Cirrhotic Liver Sustains In Situ Regeneration of Acellular Liver Scaffolds after Transplantation into G-CSF-Treated Animals.

Acellular liver scaffolds (ALS) produced by decellularization have been successfully explored for distinct regenerative purposes. To date, it is unknown whether transplanted ALSs are affected by cirrhotic livers, either becoming cirrhotic themselves or instead remaining as a robust template for healthy cell growth after transplantation into cirrhotic rats. Moreover, little is known about the clinical course of recipient cirrhotic livers after ALS transplantation. To address these questions, we transplanted ALSs into cirrhotic rats previously treated with the granulocyte colony-stimulating factor. Here, we report successful cellular engraftment within the transplanted ALSs at 7, 15, and 30 days after transplantation. Recellularization was orchestrated by liver tissue cell activation, resident hepatocytes and bile duct proliferation, and an immune response mediated by the granulocyte components. Furthermore, we showed that transplanted ALSs ensured a pro-regenerative and anti-inflammatory microenvironment, attracted vessels from the host cirrhotic tissue, and promoted progenitor cell recruitment. ALS transplantation induced cirrhotic liver regeneration and extracellular matrix remodeling. Moreover, the transplanted ALS sustained blood circulation and attenuated alterations in the ultrasonographic and biochemical parameters in cirrhotic rats. Taken together, our results confirm that transplanted ALSs are not affected by cirrhotic livers and remain a robust template for healthy cell growth and stimulated cirrhotic liver regeneration.

Human amniotic epithelial stem cells: Hepatic differentiation and regenerative properties in liver disease treatment.

The placenta and the extraembryonic tissues represent a valuable source of cells for regenerative medicine. In particular, the amniotic membrane possesses cells with stem cells characteristics that have attracted research attention. Human amniotic epithelial cells (hAECs) have unique and desirable features that position them over other stem cells, not only because of the unlimited potential supplied of, the easy access to placental tissues, and the minimal ethical and legal barriers associated, but also due to the embryonic stem cells markers expression and their ability to differentiate into the three germ layers. In addition, they are non-tumorigenic and have immunomodulatory and anti-inflammatory properties. Hepatic failure is one of the major causes of morbidity and mortality worldwide. Organ transplantation is the best way to treat acute and chronic liver failure, but there are several associated obstacles. Stem cells have been highlighted as alternative hepatocytes source because of their potential for hepatogenic differentiation. HAECs, in particular, have some properties that make them suitable for hepatocyte differentiation. In this work, we review the general characteristics of the epithelial stem cells isolated from human amniotic membrane as well as their ability to differentiate to hepatic cells. We also revise their regenerative properties, with the focus on their potential application in the liver disease treatment.

The Influence of Interdisciplinary Work towards Advancing Knowledge on Human Liver Physiology.

The knowledge accumulated throughout the years about liver regeneration has allowed a better understanding of normal liver physiology, by reconstructing the sequence of steps that this organ follows when it must rebuild itself after being injured. The scientific community has used several interdisciplinary approaches searching to improve liver regeneration and, therefore, human health. Here, we provide a brief history of the milestones that have advanced liver surgery, and review some of the new insights offered by the interdisciplinary work using animals, in vitro models, tissue engineering, or mathematical models to help advance the knowledge on liver regeneration. We also present several of the main approaches currently available aiming at providing liver support and overcoming organ shortage and we conclude with some of the challenges found in clinical practice and the ethical issues that have concomitantly emerged with the use of those approaches.

Mechanisms of regenerative preconditioning in pigs with subtotal hepatectomies.

BACKGROUND: Portal vein occlusion shortly before extended hepatic resections has hepatoprotective properties, but its molecular effects have not been elucidated. We characterized the impact of regenerative preconditioning by portal vein embolization (PVE) on hepatic energy metabolism and cytokine expression. MATERIALS AND METHODS: About 90% hepatectomies were performed in normal pigs (Control) and in pigs that underwent a PVE 24 h before the surgery (n = 10/group). Blood biochemistry and coagulation, liver damage, liver function (ICG), hepatic content of adenine nucleotides, and hepatic expression of inflammatory mediators (RT-PCR and WB) were determined before the hepatectomy, 15 min, and 24 h later. RESULTS: All PVE and hepatectomies were successfully accomplished. The 90% hepatectomy resulted in: Immediate reduction of ATP, leading to persistent decreases of energy load and ATP/ADP ratio up to the 24-h time-point; and pro-inflammatory expression profile of cytokines in the remnant liver. Prior performance of PVE attenuated the bioenergetic alterations and prevented many of the changes in hepatic cytokine expression. CONCLUSIONS: Regenerative preconditioning by PVE improved hepatic energy metabolism and modulated inflammatory mediators in the remnant liver in pigs undergoing major hepatectomies, potentially contributing to its hepatoprotective effects.

INTRODUCCIÓN: la oclusión de la vena porta precoz antes de hepatectomías extendidas tiene propiedades hepatoprotectoras, pero sus efectos moleculares no se han aclarado. Caracterizamos el impacto del preacondicionamiento regenerativo por embolización de la vena porta (PVE) sobre el metabolismo energético hepático y la expresión de citocinas. MATERIALES Y MÉTODOS: Realizamos hepatectomías del 90% en cerdos (Control) y en cerdos sometidos a PVE 24 horas antes de la cirugía (n = 10/grupo). La bioquímica y la coagulación, el daño hepático, la función hepática (ICG), los nucleótidos de adenina y la expresión de mediadores inflamatorios (RT-PCR y WB) fueron determinado antes de la hepatectomía, quince minutos y 24 horas después. RESULTADOS: Las PVE y las hepatectomías se realizaron con éxito. La hepatectomía del 90% resultó en: una reducción del ATP, lo que disminuye la carga energética y la relación ATP/ADP a las 24 horas; y en la expresión de citocinas proinflamatorias. La realización previa de PVE atenuó las alteraciones bioenergéticas y evitó muchos de los cambios en la expresión de citocinas. CONCLUSIONES: El preacondicionamiento regenerativo con PVE mejoró el metabolismo energético y moduló los mediadores inflamatorios en el hígado remanente en cerdos sometidos a hepatectomías subtotales, contribuyendo potencialmente a sus efectos hepatoprotectores.

Hepatic Epigenetic Reprogramming After Liver Resection in Offspring Alleviates the Effects of Maternal Obesity.

Obesity has become a public health problem in recent decades, and during pregnancy, it can lead to an increased risk of gestational complications and permanent changes in the offspring resulting from a process known as metabolic programming. The offspring of obese dams are at increased risk of developing non-alcoholic fatty liver disease (NAFLD), even in the absence of high-fat diet consumption. NAFLD is a chronic fatty liver disease that can progress to extremely severe conditions that require surgical intervention with the removal of the injured tissue. Liver regeneration is necessary to preserve organ function. A range of pathways is activated in the liver regeneration process, including the Hippo, TGFß, and AMPK signaling pathways that are under epigenetic control. We investigated whether microRNA modulation in the liver of the offspring of obese dams would impact gene expression of Hippo, TGFß, and AMPK pathways and tissue regeneration after partial hepatectomy (PHx). Female Swiss mice fed a standard chow or a high-fat diet (HFD) before and during pregnancy and lactation were mated with male control mice. The offspring from control (CT-O) and obese (HF-O) dams weaned to standard chow diet until day 56 were submitted to PHx surgery. Prior to the surgery, HF-O presented alterations in miR-122, miR-370, and Let-7a expression in the liver compared to CT-O, as previously shown, as well as in its target genes involved in liver regeneration. However, after the PHx (4 h or 48 h post-surgery), differences in gene expression between CT-O and HF-O were suppressed, as well as in microRNA expression in the liver. Furthermore, both CT-O and HF-O presented a similar regenerative capacity of the liver within 48 h after PHx. Our results suggest that survival and regenerative mechanisms induced by the partial hepatectomy may overcome the epigenetic changes in the liver of offspring programmed by maternal obesity.

Liver regeneration after extensive hepatectomy in rats: effect of preoperative chemotherapy with intravenous 5-fluorouracil

Purpose: To evaluate the effect of preoperative intravenous chemotherapy with 5-fluorouracil on liver regeneration in an experimental model of major hepatectomy in rats. Methods: Wistar rats were divided into two groups of 20 animals each and submitted to 70% hepatectomy 24 h after intravenous injection of 5-fluorouracil 20 mg/kg (fluorouracil group, FG) or 0.9% saline (control group, CG). After hepatectomy, each group was subdivided into two subgroups of 10 animals each according to the day of sacrifice (24 h or 7 days). Liver weight during regeneration, liver regeneration rate using Kwon formula, and the immunohistochemical markers proliferating cell nuclear antigen (PCNA) and Ki-67 were used to assess liver regeneration. Results: At early phase (24 h after hepatectomy) it was demonstrated the negative effect of 5-fluorouracil on liver regeneration when assessed by Kwon formula (p < 0.0001), PCNA analysis (p = 0.02). With regeneration process complete (7 days), it was possible to demonstrate the sustained impairment of chemotherapy with 5-fluorouracil on hepatocytes regeneration phenomenon when measured by Kwon formula (p = 0.009), PCNA analysis (p = 0.0001) and Ki-67 analysis (0.001). Conclusions: Preoperative chemotherapy with intravenous 5-fluorouracil negatively affected the mechanisms of liver regeneration after major hepatectomy in rats.

Effects of low-level laser therapy on liver regeneration and laser parameters employed / Efeitos da laserterapia de baixa potência na regeneração hepática e parâmetros empregados de laser

Low-level laser therapy has several biological effects; one of them is tissue regeneration. Recent studies have been held on the application of laser therapy on the liver of rats after partial hepatectomy to promote liver regeneration. The aim of this article was to review the recent studies on the effects of low-level laser therapy on rat liver regeneration after partial hepatectomy and the laser parameters used in those studies. A review of recent relevant literature was performed in Pubmed, Scielo, Medline, and Bireme databases. Articles related to the application of low-level laser therapy on hepatic regeneration were included. Articles with hepatic regeneration in the presence of pathologies were not included. Nine studies were found matching the study criteria. In most studies, low-level laser therapy promoted liver regeneration after partial hepatectomy, without further damage to the remaining liver. Not all laser parameters required for the reproducibility of the study were described by all authors. The therapeutic use of low-level laser therapy in liver regeneration can be promising; however, since the liver is a vital organ, and the laser application is intraoperative, future studies are necessary. The parameters used must be properly described and standardized to allow the reproducibility of the study, in order to define a therapeutic window and thus, consider its clinical use. It is also essential to clarify the mechanisms by which laser promotes liver regeneration to guarantee its safety and therapeutic efficacy.

Laserterapia de baixa potência tem vários efeitos biológicos, sendo um deles a regeneração de tecido. Sua aplicação no fígado de ratos após hepatectomia parcial para promoção de regeneração hepática tem sido estudada recentemente. O objetivo deste artigo foi revisar os estudos recentes dos efeitos da laserterapia de baixa potência na regeneração de fígado de ratos após hepatectomia parcial de fígado e os parâmetros de laser empregados. Uma revisão da literatura relevante recente foi realizada nas bases de dados Pubmed, Scielo, Medline e Bireme. Artigos sobre a aplicação da laserterapia de baixa potência na regeneração de fígado foram incluídos. Artigos sobre regeneração hepática na presença de patologias foram excluídos. Nove estudos foram encontrados correspondendo aos critérios do estudo. Na maioria dos estudos, a laserterapia de baixa potência promoveu regeneração hepática após hepatectomia parcial, sem causar danos adicionais ao fígado remanescente. Não foram descritos todos os parâmetros necessários para reprodutibilidade dos estudos por todos os autores. O uso terapêutico da laserterapia de baixa potência na regeneração de fígado pode ser promissor, entretanto, como o fígado é um órgão vital e a aplicação do laser é intraoperativa, estudos futuros são necessários, assim como os parâmetros da aplicação de laser precisam ser descritos apropriadamente e padronizados, para permitir a reprodutibilidade do estudo, para que uma janela terapêutica possa ser definida e seu uso clínico possa ser considerado. Também é essencial esclarecer através de quais mecanismos o laser promove regeneração de fígado para garantir sua segurança e eficácia terapêutica.

Liver regeneration observed across the different classes of vertebrates from an evolutionary perspective.

The liver is a key organ that performs diverse functions such as metabolic processing of nutrients or disposal of dangerous substances (xenobiotics). Accordingly, it seems to be protected by several mechanisms throughout the life of organisms, one of which is compensatory hyperplasia, also known as liver regeneration. This review is a recapitulation of the scientific reports describing the different ways in which the various classes of vertebrates deal with liver injuries, where since mammals have an improved molecular toolkit, exhibit optimized regeneration of the liver compared to lower vertebrates. The main molecules involved in the compensatory process, such as proinflammatory and inhibitory cytokines, are analyzed across vertebrates with an evolutionary perspective. In addition, the possible significance of this mechanism is discussed in the context of the long life span of vertebrates, especially in the case of mammals.

Acetylsalicylic acid (Aspirin®) and liver regeneration: experimental study in rats / Ácido acetilsalicílico (Aspirina®) e regeneração hepática: estudo experimental em ratos

ABSTRACT Objective: to evaluate the influence of acetylsalicylic acid (ASA) on cell proliferation after partial hepatectomy in rats. Methods: 40 male Wistar rats were separated into four groups of ten rats each. Groups 1 and 2 (controls): undergoing 30% partial hepatectomy and, after one day (group 1) and seven days (group 2), to euthanasia; daily administration of 0.9% saline solution (1mL per 200g of body weight). Groups 3 and 4 (experimental): undergoing 30% partial hepatectomy and, after one day (group 3) and seven days (group 4), to euthanasia; daily administration of ASA (40mg/mL, 1mL per 200g of body weight). The absolute number of cells stained with PCNA was counted in photomicrographs, in five fields, and it was calculated the mean of positive cells per animal and per group. Results: the final mean of PCNA+ cells per group was: in group 1, 17.57 ± 6.77; in group 2, 19.31 ± 5.30; in group 3, 27.46 ± 11.55; and, in group 4, 12.40 ± 5.23. There was no significant difference at the two evaluation times in the control group (p=0.491), but there was in the experimental group (p=0.020), with a lower number of PCNA+ cells on the seventh day. The comparison between the two groups, on the first day, showed more PCNA+ cells in the livers of the animals that received ASA (p=0.047), and on the seventh day the number was lower in the experimental group (p=0.007). Conclusion: ASA induced greater hepatocyte proliferation.

RESUMO Objetivo: avaliar a influência do ácido acetilsalicílico (AAS) na proliferação celular após hepatectomia parcial em ratos. Métodos: 40 ratos Wistar machos foram separados em quatro grupos com dez ratos cada. Grupos 1 e 2 (controles): submetidos à hepatectomia parcial de 30% e, após um (grupo 1) e sete dias (grupo 2), à eutanásia; administração diária de solução fisiológica 0,9% (1mL por 200g de peso). Grupos 3 e 4 (experimentos): submetidos à hepatectomia parcial de 30% e, após um (grupo 3) e sete dias (grupo 4), à eutanásia; administração diária de AAS (40mg/mL, 1mL por 200g de peso). Realizou-se a contagem do número absoluto de células coradas com PCNA em fotomicrografias, em cinco campos e cálculo da média de células positivas por animal e por grupo. Resultados: A média final de células PCNA+ por grupo foi: no grupo 1, de 17,57 ± 6,77; no grupo 2 de 19,31 ± 5,30; no grupo 3, de 27,46 ± 11,55; e, no grupo 4, de 12,40 ± 5,23. Não houve diferença significante nos dois tempos de avaliação no grupo controle (p=0,491), mas houve no grupo experimento (p=0,020), observando-se menor número de células PCNA+ no sétimo dia. A comparação entre os dois grupos, no primeiro dia, mostrou mais células PCNA+ nos fígados dos animais que receberam AAS (p=0,047), e no sétimo dia o número foi menor no grupo experimento (p=0,007). Conclusão: O AAS induziu maior proliferação hepatocitária.

The role of associating liver partition and portal vein ligation for staged hepatectomy in the management of patients with colorectal liver metastasis.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) approach emerged as a promising surgical strategy for rapid and large hypertrophy of the future liver remnant (FLR) when a major liver resection is necessary. Colorectal liver metastasis (CRLM) is their main indication. However, the promising results published so far, are very difficult to interpret since they usually focus on the technique and not on the underlying disease. Moreover, they are usually made up of complex populations, which received different chemotherapy schemes, with the ALPPS technical variations implemented over time and without consistent long-term follow-up results as well. Whereby, its role in CRLM should be analyzed as carefully as possible to indicate and select the best candidates who will benefit the most from this approach. We conducted a computerized search using PubMed and Google Scholar for reports published so far, using mesh headings and keywords related to the ALPPS and CRLM.

Assessment of remnant liver function and volume after selective ligation of portal vein and hepatic artery in a rat model

Abstract 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.

Pine (Pinus densiflora) needle extract could promote the expression of PCNA and Ki-67 after partial hepatectomy in rat

Purpose: To investigate the effects of pine needle extract (PNE) on the expression of proliferating cell nuclear antigen (PCNA) and Ki-67 during liver regeneration induced by 70% partial hepatectomy (PH) in rat. Methods: Forty-eight male rats (SD, 7 weeks) had surgery (70% PH). They were randomly divided into two groups. PH + PNE group was only provided PNE diluted in water (10%) for drinking and PH group was provided water from 5 days before surgery to the time of sacrifice. PNE was made by pressing and filtering. Animals were sacrificed at 12h, 24h, 36h, 60h, 84h, 168h after PH, respectively. The expressions of PCNA and Ki-67 were determined as proliferation indices. Results: Immunohistochemistry turned out to increase the expression of PCNA and Ki-67. PCNA expression of PH+PNE group increased up to twice of that of PH group. Western blot also seemed to increase the PCNA expression. These results indicated the promotion of cell proliferation in liver tissue and hepatic regeneration. Conclusions: Pine needle extract stimulates the expression of some mitotic proteins during liver regeneration induced by 70% PH in rats. It suggests that administration of pine needle extract could accelerate the liver regeneration after partial hepatectomy.(AU)

The basis of liver regeneration: A systems biology approach.

INTRODUCTION: Liver regeneration is a normal response to liver injury. The aim of this study was to determine the molecular basis of liver regeneration, through an integrative analysis of high-throughput gene expression datasets. METHODS: We identified and curated datasets pertaining to liver regeneration from the Gene Expression Omnibus, where regenerating liver tissue was compared to healthy liver samples. The key dysregulated genes and pathways were identified using Ingenuity Pathway Analysis software. There were three eligible datasets in total. RESULTS: In the early phase after hepatectomy, inflammatory pathways such as Nrf2 oxidative stress-mediated response and cytokine signaling were significantly upregulated. At peak regeneration, we discovered that cell cycle genes were predominantly expressed to promote cell proliferation. Using the Betweenness centrality algorithm, we discovered that Jun is the key central gene in liver regeneration. Calcineurin inhibitors may inhibit liver regeneration, based on predictive modeling. CONCLUSION: There is a paucity of human literature in defining the molecular mechanisms of liver regeneration along a time continuum. Nonetheless, using an integrative computational analysis approach to the available high-throughput data, we determine that the oxidative stress response and cytokine signaling are key early after hepatectomy, whereas cell cycle control is important at peak regeneration. The transcription factor Jun is central to liver regeneration and a potential therapeutic target. Future studies of regeneration in humans along a time continuum are needed to better define the underlying mechanisms, and ultimately enhance care of patients with acute and chronic liver failure while awaiting transplant.

Assessment of remnant liver function and volume after selective ligation of portal vein and hepatic artery in a rat model

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.(AU)

Pine ( Pinus densiflora ) needle extract could promote the expression of PCNA and Ki-67 after partial hepatectomy in rat

Abstract Purpose To investigate the effects of pine needle extract (PNE) on the expression of proliferating cell nuclear antigen (PCNA) and Ki-67 during liver regeneration induced by 70% partial hepatectomy (PH) in rat. Methods Forty-eight male rats (SD, 7 weeks) had surgery (70% PH). They were randomly divided into two groups. PH + PNE group was only provided PNE diluted in water (10%) for drinking and PH group was provided water from 5 days before surgery to the time of sacrifice. PNE was made by pressing and filtering. Animals were sacrificed at 12h, 24h, 36h, 60h, 84h, 168h after PH, respectively. The expressions of PCNA and Ki-67 were determined as proliferation indices. Results Immunohistochemistry turned out to increase the expression of PCNA and Ki-67. PCNA expression of PH+PNE group increased up to twice of that of PH group. Western blot also seemed to increase the PCNA expression. These results indicated the promotion of cell proliferation in liver tissue and hepatic regeneration. Conclusions Pine needle extract stimulates the expression of some mitotic proteins during liver regeneration induced by 70% PH in rats. It suggests that administration of pine needle extract could accelerate the liver regeneration after partial hepatectomy.

Multiple factors affect the regeneration of liver

SUMMARY OBJECTIVE To study factors affecting the liver regeneration after hepatectomy METHODS With 3D reconstitution technology, liver regeneration ability of 117 patients was analysed, and relative factors were studied. RESULTS There was no statistically difference between the volume of simulated liver resection and the actual liver resection. All livers had different degrees of regeneration after surgery. Age, gender and blood indicators had no impact on liver regeneration, while surgery time, intraoperative blood loss, blood flow blocking time and different ways of liver resection had a significant impact on liver regeneration; In addition, the patients' own pathological status, including, hepatitis and liver fibrosis all had a significant impact on liver regeneration. CONCLUSION 3D reconstitution model is a good model to calculate liver volume. Age, gender, blood indicators and biochemistry indicators have no impact on liver regeneration, but surgery indicators and patients' own pathological status have influence on liver regeneration.

RESUMO OBJETIVO Estudar os fatores que afetam a regeneração hepática após hepatectomia. MÉTODOS A capacidade de regeneração hepática de 117 pacientes foi analisada com a tecnologia de reconstituição 3D e foram estudados os fatores relacionados. RESULTADOS Não houve diferença estatística significante entre o volume de ressecção hepática simulada e a ressecção atual. Todos os fígados apresentaram diferentes graus de regeneração após cirurgia. Idade, gênero e indicadores sanguíneos não tiveram impacto na regeneração hepática, enquanto que tempo de cirurgia, perda sanguínea intraoperatória, tempo de bloqueio do fluxo sanguíneo e diferentes formas de ressecção mostraram impacto significante na regeneração do órgão. Além disso, condições patológicas dos pacientes, incluindo hepatite e fibrose hepática, tiveram impacto significante na regeneração hepática. CONCLUSÃO O modelo de reconstituição 3D é um bom modelo para calcular o volume do fígado. Idade, gênero, indicadores sanguíneos e bioquímicos não tiveram impacto na regeneração hepática, mas indicadores operatórios e condição patológica dos pacientes mostraram influência na regeneração do órgão.

Cholesterol-enriched membrane microdomains are needed for insulin signaling and proliferation in hepatic cells.

Hepatocyte proliferation during liver regeneration is a well-coordinated process regulated by the activation of several growth factor receptors, including the insulin receptor (IR). The IR can be localized in part to cholesterol-enriched membrane microdomains, but the role of such domains in insulin-mediated events in hepatocytes is not known. We investigated whether partitioning of IRs into cholesterol-enriched membrane rafts is important for the mitogenic effects of insulin in the hepatic cells. IR and lipid rafts were labeled in HepG2 cells and primary rat hepatocytes. Membrane cholesterol was depleted in vitro with metyl-ß-cyclodextrin (MßCD) and in vivo with lovastatin. Insulin-induced calcium (Ca2+) signals studies were examined in HepG2 cells and in freshly isolated rat hepatocytes as well as in whole liver in vivo by intravital confocal imaging. Liver regeneration was studied by 70% partial hepatectomy (PH), and hepatocyte proliferation was assessed by PCNA staining. A subpopulation of IR was found in membrane microdomains enriched in cholesterol. Depletion of cholesterol from plasma membrane resulted in redistribution of the IR along the cells, which was associated with impaired insulin-induced nuclear Ca2+ signals, a signaling event that regulates hepatocyte proliferation. Cholesterol depletion also led to ERK1/2 hyper-phosphorylation. Lovastatin administration to rats decreased hepatic cholesterol content, disrupted lipid rafts and decreased insulin-induced Ca2+ signaling in hepatocytes, and delayed liver regeneration after PH. Therefore, membrane cholesterol content and lipid rafts integrity showed to be important for the proliferative effects of insulin in hepatic cells. NEW & NOTEWORTHY One of insulin's actions is to stimulate liver regeneration. Here we show that a subpopulation of insulin receptors is in a specialized cholesterol-enriched region of the cell membrane and this subfraction is important for insulin's proliferative effects.

Effects of thymoquinone and curcumin on the regeneration of rat livers subject to 70% hepatectomy

Purpose: To investigate thymoquinone, curcumin and a combination of these two drugs were effective or not at the growth of liver.Methods: Forty female Wistar-Albino rats distributed into five groups of eight rats each, control, thymoquinone, curcumin, and thymoquinone/curcumin groups. Pathological specimens were studied using the Ki-67 Proliferation Index(PI); and arginase(Arg), tissue plasminogen activator(tPA), ceruloplasmin(Cer) and nitric oxide(NO) were studied in biochemical analysis.Results: Our results showed that Ki-67 proliferation index was low in Groups 1. The proliferation coefficient was significantly higher in the Group 2 and Group 4 than in the Group 1 and Group 3.(P < 0.001 between Groups 1 and 2, 1 and 4, and 3 and 4). There was no difference between Groups 2 and 4 (P = 1). The results of the biochemical Arg, tPA and Cer test showed statistically between the Group 1 and Group 2. NO showed significant differences Group 1 and 3.Conclusions: Thymoquinone and curcumin both have known positive effects on the organism. Histological and biochemical tests showed that thymoquinone is more effective than curcumin.(AU)

Effects of thymoquinone and curcumin on the regeneration of rat livers subject to 70% hepatectomy

Abstract Purpose: To investigate thymoquinone, curcumin and a combination of these two drugs were effective or not at the growth of liver. Methods: Forty female Wistar-Albino rats distributed into five groups of eight rats each, control, thymoquinone, curcumin, and thymoquinone/curcumin groups. Pathological specimens were studied using the Ki-67 Proliferation Index(PI); and arginase(Arg), tissue plasminogen activator(tPA), ceruloplasmin(Cer) and nitric oxide(NO) were studied in biochemical analysis. Results: Our results showed that Ki-67 proliferation index was low in Groups 1. The proliferation coefficient was significantly higher in the Group 2 and Group 4 than in the Group 1 and Group 3.(P < 0.001 between Groups 1 and 2, 1 and 4, and 3 and 4). There was no difference between Groups 2 and 4 (P = 1). The results of the biochemical Arg, tPA and Cer test showed statistically between the Group 1 and Group 2. NO showed significant differences Group 1 and 3. Conclusions: Thymoquinone and curcumin both have known positive effects on the organism. Histological and biochemical tests showed that thymoquinone is more effective than curcumin.

Low-Power Laser Irradiation (LPLI): A Clinical Point of View on a Promising Strategy to Improve Liver Regeneration.

The capacity of the liver to regenerate is an important clinical issue after major hepatectomies and makes the difference between life and death in some cases of post-operative malfunction when the liver remnant is too small or has an impaired regenerative capacity. Several approaches have been tested to stimulate hepatic regeneration after post-operative hepatic failure syndrome; however, they have produced controversial results. A quick, simple, and harmless method that can be used intraoperatively and capable of promoting an increased regenerative capacity of the remaining liver would be very welcome. Thus, based on the data in the literature, we presented low-power laser irradiation (LPLI) as a quick, simple, and harmless method to improve liver regeneration after major hepatectomies. This article highlights the current evidence about the effects of LPLI on liver regeneration, and also suggests laser therapy as an important tool for regenerative stimulation in clinical practice.