Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 11.458
Filtrar
1.
Medicine (Baltimore) ; 99(22): e20003, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481371

RESUMO

BACKGROUND: Blood flow factors, such as congestion or ischemia after hepatectomy, have a significant impact on liver regeneration, but with the popularization of precise hepatectomy technology, segmental hepatectomy without congestion or ischemia has become the preferred treatment. Our aim is to investigate the factors affecting liver regeneration after hepatectomy without blood flow changes, and to provide clinical evidence for surgeons on the timing of second hepatectomy for cirrhosis patients with hepatocellular carcinoma (HCC). METHODS: This study retrospectively analyzed data from patients who underwent right hepatectomy without middle hepatic vein (MHV) in West China Hospital between January 2016 and January 2018. Eighteen living-donors without MHV as normal group and 45 HCC patients, further classified into 3 subgroups based on the severity of fibrosis using the Scheure system. Demographic data, pre- and postoperative liver function indexes, and remnant liver volume (RLV) were retrospectively compared. We also analyzed the remnant liver regeneration rate (RLRR) post-operatively in each group. The significant indexes in univariate analysis were further analyzed using both receiver operating characteristic (ROC) analysis and multivariate regression analysis. RESULTS: Liver regeneration occurred in both living-donor and HCC groups after hepatectomy; the RLRRs at 1 month were 59.46 ±â€Š10.39% and 57.27 ±â€Š4.77% (P = .509), respectively. Regeneration in the cirrhosis group occurred more slowly and less completely compared with that in other groups. The regeneration rate in the first 6 months showed rapid increase and the RLRR reached above 70% in cirrhosis group. Multivariate and ROC analyses revealed that Alb and the hepatic fibrosis grade in the early postoperative period were significant predictors of remnant liver regeneration. CONCLUSION: The liver regenerated in all HCC patients; however, regeneration was significantly slower and less complete compared with the normal liver, especially in the patients with cirrhosis. Therefore, it can be concluded that the degree of liver fibrosis is a major predictor of liver regeneration. Furthermore, the optimal time for second resection in recurrent HCC patients with cirrhosis was 6 months after the first operation.


Assuntos
Hepatectomia , Cirrose Hepática/fisiopatologia , Regeneração Hepática , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
2.
Khirurgiia (Mosk) ; (4): 47-52, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32352668

RESUMO

The researches devoted to postoperative liver regeneration and influence in this process were analyzed. Liver injury is followed by hypertrophy of residual liver parenchyma. The use of various cytokines is perspective for activation, acceleration and inhibition of liver recovery. Cellular technologies in the treatment of liver diseases can affect its repair. Moreover, these methods could make unnecessary resection and transplantation of liver in certain cases. It is generally accepted that the main effect of multipotent stromal cells (MSC) in liver failure is associated with their differentiation to the cellular elements of this organ. At the same time, recent reports revealed that MSC injection to the liver is followed by their quick death, dissemination to other organs and tissues or even elimination from the organism. Regeneration of non-parenchymal structures (vascular network and bile ducts) should be considered in addition to functional recovery of liver parenchyma after resection. Clarification of indications and contraindications for MSC therapy, as well as prevention of possible complications associated with cellular technologies are required.


Assuntos
Hepatectomia , Hepatopatias/fisiopatologia , Hepatopatias/cirurgia , Regeneração Hepática/fisiologia , Fígado/fisiologia , Humanos , Recuperação de Função Fisiológica
3.
Cell Prolif ; 53(5): e12808, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32347601

RESUMO

OBJECTIVES: Although the hepatomitogenic activity of triiodothyronine (T3) is well established, the wide range of harmful effects exerted by this hormone precludes its use in liver regenerative therapy. Selective agonists of the beta isoform of thyroid hormone receptor (TRß) do not exhibit T3-induced cardiotoxicity and show a good safety profile in patients with NASH. The aim of this study was to investigate whether two novel TRß agonists, the prodrug TG68 and the active compound IS25 could stimulate hepatocyte proliferation without T3/TRα-dependent side effects. METHODS: Rats were treated with three different doses (12.5, 25 and 50 µg/100 g body weight) for one week. Hepatocyte proliferation, liver injury and serum biochemical parameters were measured by immunohistochemistry, qRT-PCR and Western blot. RESULTS: Both drugs increased hepatocyte proliferation as assessed by bromodeoxyuridine incorporation (from 14% to 28% vs 5% of controls) and mitotic activity. Enhanced proliferation occurred in the absence of significant signs of liver injury as shown by lack of increased serum transaminase levels or of apoptosis. No cardiac or renal hypertrophy typically associated with treatment with T3 was observed. Importantly, no proliferation of pancreatic acinar cells, such as that seen after administration of T3 or the TRß agonist GC1 was detected following either TG68 or IS25, demonstrating the hepato-specificity of these novel TRß agonists. CONCLUSIONS: The present study shows that TG68 and IS25 induce massive hepatocyte proliferation without overt toxicity. Hence, these agents may have a significant clinical application for regenerative therapies in liver transplantation or other surgical settings.


Assuntos
Regeneração Hepática/efeitos dos fármacos , Fígado/efeitos dos fármacos , Pró-Fármacos/farmacologia , Receptores beta dos Hormônios Tireóideos/agonistas , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Fígado/metabolismo , Masculino , Ratos , Ratos Endogâmicos F344 , Tri-Iodotironina/metabolismo
4.
Genes Dev ; 34(7-8): 463-464, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32238449

RESUMO

The mammalian liver possesses a unique capacity for regeneration. However, this regenerative potential declines with age due to unknown mechanisms. In this issue of Genes & Development, Ritschka and colleagues (pp. 489-494). compare liver regeneration upon partial hepatectomy in young and adult mice. Partial hepatectomy causes a transient increase in p21 in a subpopulation of hepatocytes that persists in adult mice. Remarkably, treatment with the BCL-2 family inhibitor ABT-737 blunts p21 expression, enhancing liver regeneration.


Assuntos
Hepatectomia , Regeneração Hepática , Animais , Hepatócitos , Fígado , Camundongos
5.
Chem Biol Interact ; 324: 109090, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32283070

RESUMO

Epidermal growth factor receptor (EGFR) is conventionally known to play a crucial role in hepatocyte proliferation, liver regeneration and is also associated with hepatocellular carcinogenesis. In addition to these proliferative roles, EGFR has also implicated in apoptotic cell death signaling in various hepatic cells, mitochondrial dysfunction and acute liver necrosis in a clinically relevant murine model of acetaminophen overdose, warranting further comprehensive exploration of this paradoxical role of EGFR in hepatotoxicity. Apart from ligand dependent activation, EGFR can also be activated in ligand-independent manner, which is mainly associated to liver injury. Recent evidence has also emerged demonstrating important role of EGFR in lipid and fatty acid metabolism in quiescent and regenerating liver. Based on these findings, EGFR has also been shown to play an important role in steatosis in clinically relevant murine NAFLD models via regulating master transcription factors governing fatty acid synthesis and lipolysis. Moreover, several lines of evidences indicate that EGFR is also involved in hepatocellular injury, oxidative stress, inflammation, direct stellate cell activation and fibrosis in chronic liver injury models, including repeated CCl4 exposure, high-fat diet and fast-food diet models. In addition to briefly summarizing role of EGFR in liver regeneration, this review comprehensively discusses all these non-conventional emerging roles of EGFR. Considering evidences of multi-facet role of EGFR at various levels in these pathophysiological process, EGFR can be a promising therapeutic target for various liver diseases, including acute liver failure and NAFLD, requiring further exploration. These roles of EGFR are relevant for alcoholic liver diseases (ALD) as well, thus providing a valid rationale for future investigations exploring a role of EGFR in ALD.


Assuntos
Receptores ErbB/fisiologia , Metabolismo dos Lipídeos/fisiologia , Hepatopatias/fisiopatologia , Animais , Morte Celular/fisiologia , Células Estreladas do Fígado/fisiologia , Humanos , Regeneração Hepática/fisiologia
6.
Arq Bras Cir Dig ; 33(1): e1484, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32236290

RESUMO

BACKGROUND: Hepatectomies promote considerable amount of blood loss and the need to administrate blood products, which are directly linked to higher morbimortality rates. The blood-conserving hepatectomy (BCH) is a modification of the selective vascular occlusion technique. It could be a surgical maneuver in order to avoid or to reduce the blood products utilization in the perioperative period. AIM: To evaluate in rats the BCH effects on the hematocrit (HT) variation, hemoglobin serum concentration (HB), and on liver regeneration. METHODS: Twelve Wistar rats were divided into two groups: control (n=6) and intervention (n=6). The ones in the control group had their livers partially removed according to the Higgins and Anderson technique, while the rats in the treatment group were submitted to BCH technique. HT and HB levels were measured at day D0, D1 and D7. The rate between the liver and rat weights was calculated in D0 and D7. Liver regeneration was quantitatively and qualitatively evaluated. RESULTS: The HT and HB levels were lower in the control group as of D1 onwards, reaching an 18% gap at D7 (p=0.01 and p=0.008, respectively); BCH resulted in the preservation of HT and HB levels to the intervention group rats. BCH did not alter liver regeneration in rats. CONCLUSION: The BCH led to beneficial effects over the postoperative HT and serum HB levels with no setbacks to liver regeneration. These data are the necessary proof of evidence for translational research into the surgical practice. A) Unresected liver; B) liver appearance after the partial hepatectomy (1=vena cava; 2=portal vein; 3=hepatic vein; 4=biliary drainage; 5=hepatic artery).


Assuntos
Hepatectomia/métodos , Regeneração Hepática , Fígado/irrigação sanguínea , Fígado/cirurgia , Veias/fisiologia , Animais , Volume Sanguíneo/fisiologia , Hematócrito , Hemoglobinas/análise , Hepatopatia Veno-Oclusiva/fisiopatologia , Masculino , Veia Porta/cirurgia , Período Pós-Operatório , Ratos , Ratos Wistar
8.
Med Sci Monit ; 26: e920310, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32144233

RESUMO

The development, progression, recurrence, and metastasis of hepatocellular carcinoma (HCC) are closely associated with an abnormal liver-regenerating microenvironment (LRM). Therefore, preventing and reversing an abnormal LRM is a potential therapeutic strategy against HCC. Studies are increasingly focusing on the impact of regeneration, fibrosis, angiogenesis, inflammation, immunomodulation, and hepatic stem cells on HCC development and progression. As a key epigenetic mechanism, DNA methylation is extensively involved in regulating physiological and pathological pathways. In this review, we summarize recent findings on the role of DNA methylation in the fibrotic, angiogenic, inflammatory/immune, and stem cell microenvironments of HCC, and discuss new advances in Traditional Chinese Medicine (TCM) on influencing the abnormal LRM, so as to gain new insights into alleviating the abnormal LRM via regulating DNA methylation by TCM.


Assuntos
Carcinoma Hepatocelular/genética , Metilação de DNA , Regeneração Hepática , Medicina Tradicional Chinesa , Epigênese Genética , Humanos , Imunomodulação , Cirrose Hepática , Neovascularização Patológica , Microambiente Tumoral
9.
Life Sci ; 250: 117561, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32198052

RESUMO

AIMS: Pyruvate kinase M2 (PKM2), a unique isoform of the pyruvate kinases, not only acts as a crucial metabolic enzyme when it locates in the cytoplasm, but also plays important roles in tumor formation and growth when it accumulates in the nuclei. Our aim was to investigate the potential role of PKM2 in liver regeneration in mice insulted with carbon tetrachloride (CCl4). MATERIAL AND METHODS: The liver regeneration model was established by intraperitoneal injection of CCl4 for 48 h in male BALB/c mice. The expression of PKM2, phospho-STAT3, STAT3, proliferating cell nuclear antigen (PCNA) and Cyclin D1 were evaluated by western blot. The distribution of PKM2 was verified by immunofluorescence staining. The degree of injured region was assessed by hematoxylin and eosin (HE) staining. The proliferation of liver cells was tested by Immunohistochemistry. KEY FINDINGS: The nuclear accumulation of PKM2 increased in the liver treated with CCl4, but treatment with ML-265 significantly suppressed CCl4-induced nuclear accumulation of PKM2. In addition, treatment with ML-265 suppressed the level of cyclin D1 and proliferating cell nuclear antigen (PCNA), reduced the count of Ki67-positive hepatocytes, and expanded the damaged region in histological examination. Meanwhile, treatment with ML-265 suppressed the phosphorylation of nuclear signal transducer and activator of transcription 3 (STAT3). Inhibition of STAT3 by stattic made the same effects as ML-265. SIGNIFICANCE: These data uncovered the role of nuclear PKM2 in liver regeneration and the pro-proliferation effects of nuclear PKM2 may be through targeting its downstream transcription factor STAT3.


Assuntos
Núcleo Celular/metabolismo , Regeneração Hepática , Piruvato Quinase/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Tetracloreto de Carbono , Proliferação de Células , Citoplasma/metabolismo , Hepatócitos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/metabolismo , Hepatopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo
10.
Am J Physiol Gastrointest Liver Physiol ; 318(4): G772-G780, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32003603

RESUMO

Liver resection induces robust liver regrowth or regeneration to compensate for the lost tissue mass. In a clinical setting, pregnant women may need liver resection without terminating pregnancy in some cases. However, how pregnancy affects maternal liver regeneration remains elusive. We performed 70% partial hepatectomy (PH) in nonpregnant mice and gestation day 14 mice, and histologically and molecularly compared their liver regrowth during the next 4 days. We found that compared with the nonpregnant state, pregnancy altered the molecular programs driving hepatocyte replication, indicated by enhanced activities of epidermal growth factor receptor and STAT5A, reduced activities of cMet and p70S6K, decreased production of IL-6, TNFα, and hepatocyte growth factor, suppressed cyclin D1 expression, increased cyclin A1 expression, and early activated cyclin A2 expression. As a result, pregnancy allowed the remnant hepatocytes to enter the cell cycle at least 12 h earlier, increased hepatic fat accumulation, and enhanced hepatocyte mitosis. Consequently, pregnancy ameliorated maternal liver regeneration following PH. In addition, a report showed that maternal liver regrowth after PH is driven mainly by hepatocyte hypertrophy rather than hyperplasia during the second half of gestation in young adult mice. In contrast, we demonstrate that maternal liver relies mainly on hepatocyte hyperplasia instead of hypertrophy to restore the lost mass after PH. Overall, we demonstrate that pregnancy facilitates maternal liver regeneration likely via triggering an early onset of hepatocyte replication, accumulating excessive liver fat, and promoting hepatocyte mitosis. The results from our current studies enable us to gain more insights into how maternal liver regeneration progresses during gestation.NEW & NOTEWORTHY We demonstrate that pregnancy may generate positive effects on maternal liver regeneration following partial hepatectomy, which are manifested by early entry of the cell cycle of remnant hepatocytes, increased hepatic fat accumulation, enhanced hepatocyte mitosis, and overall accelerated liver regrowth.


Assuntos
Hepatectomia , Regeneração Hepática/fisiologia , Animais , Peso Corporal , Feminino , Fígado/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Mitose , Tamanho do Órgão , Gravidez
11.
Cell Mol Life Sci ; 77(15): 2887-2898, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32060582

RESUMO

Liver regeneration (LR) capacity in vertebrates developed through natural selection over a hundred million years of evolution. To maintain homeostasis or recover from various injuries, liver cells must regenerate; this process includes the renewal of parenchymal and nonparenchymal cells as well as the formation of liver structures. The cellular origin of newly grown tissue is one of the critical questions in this area and has been a subject of prolonged debate. The regenerative tissue may derive from either hepatocyte self-duplication or liver stem/progenitor cells (LSPCs). Recently, hepatocyte subpopulations and cholangiocytes were also described as important founder cells. The niche that triggers the proliferation of hepatocytes and the differentiation of LSPCs has been extensively studied. Meanwhile, in vitro culture systems for liver founder cells and organoids have been developed rapidly for mechanistic studies and potential therapeutic purposes. This review summarizes the cellular sources and niches that give rise to renewed hepatocytes during LR, and it also describes in vitro culture studies of those founder cells for future applications, as well as current reports for stem cell-based therapies for liver diseases.


Assuntos
Hepatócitos/citologia , Regeneração Hepática/fisiologia , Animais , Diferenciação Celular , Terapia Baseada em Transplante de Células e Tecidos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/terapia , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/transplante , Hepatócitos/metabolismo , Hepatócitos/transplante , Humanos , Células-Tronco/citologia , Células-Tronco/metabolismo
12.
Surgery ; 167(6): 917-923, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32014304

RESUMO

BACKGROUND: To assess the safety and efficacy of liver venous deprivation (simultaneous hepatic vein embolization with portal vein embolization) compared with portal vein embolization alone before major hepatectomy in patients with small future liver remnant. METHODS: We assessed all consecutive patients who underwent ipsilateral liver venous deprivation before major hepatectomy (>4 Couinaud's segments) at the University Hospital Lausanne from 2016 to 2018. Postembolization, volumetric analysis after liver venous deprivation and postoperative outcomes were compared with patients who underwent portal vein embolization alone (portal vein embolization group) from 2010 to 2016. RESULTS: During the study period, 21 patients underwent liver venous deprivation and 39 portal vein embolization alone. In the liver venous deprivation versus portal vein embolization groups, dropout rate owing to disease progression was 1 of 21 vs 9 of 39 (P = .053). There were no per procedural complications after liver venous deprivation and no difference in the postoperative outcomes. Future liver remnant hypertrophy was greater in the liver venous deprivation group (median 135%, interquartile range: 123%-154%) than in the portal vein embolization group (median 124%, interquartile range: 107%-140%) at a median time of 22 days after liver venous deprivation vs 26 days after portal vein embolization (P = .034). The median kinetic growth rate was also greater (2.9%/week, interquartile range: 1.9-4.3% vs 1.4%/week, interquartile range: 0.7-2.1%; P < .001). CONCLUSION: Ipsilateral liver venous deprivation before major hepatectomy is safe and seems to induce a greater and faster future liver remnant hypertrophy than after portal vein embolization alone. More data are needed to analyze the impact of liver venous deprivation on tumor growth.


Assuntos
Embolização Terapêutica , Hepatectomia , Veias Hepáticas , Hipertrofia , Fígado/patologia , Veia Porta , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Fígado/diagnóstico por imagem , Testes de Função Hepática , Neoplasias Hepáticas/cirurgia , Regeneração Hepática , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Tomografia Computadorizada por Raios X
13.
BMC Surg ; 20(1): 31, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32050952

RESUMO

BACKGROUND: Post-hepatectomy liver failure contributes significantly to postoperative mortality after liver resection. The prediction of the individual risk for liver failure is challenging. This review aimed to provide an overview of cytokine and growth factor triggered signaling pathways involved in liver regeneration after resection. METHODS: MEDLINE and Cochrane databases were searched without language restrictions for articles from the time of inception of the databases till March 2019. All studies with comparative data on the effect of cytokines and growth factors on liver regeneration in animals and humans were included. RESULTS: Overall 3.353 articles comprising 40 studies involving 1.498 patients and 101 animal studies were identified and met the inclusion criteria. All included trials on humans were retrospective cohort/observational studies. There was substantial heterogeneity across all included studies with respect to the analyzed cytokines and growth factors and the described endpoints. CONCLUSION: High-level evidence on serial measurements of growth factors and cytokines in blood samples used to predict liver regeneration after resection is still lacking. To address the heterogeneity of patients and potential markers, high throughput serial analyses may offer a method to predict an individual's regenerative potential in the future.


Assuntos
Citocinas/metabolismo , Regeneração Hepática/fisiologia , Fígado/cirurgia , Animais , Biomarcadores/metabolismo , Hepatectomia/métodos , Humanos , Período Pós-Operatório
14.
Am J Pathol ; 190(4): 817-829, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32035060

RESUMO

Liver regeneration is a fundamental biological process required for sustaining body homeostasis and restoring liver function after injury. Emerging evidence demonstrates that cytokines, growth factors, and multiple signaling pathways contribute to liver regeneration. Mammalian target of rapamycin complex 2 (mTORC2) regulates cell metabolism, proliferation and survival. The major substrates for mTORC2 are the AGC family members of kinases, including AKT, SGK, and PKC-α. We investigated the functional roles of mTORC2 during liver regeneration. Partial hepatectomy (PHx) was performed in liver-specific Rictor (the pivotal unit of mTORC2 complex) knockout (RictorLKO) and wild-type (Rictorfl/fl) mice. Rictor-deficient mice were found to be more intolerant to PHx and displayed higher mortality after PHx. Mechanistically, loss of Rictor resulted in decreased Akt phosphorylation, leading to a delay in hepatocyte proliferation and lipid droplets formation along liver regeneration. Overall, these results indicate an essential role of the mTORC2 signaling pathway during liver regeneration.


Assuntos
Proliferação de Células , Hepatectomia , Regeneração Hepática , Fígado/citologia , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Proteína Companheira de mTOR Insensível à Rapamicina/fisiologia , Animais , Pontos de Checagem do Ciclo Celular , Feminino , Lipídeos/análise , Fígado/metabolismo , Fígado/cirurgia , Masculino , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Transdução de Sinais
15.
Cell Stem Cell ; 26(1): 2-3, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31951586

RESUMO

Despite minimal turnover, liver cells possess immense regenerative capacity. Some studies suggest existence of a hepatocyte subset with such unique capabilities. However, in the current issue of Cell Stem Cell, three independent studies (Chen et al., 2020; Matsumoto et al., 2020, and Sun et al., 2020) demonstrate an equitable homeostatic and reparative potential of all hepatocytes, irrespective of their lobular location or ploidy status.


Assuntos
Hepatócitos , Regeneração Hepática , Proliferação de Células , Homeostase , Humanos , Fígado , Poliploidia
16.
Dev Cell ; 52(3): 335-349.e7, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-31983631

RESUMO

E2F transcription factors control the cytokinesis machinery and thereby ploidy in hepatocytes. If or how these proteins limit proliferation of polyploid cells with extra centrosomes remains unknown. Here, we show that the PIDDosome, a signaling platform essential for caspase-2-activation, limits hepatocyte ploidy and is instructed by the E2F network to control p53 in the developing as well as regenerating liver. Casp2 and Pidd1 act as direct transcriptional targets of E2F1 and its antagonists, E2F7 and E2F8, that together co-regulate PIDDosome expression during juvenile liver growth and regeneration. Of note, whereas hepatocyte aneuploidy correlates with the basal ploidy state, the degree of aneuploidy itself is not limited by PIDDosome-dependent p53 activation. Finally, we provide evidence that the same signaling network is engaged to control ploidy in the human liver after resection. Our study defines the PIDDosome as a primary target to manipulate hepatocyte ploidy and proliferation rates in the regenerating liver.


Assuntos
Caspase 2/fisiologia , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/fisiologia , Fatores de Transcrição E2F/fisiologia , Hepatócitos/citologia , Regeneração Hepática , Poliploidia , Proteína Supressora de Tumor p53/fisiologia , Aneuploidia , Animais , Proteína Adaptadora de Sinalização CRADD/fisiologia , Centrossomo , Inibidor de Quinase Dependente de Ciclina p21/fisiologia , Citocinese , Feminino , Hepatócitos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout
17.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G390-G400, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961717

RESUMO

Hepatic ischemia-reperfusion (I/R) is a major complication of liver resection, trauma, and liver transplantation; however, liver repair after I/R in diseased liver has not been studied. The present study sought to determine the manner in which the fibrotic liver repairs itself after I/R. Liver fibrosis was established in mice by CCl4 administration for 6 wk, and then liver I/R was performed to investigate liver injury and subsequent liver repair in fibrotic and control livers. After I/R, fibrotic liver had more injury compared with nonfibrotic, control liver; however, fibrotic liver showed rapid resolution of liver necrosis and reconstruction of liver parenchyma. Marked accumulation of hepatic stellate cells and macrophages were observed specifically in the fibrotic septa in early reparative phase. Fibrotic liver had higher numbers of hepatic stellate cells, macrophages, and hepatic progenitor cells during liver recovery after I/R than did control liver, but hepatocyte proliferation was unchanged. Fibrotic liver also had significantly greater number of phagocytic macrophages than control liver. Clodronate liposome injection into fibrotic mice after I/R caused decreased macrophage accumulation and delay of liver recovery. Conversely, CSF1-Fc injection into normal mice after I/R resulted in increased macrophage accumulation and concomitant decrease in necrotic tissue during liver recovery. In conclusion, fibrotic liver clears necrotic areas and restores normal parenchyma faster than normal liver after I/R. This beneficial response appears to be directly related to the increased numbers of nonparenchymal cells, particularly phagocytic macrophages, in the fibrotic liver.NEW & NOTEWORTHY This study is the first to reveal how diseased liver recovers after ischemia-reperfusion (I/R) injury. Although it was not completely unexpected that fibrotic liver had increased hepatic injury after I/R, a novel finding was that fibrotic liver had accelerated recovery and repair compared with normal liver. Enhanced repair after I/R in fibrotic liver was associated with increased expansion of phagocytic macrophages, hepatic stellate cells, and progenitor cells.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Cirrose Hepática Experimental/fisiopatologia , Regeneração Hepática , Fígado/fisiopatologia , Traumatismo por Reperfusão/fisiopatologia , Animais , Proliferação de Células , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Necrose , Fagocitose , Recuperação de Função Fisiológica , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Células-Tronco/metabolismo , Células-Tronco/patologia , Fatores de Tempo
18.
Acta Cir Bras ; 34(11): e201901103, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31939502

RESUMO

PURPOSE: To evaluate liver regeneration after selective ligation of portal vein and hepatic artery by 3D Computed Tomography in an experimental model. METHODS: Sixteen Wistar rats were randomized into four equal groups: Group I- control (sham), Group II- isolated selective ligation of the hepatic artery, Group III- isolated selective ligation of the portal vein and Group IV- combined ligation of portal vein and hepatic artery. Before procedure and five days after a 3D CT Scan was performed to analyze the hypertrophy, weight and function of the remnant liver. RESULTS: The largest regeneration rate and increase of weight in the hypertrophied lobe was detected in group IV, the first with an average of 3.99 (p=0.006) and the last varying from 6.10g to 9.64g (p=0.01). However, total liver weight and the R1 ratio (Hypertrophied Lobe Weight/Total Liver Weight) was higher in group III (P<0.001) when compared with groups I, II and IV and showed no difference between them. The immunohistochemical examination with PCNA also found higher percentages with statistical significance differences in rats of groups III and IV. It was possible to confirm a strong correlation between hypertrophied lobe weight and its imaging volumetric study. Liver function tests only showed a significant difference in serum gamma-glutamyltransferase and phosphorous. CONCLUSION: There is a largest liver regeneration after combined ligation of portal vein and hepatic artery and this evidence may improve the knowledge of surgical treatment of liver injuries, with a translational impact in anima nobile.


Assuntos
Artéria Hepática/cirurgia , Regeneração Hepática/fisiologia , Fígado/diagnóstico por imagem , Veia Porta/cirurgia , Animais , Hepatomegalia/diagnóstico por imagem , Hepatomegalia/fisiopatologia , Imageamento Tridimensional/métodos , Imuno-Histoquímica , Ligadura , Fígado/irrigação sanguínea , Fígado/patologia , Masculino , Tamanho do Órgão/fisiologia , Distribuição Aleatória , Ratos Wistar , Reprodutibilidade dos Testes , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
19.
Expert Opin Investig Drugs ; 29(2): 179-190, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31948298

RESUMO

Introduction: Globally, deaths from liver disease are increasing and for most patients there are few curative options. Fibrosis or scarring is often associated with the formation and progression of liver disease; however, clinical anti-fibrotic therapies are lacking. Recent work has shown that Wnt signaling, a signaling pathway that is necessary for embryonic development and cancer, can also regulate scar formation in the liver.Areas covered: This article seeks to shed light on the dualistic role of Wnt signaling in liver regeneration following injury and how Wnt signaling can regulate scar formation. It also discusses how Wnt signaling cooperates with other classical fibrogenic signaling cascades, such as TGFß signaling. Finally, the article examines recent advances in the development of Wnt signaling pathway inhibitors and asks whether repurposing these agents as anti-fibrotic therapies is a realistic option.Expert opinion: The understanding of Wnt signaling in liver regeneration and fibrosis is in its infancy and whilst new generations of Wnt pathway inhibitors have shown anti-fibrotic effects, further research is necessary to enhance our understanding of the Wnt-landscape in different patterns of liver disease. This will accelerate the development of more specific Wnt inhibitor-based anti-fibrotics.


Assuntos
Cirrose Hepática/tratamento farmacológico , Hepatopatias/tratamento farmacológico , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Cicatriz/prevenção & controle , Progressão da Doença , Desenvolvimento de Medicamentos , Humanos , Cirrose Hepática/fisiopatologia , Hepatopatias/fisiopatologia , Regeneração Hepática/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA