=1.02(1.00-1.05),P=0.04;per 1.0 up]were found to be independent risk factors associated with volume restoration failure.CONCLUSION Liver regeneration posthepatectomy was determined by the resection percentage and preoperative ALBI score.This knowledge helps surgeons decide the timing and type of rehepatectomy for recurrent cases.
文摘BACKGROUND The function of prohibitin 1(Phb1)during liver regeneration(LR)remains relatively unexplored.Our previous research identified downregulation of Phb1 in rat liver mitochondria 24 h after 70%partial hepatectomy(PHx),as determined by subcellular proteomic analysis.AIM To investigate the potential role of Phb1 during LR.METHODS We examined changes in Phb1 mRNA and protein levels,subcellular distribution,and abundance in rat liver during LR following 70%PHx.We also evaluated mitochondrial changes and apoptosis using electron microscopy and flow cytometry.RNA-interference-mediated knockdown of Phb1(PHBi)was performed in BRL-3A cells.RESULTS Compared with sham-operation control groups,Phb1 mRNA and protein levels in 70%PHx test groups were downregulated at 24 h,then upregulated at 72 and 168 h.Phb1 was mainly located in mitochondria,showed a reduced abundance at 24 h,significantly increased at 72 h,and almost recovered to normal at 168 h.Phb1 was also present in nuclei,with continuous increase in abundance observed 72 and 168 h after 70%PHx.The altered ultrastructure and reduced mass of mitochondria during LR had almost completely recovered to normal at 168 h.PHBi in BRL-3A cells resulted in increased S-phase entry,a higher number of apoptotic cells,and disruption of mitochondrial membrane potential.CONCLUSION Phb1 may contribute to maintaining mitochondrial stability and could play a role in regulating cell proliferation and apoptosis of rat liver cells during LR.
文摘BACKGROUND Although the associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)induces more rapid liver regeneration than portal vein embolization,the mechanism remains unclear.AIM To assess the influence of inflammatory cytokines and endothelial nitric oxide synthase(eNOS)activation on liver regeneration in ALPPS.METHODS The future liver remnant/body weight(FLR/BW)ratio,hepatocyte proliferation,inflammatory cytokine expression,and activation of the Akt-eNOS pathway were evaluated in rat ALPPS and portal vein ligation(PVL)models.Hepatocyte proliferation was assessed based on Ki-67 expression,which was confirmed using immunohistochemistry.The serum concentrations of inflammatory cytokines were measured using enzyme linked immune-solvent assays.The Akt-eNOS pathway was assessed using western blotting.To explore the role of inflammatory cytokines and NO,Kupffer cell inhibitor gadolinium chloride(GdCl3),NOS inhibitor N-nitro-arginine methyl ester(L-NAME),and NO enhancer molsidomine were administered intraperitoneally.RESULTS The ALPPS group showed significant FLR regeneration(FLR/BW:1.60%±0.08%,P<0.05)compared with that observed in the PVL group(1.33%±0.11%)48 h after surgery.In the ALPPS group,serum interleukin-6 expression was suppressed using GdCl3 to the same extent as that in the PVL group.However,the FLR/BW ratio and Ki-67 labeling index were significantly higher in the ALPPS group administered GdCl3(1.72%±0.19%,P<0.05;22.25%±1.30%,P<0.05)than in the PVL group(1.33%±0.11%and 12.78%±1.55%,respectively).Phospho-Akt Ser473 and phospho-eNOS Ser1177 levels were enhanced in the ALPPS group compared with those in the PVL group.There was no difference between the ALPPS group treated with L-NAME and the PVL group in the FLR/BW ratio and Ki-67 labeling index.In the PVL group treated with molsidomine,the FLR/BW ratio and Ki-67 labeling index increased to the same level as in the ALPPS group.CONCLUSION Early induction of inflammatory cytokines may not be pivotal for accelerated FLR regeneration after ALPPS,whereas Akt-eNOS pathway activation may contribute to accelerated regeneration of the FLR.
基金the Natural Science Foundation of Zhejiang Province,No.LQ21H030005
文摘Partial hepatectomy(PH)can lead to severe complications,including liver failure,due to the low regenerative capacity of the remaining liver,especially after extensive hepatectomy.Liver sinusoidal endothelial cells(LSECs),whose proliferation occurs more slowly and later than hepatocytes after PH,compose the lining of the hepatic sinusoids,which are the smallest blood vessels in the liver.Vascular endothelial growth factor(VEGF),secreted by hepatocytes,promotes LSEC proliferation.Supplementation of exogenous VEGF after hepatectomy also increases the number of LSECs in the remaining liver,thus promoting the reestablishment of the hepatic sinusoids and accelerating liver regeneration.At present,some shortcomings exist in the methods of supplementing exogenous VEGF,such as a low drug concentration in the liver and the reaching of other organs.Moreover,VEGF should be administered multiple times and in large doses because of its short half-life.This review summarized the most recent findings on liver regeneration and new strategies for the localized delivery VEGF in the liver.
基金Supported by the Natural Science Foundation of Zhejiang Province,No.LQ20H310002the Scientific Technology Projects of Health and Medicine of Zhejiang Province,No.2020KY308and the Huzhou Science and Technology Fund,No.2020GY39.
文摘BACKGROUND Rapid regeneration of the residual liver is one of the key determinants of successful partial hepatectomy(PHx).At present,there is a lack of recognized safe,effective,and stable drugs to promote liver regeneration.It has been reported that vagus nerve signaling is beneficial to liver regeneration,but the potential mechanism at play here is not fully understood.AIM To explore the effect and mechanism of hepatic vagus nerve in liver regeneration after PHx.METHODS A PHx plus hepatic vagotomy(Hv)mouse model was established.The effect of Hv on liver regeneration after PHx was determined by comparing the liver regeneration levels of the PHx-Hv group and the PHx-sham group mice.In order to further investigate the role of interleukin(IL)-22 in liver regeneration inhibition mediated by Hv,the levels of IL-22 in the PHx-Hv group and the PHx-sham group was measured.The degree of liver injury in the PHx-Hv group and the PHx-sham group mice was detected to determine the role of the hepatic vagus nerve in liver injury after PHx.RESULTS Compared to control-group mice,Hv mice showed severe liver injury and weakened liver regeneration after PHx.Further research found that Hv downregulates the production of IL-22 induced by PHx and blocks activation of the signal transducer and activator of transcription 3(STAT3)pathway then reduces the expression of various mitogenic and anti-apoptotic proteins after PHx.Exogenous IL-22 reverses the inhibition of liver regeneration induced by Hv and alleviates liver injury,while treatment with IL-22 binding protein(an inhibitor of IL-22 signaling)reduce the concentration of IL-22 induced by PHx,inhibits the activation of the STAT3 signaling pathway in the liver after PHx,thereby hindering liver regeneration and aggravating liver injury in PHx-sham mice.CONCLUSION Hv attenuates liver regeneration after hepatectomy,and the mechanism may be related to the fact that Hv downregulates the production of IL-22,then blocks activation of the STAT3 pathway.
文摘The present study attempted to examine the effects of bile acid pool size on liver regeneration after hepatectomy.The rats were fed on 0.2% cholic acid(CA)or 2% cholestyramine for 7 days to induce a change in the bile acid size,and then a partial hepatectomy(PH)was performed.Rats fed on the normal diet served as the controls.Measurements were made on the rate of liver regeneration,the labeling indices of PCNA,the plasma total bile acids(TBA),and the mRNA expression of cholesterol 7alpha-hydroxylase(CYP7A1),farnesoid X receptor(FXR),and transcription factor c-Jun or c-fos.As compared with the normal and CA groups,the rate of liver regeneration was decreased on the day 3,and 7 after PH;the peak of the labeling indices of PCNA was delayed and the labeling indices were significantly reduced on the day 1;the TBA were also decreased on the day 1;the expression of FXR decreased but that of CYP7A1 increased at any given time;at the 1st,and 3rd h,the expression of c-Jun was declined in the cholestyramine group.The reduction in the bile acid pool size was found to delay the liver regeneration,which may be caused by the down-regulation of FXR and c-Jun expression.
文摘The liver is an exceptional organ,not only because of its unique anatomical and physiological characteristics,but also because of its unlimited regenerative capacity.Unfolding of the molecular mechanisms that govern liver regeneration has allowed researchers to exploit them to augment liver regeneration.Dramatic progress in the field,however,was made by the introduction of the powerful tool of gene therapy.Transfer of genetic materials,such as hepatocyte growth factor,using both viral and non-viral vectors has proved to be successful in augmenting liver regeneration in various animal models.For future clinical studies,ongoing research aims at eliminating toxicity of viral vectors and increasing transduction efficiency of non-viral vectors,which are the main drawbacks of these systems.Another goal of current research is to develop gene therapy that targets specific liver cells using receptors that are unique to and highly expressed by different liver cell types.The outcome of such investigations will,undoubtedly,pave the way for future successful clinical trials.
基金Supported by Chinese Human Liver Proteome Project,No.2004BA711A19-08National 863 Project,No.2007AA02Z100
文摘Recent studies indicate that the process of liver regeneration involves multiple signaling pathways and a variety of genes,cytokines and growth factors. Protein-protein interactions(PPIs)play a role in nearly all events that take place within the cell and PPI maps should be helpful in further understanding the process of liver regeneration.In this review,we discuss recent progress in understanding the PPIs that occur during liver regeneration especially those in the transforming growth factorβsignaling pathways.We believe the use of large-scale PPI maps for integrating the information already known about the liver regeneration is a useful approach in understanding liver regeneration from the standpoint of systems biology.
基金the National Natural Science Foundation of China(81800561)the State Key Laboratory of Proteomics(SKLP-K201404).
文摘Background:Toll-like receptor 5(TLR5)-mediated pathways play critical roles in regulating the hepatic immune response and show hepatoprotective effects in mouse models of hepatic diseases.However,the role of TLR5 in experimental models of liver regeneration has not been reported.This study aimed to investigate the role of TLR5 in partial hepatectomy(PHx)-induced liver regeneration.Methods:We performed 2/3 PHx in wild-type(WT)mice,TLR5 knockout mice,or TLR5 agonist CBLB502 treated mice,as a model of liver regeneration.Bacterial flagellin content was measured with ELISA,and hepatic TLR5 expression was determined with quantitative PCR analyses and flow cytometry.To study the effects of TLR5 on hepatocyte proliferation,we analyzed bromodeoxyuridine(BrdU)incorporation and proliferating cell nuclear antigen(PCNA)expression with immunohistochemistry(IHC)staining.The effects of TLR5 during the priming phase of liver regeneration were examined with quantitative PCR analyses of immediate early gene mRNA levels,and with Western blotting analysis of hepatic NF-κB and STAT3 activation.Cytokine and growth factor production after PHx were detected with real-time PCR and cytometric bead array(CBA)assays.Oil Red O staining and hepatic lipid concentrations were analyzed to examine the effect of TLR5 on hepatic lipid accumulation after PHx.Results:The bacterial flagellin content in the serum and liver increased,and the hepatic TLR5 expression was significantly up-regulated in WT mice after PHx.TLR5-deficient mice exhibited diminished numbers of BrdU-and PCNA-positive cells,suppressed immediate early gene expression,and decreased cytokine and growth factor production.Moreover,PHx-induced hepatic NF-κB and STAT3 activation was inhibited in Tlr5–/–mice,as compared with WT mice.Consistently,the administration of CBLB502 significantly promoted PHx-mediated hepatocyte proliferation,which was correlated with enhanced production of proinflammatory cytokines and the recruitment of macrophages and neutrophils in the liver.Furthermore,Tlr5–/–mice displayed significantly lower hepatic lipid concentrations and smaller Oil Red O positive areas than those in control mice after PHx.Conclusions:We reveal that TLR5 activation contributes to the initial events of liver regeneration after PHx.Our findings demonstrate that TLR5 signaling positively regulates liver regeneration and suggest the potential of TLR5 agonist to promote liver regeneration.
基金Supported by NOVO Nordisk Foundation(grant number 1013267)Savværksejer Jeppe Juhl og Hustru Ovita Juhls Mindelegat to Gr?nb?k HVillum Fonden to Nyengaard JR
文摘AIM To evaluate the liver regeneration capacity(LRC) after partial hepatectomy(PH) in experimental non-alcoholic steatohepatitis(NASH).METHODS Fifty-four female rats were fed a high-fat, high-cholesterol diet(HFCD, 65% fat, 1% cholesterol) or standard diet(STD) for 16 wk. A 70% PH was performed and the animals were euthanised before PH or 2 or 5 d postPH. LRC was evaluated using: The total number of Ki-67 positive hepatocytes in the caudate lobe, N(Ki-67, lobe) evaluated in a stereology-based design, the regenerated protein ratio(RPR), prothrombin-proconvertin ratio(PP), and m RNA expression of genes related to regeneration.RESULTS The HFCD NASH model showed significant steatosis with ballooning and inflammation, while no fibrosis was present. Mortality was similar in HFCD and STD animals following PH. HFCD groups were compared to respective STD groups and HFCD animals had a significantly elevated alanine transaminase at baseline(P < 0.001), as well as a significantly elevated bilirubin at day 2 after PH(P < 0.05). HFCD animals had a higher N(Ki-67, lobe) at baseline,(P < 0.0001), day 2 after PH(P = 0.06) and day 5 after PH(P < 0.025). We found no significant difference in RPR or PP neither 2 or 5 d post-PH. Expression of liver regeneration genes(e.g., hepatic growth factor) was higher at both day 2 and 5 post-PH in HFCD groups(P < 0.05).CONCLUSION NASH rats had a preserved LRC after hepatectomy when compared to STD rats. The methods and models of NASH are essential in understanding and evaluating LRC.
文摘The liver has remarkable regenerative potential,with the capacity to regenerate after 75%hepatectomy in humans and up to 90%hepatectomy in some rodent models,enabling it to meet the challenge of diverse injury types,including physical trauma,infection,inflammatory processes,direct toxicity,and immunological insults.Current understanding of liver regeneration is based largely on animal research,historically in large animals,and more recently in rodents and zebrafish,which provide powerful genetic manipulation experimental tools.Whilst immensely valuable,these models have limitations in extrapolation to the human situation.In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids,but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu.The process of liver regeneration is only partially understood and characterized by layers of complexity.Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine,paracrine,and endocrine ways,with much redundancy and cross-talk between biochemical pathways.The regenerative response is variable,involving both hypertrophy and true proliferative hyperplasia,which is itself variable,including both cellular phenotypic fidelity and cellular trans-differentiation,according to the type of injury.Complex interactions occur between parenchymal and non-parenchymal cells,and regeneration is affected by the status of the liver parenchyma,with differences between healthy and diseased liver.Finally,the process of termination of liver regeneration is even less well understood than its triggers.The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration.Moreover,manipulating the fundamental biochemical pathways involved would require cautious assessment,for fear of unintended consequences.Nevertheless,current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
文摘The liver is a unique parenchymal organ with a regenerative capacity allowing it to restore up to 70%of its volume.Although knowledge of this phenomenon dates back to Greek mythology(the story of Prometheus),many aspects of liver regeneration are still not understood.A variety of different factors,including inflammatory cytokines,growth factors,and bile acids,promote liver regeneration and control the final size of the organ during typical regeneration,which is performed by mature hepatocytes,and during alternative regeneration,which is performed by recently identified resident stem cells called“hepatic progenitor cells”.Hepatic progenitor cells drive liver regeneration when hepatocytes are unable to restore the liver mass,such as in cases of chronic injury or excessive acute injury.In liver maintenance,the body mass ratio is essential for homeostasis because the liver has numerous functions;therefore,a greater understanding of this process will lead to better control of liver injuries,improved transplantation of small grafts and the discovery of new methods for the treatment of liver diseases.The current review sheds light on the key molecular pathways and cells involved in typical and progenitor-dependent liver mass regeneration after various acute or chronic injuries.Subsequent studies and a better understanding of liver regeneration will lead to the development of new therapeutic methods for liver diseases.
基金the Shota Rustaveli National Science Foundation of Georgia,No.DP2016_22[New Interfaculty Interdisciplinary Structured Doctoral Programme“Translational Biomedicine”(Direction–“Hepatology”)].
文摘BACKGROUND The phenomenon of liver regeneration after partial hepatectomy(PH)is still a subject of considerable interest due to the increasing frequency of half liver transplantation on the one hand,and on the other hand,new surgical approaches which allow removal of massive space-occupying hepatic tumors,which earlier was considered as inoperable.Interestingly,the mechanisms of liver regeneration are extensively studied after PH but less attention is paid to the architectonics of the regenerated organ.Because of this,the question“How does the structure of regenerated liver differ from normal,regular liver?”has not been fully answered yet.Furthermore,almost without any attention is left the liver's structural transformation after repeated hepatectomy(of the re-regenereted liver).ATM To compare the architectonics of the lobules and circulatory bed of normal,regenerated and re-regenerated livers.METHODS The livers of 40 adult,male,albino Wistar rats were studied.14 rats were subjected to PH-the 1st study group(SG1);10 rats underwent repeated PH–the 2nd study group(SG2);16 rats were subjected to sham operation-control group(CG);The livers were studied after 9 months from PH,and after 6 months from repeated PH.Cytological(Schiff reaction for the determination of DNA concentration),histological(H&E,Masson trichrome,CK8 Immunohistochemical marker,transparent slides after Indian Ink injection,),morphometrical(hepatocytes areas,perimeters and ploidy)and Electron Microscopical(Scanning Electron Microscopy of corrosion casts)methods were used.RESULTS In the SG1 and SG2,the area of hepatocytes and their perimeter are increased compared to the CG(P<0.05).However,the areas and perimeters of the hepatocytes of the SG1 and SG2 groups reveal a lesser difference.In regenerated(SG1)and re-regenerated(SG2)livers,the hepatocytes form the remodeled lobules,which size(300-1200μm)exceeds the sizes of the lobules from CG(300-600μm).The remodeled lobules(especially the“mega-lobules”with the sizes 1000-1200μm)contain the transformed meshworks of the sinusoids,the part of which is dilated asymmetrically.This meshwork might have originated from the several portal venules(interlobular and/or inlet).The boundaries between the adjacent lobules(including mega-lobules)are widened and filled by connective tissue fibers,which gives the liver parenchyma a nodular look.In SG2 the unevenness of sinusoid diameters,as well as the boundaries between the lobules(including the mega-lobules)are more vividly expressed in comparison with SG1.The liver tissue of both SG1 and SG2 is featured by the slightly expressed ductular reaction.CONCLUSION Regenerated and re-regenerated livers in comparison with normal liver contain hypertrophied hepatocytes with increased ploidy which together with transformed sinusoidal and biliary meshworks form the remodeled lobulli.
文摘Severe alcoholic hepatitis(AH)is a distinct entity in the spectrum of alcoholrelated liver disease,with limited treatment options and high mortality.Supportive medical care with corticosteroids in selected patients is the only currently available treatment option,often with poor outcomes.Based on the insights into the pathogenetic mechanisms of AH,which are mostly obtained from animal studies,several new treatment options are being explored.Studies have implicated impaired and deranged liver regeneration processes as one of the culprit mechanisms and a potential therapeutic target.Acknowledging 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 AH.Contrary 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 pursued.Stem 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 cirrhosis.In this review,we summarize the current knowledge on the pathogenesis and experimental therapies targeting liver regeneration.The lack of high-quality studies and evidence is a major obstacle in further treatment development.New 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.
文摘BACKGROUND Liver reduction is the main curative treatment for primary liver cancer,but its use remains limited as liver regeneration requires a minimum of 30%functional parenchyma.AIM To study the dynamics of the liver regeneration process and consequent behavior of cell cycle regulators in rats after extended hepatectomy(90%)and postoperative glucose infusions.METHODS Post-hepatectomy liver failure was triggered in 84 Wistar rats by reducing their liver mass by 90%.The animals received a post-operative glucose infusion and were randomly assigned to two groups:One to investigate the survival rate and the other for biochemical analyses.Animals that underwent laparotomy or 70%hepatectomy were used as controls.Blood and liver samples were collected on postoperative days 1 to 7.Liver morphology,function,and regeneration were studied with histology,immunohistochemistry,and western blotting.RESULTS Postoperative mortality after major resection reached 20%and 55%in the first 24 h and 48 h,respectively,with an overall total of 70%7 d after surgery.No apparent signs of apoptotic cell death were detected in the extended hepatectomy rat livers,but hepatocytes displaying a clear cytoplasm and an accumulation of hyaline material testified to changes affecting their functional activities.Liver regeneration started properly,as early events initiating cell proliferation occurred within the first 3 h,and the G1 to S transition was detected in less than 12 h.However,a rise in p27(Kip1)followed by p21(Waf1/Cip1)cell cycle inhibitor levels led to a delayed S phase progression and mitosis.Overall,liver regeneration in rats with a 90%hepatectomy was delayed by 24 h and associated with a delayed onset and lower peak magnitude of hepatocellular deoxyribonucleic acid synthesis.CONCLUSION This work highlights the critical importance of the cyclin/cyclin-dependent kinase inhibitors of the Cip/Kip family in regulating the liver regeneration timeline following extended hepatectomy.
基金General Program of National Natural Science Foundation of China(No.81774236,81960841)。
文摘Hepatocytes can divide rapidly and proliferate in the absence of inflammation and fibroplasia in the damaged or partial hepatectomy(PHx)of the liver,which is essential for the recovery of related patients.Recent studies have found that bile acids(BA)play an important role in the process of liver regeneration.In the early stages of PHx,bile acid overload occurs,and liver injury is aggravated by loading.Later bile acids can induce protective and proliferative responses in the liver and promote liver regeneration.In this paper,we summarize the negative effects after bile acid overload and its positive role as a signaling molecule involved in related signaling pathways on liver regeneration,including protection of the liver and promotion of liver regeneration,and its double-edswordged"in Liver regeneration.This provides a theoretical basis for subsequent in-depth study of the mechanism and benefit avoidance in clinical treatment.
文摘A partial hepatectomy is a surgical procedure performed during the living-donor liver transplantation and sometimes the only option for patients with hepatocarcinoma. However the remnant liver after the hepatectomy is still a major concern. Therefore, the process of liver regeneration has been a constant theme of study in order to optimize this process. Erythropoietin, a hormone produced by the kidney and involved in protecting organs like heart, liver and kidney itself against injuries can be one of these factors that could accelerate the liver regeneration. This study aims to observe if erythropoietin can accelerate the process of liver regeneration after partial hepatectomy in pigs. Methods: 8 pigs were classified into 2 groups of 4 pigs each: the control group and the test group. The animals in the first group underwent an application of saline solution subcutaneous on the day before the hepatectomy. Instead of saline solution, the test groups received a subcutaneous injection of 200 UI/lg of recombinant erythropoietin also on the day before the surgical procedure. After 7 days since the hepatectomy, in each animal the liver was biopsied in two regions, one next to the hepatectomy section and other far from it. The liver regeneration was analyzed using Ki-67. Results: Pigs from control group presented the following results: Control pig I: 30% of regeneration in the hepatectomy section and 10% in the region far from it;control pig II 24% and 4%;control pig III 27% and 7%. The test group presented no significant liver regeneration since Ki-67 could not identify cell proliferation in neither the biopsied areas. Conclusion: Since the number of pigs was not statistically significant, we could not conclude any further hypothesis. We strong believe that enhancing the number of pigs and testing different doses, we will be able to reach further conclusions.
文摘AIM: To explore the mechanism of protection against acetaminophen-induced acute liver injury by Liuweiwuling tablets.METHODS: Intraperitoneal injections of acetaminophen(250 mg/kg) were used to induce acute liver injury in male C57BL/6 mice.A total of 24 healthy mice were randomly assigned to two groups: an acute liver injury group(control group) and a Liuweiwuling tablet group.Mice were given Liuweiwuling tablets or a vehicle(PBS) orally prior to the administration of acetaminophen.Serum alanine aminotransferase(ALT) and aspartate aminotransaminase(AST) levels were measured at different time points within one week,and pathological examinations of liver tissues were performed 36 h after induction of acute liver injury.Serum inflammatory cytokines,such as high mobility group box protein B1(HMGB1),tumor necrosis factor(TNF)-α and interleukin IL-1b,were detected using an ELISA method according to the manufacturer's instructions.Hepatic morphological changes at 36 h were assessed by hematoxylin and eosin staining.Expression of proliferating cell nuclear antigen(PCNA) in liver tissue was determined by Western blot analysis.The m RNA levels of hepatocyte proliferation markers(PCNA,Cyclin D1 and p21) were detected by real-time quantitative reverse transcription-polymerase chain reaction.RESULTS: The levels of ALT/AST in the Liuweiwuling tablet group were decreased significantly at 6,12 and 24 h compared to that of the control group(654.38 ± 120.87 vs 1566.17 ± 421.64,1154.18 ± 477.72 vs 4654.84 ± 913.71 and 935.13 ± 252.34 vs 4553.75 ± 727.37,P < 0.01).Serum HMGB1 levels at 6 and 12 h for the Liuweiwuling tablet group were significantly lower than those of the control group(23.49 ± 3.89 vs58.6 ± 3.65,61.62 ± 13.07 vs 27.32 ± 5.97,P < 0.01).Furthermore,serum TNF-α and IL-1b levels at 12 h in the Liuweiwuling tablet group were also significantly lower than those of the control group(299.35 ± 50.61 vs 439.03 ± 63.59,57.42 ± 12.98 vs 160.07 ± 49.87,P < 0.01).Centrilobular necrosis was evident in liver tissue of mice with acetaminophen-induced acute liver injury,but was almost abolished in the Liuweiwuling tablet group.The expression levels of PCNA and Cyclin D1 were up-regulated in liver tissue in the Liuweiwuling tablet group(321.08 ± 32.87 vs 157.91 ± 21.52,196.37 ± 25.39 vs 68.72 ± 11.27,P < 0.01); however,expression of p21 in liver tissue was downregulated compared to that of the control group(40.26 ± 9.97 vs 138.24 ± 13.66,P < 0.01).CONCLUSION: Liuweiwuling tablets can attenuate acute liver injury by decreasing inflammatory cytokine(HMGB1,TNF-α and IL-1b) levels and promoting liver regeneration.
文摘INTRODUCTIONThe liver is one of the organs,which have potentialregenerative capability in mammalian animal.The study of the canine model indicated that theliver could regenerate to original size after 70%hepatectomy in only two weeks.So it is a hotresearch topic for the cellular and molecularmechanism of liver regeneration.
基金Supported by The National Natural Science Foundation of China,No.81100306the Science and Technology Commission Medical Foundation of Shanghai,No.134119a9501
文摘Hepatocellular carcinoma(HCC),which develops from liver cirrhosis,is highly prevalent worldwide and is a malignancy that leads to liver failure and systemic metastasis.While surgery is the preferred treatment for HCC,intervention and liver transplantation are also treatment options for end-stage liver disease.However,the success of partial hepatectomy and intervention is hindered by the decompensation of liver function.Conversely,liver transplantation is difficult to carry out due to its high cost and the lack of donor organs.Fortunately,research into bone-marrow stromal cells(BMSCs)has opened a new door in this field.BMSCs are a type of stem cell with powerful proliferative and differential potential that represent an attractive tool for the establishment of successful stem cell-based therapy for liver diseases.A number of different stromal cells contribute to the therapeutic effects exerted by BMSCs because BMSCs can differentiate into functional hepatic cells and can produce a series of growth factors and cytokines capable of suppressing inflammatory responses,reducing hepatocyte apoptosis,reversing liver fibrosis and enhancing hepatocyte functionality.Additionally,it has been shown that BMSCs can increase the apoptosis rate of cancer cells and inhibit tumor metastasis in some microenvironments.This review focuses on BMSCs and their possible applications in liver regeneration and metastasis after hepatectomy.
