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Sample records for cell-mediated liver regeneration

  1. Two sides of one coin: massive hepatic necrosis and progenitor cell-mediated regeneration in acute liver failure.

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    Weng, Hong-Lei; Cai, Xiaobo; Yuan, Xiaodong; Liebe, Roman; Dooley, Steven; Li, Hai; Wang, Tai-Ling

    2015-01-01

    Massive hepatic necrosis is a key event underlying acute liver failure, a serious clinical syndrome with high mortality. Massive hepatic necrosis in acute liver failure has unique pathophysiological characteristics including extremely rapid parenchymal cell death and removal. On the other hand, massive necrosis rapidly induces the activation of liver progenitor cells, the so-called "second pathway of liver regeneration." The final clinical outcome of acute liver failure depends on whether liver progenitor cell-mediated regeneration can efficiently restore parenchymal mass and function within a short time. This review summarizes the current knowledge regarding massive hepatic necrosis and liver progenitor cell-mediated regeneration in patients with acute liver failure, the two sides of one coin.

  2. Hepatic non-parenchymal cells and extracellular matrix participate in oval cell-mediated liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Wei Zhang; Xiao-Ping Chen; Wan-Guang Zhang; Feng Zhang; Shuai Xiang; Han-Hua Dong; Lei Zhang

    2009-01-01

    AIM: To elucidate the interaction between nonparenchymal cells, extracellular matrix and oval cells during the restituting process of liver injury induced by partial hepatectomy (PH). METHODS: We examined the localization of oval cells, non-parenchymal cells, and the extracellular matrix components using immunohistochemical and double immunofluorescent analysis during the proliferation and differentiation of oval cells in N-2-acetylaminofluorene (2-AAF)/PH rat model. RESULTS: By day 2 after PH, small oval cells began to proliferate around the portal area. Most of stellate cells and laminin were present along the hepatic sinusoids in the periportal area. Kupffer cells and fibronectin markedly increased in the whole hepatic lobule. From day 4 to 9, oval cells spread further into hepatic parenchyma, closely associated with stellate cells, fibronectin and laminin. Kupffer cells admixed with oval cells by day 6 and then decreased in the periportal zone. From day 12 to 15, most of hepatic stellate cells (HSCs), laminin and fibronectin located around the small hepatocyte nodus, and minority of them appeared in the nodus. Kupffer cells were mainly limited in the pericentral sinusoids. After day 18, the normal liver lobule structures began to recover.CONCLUSION: Local hepatic microenvironment may participate in the oval cell-mediated liver regeneration through the cell-cell and cell-matrix interactions.

  3. Remarkable heterogeneity displayed by oval cells in rat and mouse models of stem cell-mediated liver regeneration

    DEFF Research Database (Denmark)

    Jelnes, Peter; Santoni-Rugiu, Eric; Rasmussen, Morten

    2007-01-01

    The experimental protocols used in the investigation of stem cell-mediated liver regeneration in rodents are characterized by activation of the hepatic stem cell compartment in the canals of Hering followed by transit amplification of oval cells and their subsequent differentiation along hepatic...... lineages. Although the protocols are numerous and often used interchangeably across species, a thorough comparative phenotypic analysis of oval cells in rats and mice using well-established and generally acknowledged molecular markers has not been provided. In the present study, we evaluated and compared...... the molecular phenotypes of oval cells in several of the most commonly used protocols of stem cell-mediated liver regeneration-namely, treatment with 2-acetylaminofluorene and partial (70%) hepatectomy (AAF/PHx); a choline-deficient, ethionine-supplemented (CDE) diet; a 3,5-diethoxycarbonyl-1,4-dihydro...

  4. Liver regeneration.

    Science.gov (United States)

    Mao, Shennen A; Glorioso, Jaime M; Nyberg, Scott L

    2014-04-01

    The liver is unique in its ability to regenerate in response to injury. A number of evolutionary safeguards have allowed the liver to continue to perform its complex functions despite significant injury. Increased understanding of the regenerative process has significant benefit in the treatment of liver failure. Furthermore, understanding of liver regeneration may shed light on the development of cancer within the cirrhotic liver. This review provides an overview of the models of study currently used in liver regeneration, the molecular basis of liver regeneration, and the role of liver progenitor cells in regeneration of the liver. Specific focus is placed on clinical applications of current knowledge in liver regeneration, including small-for-size liver transplant. Furthermore, cutting-edge topics in liver regeneration, including in vivo animal models for xenogeneic human hepatocyte expansion and the use of decellularized liver matrices as a 3-dimensional scaffold for liver repopulation, are proposed. Unfortunately, despite 50 years of intense study, many gaps remain in the scientific understanding of liver regeneration.

  5. Activin A suppressed hepatic oval cell-mediated liver regeneration in vivo%Activin A抑制卵圆细胞介导肝再生的体内研究

    Institute of Scientific and Technical Information of China (English)

    陈琳; 周巧丹; 丁则阳; 张伟; 张必翔; 梁慧芳; 陈孝平

    2012-01-01

    Objective To study the inhibitory effect and mechanism of Activin A on hepatic oval cell-mediated liver regeneratioa Methods 2-acetylaminofluorene/partial hepatectomy (2-AAF/PH) o-val cell-mediated liver regeneration model was established. One μg Activin A (Activin A group) or normal saline (control S group) was infused into portal vein immediately after 70 % partial hepatectomy. Animals were sacrificed at 2nd, 4th, 6th, and 9th day after hepatectomy. Liver regeneration rate was measured. Changes in Pan-CK positive oval cell number and nuclear bromodeoxyuridine labeling were detected by using immunohistochemistry. The expression of phosphorylated smad2, p15, and p21 were detected by using Western blotting. Results As compared with control group, the Pan-CK positive number was significantly reduced in Activin A group at 6th and 9th day after hepatectomy,and Brdu labeling nuclear number was reduced in Activin A group at 4th,6th and 9th day after hepatectomy. The liver regeneration rate in Activin A group was lower than in control group. Higher levels of phosphorylated smad2,p15 and p21 were detected in Activin A group. Conclusion Activin A could suppress o-val cell-mediated liver regeneration through smad pathway-dependent up-regulation of p15 and p21.%目的 研究Activin A对卵圆细胞介导肝再生的抑制作用及其机制.方法 建立2-乙酰胺基芴/部分肝切除卵圆细胞介导肝再生模型,肝切除后立即经门静脉注射1 μg Activin A(Activin A组),或生理盐水(对照组).肝切除后不同时间点取肝脏标本检测卵圆细胞增殖及肝再生率和磷酸化smad2,p15和p21的表达.结果 Activin A组肝脏中卵圆细胞的增殖及肝再生率均明显低于对照组;Activin A组肝脏中smad2的磷酸化水平及p15,p21的表达水平均高于对照组.结论 Activin A可以通过smad信号通路抑制卵圆细胞介导的肝再生.

  6. Mesenchymal stem cell-mediated functional tooth regeneration in swine.

    Directory of Open Access Journals (Sweden)

    Wataru Sonoyama

    Full Text Available Mesenchymal stem cell-mediated tissue regeneration is a promising approach for regenerative medicine for a wide range of applications. Here we report a new population of stem cells isolated from the root apical papilla of human teeth (SCAP, stem cells from apical papilla. Using a minipig model, we transplanted both human SCAP and periodontal ligament stem cells (PDLSCs to generate a root/periodontal complex capable of supporting a porcelain crown, resulting in normal tooth function. This work integrates a stem cell-mediated tissue regeneration strategy, engineered materials for structure, and current dental crown technologies. This hybridized tissue engineering approach led to recovery of tooth strength and appearance.

  7. Mesenchymal stem cell-mediated functional tooth regeneration in swine.

    Science.gov (United States)

    Sonoyama, Wataru; Liu, Yi; Fang, Dianji; Yamaza, Takayoshi; Seo, Byoung-Moo; Zhang, Chunmei; Liu, He; Gronthos, Stan; Wang, Cun-Yu; Wang, Songlin; Shi, Songtao

    2006-12-20

    Mesenchymal stem cell-mediated tissue regeneration is a promising approach for regenerative medicine for a wide range of applications. Here we report a new population of stem cells isolated from the root apical papilla of human teeth (SCAP, stem cells from apical papilla). Using a minipig model, we transplanted both human SCAP and periodontal ligament stem cells (PDLSCs) to generate a root/periodontal complex capable of supporting a porcelain crown, resulting in normal tooth function. This work integrates a stem cell-mediated tissue regeneration strategy, engineered materials for structure, and current dental crown technologies. This hybridized tissue engineering approach led to recovery of tooth strength and appearance.

  8. Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches.

    Science.gov (United States)

    Akram, Khondoker M; Patel, Neil; Spiteri, Monica A; Forsyth, Nicholas R

    2016-01-19

    The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases.

  9. Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches

    Directory of Open Access Journals (Sweden)

    Khondoker M. Akram

    2016-01-01

    Full Text Available The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases.

  10. Microenvironment of liver regeneration in liver cancer.

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    Li, Han-Min; Ye, Zhi-Hua

    2017-07-01

    The occurrence and development of liver cancer are essentially the most serious outcomes of uncontrolled liver regeneration. The progression of liver cancer is inevitably related to the abnormal microenvironment of liver regeneration. The deterioration observed in the microenvironment of liver regeneration is a necessary condition for the occurrence, development and metastasis of cancer. Therefore, the use of a technique to prevent and treat liver cancer via changes in the microenvironment of liver regeneration is a novel strategy. This strategy would be an effective way to delay, prevent or even reverse cancer occurrence, development and metastasis through an improvement in the liver regeneration microenvironment along with the integrated regulation of multiple components, targets, levels, channels and time sequences. In addition, the treatment of "tonifying Shen (Kidney) to regulate liver regeneration and repair by affecting stem cells and their microenvironment" can regulate "the dynamic imbalance between the normal liver regeneration and the abnormal liver regeneration"; this would improve the microenvironment of liver regeneration, which is also a mechanism by which liver cancer may be prevented or treated.

  11. Enhancement of liver regeneration and liver surgery

    NARCIS (Netherlands)

    Olthof, P.B.

    2017-01-01

    Liver regeneration allows surgical resection of up to 75% of the liver and enables curative treatment potential for patients with primary or secondary hepatic malignancies. Liver surgery is associated with substantial risks, reflected by considerable morbidity and mortality rates. Optimization of

  12. Role of liver progenitors in liver regeneration.

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    Best, Jan; Manka, Paul; Syn, Wing-Kin; Dollé, Laurent; van Grunsven, Leo A; Canbay, Ali

    2015-02-01

    During massive liver injury and hepatocyte loss, the intrinsic regenerative capacity of the liver by replication of resident hepatocytes is overwhelmed. Treatment of this condition depends on the cause of liver injury, though in many cases liver transplantation (LT) remains the only curative option. LT for end stage chronic and acute liver diseases is hampered by shortage of donor organs and requires immunosuppression. Hepatocyte transplantation is limited by yet unresolved technical difficulties. Since currently no treatment is available to facilitate liver regeneration directly, therapies involving the use of resident liver stem or progenitor cells (LPCs) or non-liver stem cells are coming to fore. LPCs are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. Non-liver stem cells include embryonic stem cells (ES cells) and mesenchymal stem cells (MSCs). In the first section, we aim to provide an overview of the role of putative cytokines, growth factors, mitogens and hormones in regulating LPC response and briefly discuss the prognostic value of the LPC response in clinical practice. In the latter section, we will highlight the role of other (non-liver) stem cells in transplantation and discuss advantages and disadvantages of ES cells, induced pluripotent stem cells (iPS), as well as MSCs.

  13. Notch Signaling Coordinates Progenitor Cell-Mediated Biliary Regeneration Following Partial Hepatectomy

    Science.gov (United States)

    Lu, Jie; Zhou, Yingqun; Hu, Tianyuan; Zhang, Hui; Shen, Miao; Cheng, Ping; Dai, Weiqi; Wang, Fan; Chen, Kan; Zhang, Yan; Wang, Chengfeng; Li, Jingjing; Zheng, Yuanyuan; Yang, Jing; Zhu, Rong; Wang, Jianrong; Lu, Wenxia; Zhang, Huawei; Wang, Junshan; Xia, Yujing; De Assuncao, Thiago M.; Jalan-Sakrikar, Nidhi; Huebert, Robert C.; Bin Zhou; Guo, Chuanyong

    2016-01-01

    Aberrant transcriptional regulation contributes to the pathogenesis of both congenital and adult forms of liver disease. Although the transcription factor RBPJ is essential for liver morphogenesis and biliary development, its specific function in the differentiation of hepatic progenitor cells (HPC) has not been investigated, and little is known about its role in adult liver regeneration. HPCs are bipotent liver stem cells that can self-replicate and differentiate into hepatocytes or cholangiocytes in vitro. HPCs are thought to play an important role in liver regeneration and repair responses. While the coordinated repopulation of both hepatocyte and cholangiocyte compartment is pivotal to the structure and function of the liver after regeneration, the mechanisms coordinating biliary regeneration remain vastly understudied. Here, we utilized complex genetic manipulations to drive liver-specific deletion of the Rbpj gene in conjunction with lineage tracing techniques to delineate the precise functions of RBPJ during biliary development and HPC-associated biliary regeneration after hepatectomy. Furthermore, we demonstrate that RBPJ promotes HPC differentiation toward cholangiocytes in vitro and blocks hepatocyte differentiation through mechanisms involving Hippo-Notch crosstalk. Overall, this study demonstrates that the Notch-RBPJ signaling axis critically regulates biliary regeneration by coordinating the fate decision of HPC and clarifies the molecular mechanisms involved. PMID:26951801

  14. Liver Development, Regeneration, and Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Janet W. C. Kung

    2010-01-01

    Full Text Available The identification of putative liver stem cells has brought closer the previously separate fields of liver development, regeneration, and carcinogenesis. Significant overlaps in the regulation of these processes are now being described. For example, studies in embryonic liver development have already provided the basis for directed differentiation of human embryonic stem cells and induced pluripotent stem cells into hepatocyte-like cells. As a result, the understanding of the cell biology of proliferation and differentiation in the liver has been improved. This knowledge can be used to improve the function of hepatocyte-like cells for drug testing, bioartificial livers, and transplantation. In parallel, the mechanisms regulating cancer cell biology are now clearer, providing fertile soil for novel therapeutic approaches. Recognition of the relationships between development, regeneration, and carcinogenesis, and the increasing evidence for the role of stem cells in all of these areas, has sparked fresh enthusiasm in understanding the underlying molecular mechanisms and has led to new targeted therapies for liver cirrhosis and primary liver cancers.

  15. Mechanisms of platelet-mediated liver regeneration.

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    Lisman, Ton; Porte, Robert J

    2016-08-04

    Platelets have multiple functions beyond their roles in thrombosis and hemostasis. Platelets support liver regeneration, which is required after partial hepatectomy and acute or chronic liver injury. Although it is widely assumed that platelets stimulate liver regeneration by local excretion of mitogens stored within platelet granules, definitive evidence for this is lacking, and alternative mechanisms deserve consideration. In-depth knowledge of mechanisms of platelet-mediated liver regeneration may lead to new therapeutic strategies to treat patients with failing regenerative responses.

  16. Calcium Signalling and Liver Regeneration

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    Isabelle Garcin

    2012-01-01

    Full Text Available After partial hepatectomy (PH the initial mass of the organ is restored through a complex network of cellular interactions that orchestrate both proliferative and hepatoprotective signalling cascades. Among agonists involved in this network many of them drive Ca2+ movements. During liver regeneration in the rat, hepatocyte cytosolic Ca2+ signalling has been shown on the one hand to be deeply remodelled and on the other hand to enhance progression of hepatocytes through the cell cycle. Mechanisms through which cytosolic Ca2+ signals impact on hepatocyte cell cycle early after PH are not completely understood, but at least they include regulation of immediate early gene transcription and ERK and CREB phosphorylation. In addition to cytosolic Ca2+, there is also evidence that mitochondrial Ca2+ and also nuclear Ca2+ may be critical for the regulation of liver regeneration. Finally, Ca2+ movements in hepatocytes, and possibly in other liver cells, not only impact hepatocyte progression in the cell cycle but more generally may regulate cellular homeostasis after PH.

  17. Erythropoietin stimulates hepatocyte regeneration after liver resection

    OpenAIRE

    Schön, Michael R.; Hogrebe, Esther; Hengstler, Jan Georg; Donaubauer, Bernd; Faber, Sonya C.; Bauer, Alexander; Pietsch, Uta-Carolin; Jelkmann, Wolfgang; Thiery, Joachim; Hauss, Johann Peter; Tannapfel, Andrea

    2008-01-01

    The increased relevance of liver surgery and transplantation as a therapeutic modality over the last two decades mandates the development of novel strategies to improve liver regeneration. Here we studied whether erythropoietin (EPO) improves liver regeneration after hepatectomy in pigs. Eighteen female pigs underwent laparoscopic left lateral liver resection and were allocated randomly into three groups. No EPO was administered to the control group (group 1, n=6). Group 2 (...

  18. Silymarin Accelerates Liver Regeneration after Partial Hepatectomy

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    Jia-Ping Wu

    2015-01-01

    Full Text Available Partial hepatectomy (PHx is a liver regeneration physiological response induced to maintain homeostasis. Liver regeneration evolved presumably to protect wild animals from catastrophic liver loss caused by toxins or tissue injury. Silymarin (Sm ability to stimulate liver regeneration has been an object of curiosity for many years. Silymarin has been investigated for use as an antioxidant and anticarcinogen. However, its use as a supportive treatment for liver damage is elusive. In this study, we fed silymarin (Sm, 25 mg/kg to male Sprague-Dawley rats for 7 weeks. Surgical 2/3 PHx was then conducted on the rats at 6 hrs, 24 hrs, and 72 hrs. Western blot and RT-PCR were conducted to detect the cell cycle activities and silymarin effects on hepatic regeneration. The results showed that silymarin enhanced liver regeneration by accelerating the cell cycle in PHx liver. Silymarin led to increased G1 phase (cyclin D1/pRb, S phase (cyclin E/E2F, G2 phase (cyclin B, and M phase (cyclin A protein and mRNA at 6 hrs, 24 hrs, and 72 hrs PHx. HGF, TGFα, and TGFβ1 growth factor expressions were also enhanced. We suggest that silymarin plays a crucial role in accelerated liver regeneration after PHx.

  19. Chronological protein synthesis in regenerating rat liver.

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    He, Jinjun; Hao, Shuai; Zhang, Hao; Guo, Fuzheng; Huang, Lingyun; Xiao, Xueyuan; He, Dacheng

    2015-07-01

    Liver regeneration has been studied for decades; however, its regulation remains unclear. In this study, we report a dynamic tracing of protein synthesis in rat regenerating liver with a new proteomic technique, (35) S in vivo labeling analysis for dynamic proteomics (SiLAD). Conventional proteomic techniques typically measure protein alteration in accumulated amounts. The SiLAD technique specifically detects protein synthesis velocity instead of accumulated amounts of protein through (35) S pulse labeling of newly synthesized proteins, providing a direct way for analyzing protein synthesis variations. Consequently, protein synthesis within short as 30 min was visualized and protein regulations in the first 8 h of regenerating liver were dynamically traced. Further, the 3.5-5 h post partial hepatectomy (PHx) was shown to be an important regulatory turning point by acute regulation of many proteins in the initiation of liver regeneration.

  20. Nicotinamide adenine dinucleotide biosynthesis promotes liver regeneration.

    Science.gov (United States)

    Mukherjee, Sarmistha; Chellappa, Karthikeyani; Moffitt, Andrea; Ndungu, Joan; Dellinger, Ryan W; Davis, James G; Agarwal, Beamon; Baur, Joseph A

    2017-02-01

    The regenerative capacity of the liver is essential for recovery from surgical resection or injuries induced by trauma or toxins. During liver regeneration, the concentration of nicotinamide adenine dinucleotide (NAD) falls, at least in part due to metabolic competition for precursors. To test whether NAD availability restricts the rate of liver regeneration, we supplied nicotinamide riboside (NR), an NAD precursor, in the drinking water of mice subjected to partial hepatectomy. NR increased DNA synthesis, mitotic index, and mass restoration in the regenerating livers. Intriguingly, NR also ameliorated the steatosis that normally accompanies liver regeneration. To distinguish the role of hepatocyte NAD levels from any systemic effects of NR, we generated mice overexpressing nicotinamide phosphoribosyltransferase, a rate-limiting enzyme for NAD synthesis, specifically in the liver. Nicotinamide phosphoribosyltransferase overexpressing mice were mildly hyperglycemic at baseline and, similar to mice treated with NR, exhibited enhanced liver regeneration and reduced steatosis following partial hepatectomy. Conversely, mice lacking nicotinamide phosphoribosyltransferase in hepatocytes exhibited impaired regenerative capacity that was completely rescued by administering NR.

  1. Preliminary study on dental pulp stem cell-mediated pulp regeneration in canine immature permanent teeth.

    Science.gov (United States)

    Wang, Yuanyuan; Zhao, Yuming; Jia, Weiqian; Yang, Jie; Ge, Lihong

    2013-02-01

    The health of human teeth depends on the integrity of the hard tissue and the activity of the pulp and periodontal tissues, which are responsible for nutritional supply. Without the nourishing of the pulp tissue, the possibility of tooth fracture can increase. In immature permanent teeth, root development may be influenced as well. This study explored the potential of using autologous dental pulp stem cells (DPSCs) to achieve pulp regeneration in a canine pulpless model. The establishment of the pulpless animal model involved pulp extirpation and root canal preparation of young permanent incisor teeth in beagles. Autologous DPSCs were obtained from extracted first molars and expanded ex vivo to obtain a larger number of cells. The biological characteristics of canine DPSCs (cDPSCs) were analyzed both in vitro and in vivo by using the same method as used in human DPSCs. cDPSCs were transplanted into the pulpless root canal with Gelfoam as the scaffold, and root development was evaluated by radiographic and histologic analyses. cDPSCs with rapid proliferation, multiple differentiation capacity, and development potential were successfully isolated and identified both in vitro and in vivo. After they were transplanted into the pulpless root canal with Gelfoam as the scaffold, DPSCs were capable of generating pulp-like tissues containing blood vessels and dentin-like tissue. Thickening of the root canal wall was also observed. This study demonstrates the feasibility of using stem cell-mediated tissue engineering to realize pulp regeneration in immature teeth. Copyright © 2013 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  2. Telocytes in liver regeneration: possible roles.

    Science.gov (United States)

    Wang, Fei; Song, Yang; Bei, Yihua; Zhao, Yingying; Xiao, Junjie; Yang, Changqing

    2014-09-01

    Telocytes (TCs) are a novel type of interstitial cells which are potentially involved in tissue regeneration and repair (www.telocytes.com). Previously, we documented the presence of TCs in liver. However, the possible roles of TCs in liver regeneration remain unknown. In this study, a murine model of partial hepatectomy (PH) was used to induce liver regeneration. The number of TCs detected by double labelling immunofluorescence methods (CD34/PDGFR-α, CD34/PDGFR-ß and CD34/Vimentin) was significantly increased when a high level of hepatic cell proliferation rate (almost doubled) as shown by 5-ethynyl-2'-deoxyuridine (EdU) immunostaining and Western Blot of Proliferating cell nuclear antigen (PCNA) was found at 48 and 72 hrs post-PH. Meanwhile, the number of CK-19 positive-hepatic stem cells peaked at 72 hrs post-PH, co-ordinating with the same time-point, when the number of TCs was most significantly increased. Taken together, the results indicate a close relationship between TCs and the cells essentially involved in liver regeneration: hepatocytes and stem cells. It remains to be determined how TCs affect hepatocytes proliferation and/or hepatic stem cell differentiation in liver regeneration. Besides intercellular junctions, we may speculate a paracrine effect via ectovesicles.

  3. Susceptibility to T cell-mediated liver injury is enhanced in asialoglycoprotein receptor-deficient mice.

    Science.gov (United States)

    McVicker, Benita L; Thiele, Geoffrey M; Casey, Carol A; Osna, Natalia A; Tuma, Dean J

    2013-05-01

    T cell activation and associated pro-inflammatory cytokine production is a pathological feature of inflammatory liver disease. It is also known that liver injury is associated with marked impairments in the function of many hepatic proteins including a hepatocyte-specific binding protein, the asialoglycoprotein receptor (ASGPR). Recently, it has been suggested that hepatic ASGPRs may play an important role in the physiological regulation of T lymphocytes, leading to our hypothesis that ASGPR defects correlate with inflammatory-mediated events in liver diseases. Therefore, in this study we investigated whether changes in hepatocellular ASGPR expression were related to the dysregulation of intrahepatic T lymphocytes and correlate with the development of T-cell mediated hepatitis. Mice lacking functional ASGPRs (receptor-deficient, RD), and wild-type (WT) controls were intravenously injected with T-cell mitogens, Concanavalin A (Con A) or anti-CD3 antibody. As a result of T cell mitogen treatment, RD mice lacking hepatic ASGPRs displayed enhancements in liver pathology, transaminase activities, proinflammatory cytokine expression, and caspase activation compared to that observed in normal WT mice. Furthermore, FACS analysis demonstrated that T-cell mitogen administration resulted in a significant rise in the percentage of CD8+ lymphocytes present in the livers of RD animals versus WT mice. Since these two mouse strains differ only in whether they express the hepatic ASGPR, it can be concluded that proper ASGPR function exerts a protective effect against T cell mediated hepatitis and that impairments to this hepatic receptor could be related to the accumulation of cytotoxic T cells that are observed in inflammatory liver diseases.

  4. Regeneration of hyaline cartilage by cell-mediated gene therapy using transforming growth factor beta 1-producing fibroblasts.

    Science.gov (United States)

    Lee, K H; Song, S U; Hwang, T S; Yi, Y; Oh, I S; Lee, J Y; Choi, K B; Choi, M S; Kim, S J

    2001-09-20

    Transforming growth factor beta (TGF-beta) has been considered as a candidate for gene therapy of orthopedic diseases. The possible application of cell-mediated TGF-beta gene therapy as a new treatment regimen for degenerative arthritis was investigated. In this study, fibroblasts expressing active TGF-beta 1 were injected into the knee joints of rabbits with artificially made cartilage defects to evaluate the feasibility of this therapy for orthopedic diseases. Two to 3 weeks after the injection there was evidence of cartilage regeneration, and at 4 to 6 weeks the cartilage defect was completely filled with newly grown hyaline cartilage. Histological analyses of the regenerated cartilage suggested that it was well integrated with the adjacent normal cartilage at the sides of the defect and that the newly formed tissue was indeed hyaline cartilage. Our findings suggest that cell-mediated TGF-beta 1 gene therapy may be a novel treatment for orthopedic diseases in which hyaline cartilage damage has occurred.

  5. Role of microRNA in liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Peng-Sheng Yi; Ming Zhang; Ming-Qing Xu

    2016-01-01

    BACKGROUND: Liver regeneration is a complex process. mi-croRNAs (miRNAs) are short, single-stranded RNAs that mod-ify gene expression at the post-transcriptional level. Recent investigations have revealed that miRNAs are closely linked to liver regeneration. DATA SOURCES: All included studies were obtained from PubMed, Embase, the ScienceDirect databases and Web of Science, with no limitation on publication year. Only studies published in English were considered. RESULTS: We grouped studies that involved miRNA and liver regeneration into two groups: miRNAs as promoters and as inhibitors of liver regeneration. We summarized the relevant miRNAs separately from the related pathways. CONCLUSIONS: Blocking or stimulating the pathways of miRNAs in liver regeneration may be novel therapeutic strat-egies in future regeneration-related liver managements. We may discover additional chemotherapy targets of miRNA.

  6. Proteomic analysis of regenerating mouse liver following 50% partial hepatectomy

    OpenAIRE

    Cao, Hongcui; Yu, Jiong; Xu, Wei; Jia, Xiaofei; Yang, Jinfeng; Pan, Qiaoling; Zhang, Qiyi; Sheng, Guoping; Li, Jun; Pan, Xiaoping; Wang, Yingjie; Li, Lanjuan

    2009-01-01

    Background Although 70% (or 2/3) partial hepatectomy (PH) is the most studied model for liver regeneration, the hepatic protein expression profile associated with lower volume liver resection (such as 50% PH) has not yet been reported. Therefore, the aim of this study was to determine the global protein expression profile of the regenerating mouse liver following 50% PH by differential proteomics, and thereby gaining some insights into the hepatic regeneration mechanism(s) under this milder b...

  7. Proteomic analysis of regenerating mouse liver following 50% partial hepatectomy

    Directory of Open Access Journals (Sweden)

    Pan Xiaoping

    2009-12-01

    Full Text Available Abstract Background Although 70% (or 2/3 partial hepatectomy (PH is the most studied model for liver regeneration, the hepatic protein expression profile associated with lower volume liver resection (such as 50% PH has not yet been reported. Therefore, the aim of this study was to determine the global protein expression profile of the regenerating mouse liver following 50% PH by differential proteomics, and thereby gaining some insights into the hepatic regeneration mechanism(s under this milder but clinically more relevant condition. Results Proteins from sham-operated mouse livers and livers regenerating for 24 h after 50% PH were separated by SDS-PAGE and analyzed by nanoUPLC-Q-Tof mass spectrometry. Compared to sham-operated group, there were totally 87 differentially expressed proteins (with 50 up-regulated and 37 down-regulated ones identified in the regenerating mouse livers, most of which have not been previously related to liver regeneration. Remarkably, over 25 differentially expressed proteins were located at mitochondria. Several of the mitochondria-resident proteins which play important roles in citric acid cycle, oxidative phosphorylation and ATP production were found to be down-regulated, consistent with the recently-proposed model in which the reduction of ATP content in the remnant liver gives rise to early stress signals that contribute to the onset of liver regeneration. Pathway analysis revealed a central role of c-Myc in the regulation of liver regeneration. Conclusions Our study provides novel evidence for mitochondria as a pivotal organelle that is connected to liver regeneration, and lays the foundation for further studies on key factors and pathways involved in liver regeneration following 50% PH, a condition frequently used for partial liver transplantation and conservative liver resection.

  8. Nitric oxide in liver inflammation and regeneration.

    Science.gov (United States)

    Martin-Sanz, Paloma; Hortelano, Sonsoles; Callejas, Nuria A; Goren, Nora; Casado, Marta; Zeini, Miriam; Boscá, Lisardo

    2002-12-01

    Hepatocytes express and release inflammatory mediators after challenge with bacterial cell wall molecules and proinflammatory cytokines. Nitric oxide synthase-2 (NOS-2) is expressed under these conditions and the high-output NO synthesis that follows contributes to the inflammatory response in this tissue and participates in the onset of several hepatopathies. However, in the course of liver regeneration, for example, after partial hepatectomy, NOS-2 is expressed at moderate levels and contributes to inhibit apoptosis and to favor progression in the cell cycle until the organ size and function are restored. The mechanisms involved in the regulation of NOS-2 expression under these conditions are revised.

  9. Signal molecule-mediated hepatic cell communication during liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Zhen-Yu Zheng; Shun-Yan Weng; Yan Yu

    2009-01-01

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

  10. Liver regeneration microenvironment of hepatocellular carcinoma for prevention and therapy

    Science.gov (United States)

    Li, Hanmin; Zhang, Lisheng

    2017-01-01

    Research on liver cancer prevention and treatment has mainly focused on the liver cancer cells themselves. Currently, liver cancers are no longer viewed as only collections of genetically altered cells but as aberrant organs with a plastic stroma, matrix, and vasculature. Improving the microenvironment of the liver to promote liver regeneration and repair by affecting immune function, inflammation and vasculature can regulate the dynamic imbalance between normal liver regeneration and repair and abnormal liver regeneration, thus improving the microenvironment of liver regeneration for the prevention and treatment of liver cancer. This review addresses the basic theory of the liver regeneration microenvironment, including the latest findings on immunity, inflammation and vasculature. Attention is given to the potential design of molecular targets in the microenvironment of hepatocellular carcinoma (HCC). In an effort to improve the liver regeneration microenvironment of HCC, researchers have extensively utilized the enhancement of immunity, anti-inflammation and the vasculature niche, which are discussed in detail in this review. In addition, the authors summarize the latest pro-fibrotic transition characteristics of the vascular niche and review potential cell therapies for liver disease. PMID:27655683

  11. Beneficial effect of hyperbaric oxygenation on liver regeneration in cirrhosis.

    Science.gov (United States)

    Ozdogan, Mehmet; Ersoy, Eren; Dundar, Kadir; Albayrak, Levent; Devay, Seda; Gundogdu, Haldun

    2005-12-01

    Underlying hepatic injury and cirrhosis are leading factors that interfere with the post-operative liver regeneration and function. Hyperbaric oxygenation (HBO) has been reported to ameliorate the ischemia-reperfusion injury of the liver, to induce compensatory hypertrophy of the predicted remnant liver in rats after portal vein ligation and to augment liver regeneration after hepatectomy in non-cirrhotic rats. Our aim was to determine the effect of HBO treatment on liver regeneration after partial hepatectomy in normal and cirrhotic mice in this experimental study. The effect of HBO on liver regeneration was studied in a mice model combining carbon tetrachloride induced cirrhosis and partial hepatectomy. Mice were divided into four groups: Control, cirrhotic, non-cirrhotic HBO-treated, and cirrhotic HBO-treated. All animals underwent 40% hepatectomy. Liver regeneration was evaluated by the proliferating cell nuclear antigen-labeling index. Serum aspartate aminotransferase and alanine aminotransferase levels were measured to evaluate liver injury. Serum alanine aminotransferase and aspartate aminotransferase levels were significantly decreased in HBO-treated cirrhotic group compared to cirrhosis group after hepatectomy (P = 0.001 and P = 0.014, respectively). The proliferating cell nuclear antigen labeling index was significantly higher in HBO treated cirrhotic group than in cirrhotic group after hepatectomy (P = 0.022). Our results suggest that HBO treatment improves liver functions and augments hepatocyte regeneration in cirrhotic mice after hepatectomy. Post-operative HBO treatment may have a beneficial effect on post-operative liver function and regeneration in cirrhotic patients.

  12. Liver regeneration is dependent on the extent of hepatectomy

    DEFF Research Database (Denmark)

    Meier, Michelle; Knudsen, Anders Riegels; Andersen, Kasper Jarlhelt;

    of liver tissue and blood for liver specific serology. The change in liver weight after PH was evaluated as liver regeneration rate (RR). Histological analyses of liver cell proliferation and proteomic analyses are in progress. The gain in liver weight as well as RR increased significantly with the size......The upper limit for the size of hepatectomy is approximately 90% in rats. The present research project is designed to investigate the molecular pathways leading to either liver regeneration or liver failure after extended hepatectomy. In this first study we investigated the impact of different size...... of hepatectomy on liver regeneration in a rat model. Male Wistar rats were divided into four groups: 30% (n=24), 70% (n=24) and 90% (n=24) partial hepatectomy (PH) was performed together with a SHAM group (n=24). Euthanization took place at postoperative day (POD) 1 (n=8), 3 (n=8), and 5 (n=8) with harvesting...

  13. Human augmenter of liver regeneration: molecular cloning, biological activity and roles in liver regeneration

    Institute of Scientific and Technical Information of China (English)

    杨晓明; 谢玲; 邱兆华; 吴祖泽; 贺福初

    1997-01-01

    The complete amino acid sequence of human augmenter of liver regeneration (hALR) was reported by deduction from nucleotide sequence of its complementary DNA . The cDNA for hALR was isolated by screening a human fetal liver cDNA library and the sequencing of this insert revealed an open reading frame encoding a protein with 125aa and highly homologous (87% ) with rat ALR encoding sequence. The recombinant hALR expressed from its cDNA in transient expression experiments in cos-7 cells could stimulate DNA synthesis of HTC hepatoma cell in the dose-dependent and heat-resistant way. Northern blot analysis with rat ALR cDNA as probe confirmed that ALR mRNA was expressed in the normal rat liver at low level and that dramatically increased in the regenerating liver after partial hepatectomied rat. This size of hALR mRNA is 1.4 kb long and expressed in human fetal liver, kidney and testis. These findings indicated that liver itself may be the resource of ALR and suggested that ALR seems to be an im-portant parac

  14. Angiogenesis in the liver : molecular mechanisms and novel treatment strategies in liver regeneration and tumor metastasis

    NARCIS (Netherlands)

    Vogten, J.M.

    2004-01-01

    Angiogenesis in liver regeneration Liver regeneration involves the coordinated proliferation of all major hepatic cell types. There are many indirect but obvious indicators of the speculation that angiogenesis must play an important role in the regeneration process. In the first part of this thesis,

  15. Mechanical unloading of bone in microgravity reduces mesenchymal and hematopoietic stem cell-mediated tissue regeneration

    Directory of Open Access Journals (Sweden)

    E.A. Blaber

    2014-09-01

    Full Text Available Mechanical loading of mammalian tissues is a potent promoter of tissue growth and regeneration, whilst unloading in microgravity can cause reduced tissue regeneration, possibly through effects on stem cell tissue progenitors. To test the specific hypothesis that mechanical unloading alters differentiation of bone marrow mesenchymal and hematopoietic stem cell lineages, we studied cellular and molecular aspects of how bone marrow in the mouse proximal femur responds to unloading in microgravity. Trabecular and cortical endosteal bone surfaces in the femoral head underwent significant bone resorption in microgravity, enlarging the marrow cavity. Cells isolated from the femoral head marrow compartment showed significant down-regulation of gene expression markers for early mesenchymal and hematopoietic differentiation, including FUT1(−6.72, CSF2(−3.30, CD90(−3.33, PTPRC(−2.79, and GDF15(−2.45, but not stem cell markers, such as SOX2. At the cellular level, in situ histological analysis revealed decreased megakaryocyte numbers whilst erythrocytes were increased 2.33 fold. Furthermore, erythrocytes displayed elevated fucosylation and clustering adjacent to sinuses forming the marrow–blood barrier, possibly providing a mechanistic basis for explaining spaceflight anemia. Culture of isolated bone marrow cells immediately after microgravity exposure increased the marrow progenitor's potential for mesenchymal differentiation into in-vitro mineralized bone nodules, and hematopoietic differentiation into osteoclasts, suggesting an accumulation of undifferentiated progenitors during exposure to microgravity. These results support the idea that mechanical unloading of mammalian tissues in microgravity is a strong inhibitor of tissue growth and regeneration mechanisms, acting at the level of early mesenchymal and hematopoietic stem cell differentiation.

  16. The effect of erythropoietin on autologous stem cell-mediated bone regeneration.

    Science.gov (United States)

    Nair, Ashwin M; Tsai, Yi-Ting; Shah, Krishna M; Shen, Jinhui; Weng, Hong; Zhou, Jun; Sun, Xiankai; Saxena, Ramesh; Borrelli, Joseph; Tang, Liping

    2013-10-01

    Mesenchymal stem cells (MSCs) although used for bone tissue engineering are limited by the requirement of isolation and culture prior to transplantation. Our recent studies have shown that biomaterial implants can be engineered to facilitate the recruitment of MSCs. In this study, we explore the ability of these implants to direct the recruitment and the differentiation of MSCs in the setting of a bone defect. We initially determined that both stromal derived factor-1alpha (SDF-1α) and erythropoietin (Epo) prompted different degrees of MSC recruitment. Additionally, we found that Epo and bone morphogenetic protein-2 (BMP-2), but not SDF-1α, triggered the osteogenic differentiation of MSCs in vitro. We then investigated the possibility of directing autologous MSC-mediated bone regeneration using a murine calvaria model. Consistent with our in vitro observations, Epo-releasing scaffolds were found to be more potent in bridging the defect than BMP-2 loaded scaffolds, as determined by computed tomography (CT) scanning, fluorescent imaging and histological analyses. These results demonstrate the tremendous potential, directing the recruitment and differentiation of autologous MSCs has in the field of tissue regeneration.

  17. Macrophage-Induced Blood Vessels Guide Schwann Cell-Mediated Regeneration of Peripheral Nerves.

    Science.gov (United States)

    Cattin, Anne-Laure; Burden, Jemima J; Van Emmenis, Lucie; Mackenzie, Francesca E; Hoving, Julian J A; Garcia Calavia, Noelia; Guo, Yanping; McLaughlin, Maeve; Rosenberg, Laura H; Quereda, Victor; Jamecna, Denisa; Napoli, Ilaria; Parrinello, Simona; Enver, Tariq; Ruhrberg, Christiana; Lloyd, Alison C

    2015-08-27

    The peripheral nervous system has remarkable regenerative capacities in that it can repair a fully cut nerve. This requires Schwann cells to migrate collectively to guide regrowing axons across a 'bridge' of new tissue, which forms to reconnect a severed nerve. Here we show that blood vessels direct the migrating cords of Schwann cells. This multicellular process is initiated by hypoxia, selectively sensed by macrophages within the bridge, which via VEGF-A secretion induce a polarized vasculature that relieves the hypoxia. Schwann cells then use the blood vessels as "tracks" to cross the bridge taking regrowing axons with them. Importantly, disrupting the organization of the newly formed blood vessels in vivo, either by inhibiting the angiogenic signal or by re-orienting them, compromises Schwann cell directionality resulting in defective nerve repair. This study provides important insights into how the choreography of multiple cell-types is required for the regeneration of an adult tissue.

  18. Nitric Oxide and Prostaglandins Potentiate the Liver Regeneration Cascade

    Directory of Open Access Journals (Sweden)

    Jodi M Schoen Smith

    2006-01-01

    Full Text Available The liver has the remarkable ability to regenerate following damage or surgical resection. Although this feature of the liver has been studied for over 100 years, the trigger of the liver regeneration cascade remains controversial. Recent experimental evidence supports the hypothesis that nitric oxide (NO and prostaglandins (PGs, released secondary to an increase in the blood flow-to-liver mass ratio following two-thirds partial hepatectomy (PHx, work synergistically to trigger liver regeneration. To extend this research, the hypothesis that NO and PGs are potential therapeutic targets to potentiate the liver regeneration cascade is tested. The NO donor s-nitroso-n-acetylpenicillamine, the phosphodiesterase V antagonist zaprinast (ZAP and PGI2 each potentiated c-fos messenger RNA expression, an index of initiation of the liver regeneration cascade, following PHx. Also, the triple combination of s-nitroso-n-acetylpenicillamine, ZAP and PGI2 potentiated c-fos messenger RNA expression. These results support the hypothesis that NO and PGs can potentiate initiation of the regeneration cascade. An additional index of liver weight restoration 48 h after PHx was also used to test the hypothesis, because this index encompasses the entire liver regeneration cascade. ZAP and 6-keto-PGF1α, a stable metabolite of PGI2, and the combination of ZAP and 6-keto-PGF1α, each potentiated liver weight restoration 48 h after PHx. These results also provide support for the hypothesis that NO and PGs are possible therapeutic targets to potentiate liver regeneration following surgical resection.

  19. The Involvement of Heat Shock Proteins in Murine Liver Regeneration

    Institute of Scientific and Technical Information of China (English)

    Qing Shi; Zhongjun Dong; Haiming Wei

    2007-01-01

    Partial hepatectomy (PHx) in mammals is a very common experimental model to investigate the process of liver regeneration. The surgery itself could give birth to a series of stresses, such as the temporary raise of body temperature and the ischaemia-reperfusion injury. Heat shock proteins (HSPs) were a family of stress-inducible proteins involved in maintaining cell homeostasis and regulating the immune system. In our study, we intended to investigate the expression and role of HSPs in liver regeneration. Using RT-PCR and Western blotting, we determined the expression in regenerating liver of HSP27, HSP60, HSP70 and HSP90 in mRNA level and protein level, respectively, with mice treated with sham operation as controls. We also used quercertin as an inhibitior of HSPs to explore their effects on liver regeneration. We found that hepatic expression of HSPs increased at the early phase of liver regeneration and declined to the constitutively low level later. Moreover, quercetin pretreatment delayed the progress of liver regeneration in mice via inhibition of HSPs. The results indicated that HSPs played an important role in liver regeneration.

  20. The genetic regulation of the terminating phase of liver regeneration

    DEFF Research Database (Denmark)

    Nygård, Ingvild E.; Mortensen, Kim E.; Hedegaard, Jakob;

    2012-01-01

    Background After partial hepatectomy (PHx), the liver regeneration process terminates when the normal liver-mass/body-weight ratio of 2.5% has been re-established. To investigate the genetic regulation of the terminating phase of liver regeneration, we performed a 60% PHx in a porcine model. Liver...... biopsies were taken at the time of resection, after three weeks and upon termination the sixth week. Gene expression profiles were obtained using porcine oligonucleotide microarrays. Our study reveals the interactions between genes regulating the cell cycle, apoptosis and angiogenesis, and the role...... of Transforming Growth Factor-β (TGF-β) signalling towards the end of liver regeneration. Results Microarray analysis revealed a dominance of genes regulating apoptosis towards the end of regeneration. Caspase Recruitment Domain-Containing Protein 11 (CARD11) was up-regulated six weeks after PHx, suggesting...

  1. CD13 Promotes Mesenchymal Stem Cell-mediated regeneration of ischemic muscle

    Directory of Open Access Journals (Sweden)

    M. Mamunur eRahman

    2014-01-01

    Full Text Available Mesenchymal stem cells (MSCs are multipotent, tissue-resident cells that can facilitate tissue regeneration and thus show great promise as potential therapeutic agents. Functional MSCs have been isolated and characterized from a wide array of adult tissues and are universally identified by the shared expression of a core panel of MSCs markers. One of these markers is the multifunctional cell surface peptidase CD13 that has been shown to be expressed on human and murine MSCs from many tissues. To investigate whether this universal expression indicates a functional role for CD13 in MSC biology we isolated, expanded and characterized MSCs from bone marrow of wild type (WT and CD13KO mice. Characterization of these cells demonstrated that both WT and CD13KO MSCs expressed the full complement of MSC markers (CD29, CD44, CD49e, CD105, Sca1, showed comparable proliferation rates and were capable of differentiating toward the adipogenic and osteogenic lineages. However, MSCs lacking CD13 were unable to differentiate into vascular cells, consistent with our previous characterization of CD13 as an angiogenic regulator. Compared to WT MSCs, adhesion and migration on various extracellular matrices of CD13KO MSCs were significantly impaired, which correlated with decreased phospho-FAK levels and cytoskeletal alterations. Crosslinking human MSCs with activating CD13 antibodies increased cell adhesion to endothelial monolayers and induced FAK activation in a time dependent manner. In agreement with these in vitro data, intramuscular injection of CD13KO MSCs in a model of severe ischemic limb injury resulted in significantly poorer perfusion, decreased ambulation, increased necrosis and impaired vascularization compared to those receiving WT MSCs. This study suggests that CD13 regulates FAK activation to promote MSC adhesion and migration, thus contributing to MSC-mediated tissue repair. CD13 may present a viable target to enhance the efficacy of mesenchymal

  2. Impaired lipid accumulation in the liver of Tsc2-heterozygous mice during liver regeneration

    Energy Technology Data Exchange (ETDEWEB)

    Obayashi, Yoko, E-mail: youko_oobayashi@ajinomoto.com [Department of Pathology, University of Washington School of Medicine, Seattle, WA (United States); Campbell, Jean S.; Fausto, Nelson [Department of Pathology, University of Washington School of Medicine, Seattle, WA (United States); Yeung, Raymond S. [Department of Surgery, University of Washington School of Medicine, Seattle, WA (United States)

    2013-07-19

    Highlights: •Tuberin phosphorylation correlated with mTOR activation in early liver regeneration. •Liver regeneration in the Tsc2+/− mice was not enhanced. •The Tsc2+/− livers failed to accumulate lipid bodies during liver regeneration. •Mortality rate increased in Tsc2+/− mice after partial hepatectomy. •Tuberin plays a critical role in hepatic lipid accumulation to support regeneration. -- Abstract: Tuberin is a negative regulator of mTOR pathway. To investigate the function of tuberin during liver regeneration, we performed 70% hepatectomy on wild-type and Tsc2+/− mice. We found the tuberin phosphorylation correlated with mTOR activation during early liver regeneration in wild-type mice. However, liver regeneration in the Tsc2+/− mice was not enhanced. Instead, the Tsc2+/− livers failed to accumulate lipid bodies, and this was accompanied by increased mortality. These findings suggest that tuberin plays a critical role in liver energy balance by regulating hepatocellular lipid accumulation during early liver regeneration. These effects may influence the role of mTORC1 on cell growth and proliferation.

  3. Functional Relationships between Lipid Metabolism and Liver Regeneration

    Directory of Open Access Journals (Sweden)

    David A. Rudnick

    2012-01-01

    Full Text Available The regenerative capacity of the liver is well known, and the mechanisms that regulate this process have been extensively studied using experimental model systems including surgical resection and hepatotoxin exposure. The response to primary mitogens has also been used to investigate the regulation of hepatocellular proliferation. Such analyses have identified many specific cytokines and growth factors, intracellular signaling events, and transcription factors that are regulated during and necessary for normal liver regeneration. Nevertheless, the nature and identities of the most proximal events that initiate hepatic regeneration as well as those distal signals that terminate this process remain unknown. Here, we review the data implicating acute alterations in lipid metabolism as important determinants of experimental liver regeneration and propose a novel metabolic model of regeneration based on these data. We also discuss the association between chronic hepatic steatosis and impaired regeneration in animal models and humans and consider important areas for future research.

  4. Effect of Gomisin A (TJN-101) on liver regeneration.

    Science.gov (United States)

    Kubo, S; Ohkura, Y; Mizoguchi, Y; Matsui-Yuasa, I; Otani, S; Morisawa, S; Kinoshita, H; Takeda, S; Aburada, M; Hosoya, E

    1992-12-01

    We studied the effect of TJN-101, a lignan component of Schisandra fruits (Schisandrae fructus), on liver regeneration after partial hepatectomy. TJN-101 was given orally to male Wistar rats 30 min before partial hepatectomy. The mitotic index and the level of DNA synthesis increased after partial hepatectomy and their increase was significantly enhanced by TJN-101. Ornithine decarboxylase (ODC) activity increased in the early stages of liver regeneration and it was also significantly enhanced by TJN-101. Besides, TJN-101 enhanced the increase in hepatic putrescine. These results suggest that TJN-101 stimulates liver regeneration after partial hepatectomy by enhancing ODC activity, which is an important biochemical event in the early stages of liver regeneration.

  5. Stem cells in liver regeneration and their potential clinical applications.

    Science.gov (United States)

    Drosos, Ioannis; Kolios, George

    2013-10-01

    Stem cells constitute a population of "primitive cells" with the ability to divide indefinitely and give rise to specialized cells under special conditions. Because of these two characteristics they have received particular attention in recent decades. These cells are the primarily responsible factors for the regeneration of tissues and organs and for the healing of lesions, a feature that makes them a central key in the development of cell-based medicine, called Regenerative Medicine. The idea of wound and organ repair and body regeneration is as old as the mankind, reflecting the human desire for inhibiting aging and immortality and it is first described in the ancient Greek myth of Prometheus. It is of interest that the myth refers to liver, an organ with remarkable regenerative ability after loss of mass and function caused by liver injury or surgical resection. Over the last decade there has been an important progress in understanding liver physiology and the mechanisms underlying hepatic development and regeneration. As liver transplantation, despite its difficulties, remains the only effective therapy for advanced liver disease so far, scientific interest has nowadays been orientated towards Regenerative Medicine and the use of stem cells to repair damaged liver. This review is focused on the available literature concerning the role of stem cells in liver regeneration. It summarizes the results of studies concerning endogenous liver regeneration and stem cell experimental protocols. Moreover, this review discusses the clinical studies that have been conducted in humans so far.

  6. A critical role for matrix metal loproteinases in liver regeneration

    NARCIS (Netherlands)

    Alwayn, Ian P. J.; Verbesey, Jennifer E.; Kim, Sendia; Roy, Roopali; Arsenault, Danielle A.; Greene, Arin K.; Novak, Katherine; Laforme, Andrea; Lee, Sang; Moses, Marsha A.; Puder, Mark

    2008-01-01

    Background. Matrix metalloproteinases (MMPs), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) are mediators of liver regeneration. To determine whether MMPs are required for normal hepatic regeneration, we performed 67% hepatectomies on mice treated with a broad-spectrum MMP-inhibi

  7. Impact of future remnant liver volume on post-hepatectomy regeneration in non-cirrhotic livers

    Directory of Open Access Journals (Sweden)

    Duilio ePagano

    2014-04-01

    Full Text Available Objective: The purpose of the study is to detect if some parameters can be considered as predictors of liver regeneration in two different patient populations composed of in living donors for adult to adult living donor liver transplant and patients with hepatic malignancies within a single institution.Summary Background Data: Preoperative multi-detector computed tomography volumetry is an essential tool to assess the volume of the remnant liver. Methods: a retrospective analysis from an ongoing clinical study on 100 liver resections, between 2004 and 2010. 70 patients were right lobe living donors for liver transplantation and 30 patients were resected for treatment of tumors. Pre-surgical factors such as age, weight, height, body mass index (BMI, original liver volume, future remnant liver volume (FRLV, spleen volume, liver function tests, creatinine, platelet count, steatosis, portal vein embolization (PVE and number of resected segments were analyzed to evidence potential markers for liver regeneration. Results: Follow-up period did not influence the amount of liver regenerated: the linear regression evidenced that there is no correlation between percentage of liver regeneration and time of follow-up (p=0.88. The pre-surgical variables that resulted markers of liver regeneration include higher preoperative values of BMI (p=0.01, bilirubin(p=0.04, glucose (p=0.05 and GGT (p=0.014; the most important association was revealed regarding the lower FRLV (pConclusions: Liver regeneration follows similar pathway in living donor and in patients resected for cancer. Small FRLV tends to regenerate more and faster, confirming that a larger resections may lead to a greater promotion of liver regeneration in patients with optimal conditions in terms of body habitus, preoperative liver function tests and glucose level.

  8. Chronic stress does not impair liver regeneration in rats

    DEFF Research Database (Denmark)

    Andersen, Kasper J; Knudsen, Anders Riegels; Wiborg, Ove;

    2015-01-01

    a 70 % partial hepatectomy (PHx). The animals were evaluated on postoperative day 2 or 4. Blood samples were collected to examine circulating markers of inflammation and liver cell damage. Additionally, liver tissues were sampled to evaluate liver weight and regeneration rate. RESULTS: None......BACKGROUND: Although wound healing is a simple regenerative process that is critical after surgery, it has been shown to be impaired under psychological stress. The liver has a unique capacity to regenerate through highly complex mechanisms. The aim of this study was to investigate the effects...... of chronic stress, which may induce a depression-like state, on the complex process of liver regeneration in rats. METHODS: Twenty rats were included in this study. The animals received either a standard housing protocol or were subjected to a Chronic Mild Stress (CMS) stress paradigm. All rats underwent...

  9. Cellular Liver Regeneration after Extended Hepatic Resection in Pigs

    Directory of Open Access Journals (Sweden)

    Ruth Ladurner

    2009-01-01

    Full Text Available Background. The liver has an enormous capacity to regenerate itself. The aim of this study was to evaluate whether the regeneration is due to hypertrophy or hyperplasia of the remnant liver after extended resection and whether a portosystemic shunt is beneficial. Material and methods. An extended left hemihepatectomy was performed in 25 pigs, and in 14 after performing a portosystemic shunt. During follow up, liver regeneration was estimated by macroscopic markers such as liver volume and size of the portal fields [mm2] as well as the amount of hepatocytes per portal field and the amount of hepatocytes per mm2. Results. Regardless of the operation procedure, the volume of the remnant liver increased about 2.5 fold at the end of the first week after resection. The size of the portal fields increased significantly as well as the number of hepatocytes in the portal fields. Interestingly, the number of hepatocytes per mm2 remained the same. Conclusion. After extended resection, liver regeneration was achieved by an extensive and significant hyperplasia of hepatocytes within the preexisting portal fields and not by de novo synthesis of new portal fields. However, there was no difference in liver regeneration regarding the operation procedure performed with or without portosystemic shunt.

  10. Role of ischaemic preconditioning in liver regeneration following major liver resection and transplantation

    Institute of Scientific and Technical Information of China (English)

    D Gomez; S Homer-Vanniasinkam; AM Graham; KR Prasad

    2007-01-01

    Liver ischaemic preconditioning (IPC) is known to protect the liver from the detrimental effects of ischaemicreperfusion injury (IRI), which contributes significantly to the morbidity and mortality following major liver surgery.Recent studies have focused on the role of IPC in liver regeneration, the precise mechanism of which are not completely understood. This review discusses the current understanding of the mechanism of liver regeneration and the role of IPC in this setting. Relevant articles were reviewed from the published literature using the Medline database. The search was performed using the keywords "liver", "ischaemic reperfusion", "ischaemic preconditioning", "regeneration", "hepatectomy"and "transplantation". The underlying mechanism of liver regeneration is a complex process involving the interaction of cytokines, growth factors and the metabolic demand of the liver. IPC, through various mediators, promotes liver regeneration by up-regulating growthpromoting factors and suppresses growth-inhibiting factors as well as damaging stresses. The increased understanding of the cellular mechanisms involved in IPC will enable the development of alternative treatment modalities aimed at promoting liver regeneration following major liver resection and transplantation.

  11. Liver graft regeneration in right lobe adult living donor liver transplantation.

    Science.gov (United States)

    Cheng, Y-F; Huang, T-L; Chen, T-Y; Tsang, L L-C; Ou, H-Y; Yu, C-Y; Concejero, A; Wang, C-C; Wang, S-H; Lin, T-S; Liu, Y-W; Yang, C-H; Yong, C-C; Chiu, K-W; Jawan, B; Eng, H-L; Chen, C-L

    2009-06-01

    Optimal portal flow is one of the essentials in adequate liver function, graft regeneration and outcome of the graft after right lobe adult living donor liver transplantation (ALDLT). The relations among factors that cause sufficient liver graft regeneration are still unclear. The aim of this study is to evaluate the potential predisposing factors that encourage liver graft regeneration after ALDLT. The study population consisted of right lobe ALDLT recipients from Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan. The records, preoperative images, postoperative Doppler ultrasound evaluation and computed tomography studies performed 6 months after transplant were reviewed. The volume of the graft 6 months after transplant divided by the standard liver volume was calculated as the regeneration ratio. The predisposing risk factors were compiled from statistical analyses and included age, recipient body weight, native liver disease, spleen size before transplant, patency of the hepatic venous graft, graft weight-to-recipient weight ratio (GRWR), posttransplant portal flow, vascular and biliary complications and rejection. One hundred forty-five recipients were enrolled in this study. The liver graft regeneration ratio was 91.2 +/- 12.6% (range, 58-151). The size of the spleen (p = 0.00015), total portal flow and GRWR (p = 0.005) were linearly correlated with the regeneration rate. Patency of the hepatic venous tributary reconstructed was positively correlated to graft regeneration and was statistically significant (p = 0.017). Splenic artery ligation was advantageous to promote liver regeneration in specific cases but splenectomy did not show any positive advantage. Spleen size is a major factor contributing to portal flow and may directly trigger regeneration after transplant. Control of sufficient portal flow and adequate hepatic outflow are important factors in graft regeneration.

  12. Expressed genes in regenerating rat liver after partial hepatectomy

    Institute of Scientific and Technical Information of China (English)

    Cun-Shuan Xu; Salman Rahrnan; Jing-Bo Zhang; Cui-Fang Chang; Jin-Yun Yuan; Wen-Qiang Li; Hong-Peng Han; Ke-Jin Yang; Li-Feng Zhao; Yu-Chang Li; Hui-Yong Zhang

    2005-01-01

    AIM: To reveal the liver regeneration (LR) and its controlas well as the occurrence of liver disease and to study the gene expression profiles of 551 genes after partial hepatectomy (PH) in regenerating rat livers.METHODS: Five hundred and fifty-one expressed sequence tags screened by suppression subtractive hybridization were made into an in-house cDNA microarray, and the expressive genes and their expressive profiles in regenerating rat livers were analyzed by microarray and bioinformatics. RESULTS: Three hundred of the analyzed 551 genes were up- or downregulated more than twofolds at one or more time points during LR. Most of the genes were up- or downregulated 2-5 folds, but the highest reached 90 folds of the control. One hundred and thirty-nine of themshowed upregulation, 135 displayed downregulation, and up or down expression of 26 genes revealed a dependence on regenerating livers. The genes expressedin 24-h regenerating livers were much more than those in the others. Cluster analysis and generalization analysis showed that there were at least six distinct temporal patterns of gene expression in the regenerating livers, that is, genes were expressed in the immediate early phase, early phase, intermediate phase, early-late phase, late phase, terminal phase. CONCLUSION: In LR, the number of down-regulated genes was almost similar to that of the upregulated genes; the successively altered genes were more than the rapidly transient genes. The temporal patterns of gene expression were similar 2 and 4 h, 12 and 16 h, 48 and 96 h, 72 and 144 h after PH. Microarray combined with suppressive subtractive hybridization can effectively identify the genes related to LR.

  13. Cellular Mechanisms of Liver Regeneration and Cell-Based Therapies of Liver Diseases

    Science.gov (United States)

    Yarygin, Konstantin N.

    2017-01-01

    The emerging field of regenerative medicine offers innovative methods of cell therapy and tissue/organ engineering as a novel approach to liver disease treatment. The ultimate scientific foundation of both cell therapy of liver diseases and liver tissue and organ engineering is delivered by the in-depth studies of the cellular and molecular mechanisms of liver regeneration. The cellular mechanisms of the homeostatic and injury-induced liver regeneration are unique. Restoration of the mass of liver parenchyma is achieved by compensatory hypertrophy and hyperplasia of the differentiated parenchymal cells, hepatocytes, while expansion and differentiation of the resident stem/progenitor cells play a minor or negligible role. Participation of blood-borne cells of the bone marrow origin in liver parenchyma regeneration has been proven but does not exceed 1-2% of newly formed hepatocytes. Liver regeneration is activated spontaneously after injury and can be further stimulated by cell therapy with hepatocytes, hematopoietic stem cells, or mesenchymal stem cells. Further studies aimed at improving the outcomes of cell therapy of liver diseases are underway. In case of liver failure, transplantation of engineered liver can become the best option in the foreseeable future. Engineering of a transplantable liver or its major part is an enormous challenge, but rapid progress in induced pluripotency, tissue engineering, and bioprinting research shows that it may be doable. PMID:28210629

  14. Signals and Cells Involved in Regulating Liver Regeneration

    Directory of Open Access Journals (Sweden)

    Liang-I. Kang

    2012-12-01

    Full Text Available Liver regeneration is a complex phenomenon aimed at maintaining a constant liver mass in the event of injury resulting in loss of hepatic parenchyma. Partial hepatectomy is followed by a series of events involving multiple signaling pathways controlled by mitogenic growth factors (HGF, EGF and their receptors (MET and EGFR. In addition multiple cytokines and other signaling molecules contribute to the orchestration of a signal which drives hepatocytes into DNA synthesis. The other cell types of the liver receive and transmit to hepatocytes complex signals so that, in the end of the regenerative process, complete hepatic tissue is assembled and regeneration is terminated at the proper time and at the right liver size. If hepatocytes fail to participate in this process, the biliary compartment is mobilized to generate populations of progenitor cells which transdifferentiate into hepatocytes and restore liver size.

  15. [Cytoskeletal reorganization in hepatocytes of the regenerating mouse liver].

    Science.gov (United States)

    Gleĭberman, A S; Troianovskiĭ, S M; Bannikov, G A

    1984-12-01

    The intracellular pattern of prekeratin and actin filaments has been studied on sections of mouse livers regenerating after CCl4 injury. Monoclonal antibodies against one of liver prekeratins and monospecific polyclonal actin antibodies were used in the indirect immunofluorescent test. The presence of alpha-fetoprotein and bile canaliculi antigen was also monitored during regeneration. In control livers, prekeratin and actin filaments formed thick bundles adjacent to plasma membranes. The cytoplasmic prekeratin network was unmarked. In contrast to the latter, the bright well developed intracytoplasmic prekeratin network and intracytoplasmic actin fibers were identified in the perinecrotic hepatocytes by the 3d-4th day of regeneration. This rearrangement of the cytoskeleton coincided in time with the appearance of alpha-fetoprotein and the loss of the bile canaliculi antigen in the perinecrotic hepatocytes.

  16. Transient von Willebrand factor-mediated platelet influx stimulates liver regeneration after partial hepatectomy in mice

    NARCIS (Netherlands)

    Kirschbaum, Marc; Jenne, Craig N; Veldhuis, Zwanida J; Sjollema, Klaas A; Lenting, Peter J; Giepmans, Ben N G; Porte, Robert J; Kubes, Paul; Denis, Cécile V; Lisman, Ton

    2017-01-01

    BACKGROUND & AIMS: In addition to their function in thrombosis and hemostasis, platelets play an important role in the stimulation of liver regeneration. It has been suggested that platelets deliver mitogenic cargo to the regenerating liver, and accumulation of platelets in the regenerating liver

  17. Transient von Willebrand factor-mediated platelet influx stimulates liver regeneration after partial hepatectomy in mice

    NARCIS (Netherlands)

    Kirschbaum, Marc; Jenne, Craig N; Veldhuis, Zwanida J; Sjollema, Klaas A; Lenting, Peter J; Giepmans, Ben N G; Porte, Robert J; Kubes, Paul; Denis, Cécile V; Lisman, Ton

    2017-01-01

    BACKGROUND & AIMS: In addition to their function in thrombosis and hemostasis, platelets play an important role in the stimulation of liver regeneration. It has been suggested that platelets deliver mitogenic cargo to the regenerating liver, and accumulation of platelets in the regenerating liver ha

  18. Whither prometheus' liver? Greek myth and the science of regeneration.

    Science.gov (United States)

    Power, Carl; Rasko, John E J

    2008-09-16

    Stem-cell biologists and those involved in regenerative medicine are fascinated by the story of Prometheus, the Greek god whose immortal liver was feasted on day after day by Zeus' eagle. This myth invariably provokes the question: Did the ancient Greeks know about the liver's amazing capacity for self-repair? The authors address this question by exploring the origins of Greek myth and medicine, adopting a 2-fold strategy. First, the authors consider what opportunities the ancient Greeks had to learn about the liver's structure and function. This involves a discussion of early battlefield surgery, the beginnings of anatomical research, and the ancient art of liver augury. In addition, the authors consider how the Greeks understood Prometheus' immortal liver. Not only do the authors examine the general theme of regeneration in Greek mythology, they survey several scholarly interpretations of Prometheus' torture.

  19. MORT1/FADD is involved in liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Marcus Schuchmann; Wolfgang Schreiber; Ansgar W Lohse; Peter R Galle; Felix Rückert; Jose F Garcia-Lazaro; Andrea Karg; Jürgen Burg; Natalia Knorr; Jürgen Siebler; Eugene E Varfolomeev; David Wallach

    2005-01-01

    AIM: To explore the role of the adaptor molecule in liver regeneration after partial hepatectomy (PH).METHODS: We used transgenic mice expressing an N-terminal truncated form of MORT1/FADD under the control of the albumin promoter. As previously shown,this transgenic protein abrogated CD95- and CD120a-mediated apoptosis in the liver. Cyclin A expression was detected using Western blotting. ELISA and RT-PCR were used to detect IL-6 and IL-6 mRNA, respectively. DNA synthesis in liver tissue was measured by BrdU staining.RESULTS: Resection of 70% of the liver was followed by a reduced early regenerative response in the transgenic group at 36 h. Accordingly, 36 h after hepatectomy, cyclin A expression was only detectable in wild-type animals. Consequently, the onset of liver mass restoration was retarded as measured by MRI volumetry and mortality was significantly higher in the transgenic group.CONCLUSION: Our data demonstrate for the first time an involvement of the death receptor molecule MORT1/FADD in liver regeneration, beyond its well described role as part of the intracellular death signaling pathway.

  20. Transformation of human liver L-02 cells mediated by stable HBx transfection

    Institute of Scientific and Technical Information of China (English)

    Wei-ying ZHANG; Na CAI; Li-hong YE; Xiao-dong ZHANG

    2009-01-01

    Aim: To explore the mechanism of hepatocarcinogenesis associated with the hepatitis B virus X protein (HBx), we investigated the role of HBx in transformation using human liver L-02 cells stably transfected with HBx as a model.Methods: Plasmids encoding HBx were stably transfected into immortalized human liver L-02 cells and rodent fibroblast NIH/3T3 cells. The expression of alfa-fetoprotein (AFP), c-Myc, HBx, and survivin in the engineered cells was examined by Western blotting. The malignant phenotype of the cells was demonstrated by anchorage-independent colony formation and tumor formation in nude mice. RNA interference assays, Western blotting, luciferase reporter gene assays and flow cytometry analysis were performed. The number of centrosomes in the L-O2-X cells was determined by Y-tubulin immunostaining. The effect of HBx on the transcriptional activity of human telomerase reverse transcriptase (hTERT) and hTERT activity in L-02-X cells and/or 3T3-X cells was detected by the luciferase reporter gene assay and telomerase repeat amplification protocol (TRAP).Results: Stable HBx transfection resulted in a malignant phenotype in the engineered cells in vivo and in vitro. Meanwhile, HBx was able to increase the transcription of the NF-κB, AP-1, and survivin genes and to upregulate the expression levels of c-Myc and survivin.Abnormal centrosome duplication and activated hTERT were responsible for the transformation.Conclusion: Stable HBx transfection leads to genomic instability of host cells, which is responsible for hepatocarcinogenesis; mean-while, transactivation by the HBx protein contributes to the development of hepatocellular carcinoma (HCC). The L-02-X cell line is an ideal model for investigating the mechanism of HBx-mediated transformation.

  1. FAK deletion accelerates liver regeneration after two-thirds partial hepatectomy

    Science.gov (United States)

    Shang, Na; Arteaga, Maribel; Chitsike, Lennox; Wang, Fang; Viswakarma, Navin; Breslin, Peter; Qiu, Wei

    2016-01-01

    Understanding the molecular mechanisms of liver regeneration is essential to improve the survival rate of patients after surgical resection of large amounts of liver tissue. Focal adhesion kinase (FAK) regulates different cellular functions, including cell survival, proliferation and cell migration. The role of FAK in liver regeneration remains unknown. In this study, we found that Fak is activated and induced during liver regeneration after two-thirds partial hepatectomy (PHx). We used mice with liver-specific deletion of Fak and investigated the role of Fak in liver regeneration in 2/3 PHx model (removal of 2/3 of the liver). We found that specific deletion of Fak accelerates liver regeneration. Fak deletion enhances hepatocyte proliferation prior to day 3 post-PHx but attenuates hepatocyte proliferation 3 days after PHx. Moreover, we demonstrated that the deletion of Fak in liver transiently increases EGFR activation by regulating the TNFα/HB-EGF axis during liver regeneration. Furthermore, we found more apoptosis in Fak-deficient mouse livers compared to WT mouse livers after PHx. Conclusion: Our data suggest that Fak is involved in the process of liver regeneration, and inhibition of FAK may be a promising strategy to accelerate liver regeneration in recipients after liver transplantation. PMID:27677358

  2. [Control of growth and expression of protooncogenes in regenerating liver].

    Science.gov (United States)

    Zou, Y; Gong, D Z; Cui, X Y; Mei, M H

    1996-01-01

    There are many humoral factors involved in the control of growth in regenerating liver. The complete hepatocyte mitogens such as hepatocyte growth factor (HGF), hepatic stimulator substance (HSS) can strongly stimulate hepatocyte DNA synthesis and mitosis. The hepatocyte growth inhibitors such as transforming growth factor beta 1 (TGF beta 1), however, do not stimulate DNA synthesis, but inhibit EGF mitogenesis. In addition, the comitogens such as norepinephrine and insulin are necessary to regulate the growth of regenerating liver. It has become clear that the hepatocyte proliferation and protooncogenes are linked closely. Some protooncogenes can express specifically as markers in the different phases of the cell cycle and in hepatocytes that enter the cell cycle (G0 to G1 transit) and continue to progress.

  3. Gene expression profiles of human liver cells mediated by hepatitis B virus X protein

    Institute of Scientific and Technical Information of China (English)

    Wei-ying ZHANG; Fu-qing XU; Chang-liang SHAN; Rong XIANG; Li-hong YE; Xiao-dong ZHANG

    2009-01-01

    Aim: To demonstrate the gene expression profiles mediated by hepatitis B virus X protein (HBx), we characterized the molecular features of pathogenesis associated with HBx in a human liver cell model.Methods: We examined gene expression profiles in L-O2-X cells, an engineered L-O2 cell line that constitutively expresses HBx, relative to L-O2 cells using an Agilent 22 K human 70-mer oligonucleotide microarray representing more than 21,329 unique, well-characterized Homo sapiens genes, Western blot analysis and RNA interference (RNAi) targeting HBx mRNA validated the overexpression of proliferating cell nuclear antigen (PCNA) and Bcl-2 in L-O2-X cells. Meanwhile, the BrdU incorporation assay was used to test cell proliferation mediated by upregulated cyclooxygenase-2 (COX-2).Results: The microarray showed that the expression levels of 152 genes were remarkably altered; 82 of the genes were upregulated and 70 genes were downregulated in L-O2-X cells. The altered genes were associated with signal transduction pathways, cell cycle, metastasis, transcriptional regulation, immune response, metabolism, and other processes. PCNA and Bcl-2 were upregulated in L-O2-X cells. Furthermore, we found that COX-2 upregulation in L-O2-X cells enhanced proliferation using the BrdU incorporation assay, whereas indomethacin (an inhibitor of COX-2) abolished the promotion.Conclusion: Our findings provide new evidence that HBx is able to regulate many genes that may be involved in the car-cinogenesis. These regulated genes mediated by HBx may serve as molecular targets for the prevention and treatment of hepatocellular carcinoma.

  4. LIVER AND BONE MARROW STEM/PROGENITOR CELLS AS REGULATORS OF REPARATIVE REGENERATION OF DAMAGED LIVER

    Directory of Open Access Journals (Sweden)

    А. V. Lundup

    2010-01-01

    Full Text Available In this review the modern information about effectiveness of liver insufficiency treatment by stem/ progenitor cells of liver (oval cells and bone marrow (hemopoietic cells and mesenchymal cells was presented. It is shown that medical action of these cells is referred on normalization of liver cell interaction and reorganization of processes of a reparative regeneration in damaged liver. It is believed that application of mesenchymal stromal cells from an autological bone marrow is the most perspective strategy. However, for definitive judgement about regenerative possibilities of the autological bone marrow cells it is necessary to carry out large-scale double blind clinical researches. 

  5. Signal Transduction of Platelet-Induced Liver Regeneration and Decrease of Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Soichiro Murata

    2014-03-01

    Full Text Available Platelets contain three types of granules: alpha granules, dense granules, and lysosomal granules. Each granule contains various growth factors, cytokines, and other physiological substances. Platelets trigger many kinds of biological responses, such as hemostasis, wound healing, and tissue regeneration. This review presents experimental evidence of platelets in accelerating liver regeneration and improving liver fibrosis. The regenerative effect of liver by platelets consists of three mechanisms; i.e., the direct effect on hepatocytes, the cooperative effect with liver sinusoidal endothelial cells, and the collaborative effect with Kupffer cells. Many signal transduction pathways are involved in hepatocyte proliferation. One is activation of Akt and extracellular signal-regulated kinase (ERK1/2, which are derived from direct stimulation from growth factors in platelets. The other is signal transducer and activator of transcription-3 (STAT3 activation by interleukin (IL-6 derived from liver sinusoidal endothelial cells and Kupffer cells, which are stimulated by contact with platelets during liver regeneration. Platelets also improve liver fibrosis in rodent models by inactivating hepatic stellate cells to decrease collagen production. The level of intracellular cyclic adenosine monophosphate (cyclic AMP is increased by adenosine through its receptors on hepatic stellate cells, resulting in inactivation of these cells. Adenosine is produced by the degradation of adenine nucleotides such as adenosine diphosphate (ADP and adenosine tri-phosphate (ATP, which are stored in abundance within the dense granules of platelets.

  6. Transcriptome atlas of eight liver cell types uncovers effects of histidine catabolites on rat liver regeneration

    Indian Academy of Sciences (India)

    C. F. Chang; J. Y. Fan; F. C. Zhang; J. Ma; C. S. Xu

    2010-12-01

    Eight liver cell types were isolated using the methods of Percoll density gradient centrifugation and immunomagnetic beads to explore effects of histidine catabolites on rat liver regeneration. Rat Genome 230 2.0 Array was used to detect the expression profiles of genes associated with metabolism of histidine and its catabolites for the above-mentioned eight liver cell types, and bioinformatic and systems biology approaches were employed to analyse the relationship between above genes and rat liver regeneration. The results showed that the urocanic acid (UA) was degraded from histidine in Kupffer cells, acts on Kupffer cells itself and dendritic cells to generate immune suppression by autocrine and paracrine modes. Hepatocytes, biliary epithelia cells, oval cells and dendritic cells can convert histidine to histamine, which can promote sinusoidal endothelial cells proliferation by GsM pathway, and promote the proliferation of hepatocytes and biliary epithelia cells by GqM pathway.

  7. Transcriptome atlas of eight liver cell types uncovers effects of histidine catabolites on rat liver regeneration.

    Science.gov (United States)

    Chang, C F; Fan, J Y; Zhang, F C; Ma, J; Xu, C S

    2010-12-01

    Eight liver cell types were isolated using the methods of Percoll density gradient centrifugation and immunomagnetic beads to explore effects of histidine catabolites on rat liver regeneration. Rat Genome 230 2.0 Array was used to detect the expression profiles of genes associated with metabolism of histidine and its catabolites for the above-mentioned eight liver cell types, and bioinformatic and systems biology approaches were employed to analyse the relationship between above genes and rat liver regeneration. The results showed that the urocanic acid (UA) was degraded from histidine in Kupffer cells, acts on Kupffer cells itself and dendritic cells to generate immune suppression by autocrine and paracrine modes. Hepatocytes, biliary epithelia cells, oval cells and dendritic cells can convert histidine to histamine, which can promote sinusoidal endothelial cells proliferation by GsM pathway, and promote the proliferation of hepatocytes and biliary epithelia cells by GqM pathway.

  8. Insights on augmenter of liver regeneration cloning and function

    Institute of Scientific and Technical Information of China (English)

    Elisavet Gatzidou; Gregory Kouraklis; Stamatios Theocharis

    2006-01-01

    Hepatic stimulator substance (HSS) has been referred to as a liver-specific but species non-specific growth factor. Gradient purification and sequence analysis of HSS protein indicated that it contained the augmenter of liver regeneration (ALR), also known as hepatopoietin (HPO).ALR, acting as a hepatotrophic growth factor, specifically stimulated proliferation of cultured hepatocytes as well as hepatoma cells in vitro, promoted liver regeneration and recovery of damaged hepatocytes and rescued acute hepatic failure in vivo. ALR belongs to the new Erv1/Alr protein family, members of which are found in lower and higher eukaryotes from yeast to man and even in some double-stranded DNA viruses. The present review article focuses on the molecular biology of ALR, examining the ALR gene and its expression from yeast to man and the biological function of ALR protein. ALR protein seems to be non-liver-specific as was previously believed, increasing the necessity to extend research on mammalian ALR protein in different tissues, organs and developmental stages in conditions of normal and abnormal cellular growth.

  9. SOCS2 Balances Metabolic and Restorative Requirements during Liver Regeneration.

    Science.gov (United States)

    Masuzaki, Ryota; Zhao, Sophia; Valerius, M Todd; Tsugawa, Daisuke; Oya, Yuki; Ray, Kevin C; Karp, Seth J

    2016-02-12

    After significant injury, the liver must maintain homeostasis during the regenerative process. We hypothesized the existence of mechanisms to limit hepatocyte proliferation after injury to maintain metabolic and synthetic function. A screen for candidates revealed suppressor of cytokine signaling 2 (SOCS2), an inhibitor of growth hormone (GH) signaling, was strongly induced after partial hepatectomy. Using genetic deletion and administration of various factors we investigated the role of SOCS2 during liver regeneration. SOCS2 preserves liver function by restraining the first round of hepatocyte proliferation after partial hepatectomy by preventing increases in growth hormone receptor (GHR) via ubiquitination, suppressing GH pathway activity. At later times, SOCS2 enhances hepatocyte proliferation by modulating a decrease in serum insulin-like growth factor 1 (IGF-1) that allows GH release from the pituitary. SOCS2, therefore, plays a dual role in modulating the rate of hepatocyte proliferation. In particular, this is the first demonstration of an endogenous mechanism to limit hepatocyte proliferation after injury.

  10. Portal vein arterialization increases hepatocellular apoptosis and inhibits liver regeneration.

    Science.gov (United States)

    Schleimer, Karina; Stippel, Dirk L; Kasper, Hans U; Prenzel, Klaus; Gaudig, Cindy; Tawadros, Samir; Hoelscher, Arnulf H; Beckurts, K Tobias E

    2008-10-01

    Portal vein arterialization is performed in particular situations to guarantee sufficient blood flow in the portal vein. In addition, some authors have postulated a proliferation-promoting influence of portal vein arterialization on the liver tissue. However, portal vein arterialization is an unphysiological procedure: It increases portal blood flow and blood pressure as well as oxygenation of the liver tissue. On the other hand, it reduces the influx of hepatotrophic factors from the portal venous blood. The aim of these experiments was to investigate apoptosis and proliferation of hepatocytes during various conditions of the portal perfusion. After 70% liver resection in Lewis rats, the following four experimental groups were formed differing in portal perfusion: (I) hyperperfused, nonarterialized; (II) flow-regulated, nonarterialized; (III) hyperperfused, arterialized; (IV) flow-regulated, arterialized. A warm ischemia of 30 min was kept in all groups. Portal vein arterialization of 70% reduced rat livers significantly reduced liver regeneration as shown by a significant reduction in liver weight, body weight, and liver function after 6 wk, in contrast to the group with 70% liver mass reduction and portal venous inflow of the portal vein. Furthermore, we found a significantly elevated number of apoptotic hepatocytes after portal vein arterialization. These results were independent from blood flow regulation of the arterialized portal vein, which caused no improvement of the results. Portal vein arterialization should be performed only temporarily and is clinically not recommended as a permanent option, because of the increased hepatocellular apoptosis and the very distinctive, negative long-term effects on liver weight.

  11. Effects of Neurolytic Celiac Plexus Block on Liver Regeneration in Rats with Partial Hepatectomy

    OpenAIRE

    Jun Li; Hong-Tao Yan; Jian-Xiang Che; Shu-Rong Bai; Qing-Ming Qiu; Ling Ren; Fan Pan; Xiao-Qin Sun; Fu-Zhou Tian; Dong-Xuan Li; Li-Jun Tang

    2013-01-01

    Liver regeneration is the basic physiological process after partial hepatectomy (PH), and is important for the functional rehabilitation of the liver after acute hepatic injury. This study was designed to explore the effects of neurolytic celiac plexus block (NCPB) on liver regeneration after PH. We established a model of PH in rats, assessing hepatic blood flow, liver function, and serum CRP, TNF-α, IL-1β and IL-6 concentrations of the residuary liver after PH. Additionally, histopathologica...

  12. Genetic tracing of hepatocytes in liver homeostasis, injury, and regeneration.

    Science.gov (United States)

    Wang, Yue; Huang, XiuZhen; He, Lingjuan; Pu, Wenjuan; Li, Yan; Liu, Qiaozhen; Li, Yi; Zhang, Libo; Yu, Wei; Zhao, Huan; Zhou, Yingqun; Zhou, Bin

    2017-05-26

    The liver possesses a remarkable capacity to regenerate after damage. There is a heated debate on the origin of new hepatocytes after injuries in adult liver. Hepatic stem/progenitor cells have been proposed to produce functional hepatocytes after injury. Recent studies have argued against this model and suggested that pre-existing hepatocytes, rather than stem cells, contribute new hepatocytes. This hepatocyte-to-hepatocyte model is mainly based on labeling of hepatocytes with Cre-recombinase delivered by the adeno-associated virus. However, the impact of virus infection on cell fate determination, consistency of infection efficiency, and duration of Cre-virus in hepatocytes remain confounding factors that interfere with the data interpretation. Here, we generated a new genetic tool Alb-DreER to label almost all hepatocytes (>99.5%) and track their contribution to different cell lineages in the liver. By "pulse-and-chase" strategy, we found that pre-existing hepatocytes labeled by Alb-DreER contribute to almost all hepatocytes during normal homeostasis and after liver injury. Virtually all hepatocytes in the injured liver are descendants of pre-existing hepatocytes through self-expansion. We concluded that stem cell differentiation is unlikely to be responsible for the generation of a substantial number of new hepatocytes in adult liver. Our study also provides a new mouse tool for more precise in vivo genetic study of hepatocytes in the field. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Regulation of Signal Transduction and Role of Platelets in Liver Regeneration

    Directory of Open Access Journals (Sweden)

    Takeshi Nowatari

    2012-01-01

    Full Text Available Among all organs, the liver has a unique regeneration capability after sustaining injury or the loss of tissue that occurs mainly due to mitosis in the hepatocytes that are quiescent under normal conditions. Liver regeneration is induced through a cascade of various cytokines and growth factors, such as, tumor necrosis factor alpha, interleukin-6, hepatocyte growth factor, and insulin-like growth factor, which activate nuclear factor κB, signal transducer and activator of transcription 3, and phosphatidyl inositol 3-kinase signaling pathways. We previously reported that platelets can play important roles in liver regeneration through a direct effect on hepatocytes and collaborative effects with the nonparenchymal cells of the liver, including Kupffer cells and liver sinusoidal endothelial cells, which participate in liver regeneration through the production of various growth factors and cytokines. In this paper, the roles of platelets and nonparenchymal cells in liver regeneration, including the associated cytokines, growth factors, and signaling pathways, are described.

  14. Structural changes in the cytoskeleton in regenerating mouse liver cells

    Energy Technology Data Exchange (ETDEWEB)

    Gleiberman, A.S.; Bannikov, G.A.; Troyanovskii, S.M.

    1985-05-01

    After CCl/sub 4/ poisoning induced in rats poisoning centrilobular necroses formed in the liver during the next 24 h. Single a-feto protein-containing cells appeared onnthe second day of regeneration. By the end of the 2nd day a perinecrotic layer of cells containing AFP was formed. There is a definite correlation between loss of biliary capillary antigen, the appearance of bundles of prekeratin and actin, and expression of AFP synthesis. It is possible to include all these features in a single marker ocmplex of ''embronalization'' of the hepatocyte.

  15. Hyperplasia vs hypertrophy in tissue regeneration after extensive liver resection.

    Science.gov (United States)

    Marongiu, Fabio; Marongiu, Michela; Contini, Antonella; Serra, Monica; Cadoni, Erika; Murgia, Riccardo; Laconi, Ezio

    2017-03-14

    To address to what extent hypertrophy and hyperplasia contribute to liver mass restoration after major tissue loss. The ability of the liver to regenerate is remarkable on both clinical and biological grounds. Basic mechanisms underlying this process have been intensively investigated. However, it is still debated to what extent hypertrophy and hyperplasia contribute to liver mass restoration after major tissue loss. We addressed this issue using a genetically tagged system. We were able to follow the fate of single transplanted hepatocytes during the regenerative response elicited by 2/3 partial surgical hepatectomy (PH) in rats. Clusters of transplanted cells were 3D reconstructed and their size distribution was evaluated over time after PH. Liver size and liver DNA content were largely recovered 10 d post-PH, as expected (e.g., total DNA/liver/100 g b.w. was 6.37 ± 0.21 before PH and returned to 6.10 ± 0.36 10 d after PH). Data indicated that about 2/3 of the original residual hepatocytes entered S-phase in response to PH. Analysis of cluster size distribution at 24, 48, 96 h and 10 d after PH revealed that about half of the remnant hepatocytes completed at least 2 cell cycles. Average size of hepatocytes increased at 24 h (248.50 μm(2) ± 7.82 μm(2), P = 0.0015), but returned to control values throughout the regenerative process (up to 10 d post-PH, 197.9 μm(2) ± 6.44 μm(2), P = 0.11). A sizeable fraction of the remnant hepatocyte population does not participate actively in tissue mass restoration. Hyperplasia stands as the major mechanism contributing to liver mass restoration after PH, with hypertrophy playing a transient role in the process.

  16. Inhibition of Glycogen Synthase Kinase 3 Accelerated Liver Regeneration after Acetaminophen-Induced Hepatotoxicity in Mice.

    Science.gov (United States)

    Bhushan, Bharat; Poudel, Samikshya; Manley, Michael W; Roy, Nairita; Apte, Udayan

    2017-03-01

    Overdose of acetaminophen (APAP) is the leading cause of acute liver failure (ALF) in the United States. Timely initiation of compensatory liver regeneration after APAP hepatotoxicity is critical for final recovery, but the mechanisms of liver regeneration after APAP-induced ALF have not been extensively explored yet. Previous studies from our laboratory have demonstrated that activation of β-catenin signaling after APAP overdose is associated with timely liver regeneration. Herein, we investigated the role of glycogen synthase kinase 3 (GSK3) in liver regeneration after APAP hepatotoxicity using a pharmacological inhibition strategy in mice. Treatment with specific GSK3 inhibitor (L803-mts), starting from 4 hours after 600 mg/kg dose of APAP, resulted in early initiation of liver regeneration in a dose-dependent manner, without modifying the peak regenerative response. Acceleration of liver regeneration was not secondary to alteration of APAP-induced hepatotoxicity, which remained unchanged after GSK3 inhibition. Early cell cycle initiation in hepatocytes after GSK3 inhibition was because of rapid induction of cyclin D1 and phosphorylation of retinoblastoma protein. This was associated with increased activation of β-catenin signaling after GSK3 inhibition. Taken together, our study has revealed a novel role of GSK3 in liver regeneration after APAP overdose and identified GSK3 as a potential therapeutic target to improve liver regeneration after APAP-induced ALF. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  17. Farnesoid X receptor, the bile acid sensing nuclear receptor, in liver regeneration

    Directory of Open Access Journals (Sweden)

    Guodong Li

    2015-03-01

    Full Text Available The liver is unique in regenerative potential, which could recover the lost mass and function after injury from ischemia and resection. The underlying molecular mechanisms of liver regeneration have been extensively studied in the past using the partial hepatectomy (PH model in rodents, where 2/3 PH is carried out by removing two lobes. The whole process of liver regeneration is complicated, orchestrated event involving a network of connected interactions, which still remain fully elusive. Bile acids (BAs are ligands of farnesoid X receptor (FXR, a nuclear receptor of ligand-activated transcription factor. FXR has been shown to be highly involved in liver regeneration. BAs and FXR not only interact with each other but also regulate various downstream targets independently during liver regeneration. Moreover, recent findings suggest that tissue-specific FXR also contributes to liver regeneration significantly. These novel findings suggest that FXR has much broader role than regulating BA, cholesterol, lipid and glucose metabolism. Therefore, these researches highlight FXR as an important pharmaceutical target for potential use of FXR ligands to regulate liver regeneration in clinic. This review focuses on the roles of BAs and FXR in liver regeneration and the current underlying molecular mechanisms which contribute to liver regeneration.

  18. Akt-mediated foxo1 inhibition is required for liver regeneration.

    Science.gov (United States)

    Pauta, Montse; Rotllan, Noemi; Fernández-Hernando, Ana; Langhi, Cedric; Ribera, Jordi; Lu, Mingjian; Boix, Loreto; Bruix, Jordi; Jimenez, Wladimiro; Suárez, Yajaira; Ford, David A; Baldán, Angel; Birnbaum, Morris J; Morales-Ruiz, Manuel; Fernández-Hernando, Carlos

    2016-05-01

    Understanding the hepatic regenerative process has clinical interest as the effectiveness of many treatments for chronic liver diseases is conditioned by efficient liver regeneration. Experimental evidence points to the need for a temporal coordination between cytokines, growth factors, and metabolic signaling pathways to enable successful liver regeneration. One intracellular mediator that acts as a signal integration node for these processes is the serine-threonine kinase Akt/protein kinase B (Akt). To investigate the contribution of Akt during hepatic regeneration, we performed partial hepatectomy in mice lacking Akt1, Akt2, or both isoforms. We found that absence of Akt1 or Akt2 does not influence liver regeneration after partial hepatectomy. However, hepatic-specific Akt1 and Akt2 null mice show impaired liver regeneration and increased mortality. The major abnormal cellular events observed in total Akt-deficient livers were a marked reduction in cell proliferation, cell hypertrophy, glycogenesis, and lipid droplet formation. Most importantly, liver-specific deletion of FoxO1, a transcription factor regulated by Akt, rescued the hepatic regenerative capability in Akt1-deficient and Akt2-deficient mice and normalized the cellular events associated with liver regeneration. The Akt-FoxO1 signaling pathway plays an essential role during liver regeneration. © 2015 by the American Association for the Study of Liver Diseases.

  19. Anti-inflammatory liposomes have no impact on liver regeneration in rats

    DEFF Research Database (Denmark)

    Jepsen, Betina Norman; Andersen, Kasper Jarlhelt; Knudsen, Anders Riegels;

    2015-01-01

    ; liver tissue was sampled for analysis of regeneration rate and proliferation index. Results: The high dose dexamethasone group had significantly lower body and liver weight than the placebo and anti-CD163-dex groups. There were no differences in liver regeneration rates between groups. Hepatocyte......Introduction: Surgical resection is the gold standard in treatment of hepatic malignancies, giving the patient the best chance to be cured. The liver has a unique capacity to regenerate. However, an inflammatory response occurs during resection, in part mediated by Kupffer cells, that influences...... the speed of regeneration. The aim of this study was to investigate the effect of a Kupffer cell targeted anti-inflammatory treatment on liver regeneration in rats. Methods: Two sets of animals, each including four groups of eight rats, were included. Paired groups from each set received treatment...

  20. Fetal and adult liver stem cells for liver regeneration and tissue engineering.

    Science.gov (United States)

    Fiegel, H C; Lange, Claudia; Kneser, U; Lambrecht, W; Zander, A R; Rogiers, X; Kluth, D

    2006-01-01

    For the development of innovative cell-based liver directed therapies, e.g. liver tissue engineering, the use of stem cells might be very attractive to overcome the limitation of donor liver tissue. Liver specific differentiation of embryonic, fetal or adult stem cells is currently under investigation. Different types of fetal liver (stem) cells during development were identified, and their advantageous growth potential and bipotential differentiation capacity were shown. However, ethical and legal issues have to be addressed before using fetal cells. Use of adult stem cells is clinically established, e.g. transplantation of hematopoietic stem cells. Other bone marrow derived liver stem cells might be mesenchymal stem cells (MSC). However, the transdifferentiation potential is still in question due to the observation of cellular fusion in several in vivo experiments. In vitro experiments revealed a crucial role of the environment (e.g. growth factors and extracellular matrix) for specific differentiation of stem cells. Co-cultured liver cells also seemed to be important for hepatic gene expression of MSC. For successful liver cell transplantation, a novel approach of tissue engineering by orthotopic transplantation of gel-immobilized cells could be promising, providing optimal environment for the injected cells. Moreover, an orthotopic tissue engineering approach using bipotential stem cells could lead to a repopulation of the recipients liver with healthy liver and biliary cells, thus providing both hepatic functions and biliary excretion. Future studies have to investigate, which stem cell and environmental conditions would be most suitable for the use of stem cells for liver regeneration or tissue engineering approaches.

  1. Bile acid flux is necessary for normal liver regeneration.

    Directory of Open Access Journals (Sweden)

    Willscott E Naugler

    Full Text Available BACKGROUND & AIMS: Many signals governing liver regeneration (LR following 2/3 partial hepatectomy (PH are recognized, but the primary signal(s remains unknown. The aim of the study was to confirm that the remnant liver after PH lacks capacity to secrete the BA pool returning via the enterohepatic ciruculation (EHC, which may in turn stimulate LR. METHODS: After standard PH, BA flux was documented and BA signaling (Fgf15 and synthesis (Cyp7a determined by qPCR. Rat biliary fistula (BF and Asbt knockout mouse models interrupted the EHC prior to PH, and standard assays for LR employed along with complete RNA sequencing. CCl4 intoxication after BF tested the hypothesis in an alternate injury model. RESULTS: BA rise in systemic blood immediately following PH, confirming that the remnant liver cannot handle the BA returning via portal circulation. When the BA pool is drained prior to PH in the rat BF model, LR is markedly attenuated, a phenomenon reversed with duodenal BA replacement. Hepatocyte proliferation is similarly attenuated after PH in the Asbt knockout mouse as well as after CCl44 intoxication in rats with BF. Complete RNA sequencing in the rat PH model shows that early c-jun and AP-1 gene expression pathways are down regulated in the absence of BA, coincident with attenuated LR. CONCLUSIONS: Absent BA return to the liver after PH or CCl4 injury markedly attenuates LR, though hepatocyte proliferation still occurs, inferring that BA flux and signaling are not the sole signals governing LR. Transcriptional networks involving c-jun and AP-1 are involved in the BA-specific effects on hepatocyte proliferation.

  2. TWEAK/Fn14 Signaling Is Required for Liver Regeneration after Partial Hepatectomy in Mice

    OpenAIRE

    Gamze Karaca; Marzena Swiderska-Syn; Guanhua Xie; Wing-Kin Syn; Leandi Krüger; Mariana Verdelho Machado; Katherine Garman; Choi, Steve S.; Michelotti, Gregory A.; Burkly, Linda C.; Begoña Ochoa; Anna Mae Diehl

    2014-01-01

    Background & Aims: Pro-inflammatory cytokines are important for liver regeneration after partial hepatectomy (PH). Expression of Fibroblast growth factor-inducible 14 (Fn14), the receptor for TNF-like weak inducer of apoptosis (TWEAK), is induced rapidly after PH and remains elevated throughout the period of peak hepatocyte replication. The role of Fn14 in post-PH liver regeneration is uncertain because Fn14 is expressed by liver progenitors and TWEAK-Fn14 interactions stimulate progenitor gr...

  3. Phenotypic changes of human cells in human-rat liver during partial hepatectomy-induced regeneration

    Institute of Scientific and Technical Information of China (English)

    Yan Sun; Dong Xiao; Hong-An Li; Jin-Fang Jiang; Qing Li; Ruo-Shuang Zhang; Xi-Gu Chen

    2009-01-01

    AIM: To examine the human hepatic parenchymal and stromal components in rat liver and the phenotypic changes of human cells in liver of human-rat chimera (HRC) generated by in utero transplantation of human cells during partial hepatectomy (PHx)-induced liver regeneration. METHODS: Human hepatic parenchymal and stromal components and phenotypic changes of human cells during liver regeneration were examined by flow cytometry, in situ hybridization and immunohistochemistry. RESULTS: ISH analysis demonstrated human Alupositive cells in hepatic parenchyma and stroma of recipient liver. Functional human hepatocytes generated in this model potentially constituted human hepatic functional units with the presence of donor-derived human endothelial and biliary duct cells in host liver. Alpha fetoprotein (AFP)+, CD34+ and CD45+ cells were observed in the chimeric liver on day 10 after PHxinduced liver regeneration and then disappeared in PHx group, but not in non-PHx group, suggesting that dynamic phenotypic changes of human cells expressing AFP, CD34 and CD45 cells may occur during the chimeric liver regeneration. Additionally, immunostaining for human proliferating cell nuclear antigen (PCNA) showed that the number of PCNA-positive cells in the chimeric liver of PHx group was markedly increased, as compared to that of control group, indicating that donor-derived human cells are actively proliferated during PHx-induced regeneration of HRC liver.

  4. Elevated liver regeneration in response to pharmacological reduction of elevated portal venous pressure by terlipressin after partial hepatectomy.

    OpenAIRE

    Fahrner, René; Patsenker, Eleanora; De Gottardi, Andrea; Stickel, Felix; Montani, Matteo; Keogh-Stroka, Deborah M.; CANDINAS, DANIEL; Beldi, Guido

    2014-01-01

    BACKGROUND Liver regeneration is of crucial importance for patients undergoing living liver transplantations or extended liver resections and can be associated with elevated portal venous pressure, impaired hepatic regeneration, and postoperative morbidity. The aim of this study was to assess whether reduction of portal venous pressure by terlipressin improves postoperative liver regeneration in normal and steatotic livers after partial hepatectomy in a rodent model. METHODS Porta...

  5. Expression patterns and action analysis of genes associated with blood coagulation responses during rat liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Li-Feng Zhao; Wei-Min Zhang; Cun-Shuan Xu

    2006-01-01

    AIM:To study the blood coagulation response after partial hepatectomy (PH) at transcriptional level.METHODS:After PH of rats, the associated genes with blood coagulation were obtained through reference to the databases, and the gene expression changes in rat regenerating liver were analyzed by the Rat Genome 230 2.0 array.RESULTS: It was found that 107 genes were associated with liver regeneration. The initially and totally expressing gene numbers occurring in initiation phase of liver regeneration (0.5-4 h after PH), G0/G1 transition (4-6 h after PH), cell proliferation (6-66 h after PH), cell differentiation and structure-function reconstruction (66-168 h after PH) were 44, 11, 58, 7 and 44, 33,100, 71 respectively, showing that the associated genes were mainly triggered in the forepart and prophase, and worked at different phases. According to their expression similarity, these genes were classified into 5 groups:only up-, predominantly up-, only down-, predominantly down-, up- and down-regulation, involving 44, 8, 36,13 and 6 genes, respectively, and the total times of their up- and down-regulation expression were 342 and 253, respectively, demonstrating that the number of the up-regulated genes was more than that of the downregulated genes. Their time relevance was classified into 15 groups, showing that the cellular physiological and biochemical activities were staggered during liver regeneration. According to gene expression patterns,they were classified into 29 types, suggesting that their protein activities were diverse and complex during liver regeneration.CONCLUSION: The blood coagulation response is enhanced mainly in the forepart, prophase and anaphase of liver regeneration, in which the response in the forepart, prophase of liver regeneration can prevent the bleeding caused by partial hepatectomy, whereas that in the anaphase contributes to the structure-function reorganization of regenerating liver. In the process,107 genes associated with liver

  6. The impact of hepatic steatosis on liver regeneration after partial hepatectomy

    NARCIS (Netherlands)

    Kele, Petra G.; van der Jagt, Eric J.; Gouw, Annette S. H.; Lisman, Ton; Porte, Robert J.; de Boer, Marieke T.

    2013-01-01

    Background & Aim Experimental studies in animals have suggested that liver regeneration is impaired in steatotic livers. However, few studies have focused on the impact of steatosis in patients undergoing partial hepatectomy (PH). This study aims to determine the role of steatosis on liver regenerat

  7. Laminin and Fibronectin in Cell Adhesion: Enhanced Adhesion of Cells from Regenerating Liver to Laminin

    Science.gov (United States)

    Carlsson, Roland; Engvall, Eva; Freeman, Aaron; Ruoslahti, Erkki

    1981-04-01

    Laminin, a basement membrane glycoprotein isolated from cultures of mouse endodermal cells and rat yolk sac carcinoma cells, promoted the attachment of liver cells obtained from regenerating mouse liver. Cells from normal mouse liver attached readily to dishes coated with fibronectin but attached poorly to surfaces coated with laminin. Both proteins efficiently promoted the attachment of cells from livers undergoing regeneration. After regeneration, the attachment to laminin returned to the low levels found in animals not subjected to partial hepatectomy but attachment to fibronectin remained high. Immunofluorescent staining of sections of normal liver with antilaminin revealed the presence of laminin in or adjacent to the walls of the bile ducts and blood vessels. After induction of regeneration by partial hepatectomy, increased amounts of laminin appeared in the sinusoidal areas. After carbon tetrachloride poisoning, staining for laminin was especially pronounced in the necrotic and postnecrotic areas around the central veins. This additional expression of laminin was transient. It reached a maximum around 5-6 days after the injury and then gradually disappeared. These findings show that laminin is an adhesive protein. The increase of laminin in regenerating liver and the adhesiveness of cells from such livers to laminin suggest a role for laminin in the maintenance of a proper tissue organization during liver regeneration.

  8. Advances in Translational Medicine of Liver Regeneration-Associated Regulatory Factors

    Institute of Scientific and Technical Information of China (English)

    HAN Jin-bin; MA Cong; SHI Yan-qiong

    2016-01-01

    The liver is an important organ that has strong regeneration and defensive ability in human body. The cell types participating in liver regeneration have close association with the severity of liver injury. When the liver is in mild injury, it mainly repairs the injury through the cellular proliferation of liver parenchyma, whereas when the liver is in severe injury complicated with liver cell aplasia, the liver tissues will launch stem cell proliferative responses. Liver cells and stem cells have different responses to injury, so there may be specific regulation of signal routines and factors. Translational medicine mainly guides clinical practice through basic research, which not only promotes the development of modern medicine, but also is the strong impetus that promotes the development of modern medicine. The application of translational medicine has greatly improved the therapeutic efifcacy of liver surgery, liver cancer and liver transplantation around the world. This study mainly reviewed the advances in translational medicine of liver regeneration-associated regulatory factors, hoping to provide references for the clinical diagnosis and treatment of liver diseases.

  9. Cloning and characterization of a mouse liver-specific gene mfrep-1, upregulated in liver regeneration

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Human fibrinogen-related protein-1/liver fibrinogen-related protein-1 (HFREP-1/LFIRE-1), a liver-specificprotein, is a member of fibrinogen superfamily that exerts various biological activities. However, the func-tion of HFREP-1/LFIRE-1 in liver remains unknown. Here we isolated its mouse ortholog gene-mousefibrinogen-related protein-1 (mfrep-1), which encoded 314 amino acids, exhibiting 80.4% similarity toHFREP-1/LFIRE-1. Northern blot analysis revealed that 1.2-kb mfrep-1 mRNA was detected selectivelyin mouse liver. To explore the function of MFREP-1, we examined the levels of mfrep-1 mRNA duringregeneration after 70% partial hepatectomy (PHx) in mice. mfrep-1 mRNA increased in the regeneratingliver and reached the first shoulder peak at 2-4 h after PHx. Cycloheximide pretreatment could suppress theinduction of mfrep-1, indicating the up-regulation of this gene need de novo protein synthesis. Its mRNAcontinued to elevate at 6 h thereafter and reached the second peak at 24 h. The enhanced expression ofmfrep-1 maintained high until 72 h and then declined slowly to the basal level. Immunohistochemistryassessment confirmed the up-regulated expression of MFREP-1 protein in parenchymal cells during liverregeneration. These data suggested that MFREP-1 might play an important role in liver regeneration andbe involved in the regulation of cell growth.

  10. Decorin accelerates the liver regeneration after partial hepatectomy in fibrotic mice

    Institute of Scientific and Technical Information of China (English)

    Ma Rui; Chen Jiang; Li Zheyong; Tang Jiacheng; Wang Yifan; Cai Xiujun

    2014-01-01

    Background Considering the existence of a large number of liver cell degeneration and necrosis in fibrotic liver,liver function was damaged severely and could not effectively regenerate after partial hepatectomy (PHx).The aim of this study was to investigate whether decorin (DCN) could promote the liver regeneration after PHx in fibrotic mice.Methods Forty mice (5-week-old,Balb/c) were injected with CCl4 intraperitoneally and liver fibrosis model was established after 5 weeks.The survival mice were randomly divided into two groups:control group and DCN group.Then,we performed 70% PHx on all these mice and injected DCN or phosphate-buffered saline plus normal saline (NS) to each group,respectively,after surgery.Liver body weight ratio (/BR),quantitative real-time polymerase chain reaction,and immunohistochemistry were used to analyze liver regeneration and fibrosis degree in both groups,and to find out whether exogenous protein DCN could promote the regeneration of fibrosis liver after PHx.Results Expressions of α-smooth muscle actin (SMA) mRNA and LBR had significant increases in the DCN group at postoperative Day 3 (POD 3,P<0.05).The protein expressions of CD31,α-SMA,and tumor necrosis factor (TNF)-α were higher in the DCN group than those in the control group by immunohistochemistry at POD 3 (P<0.05).Conclusion Exogenous protein DCN could promote liver regeneration after PHx in fibrotic mice.

  11. Cloning and sequence analysis of human genomic DNA of augmenter of liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Jun Cheng; Yan Wei Zhong; Yan Liu; Jing Dong; Ji Zhen Yang; Ju Mei Chen

    2000-01-01

    @@INTRODUCTION The liver is one of the organs, which have potential regenerative capability in mammalian animal[1].The study of the canine model indicated that the liver could regenerate to original size after 70% hepatectomy in only two weeks[2]. So it is a hot research topic for the cellular and molecular mechanism of liver regeneration. Accumulated results demonstrated that the hepatocyte growth factor (HGF)[3], insulin-like growth factor Ⅰ and Ⅱ (IGF-Ⅰ, Ⅱ )[4], epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha)[5] and insulin[6] are among the most important growth factors for liver regenerative regulation. In recent years, a heat-stable protein in the serum of the patients with various liver diseases has been noted for its potential stimulation effects on the liver regeneration, and this growth factor is called hepatocyte-stimulatory substance (HSS).

  12. Expression of isgylation related genes in regenerating rat liver

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    Kuklin A. V.

    2015-10-01

    Full Text Available Our recent studies have revealed the early up-regulated expression of interferon alpha (IFNα in the liver, induced by partial hepatectomy. The role of this cytokine of innate immune response in liver regeneration is still controversial. Aim. To analyze expression of canonical interferon-stimulated genes Ube1l, Ube2l6, Trim25, Usp18 and Isg15 during the liver transition from quiescence to proliferation induced by partial hepatectomy, and acute phase response induced by laparotomy. These genes are responsible for posttranslational modification of proteins by ISGylation. The expression of genes encoding TATA binding protein (TBP and 18S rRNA served as indirect general markers of transcriptional and translational activities. Methods. The abundance of investigated RNAs was assessed in total liver RNA by real time RT–qPCR. Results. Partial hepatecomy induced steady upregulation of the Tbp and 18S rRNA genes expression during 12 hours post-surgery and downregulation or no change in expression of ISGylation-related genes during the first 3 hours followed by slight upregulation at 12 hours. The level of Isg15 transcripts was permanently below that of the control during the prereplicative period. Laparotomy induced a continuous downregulation of Tbp and 18S rRNA expression and early (1–3h upregulation of ISGylation–related transcripts followed by a sharp drop at 6 hours and slight increase/decrease at 12 hours. The changes in the abundance of Ifnα and ISGylation-related mRNAs were oppositely directed at each stage of the response to partial hepatectomy and laparotomy. Conclusion. We suggest that the expression of ISGylation-related genes does not depend on the expression of Ifnα gene after both surgeries. The indirect indices of transcription and translation as well as the expression of ISGylation-relaled genes are principally different in response to partial hepatectomy and laparotomy and argue for the high specificity of innate immune response.

  13. Anti-inflammatory liposomes have no impact on liver regeneration in rats

    Directory of Open Access Journals (Sweden)

    Betina Norman Jepsen

    2015-12-01

    Conclusion: Low dose dexamethasone targeted to Kupffer cells does not affect histological liver cell regeneration after 70% hepatectomy in rats, but reduces the inflammatory response judged by circulating markers of inflammation.

  14. Effect of the aqueous extract of Sida cordifolia on liver regeneration after partial hepatectomy.

    Science.gov (United States)

    Silva, Renata Lemos; Melo, Gustavo Barreto de; Melo, Valdinaldo Aragão de; Antoniolli, Angelo Roberto; Michellone, Paulo Roberto Teixeira; Zucoloto, Sérgio; Picinato, Maria Aparecida Neves Cardoso; Franco, Clarice Fleury Fina; Mota, Gustavo de Assis; Silva, Orlando de Castro e

    2006-01-01

    The use of medicinal plants for the treatment of human diseases has increased worldwide. Many of them are used by oral administration and, after absorption, may affect many organs. Therefore, this study aimed at assessing the effects of the aqueous extract of Sida cordifolia leaves, popularly known in Brazil as "malva-branca", on liver regeneration. Twenty rats were divided into four groups: control, Sida100, Sida200 and Sida400 groups. All animals were submitted to oral administration of distilled water, 100, 200 and 400 mg/kg of the aqueous extract of Sida cordifolia, respectively. Immediately after this, they underwent 67% partial hepatectomy. Twenty four hours later, their livers were removed. Hepatic regeneration was assessed by immunohistochemical staining for proliferating cell nuclear antigen (PCNA) using the PC-10 monoclonal antibody. Sida100 and Sida200 groups disclosed higher liver regeneration indices than control group (pSida cordifolia stimulates liver regeneration after 67% partial hepatectomy in rats.

  15. Up-regulated extracellular matrix components and inflammatory chemokines may impair the regeneration of cholestatic liver

    OpenAIRE

    Shuai Zhang; Tao-Sheng Li; Akihiko Soyama; Takayuki Tanaka; Chen Yan; Yusuke Sakai; Masaaki Hidaka; Ayaka Kinoshita; Koji Natsuda; Mio Fujii; Tota Kugiyama; Zhassulan Baimakhanov; Tamotsu Kuroki; Weili Gu; Susumu Eguchi

    2016-01-01

    Although the healthy liver is known to have high regenerative potential, poor liver regeneration under pathological conditions remains a substantial problem. We investigated the key molecules that impair the regeneration of cholestatic liver. C57BL/6 mice were randomly subjected to partial hepatectomy and bile duct ligation (PH+BDL group, n = 16), partial hepatectomy only (PH group, n = 16), or sham operation (Sham group, n = 16). The liver sizes and histological findings were similar in the ...

  16. Effect of 5-HT7 receptor blockade on liver regeneration after 60-70% partial hepatectomy

    OpenAIRE

    Tzirogiannis, Konstantinos N; Kourentzi, Kalliopi T; Zyga, Sofia; Papalimneou, Vassiliki; Tsironi, Maria; Grypioti, Agni D; Protopsaltis, Ioannis; Panidis, Dimitrios; Panoutsopoulos, Georgios I

    2014-01-01

    Background Serotonin exhibits a vast repertoire of actions including cell proliferation and differentiation. The effect of serotonin, as an incomplete mitogen, on liver regeneration has recently been unveiled and is mediated through 5-HT2 receptor. The aim of the present study was to investigate the effect of 5-HT7 receptor blockade on liver regeneration after partial hepatectomy. Methods Male Wistar rats were subjected to 60-70% partial hepatectomy. 5-HT7 receptor blockade was applied by int...

  17. [Regulation of autophagy on dendritic cells during rat liver regeneration by IPA].

    Science.gov (United States)

    Qiwen, Wang; Wei, Jin; Cuifang, Chang; Cunshuan, Xu

    2015-03-01

    To understand the mechanism underlying autophagy in regulating dendritic cells during rat liver regeneration, we used the method of percoll density gradient centrifugation combined with immunomagnetic bead to isolate dendritic cells, the Rat Genome 230 2.0 Array to determine the expression changes of autophagy-related genes, and Ingenuity Pathway Analysis 9.0 (IPA) to determine the autophagy activities. The results indicated that LC3, BECN1, ATG7 and SQSTM1 genes had significant expression changes during rat liver regeneration. There were 593 genes related to autophagy, among which 210 genes were identified as significant. We also showed that the activity of autophagy was enhanced in the priming phase and teminal phase of liver regeneration, weakened in the proliferative stage by comparative analysis method of IPA. The autophagy-related physiological activities mainly included RNA expression, RNA transcription, cell differentiation and proliferation, involving in PPARα/RXRα activation, acute phase response signaling, TREM1 signaling, IL-6 signaling, IL-8 signaling and IL-1 signaling, whose activities were increased or decreased in liver regeneration. Cluster analysis found that P53 and AMPK signaling participated in the regulation of dendritic cells autophagy, with AMPK signaling in the priming phase of liver regeneration, and both signaling pathways in the terminal phase. We conclude that dendritic cells autophagy played an important role in initiation of the immune response in priming phase and depletion of dendritic cells in late phase during rat liver regeneration.

  18. Postponing the Hypoglycemic Response to Partial Hepatectomy Delays Mouse Liver Regeneration.

    Science.gov (United States)

    Huang, Jiansheng; Schriefer, Andrew E; Cliften, Paul F; Dietzen, Dennis; Kulkarni, Sakil; Sing, Sucha; Monga, Satdarshan P S; Rudnick, David A

    2016-03-01

    All serious liver injuries alter metabolism and initiate hepatic regeneration. Recent studies using partial hepatectomy (PH) and other experimental models of liver regeneration implicate the metabolic response to hepatic insufficiency as an important source of signals that promote regeneration. Based on these considerations, the analyses reported here were undertaken to assess the impact of interrupting the hypoglycemic response to PH on liver regeneration in mice. A regimen of parenteral dextrose infusion that delays PH-induced hypoglycemia for 14 hours after surgery was identified, and the hepatic regenerative response to PH was compared between dextrose-treated and control mice. The results showed that regenerative recovery of the liver was postponed in dextrose-infused mice (versus vehicle control) by an interval of time comparable to the delay in onset of PH-induced hypoglycemia. The regulation of specific liver regeneration-promoting signals, including hepatic induction of cyclin D1 and S-phase kinase-associated protein 2 expression and suppression of peroxisome proliferator-activated receptor γ and p27 expression, was also disrupted by dextrose infusion. These data support the hypothesis that alterations in metabolism that occur in response to hepatic insufficiency promote liver regeneration, and they define specific pro- and antiregenerative molecular targets whose regenerative regulation is postponed when PH-induced hypoglycemia is delayed.

  19. Consequences of TCDD treatment on intra-hepatic lymphocytes during liver regeneration.

    Science.gov (United States)

    Horras, Christopher J; Lamb, Cheri L; King, Allie L; Hanley, Jason R; Mitchell, Kristen A

    2012-01-01

    Increasing evidence demonstrates a physiological role for the aryl hydrocarbon receptor (AhR) in regulating hepatocyte cell cycle progression. Previous studies have used a murine model of liver regeneration to show that exposure to the potent exogenous AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), suppresses hepatocyte proliferation in vivo. Based on recent reports that natural killer (NK) cells negatively regulate liver regeneration, coupled with the well-established immunomodulatory effects of TCDD, it was hypothesized that alterations in lymphocyte activation contribute to the suppression of liver regeneration in TCDD-treated mice. To test this, mice were treated with TCDD (20 μg/kg) 1 day prior to 70% partial hepatectomy (PH), in which two-thirds of the liver was surgically resected. Lymphocytes were collected from the remnant liver and analyzed by flow cytometry. Whereas exposure to TCDD did not alter the number of NK cells or CD3(+) T-cells recovered from the regenerating liver, it reduced the percentage and number of intra-hepatic NKT cells 42 h after PH. With regard to lymphocyte activation, TCDD treatment transiently increased CD69 expression on NK and NKT cells 12 h after PH, but had no effect on intracellular levels of IFNγ in NK, NKT, or CD3(+) T-cells. To determine the relevance of NK cells to the suppression of liver regeneration by TCDD, mice were treated with anti-Asialo GM-1 (ASGM-1) antibody to deplete NK cells prior to TCDD treatment and PH, and hepatocyte proliferation was measured using bromodeoxyuridine incorporation. Exposure to TCDD was found to inhibit hepatocyte proliferation in the regenerating liver of NK cell-depleted mice and control mice to the same extent. Hence, it is unlikely that enhanced numbers or increased activation of NK cells contribute to the suppression of liver regeneration in TCDD-treated mice.

  20. Impairment of liver regeneration by the histone deacetylase inhibitor valproic acid in mice

    Institute of Scientific and Technical Information of China (English)

    Qi KE; Rui-na YANG; Feng YE; Yu-jia WANG; Qiong WU; Li LI; Hong BU

    2012-01-01

    Background and objective:Liver regeneration is a complex process regulated by a group of genetic and epigenetic factors.A variety of genetic factors have been reported,whereas few investigations have focused on epigenetic regulation during liver regeneration.In the present study,valproic acid (VPA),a histone deacetylase (HDAC)inhibitor,was used to investigate the effect of HDAC on liver regeneration.Methods:VPA was administered via intraperitoneal injection to 2/3 partially hepatectomized mice to detect hepatocyte proliferation during liver regeneration.The mice were sacrificed,and their liver tissues were harvested at sequential time points from 0 to 168 h after treatment.DNA synthesis was detected via a BrdU assay,and cell proliferation was tested using Ki-67.The expressions of cyclin D1,cyclin E,cyclin dependent kinase 2 (CDK2),and CDK4 were detected by Western blot analysis.Chromatin immunoprecipitation (ChIP) assay was used to examine the recruitment of HDACs to the target promoter regions and the expression of the target gene was detected by Western blot.Results:Immunohistochemical analysis showed that cells positive for BrdU and Ki-67 decreased,and the peak of BrdU was delayed in the VPA-administered mice.Consistently,cyclin D1 expression was also delayed.We identified B-myc as a target gene of HDACs by complementary DNA (cDNA) microarray.The expression of B-myc increased in the VPA-administered mice after hepatectomy (PH).The ChIP assay confirmed the presence of HDACs at the B-myc promoter.Conclusions:HDAC activities are essential for liver regeneration,inhibiting HDAC activities delays liver regeneration and induces liver cell cycle arrest,thereby causing an anti-proliferative effect on liver regeneration.

  1. Liver regeneration after living donor transplantation: adult-to-adult living donor liver transplantation cohort study.

    Science.gov (United States)

    Olthoff, Kim M; Emond, Jean C; Shearon, Tempie H; Everson, Greg; Baker, Talia B; Fisher, Robert A; Freise, Chris E; Gillespie, Brenda W; Everhart, James E

    2015-01-01

    of the rate of regeneration, and donor remnant fraction affects postresection function. Liver Transpl 21:79-88, 2015. © 2014 AASLD.

  2. Expression of AFP and Rev-Erb A/Rev-Erb B and N-CoR in fetal rat liver, liver injury and liver regeneration

    OpenAIRE

    Meier, Volker; Tron, Kyrylo; Batusic, Danko; Elmaouhoub, Abderrahim; Ramadori, Giuliano

    2006-01-01

    Background Alpha-fetoprotein (AFP) expression can resume in the adult liver under pathophysiological conditions. Orphan nuclear receptors were supposed to regulate AFP gene expression, in vitro. We were interested to study the expression of AFP and orphan nuclear receptors, in vivo. Results The expression of AFP gene and orphan nuclear receptors in the liver was examined in different rat models: (a) fetal liver (b) liver regeneration [partial hepatectomy (PH) with and without 2-acetyl-aminofl...

  3. Effects of adenoviral-mediated hepatocyte growth factor on liver regeneration after massive hepatectomy in rats

    Directory of Open Access Journals (Sweden)

    Doihara,Hiroyoshi

    2007-04-01

    Full Text Available Resection is the only curative treatment for liver metastasis of colorectal cancers. Despite the supreme regenerative potential of the liver, major hepatectomy sometimes leads to liver failure, and the limitation of resectable liver volumes makes advanced tumors inoperable. This study was attempted to promote liver regeneration using hepatocyte growth factor (HGF gene transfection by venous-administered adenovirus and to improve the survival of rats after massive hepatectomy. The adenovirus that encodes HGF was administered to rats before 85%-hepatectomy. The administration of HGF gene improved the survival of rats after massive hepatectomy, while the administration of control adenovirus deteriorated their survival. Gene transfection of HGF showed up-regulation of serum HGF, stimulation of hepatocellular proliferation and rapid liver regeneration. Moreover, HGF administration reduced apoptosis of hepatocytes. The administration of HGF gene prevented liver dysfunction after major hepatectomy and may be a new assist for surgery.

  4. Adult liver stem cells in hepatic regeneration and cancer

    NARCIS (Netherlands)

    Nantasanti, Sathidpak

    2015-01-01

    An alternative source of livers for transplantation in patients with (genetic) liver diseases and liver failure is needed because liver donors are scarce. HPC-derived hepatocyte-like cells could be one of the options. Because dogs and humans share liver-pathologies and disease-pathways, the dog is c

  5. Regeneration and Cell Recruitment in an Improved Heterotopic Auxiliary Partial Liver Transplantation Model in the Rat.

    Science.gov (United States)

    Ono, Yoshihiro; Pérez-Gutiérrez, Angelica; Yovchev, Mladen I; Matsubara, Kentaro; Yokota, Shinichiro; Guzman-Lepe, Jorge; Handa, Kan; Collin de l'Hortet, Alexandra; Thomson, Angus W; Geller, David A; Yagi, Hiroshi; Oertel, Michael; Soto-Gutierrez, Alejandro

    2017-01-01

    Auxiliary partial liver transplantation (APLT) in humans is a therapeutic modality used especially to treat liver failure in children or congenital metabolic disease. Animal models of APLT have helped to explore therapeutic options. Though many groups have suggested improvements, standardizing the surgical procedure has been challenging. Additionally, the question of whether graft livers are reconstituted by recipient-derived cells after transplantation has been controversial. The aim of this study was to improve experimental APLT in rats and to assess cell recruitment in the liver grafts. To inhibit recipient liver regeneration and to promote graft regeneration, we treated recipients with retrorsine and added arterial anastomosis. Using green fluorescence protein transgenic rats as recipients, we examined liver resident cell recruitment within graft livers by immunofluorescence costaining. In the improved APLT model, we achieved well-regenerated grafts that could maintain regeneration for at least 4 weeks. Regarding the cell recruitment, there was no evidence of recipient-derived hepatocyte, cholangiocyte, or hepatic stellate cell recruitment into the graft. Macrophages/monocytes, however, were consistently recruited into the graft and increased over time, which might be related to inflammatory responses. Very few endothelial cells showed colocalization of markers. We have successfully established an improved rat APLT model with arterial anastomosis as a standard technique. Using this model, we have characterized cell recruitment into the regenerating grafts.

  6. Effect of the Human Amniotic Membrane on Liver Regeneration in Rats

    Science.gov (United States)

    Sipahi, Mesut; Şahin, Sevinç; Arslan, Ergin; Börekci, Hasan; Metin, Bayram; Cantürk, Nuh Zafer

    2015-01-01

    Introduction. Operations are performed for broader liver surgery indications for a better understanding of hepatic anatomy/physiology and developments in operation technology. Surgery can cure some patients with liver metastasis of some tumors. Nevertheless, postoperative liver failure is the most feared complication causing mortality in patients who have undergone excision of a large liver mass. The human amniotic membrane has regenerative effects. Thus, we investigated the effects of the human amniotic membrane on regeneration of the resected liver. Methods. Twenty female Wistar albino rats were divided into control and experimental groups and underwent a 70% hepatectomy. The human amniotic membrane was placed over the residual liver in the experimental group. Relative liver weight, histopathological features, and biochemical parameters were assessed on postoperative day 3. Results. Total protein and albumin levels were significantly lower in the experimental group than in the control group. No difference in relative liver weight was observed between the groups. Hepatocyte mitotic count was significantly higher in the experimental group than in the control group. Hepatic steatosis was detected in the experimental group. Conclusion. Applying the amniotic membrane to residual liver adversely affected liver regeneration. However, mesenchymal stem cell research has the potential to accelerate liver regeneration investigations. PMID:26457000

  7. Effect of the Human Amniotic Membrane on Liver Regeneration in Rats

    Directory of Open Access Journals (Sweden)

    Mesut Sipahi

    2015-01-01

    Full Text Available Introduction. Operations are performed for broader liver surgery indications for a better understanding of hepatic anatomy/physiology and developments in operation technology. Surgery can cure some patients with liver metastasis of some tumors. Nevertheless, postoperative liver failure is the most feared complication causing mortality in patients who have undergone excision of a large liver mass. The human amniotic membrane has regenerative effects. Thus, we investigated the effects of the human amniotic membrane on regeneration of the resected liver. Methods. Twenty female Wistar albino rats were divided into control and experimental groups and underwent a 70% hepatectomy. The human amniotic membrane was placed over the residual liver in the experimental group. Relative liver weight, histopathological features, and biochemical parameters were assessed on postoperative day 3. Results. Total protein and albumin levels were significantly lower in the experimental group than in the control group. No difference in relative liver weight was observed between the groups. Hepatocyte mitotic count was significantly higher in the experimental group than in the control group. Hepatic steatosis was detected in the experimental group. Conclusion. Applying the amniotic membrane to residual liver adversely affected liver regeneration. However, mesenchymal stem cell research has the potential to accelerate liver regeneration investigations.

  8. PPARβ Regulates Liver Regeneration by Modulating Akt and E2f Signaling.

    Directory of Open Access Journals (Sweden)

    Hui-Xin Liu

    Full Text Available The current study tests the hypothesis that peroxisome proliferator-activated receptor β (PPARβ has a role in liver regeneration due to its effect in regulating energy homeostasis and cell proliferation. The role of PPARβ in liver regeneration was studied using two-third partial hepatectomy (PH in Wild-type (WT and PPARβ-null (KO mice. In KO mice, liver regeneration was delayed and the number of Ki-67 positive cells reached the peak at 60 hr rather than at 36-48 hr after PH shown in WT mice. RNA-sequencing uncovered 1344 transcriptomes that were differentially expressed in regenerating WT and KO livers. About 70% of those differentially expressed genes involved in glycolysis and fatty acid synthesis pathways failed to induce during liver regeneration due to PPARβ deficiency. The delayed liver regeneration in KO mice was accompanied by lack of activation of phosphoinositide-dependent kinase 1 (PDK1/Akt. In addition, cell proliferation-associated increase of genes encoding E2f transcription factor (E2f 1-2 and E2f7-8 as well as their downstream target genes were not noted in KO livers 36-48 hr after PH. E2fs have dual roles in regulating metabolism and proliferation. Moreover, transient steatosis was only found in WT, but not in KO mice 36 hr after PH. These data suggested that PPARβ-regulated PDK1/Akt and E2f signaling that controls metabolism and proliferation is involved in the normal progression of liver regeneration.

  9. Effect of L-arginine supplement on liver regeneration after partial hepatectomy in rats

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    Kurokawa Tsuyoshi

    2012-05-01

    Full Text Available Abstract Background Nitric oxide (NO has been reported to be a key mediator in hepatocyte proliferation during liver regeneration. NO is the oxidative metabolite of L-arginine, and is produced by a family of enzymes, collective termed nitric oxide synthase (NOS. Thus, administration of L-arginine might enhance liver regeneration after a hepatectomy. Another amino acid, L-glutamine, which plays an important role in catabolic states and is a crucial factor in various cellular and organ functions, is widely known to enhance liver regeneration experimentally. Thus, the present study was undertaken to evaluate the effects of an L-arginine supplement on liver regeneration, and to compared this with supplementation with L-glutamine and L-alanine (the latter as a negative control, using a rat partial hepatectomy model. Methods Before and after a 70% hepatectomy, rats received one of three amino acid solutions (L-arginine, L-glutamine, or L-alanine. The effects on liver regeneration of the administered solutions were examined by assessment of restituted liver mass, staining for proliferating cell nuclear antigen (PCNA, and total RNA and DNA content 24 and 72 hours after the operation. Results At 72 hours after the hepatectomy, the restituted liver mass, the PCNA labeling index and the DNA quantity were all significantly higher in the L-arginine and L-glutamine groups than in the control. There were no significant differences in those parameters between the L-arginine and L-glutamine groups, nor were any significant differences found between the L-alanine group and the control. Conclusion Oral supplements of L-arginine and L-glutamine enhanced liver regeneration after hepatectomy in rats, suggesting that an oral arginine supplement can clinically improve recovery after a major liver resection.

  10. Prediction of postoperative liver regeneration from clinical information using a data-led mathematical model

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    Yamamoto, Kimiyo N.; Ishii, Masatsugu; Inoue, Yoshihiro; Hirokawa, Fumitoshi; MacArthur, Ben D.; Nakamura, Akira; Haeno, Hiroshi; Uchiyama, Kazuhisa

    2016-10-01

    Although the capacity of the liver to recover its size after resection has enabled extensive liver resection, post-hepatectomy liver failure remains one of the most lethal complications of liver resection. Therefore, it is clinically important to discover reliable predictive factors after resection. In this study, we established a novel mathematical framework which described post-hepatectomy liver regeneration in each patient by incorporating quantitative clinical data. Using the model fitting to the liver volumes in series of computed tomography of 123 patients, we estimated liver regeneration rates. From the estimation, we found patients were divided into two groups: i) patients restored the liver to its original size (Group 1, n = 99) and ii) patients experienced a significant reduction in size (Group 2, n = 24). From discriminant analysis in 103 patients with full clinical variables, the prognosis of patients in terms of liver recovery was successfully predicted in 85–90% of patients. We further validated the accuracy of our model prediction using a validation cohort (prediction = 84–87%, n = 39). Our interdisciplinary approach provides qualitative and quantitative insights into the dynamics of liver regeneration. A key strength is to provide better prediction in patients who had been judged as acceptable for resection by current pragmatic criteria.

  11. Prediction of postoperative liver regeneration from clinical information using a data-led mathematical model

    Science.gov (United States)

    Yamamoto, Kimiyo N.; Ishii, Masatsugu; Inoue, Yoshihiro; Hirokawa, Fumitoshi; MacArthur, Ben D.; Nakamura, Akira; Haeno, Hiroshi; Uchiyama, Kazuhisa

    2016-01-01

    Although the capacity of the liver to recover its size after resection has enabled extensive liver resection, post-hepatectomy liver failure remains one of the most lethal complications of liver resection. Therefore, it is clinically important to discover reliable predictive factors after resection. In this study, we established a novel mathematical framework which described post-hepatectomy liver regeneration in each patient by incorporating quantitative clinical data. Using the model fitting to the liver volumes in series of computed tomography of 123 patients, we estimated liver regeneration rates. From the estimation, we found patients were divided into two groups: i) patients restored the liver to its original size (Group 1, n = 99); and ii) patients experienced a significant reduction in size (Group 2, n = 24). From discriminant analysis in 103 patients with full clinical variables, the prognosis of patients in terms of liver recovery was successfully predicted in 85–90% of patients. We further validated the accuracy of our model prediction using a validation cohort (prediction = 84–87%, n = 39). Our interdisciplinary approach provides qualitative and quantitative insights into the dynamics of liver regeneration. A key strength is to provide better prediction in patients who had been judged as acceptable for resection by current pragmatic criteria. PMID:27694914

  12. Liver graft hyperperfusion in the early postoperative period promotes hepatic regeneration 2 weeks after living donor liver transplantation

    Science.gov (United States)

    Byun, Sung Hye; Yang, Hae Soo; Kim, Jong Hae

    2016-01-01

    Abstract Hepatic regeneration is essential to meet the metabolic demands of partial liver grafts following living donor liver transplantation (LDLT). Hepatic regeneration is promoted by portal hyperperfusion of partial grafts, which produces shear stress on the sinusoidal endothelium. Hepatic regeneration is difficult to assess within the first 2 weeks after LDLT as the size of liver graft could be overestimated in the presence of postsurgical graft edema. In this study, we evaluated the effects of graft hyperperfusion on the rate of hepatic regeneration 2 weeks after LDLT by measuring hepatic hemodynamic parameters. Thirty-six patients undergoing LDLT were enrolled in this study. Hepatic hemodynamic parameters including peak portal venous flow velocity (PVV) were measured using spectral Doppler ultrasonography on postoperative day 1. Subsequently, we calculated the ratio of each velocity to 100 g of the initial graft weight (GW) obtained immediately after graft retrieval on the day of LDLT. Ratios of GW to recipient weight (GRWR) and to standard liver volume (GW/SLV) were also obtained. The hepatic regeneration rate was defined as the ratio of the regenerated volume measured using computed tomographic volumetry at postoperative week 2 to the initial GW. Correlations of the hemodynamic parameters, GRWR, and GW/SLV with the hepatic regeneration rate were assessed using a linear regression analysis. The liver grafts regenerated to approximately 1.7 times their initial GW (1.7 ± 0.3 [mean ± standard deviation]). PVV/100 g of GW (r2 = 0.224, β1 [slope coefficient] = 2.105, P = 0.004) and velocities of the hepatic artery and vein per 100 g of GW positively correlated with the hepatic regeneration rate, whereas GRWR (r2 = 0.407, β1 = –81.149, P < 0.001) and GW/SLV (r2 = 0.541, β1 = –2.184, P < 0.001) negatively correlated with the hepatic regeneration rate. Graft hyperperfusion demonstrated by increased hepatic

  13. Adiponectin fine-tuning of liver regeneration dynamics revealed through cellular network modeling.

    Science.gov (United States)

    Correnti, Jason M; Cook, Daniel; Aksamitiene, Edita; Swarup, Aditi; Ogunnaike, Babatunde; Vadigepalli, Rajanikanth; Hoek, Jan B

    2014-11-10

    Following partial hepatectomy, the liver initiates a regenerative program involving hepatocyte priming and replication driven by coordinated cytokine and growth factor actions. We investigated the mechanisms underlying Adiponectin's (Adn) regulation of liver regeneration through modulation of these mediators. Adn-/- mice showed delayed onset of hepatocyte replication, but accelerated cell cycle progression relative to wild-type mice, suggesting Adn has multiple effects fine-tuning the kinetics of liver regeneration. We developed a computational model describing the molecular and physiological kinetics of liver regeneration in Adn-/- mice. We employed this computational model to evaluate the underlying regulatory mechanisms. Our analysis predicted that Adn is required for an efficient early cytokine response to partial hepatectomy, but is inhibitory to later growth factor actions. Consistent with this prediction, Adn knockout reduced hepatocyte responses to IL-6 during the priming phase, but enhanced growth factor levels through peak hepatocyte replication. By contrast, supraphysiological concentrations of Adn resulting from rosiglitazone treatment suppressed regeneration by reducing growth factor levels during S phase, consistent with computational predictions. Together, these results revealed that Adn fine-tunes the progression of liver regeneration through dynamically modulating molecular mediator networks and cellular interactions within the liver. This article is protected by copyright. All rights reserved.

  14. Adiponectin fine-tuning of liver regeneration dynamics revealed through cellular network modelling.

    Science.gov (United States)

    Correnti, Jason M; Cook, Daniel; Aksamitiene, Edita; Swarup, Aditi; Ogunnaike, Babatunde; Vadigepalli, Rajanikanth; Hoek, Jan B

    2015-01-15

    Following partial hepatectomy, the liver initiates a regenerative programme involving hepatocyte priming and replication driven by the coordinated actions of cytokine and growth factors. We investigated the mechanisms underlying adiponectin's (Adn) regulation of liver regeneration through modulation of these mediators. Adn(-/-) mice showed delayed onset of hepatocyte replication, but accelerated cell cycle progression relative to wild-type mice, suggesting Adn has multiple effects fine-tuning the kinetics of liver regeneration. We developed a computational model describing the molecular and physiological kinetics of liver regeneration in Adn(-/-) mice. We employed this computational model to evaluate the underlying regulatory mechanisms. Our analysis predicted that Adn is required for an efficient early cytokine response to partial hepatectomy, but is inhibitory to later growth factor actions. Consistent with this prediction, Adn knockout reduced hepatocyte responses to interleukin-6 during the priming phase, but enhanced growth factor levels through peak hepatocyte replication. By contrast, supraphysiological concentrations of Adn resulting from rosiglitazone treatment suppressed regeneration by reducing growth factor levels during S phase, consistent with computational predictions. Together, these results revealed that Adn fine-tunes the progression of liver regeneration through dynamically modulating molecular mediator networks and cellular interactions within the liver.

  15. Inhibition of VEGF- and NO-dependent angiogenesis does not impair liver regeneration

    Science.gov (United States)

    Shergill, U.; Das, A.; Langer, D.; Adluri, RS.; Maulik, N.

    2010-01-01

    Angiogenesis occurs through a convergence of diverse signaling mechanisms with prominent pathways that include autocrine effects of endothelial nitric oxide (NO) synthase (eNOS)-derived NO and vascular endothelial growth factor (VEGF). However, the redundant and distinct roles of NO and VEGF in angiogenesis remain incompletely defined. Here, we use the partial hepatectomy model in mice genetically deficient in eNOS to ascertain the influence of eNOS-derived NO on the angiogenesis that accompanies liver regeneration. While sinusoidal endothelial cell (SEC) eNOS promotes angiogenesis in vitro, surprisingly the absence of eNOS did not influence the angiogenesis that occurs after partial hepatectomy in vivo. While this observation could not be attributed to induction of alternate NOS isoforms, it was associated with induction of VEGF signaling as evidenced by enhanced levels of VEGF ligand in regenerating livers from mice genetically deficient in eNOS. However, surprisingly, mice that were genetically heterozygous for deficiency in the VEGF receptor, fetal liver kinase-1, also maintained unimpaired capacity for liver regeneration. In summary, inhibition of VEGF- and NO-dependent angiogenesis does not impair liver regeneration, indicating signaling redundancies that allow liver regeneration to continue in the absence of this canonical vascular pathway. PMID:20421635

  16. Isolation and analysis of a novel gene over-expressed during liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Yu-Chang Li; Cun-Shuan Xu; Wu-Lin Zhu; wen-Qiang Li

    2003-01-01

    AIM: To isolate and analyze a novel gene over-expressed during liver regeneration. METHODS: Total RNA of regenerating liver was extracted from liver tissue after 0-4-36-36-36 hr short interval successive partial hepatectomy (SISPH). Reverse transcription-polymerase chain reaction was used to synthesize double strand cDNA, after the tissue was digested by proteinase K and Sfi A/B. The double-strand cDNA was ligated to λTriplEx2.λphage packaging reaction was performed and E. coli XL1-Blue was infected for titering and amplifying. One expressed sequence tag was probed by Dig and phagein situ hybridization was carried out to isolate positive clones. Positive recombinant λTriplEx2 was converted to the corresponding pTriplEx2, and bioinformatics was used to analyze full-length cDNA. RESULTS: We isolated a novel full-length cDNA during liver regeneration following SISPH.CONCLUSION: We have succeeded in cloning a novel gene,based on bioinformatics. We postulate that this gene may function in complicated network in liver regeneration. On the one hand, it may exert initiation of liver regeneration via regulating nitric oxide synthesis. On the other hand, it may protect damaged residue lobus following SISPH.

  17. The Roles of Innate Immune Cells in Liver Injury and Regeneration

    Institute of Scientific and Technical Information of China (English)

    Zhongjun Dong; Haiming Wei; Rui Sun; Zhigang Tian

    2007-01-01

    For predominant abundance with liver-specific Kupffer cells, natural killer (NK) cells, and natural killer T (NKT)cells and their rapid responses to several stimuli, the liver is considered as an organ with innate immune features.In contrast to their roles in the defense of many infectious agents like hepatitis viruses and parasites, hepatic innate immune cells are also involved in the immunopathogenesis of human clinical liver diseases and several murine hepatitis models such as concanavalin A (Con A), lipopolysaccharide (LPS), or polyinosinic-polycytidylic acid (Poly I:C)-induced liver injury. In this review, the destructive roles of NK cells, NKT cells and Kupffer cells in the processes of immune-mediated liver injury and regeneration will be discussed, and some putative mechanisms involving the impairment of liver regeneration caused by activated hepatic innate immune cells are also proposed.

  18. Expression patterns and action analysis of genes associated with inflammatory responses during rat liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Heng-Yi Shao; Li-Feng Zhao; Cun-Shuan Xu

    2007-01-01

    AIM: To study the relationship between inflammatory response and liver regeneration (LR) at transcriptional level.METHODS: After partial hepatectomy (PH) of rats,the genes associated with inflammatory response were obtained according to the databases, and the gene expression changes during LR were checked by the Rat Genome 230 2.0 array.RESULTS: Two hundred and thirty-nine genes were associated with liver regeneration. The initial and total expressing gene numbers found in initiation phase (0.5-4 h after PH), G0/G1 transition (4-6 h after PH),cell proliferation (6-66 h after PH), cell differentiation and structure-function reconstruction (66-168 h after PH) of liver regeneration were 107, 34, 126, 6 and 107,92, 233, 145 respectively, showing that the associated genes were mainly triggered at the beginning of liver regeneration, and worked at different phases. According to their expression similarity, these genes were classified into 5 groups: only up-regulated, predominantly up-,only down-, predominantly down-, up- and down-,involving 92, 25, 77, 14 and 31 genes, respectively. The total times of their up- and down-regulated expression were 975 and 494, respectively, demonstrating that the expressions of the majority of genes were increased,and that of a few genes were decreased. Their time relevance was classified into 13 groups, showing that the cellular physiological and biochemical activities were staggered during liver regeneration. According to gene expression patterns, they were classified into 33 types,suggesting that the activities were diverse and complex during liver regeneration.CONCLUSION: Inflammatory response is closely associated with liver regeneration, in which 239 LRassociated genes play an important role.

  19. Progenitor cells in liver regeneration: molecular responses controlling their activation and expansion

    DEFF Research Database (Denmark)

    Santoni-Rugiu, Eric; Jelnes, Peter; Thorgeirsson, Snorri S

    2005-01-01

    Although normally quiescent, the adult mammalian liver possesses a great capacity to regenerate after different types of injuries in order to restore the lost liver mass and ensure maintenance of the multiple liver functions. Major players in the regeneration process are mature residual cells...... cells, and recruited inflammatory cells as well as the variety of growth-modulating molecules produced and/or harboured by these elements. The cellular and molecular responses to different regenerative stimuli seem to depend on the injury inflicted and consequently on the molecular microenvironment...... created in the liver by a certain insult. This review will focus on molecular responses controlling activation and expansion of the hepatic progenitor cell niche, emphasizing similarities and differences in the microenvironments orchestrating regeneration by recruitment of progenitor cell populations...

  20. The combined effect of erythropoietin and granulocyte macrophage colony stimulating factor on liver regeneration after major hepatectomy in rats

    OpenAIRE

    Frangou Matrona; Fragulidis George; Dafnios Nikolaos; Theodosopoulos Theodosios; Tympa Aliki; Nastos Constantinos; Lolis Evangelos; Vassiliou Ioannis; Kondi-Pafiti Agathi; Smyrniotis Vassilios

    2010-01-01

    Abstract Background The liver presents a remarkable capacity for regeneration after hepatectomy but the exact mechanisms and mediators involved are not yet fully clarified. Erythropoietin (EPO) and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) have been shown to promote liver regeneration after major hepatectomy. Aim of this experimental study is to compare the impact of exogenous administration of EPO, GM-CSF, as well as their combination on the promotion of liver regeneration af...

  1. Targeted antigen delivery to dendritic cells elicits robust antiviral T cell-mediated immunity in the liver

    Science.gov (United States)

    Volckmar, Julia; Gereke, Marcus; Ebensen, Thomas; Riese, Peggy; Philipsen, Lars; Lienenklaus, Stefan; Wohlleber, Dirk; Klopfleisch, Robert; Stegemann-Koniszewski, Sabine; Müller, Andreas J.; Gruber, Achim D.; Knolle, Percy; Guzman, Carlos A.; Bruder, Dunja

    2017-01-01

    Hepatotropic viruses such as hepatitis C virus cause life-threatening chronic liver infections in millions of people worldwide. Targeted in vivo antigen-delivery to cross-presenting dendritic cells (DCs) has proven to be extraordinarily efficient in stimulating antigen-specific T cell responses. To determine whether this approach would as well be suitable to induce local antiviral effector T cells in the liver we compared different vaccine formulations based on either the targeting of DEC-205 or TLR2/6 on cross-presenting DCs or formulations not involving in vivo DC targeting. As read-outs we used in vivo hepatotropic adenovirus challenge, histology and automated multidimensional fluorescence microscopy (MELC). We show that targeted in vivo antigen delivery to cross-presenting DCs is highly effective in inducing antiviral CTLs capable of eliminating virus-infected hepatocytes, while control vaccine formulation not involving DC targeting failed to induce immunity against hepatotropic virus. Moreover, we observed distinct patterns of CD8+ T cell interaction with virus-infected and apoptotic hepatocytes in the two DC-targeting groups suggesting that the different vaccine formulations may stimulate distinct types of effector functions. Our findings represent an important step toward the future development of vaccines against hepatotropic viruses and the treatment of patients with hepatic virus infection after liver transplantation to avoid reinfection. PMID:28266658

  2. Liver regeneration signature in hepatitis B virus (HBV-associated acute liver failure identified by gene expression profiling.

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    Oriel Nissim

    Full Text Available INTRODUCTION: The liver has inherent regenerative capacity via mitotic division of mature hepatocytes or, when the hepatic loss is massive or hepatocyte proliferation is impaired, through activation of hepatic stem/progenitor cells (HSPC. The dramatic clinical course of acute liver failure (ALF has posed major limitations to investigating the molecular mechanisms of liver regeneration and the role of HSPC in this setting. We investigated the molecular mechanisms of liver regeneration in 4 patients who underwent liver transplantation for hepatitis B virus (HBV-associated ALF. METHODS AND FINDINGS: Gene expression profiling of 17 liver specimens from the 4 ALF cases and individual specimens from 10 liver donors documented a distinct gene signature for ALF. However, unsupervised multidimensional scaling and hierarchical clustering identified two clusters of ALF that segregated according to histopathological severity massive hepatic necrosis (MHN; 2 patients and submassive hepatic necrosis (SHN; 2 patients. We found that ALF is characterized by a strong HSPC gene signature, along with ductular reaction, both of which are more prominent in MHN. Interestingly, no evidence of further lineage differentiation was seen in MHN, whereas in SHN we detected cells with hepatocyte-like morphology. Strikingly, ALF was associated with a strong tumorigenesis gene signature. MHN had the greatest upregulation of stem cell genes (EpCAM, CK19, CK7, whereas the most up-regulated genes in SHN were related to cellular growth and proliferation. The extent of liver necrosis correlated with an overriding fibrogenesis gene signature, reflecting the wound-healing process. CONCLUSION: Our data provide evidence for a distinct gene signature in HBV-associated ALF whose intensity is directly correlated with the histopathological severity. HSPC activation and fibrogenesis positively correlated with the extent of liver necrosis. Moreover, we detected a tumorigenesis gene signature

  3. A new technique for accelerated liver regeneration: An experimental study in rats.

    Science.gov (United States)

    Andersen, Kasper Jarlhelt; Knudsen, Anders Riegels; Jepsen, Betina Norman; Meier, Michelle; Gunnarsson, Anders Patrik Alexander; Jensen, Uffe Birk; Nyengaard, Jens Randel; Hamilton-Dutoit, Stephen; Mortensen, Frank Viborg

    2017-08-01

    Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is used to accelerate growth of the future liver remnant. We investigated alternative methods for increasing the future liver remnant. A total of 152 rats were randomized as follows: (1) sham; (2) portal vein ligation; (3) portal vein ligation/surgical split (ALPPS); (4) portal vein ligation/split of the liver with a radiofrequency ablation needle; (5) portal vein ligation/radiofrequency ablation of the deportalized liver (portal vein ligation/radiofrequency ablation necrosis in the deportalized liver); (6) portal vein ligation/radiofrequency ablation of the future liver remnant (portal vein ligation/radiofrequency ablation-future liver remnant); and (7) controls. Animals were evaluated on postoperative days 2 and 4. Bodyweight, liver parameters, hepatic regeneration rate, proinflammatory cytokines, hepatocyte proliferation, and gene expression were measured. Hepatic regeneration rate indicated a steady increase in all intervention groups compared with sham rats (P rats. On postoperative day 4, we found a significantly higher proliferation in groups 3, 4, 5, and 6 compared to portal vein ligation. Gene analysis revealed upregulation of genes involved in cellular proliferation and downregulation of genes involved in cellular homeostasis in all intervention groups. Between the intervention groups, gene expression was nearly identical. Biochemical markers and proinflammatory cytokines were comparable between groups. The surplus liver regeneration after ALPPS is probably mediated through parenchymal damage and subsequent release of growth stimulators, which again upregulates genes involved in cellular regeneration and downregulates genes involved in cellular homeostasis. We also demonstrate that growth of the future liver remnant, comparable to that seen after ALPPS, could be achieved by radiofrequency ablation treatment of the deportalized liver, that is, a procedure in which the

  4. TLR4 Expression by Liver Resident Cells Mediates the Development of Glucose Intolerance and Insulin Resistance in Experimental Periodontitis.

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    Vladimir Ilievski

    Full Text Available Results from epidemiological studies indicate a close association between periodontitis and type 2 diabetes mellitus. However, the mechanism linking periodontitis to glucose intolerance (GI and insulin resistance (IR is unknown. We therefore tested the hypothesis that periodontitis induces the development of GI/IR through a liver Toll-like receptor 4 (TLR4 dependent mechanism.TLR4 chimeric mice were developed by bone marrow transplantation using green fluorescent protein expressing TLR4WT mouse (GFPWT as donor and TLR4 WT or TLR4-/- as recipient mice (GFPWT:WT and GFPWT:KO chimeras respectively. These chimeras were subjected to experimental chronic periodontitis induced by repeated applications of LPS to the gingival sulci for 18 weeks. The levels of GI/IR were monitored and plasma cytokines and LPS were determined at 18 weeks when differences in glucose tolerance were most apparent. Cytokine gene expression was measured in liver tissue by qPCR.Alveolar bone loss was significantly greater in GFPWT:WT chimeras treated with LPS compared with chimeras treated with PBS or GFPWT:KO chimeras. However, the degree of gingival inflammation was similar between GFPWT:WT and GFPWT:KO mice with LPS application. Severe GI/IR occurred in GFPWT:WT chimeras but not in the GFPWT:KO chimeras that were subjected to 18 weeks of LPS. Serum LPS was detected only in animals to which LPS was applied and the level was similar in GFPWT:WT and GFPWT:KO mice at the 18 week time point. Surprisingly, there was no significant difference in the plasma levels of IL1β, IL6 and TNFα at 18 weeks in spite of the severe GI/IR in the GFPWT:WT chimeras with LPS application. Also, no difference in the expression of TNFα or IL6 mRNA was detected in the liver of GFPWT:WT vs GFPWT:KO mice. In contrast, liver IL1β expression was significantly greater in GFPWT:WT chimeras compared to GFPWT:KO chimeras treated with LPS.We observed that GFPWT:WT, but not GFPWT:KO chimeras, treated with LPS

  5. Liver regeneration with l-glutamine supplemented diet: experimental study in rats

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    Cibelle Ribeiro Magalhães

    2014-04-01

    Full Text Available OBJECTIVE: To assess liver regeneration in rats after 60% hepatectomy with and without supplementation of L-glutamine through liver weight changes, laboratory parameters and histological study. METHODS: 36 male rats were divided into two groups: glutamine group and control group. Each group was subdivided into three subgroups, with death in 24h, 72h and seven days. The glutamine group received water and standard diet supplemented with L-glutamine, and the control recieved 0.9% saline. In all subgroups analysis of liver regeneration was made by the Kwon formula, study of liver function (AST, ALT, GGT, total bilirubin, indirect and indirect bilirubin and albumin and analysis of cell mitosis by hematoxylin-eosin. RESULTS: In both groups there was liver regeneration by weight gain. Gamma-GT increased significantly in the control group (p < 0.05; albumin increased in the glutamine group. The other indicators of liver function showed no significant differences. Histological analysis at 72h showed a higher number of mitoses in the glutamine group, with no differences in other subgroups. CONCLUSION: Diet supplementation with L glutamine is beneficial for liver regeneration.

  6. Up-regulated extracellular matrix components and inflammatory chemokines may impair the regeneration of cholestatic liver.

    Science.gov (United States)

    Zhang, Shuai; Li, Tao-Sheng; Soyama, Akihiko; Tanaka, Takayuki; Yan, Chen; Sakai, Yusuke; Hidaka, Masaaki; Kinoshita, Ayaka; Natsuda, Koji; Fujii, Mio; Kugiyama, Tota; Baimakhanov, Zhassulan; Kuroki, Tamotsu; Gu, Weili; Eguchi, Susumu

    2016-01-01

    Although the healthy liver is known to have high regenerative potential, poor liver regeneration under pathological conditions remains a substantial problem. We investigated the key molecules that impair the regeneration of cholestatic liver. C57BL/6 mice were randomly subjected to partial hepatectomy and bile duct ligation (PH+BDL group, n = 16), partial hepatectomy only (PH group, n = 16), or sham operation (Sham group, n = 16). The liver sizes and histological findings were similar in the PH and sham groups 14 days after operation. However, compared with those in the sham group, the livers in mice in the PH+BDL group had a smaller size, a lower cell proliferative activity, and more fibrotic tissue 14 days after the operation, suggesting the insufficient regeneration of the cholestatic liver. Pathway-focused array analysis showed that many genes were up- or down-regulated over 1.5-fold in both PH+BDL and PH groups at 1, 3, 7, and 14 days after treatment. Interestingly, more genes that were functionally related to the extracellular matrix and inflammatory chemokines were found in the PH+BDL group than in the PH group at 7 and 14 days after treatment. Our data suggest that up-regulated extracellular matrix components and inflammatory chemokines may impair the regeneration of cholestatic liver.

  7. Initiation of liver growth by tumor necrosis factor: Deficient liver regeneration in mice lacking type I tumor necrosis factor receptor

    OpenAIRE

    Yamada, Yasuhiro; Kirillova, Irina; Peschon, Jacques J.; Fausto, Nelson

    1997-01-01

    The mechanisms that initiate liver regeneration after resection of liver tissue are not known. To determine whether cytokines are involved in the initiation of liver growth, we studied the regeneration of the liver after partial hepatectomy (PH) in mice lacking type I tumor necrosis factor receptor (TNFR-I). DNA synthesis after PH was severely impaired in these animals, and the expected increases in the binding of the NF-κB and STAT3 transcription factors shortly after...

  8. Effects of Kupffer cell inactivation on graft survival and liver regeneration after partial liver transplantation in rats

    Institute of Scientific and Technical Information of China (English)

    Hang-Yu Luo; Shan-Fang Ma; Ji-Fu Qu; De-Hu Tian

    2015-01-01

    BACKGROUND: Gadolinium chloride (GdCl3) selectively in-activates Kupffer cells and protects against ischemia/reperfu-sion and endotoxin injury. However, the effect of Kupffer cell inactivation on liver regeneration after partial liver transplan-tation (PLTx) is not clear. This study was to investigate the role of GdCl3 pretreatment in graft function after PLTx, and to explore the potential mechanism involved in this process. METHODS: PLTx (30% partial liver transplantation) was per-formed using Kamada's cuff technique, without hepatic artery reconstruction. Rats were randomly divided into the control low-dose (5 mg/kg) and high-dose (10 mg/kg) GdCl3 groups. Liver injury was determined by the plasma levels of alanine aminotransferase and aspartate aminotransferase, liver regen-eration by PCNA staining and BrdU uptake, apoptosis by TU-NEL assay. IL-6 and p-STAT3 levels were measured by ELISA and Western blotting. RESULTS: GdCl3 depleted Kupffer cells and decreased animal survival rates, but did not significantly affect alanine amino-transferase and aspartate aminotransferase (P>0.05). GdCl3 pretreatment induced apoptosis and inhibited IL-6 overex-pression and STAT3 phosphorylation after PLTx in graft tissues. CONCLUSION: Kupffer cells may contribute to the liver re-generation after PLTx through inhibition of apoptosis and activation of the IL-6/p-STAT3 signal pathway.

  9. Regulation of microRNAs and their role in liver development, regeneration and disease.

    Science.gov (United States)

    Finch, Megan L; Marquardt, Jens U; Yeoh, George C; Callus, Bernard A

    2014-09-01

    Since their discovery more than a decade ago microRNAs have been demonstrated to have profound effects on almost every aspect of biology. Numerous studies in recent years have shown that microRNAs have important roles in development and in the etiology and progression of disease. This review is focused on microRNAs and the roles they play in liver development, regeneration and liver disease; particularly chronic liver diseases such as alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, viral hepatitis and primary liver cancer. The key microRNAs identified in liver development and chronic liver disease will be discussed together with, where possible, the target messenger RNAs that these microRNAs regulate to profoundly alter these processes. This article is part of a Directed Issue entitled: The Non-coding RNA Revolution.

  10. Expression, purification and bioactivity of human augmenter of liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Yang-De Zhang; Jian Zhou; Jin-Feng Zhao; Jian Peng; Xiao-Dong Liu; Xin-Sheng Liu; Ze-Ming Jia

    2006-01-01

    AIM: To construct the expression vectors for prokaryotic and eukaryotic human augmenter of liver regeneration (hALR) and to study their biological activity.METHODS: hALRcDNA clone was obtained from plasmid pGEM-T-hALR, and cDNA was subcloned into the prokatyotic expression vector pGEX-4T-2.The recombinant vector and pGEX-4T-2hALR were identified by enzyme digestion and DNA sequencing and transformed into E coli JM109. The positively selected clone was induced by the expression of GST-hALR fusion protein with IPTG, then the fusion protein was purified by glutathine s-transferase (GST) sepharose 4B affinity chromatography, cleaved by thrombin and the hALR monomer was obtained and detected by measuring H thymidine incorporation.RESULTS: The product of PCR from plasmid pGEM-ThALR was examined by 1.5% sepharose electrophoresis.The specific strap was coincident with the theoretical one. The sequence was accurate and pGEX-4T-hALP digested by enzymes was coincident with the theoretical one. The sequence was accurate and the fragment was inserted in the positive direction. The recombinant vector was transformed into E coli JM109. SDS-PAGE proved that the induced expressive fusion protein showed a single band with a molecular weight of 41 kDa. The product was purified and cleaved. The molecular weights of GST and hALR were 26 kDa, 15 kDa respectively. The recombinant fusion protein accounted for 31% of the total soluble protein of bacterial lysate. HALR added to the culture medium of adult rat hepatocytes in primary culture and HepG2 cell line could significantly enhance the rate of DNA synthesis compared to the relevant control groups (P < 0.01).CONCLUSION: Purified hALR has the ability to stimulate DNA synthesis of adult rat hepatocytes in primary culture and HepG2 cells in vitro, and can provide evidence for its clinical application.

  11. Self-assembling functionalized nanopeptides for immediate hemostasis and accelerative liver tissue regeneration

    Science.gov (United States)

    Cheng, Tzu-Yun; Wu, Hsi-Chin; Huang, Ming-Yuan; Chang, Wen-Han; Lee, Chao-Hsiung; Wang, Tzu-Wei

    2013-03-01

    Traumatic injury or surgery may trigger extensive bleeding. However, conventional hemostatic methods have limited efficacy and may cause surrounding tissue damage. In this study, we use self-assembling peptides (SAPs) and specifically extend fragments of functional motifs derived from fibronectin and laminin to evaluate the capability of these functionalized SAPs in the effect of hemostasis and liver tissue regeneration. From the results, these peptides can self-assemble into nanofibrous network structure and gelate into hydrogel with pH adjustment. In animal studies, the efficacy of hemostasis is achieved immediately within seconds in a rat liver model. The histological analyses by hematoxylin-eosin stain and immunohistochemistry reveal that SAPs with these functionalized motifs significantly enhance liver tissue regeneration. In brief, these SAPs may have potential as pharmacological tools to extensively advance clinical therapeutic applications in hemostasis and tissue regeneration in the field of regenerative medicine.Traumatic injury or surgery may trigger extensive bleeding. However, conventional hemostatic methods have limited efficacy and may cause surrounding tissue damage. In this study, we use self-assembling peptides (SAPs) and specifically extend fragments of functional motifs derived from fibronectin and laminin to evaluate the capability of these functionalized SAPs in the effect of hemostasis and liver tissue regeneration. From the results, these peptides can self-assemble into nanofibrous network structure and gelate into hydrogel with pH adjustment. In animal studies, the efficacy of hemostasis is achieved immediately within seconds in a rat liver model. The histological analyses by hematoxylin-eosin stain and immunohistochemistry reveal that SAPs with these functionalized motifs significantly enhance liver tissue regeneration. In brief, these SAPs may have potential as pharmacological tools to extensively advance clinical therapeutic applications

  12. Mitochondrial DNA Unwinding Enzyme Required for Liver Regeneration | Center for Cancer Research

    Science.gov (United States)

    The liver has an exceptional capacity to proliferate. This ability allows the liver to regenerate its mass after partial surgical removal or injury and is the key to successful partial liver transplants. Liver cells, called hepatocytes, are packed with mitochondria, and regulating mitochondrial DNA (mtDNA) copy number is crucial to mitochondrial function, including energy production, during proliferation. Yves Pommier, M.D., Ph.D., of CCR’s Developmental Therapeutics Branch, and his colleagues recently showed that the vertebrate mitochondrial topoisomerase, Top1mt, was critical in maintaining mitochondrial function in the heart after doxorubicin-induced damage. The group wondered whether Top1mt might play a similar role in liver regeneration.

  13. Zonal induction of mixed lineage kinase ZPK/DLK/MUK gene expression in regenerating mouse liver.

    Science.gov (United States)

    Douziech, M; Grondin, G; Loranger, A; Marceau, N; Blouin, R

    1998-08-28

    ZPK/DLK/MUK is a serine/theronine kinase believed to be involved in the regulation of cell growth and differentiation. To further explore the suggested participation of ZPK/DLK/MUK in this process, we examined the expression and cellular localization of ZPK/DLK/MUK mRNA in regenerating mouse liver following partial hepatectomy by ribonuclease protection assay and in situ hybridization. The steady-state level of APK/DLKMUK mRNA was very low in normal and sham-operated mouse livers, whereas a marked and transient increase was observed in the regenerating liver. While ZPK/DLK/MUK mRNAs were rarely detected in hepatocytes from all zones of the normal liver, hepatocytes of regenerating liver exhibit a gradient of expression ranging from low in the periportal zone, to intermediate in the mid-zone, to high in the pericentral zone. These findings demonstrate a transient stimulation of ZPK/DLK/MUK gene expression that correlates with the growth response of hepatocyte subpopulations in regenerating liver.

  14. CCR5 and CXCR3 Are Dispensable for Liver Infiltration, but CCR5 Protects against Virus-Induced T-Cell-Mediated Hepatic Steatosis▿

    Science.gov (United States)

    Holst, P. J.; Orskov, C.; Qvortrup, K.; Christensen, J. P.; Thomsen, A. R.

    2007-01-01

    CCR5 and CXCR3 are important molecules in regulating the migration of activated lymphocytes. Thus, the majority of tissue-infiltrating T cells found in the context of autoimmune conditions and viral infections express CCR5 and CXCR3, and the principal chemokine ligands are expressed within inflamed tissues. Accordingly, intervention studies have pointed to nonredundant roles of these receptors in models of allograft rejection, viral infection, and autoimmunity. In spite of this, considerable controversy exists, with many studies failing to support a role for CCR5 or CXCR3 in disease pathogenesis. One possible explanation is that different chemokine receptors may take over in the absence of any individual receptor, thus rendering individual receptors redundant. We have attempted to address this issue by analyzing CCR5−/−, CXCR3−/−, and CCR5/CXCR3−/− mice with regard to virus-induced liver inflammation, generation and recruitment of effector cells, virus control, and immunopathology. Our results indicate that CCR5 and CXCR3 are largely dispensable for tissue infiltration and virus control. In contrast, the T-cell response is accelerated in CCR5−/− and CCR5/CXCR3−/− mice and the absence of CCR5 is associated with the induction of CD8+ T-cell-mediated immunopathology consisting of marked hepatic microvesicular steatosis. PMID:17626099

  15. CXC chemokines function as a rheostat for hepatocyte proliferation and liver regeneration.

    Directory of Open Access Journals (Sweden)

    Gregory C Wilson

    Full Text Available Our previous in vitro studies have demonstrated dose-dependent effects of CXCR2 ligands on hepatocyte cell death and proliferation. In the current study, we sought to determine if CXCR2 ligand concentration is responsible for the divergent effects of these mediators on liver regeneration after ischemia/reperfusion injury and partial hepatectomy.Murine models of partial ischemia/reperfusion injury and hepatectomy were used to study the effect of CXCR2 ligands on liver regeneration.We found that hepatic expression of the CXCR2 ligands, macrophage inflammatory protein-2 (MIP-2 and keratinocyte-derived chemokine (KC, was significantly increased after both I/R injury and partial hepatectomy. However, expression of these ligands after I/R injury was 30-100-fold greater than after hepatectomy. Interestingly, the same pattern of expression was found in ischemic versus non-ischemic liver lobes following I/R injury with expression significantly greater in the ischemic liver lobes. In both systems, lower ligand expression was associated with increased hepatocyte proliferation and liver regeneration in a CXCR2-dependent fashion. To confirm that these effects were related to ligand concentration, we administered exogenous MIP-2 and KC to mice undergoing partial hepatectomy. Mice received a "high" dose that replicated serum levels found after I/R injury and a "low" dose that was similar to that found after hepatectomy. Mice receiving the "high" dose had reduced levels of hepatocyte proliferation and regeneration whereas the "low" dose promoted hepatocyte proliferation and regeneration.Together, these data demonstrate that concentrations of CXC chemokines regulate the hepatic proliferative response and subsequent liver regeneration.

  16. Influence of epidermal growth factor on liver regeneration after partial hepatectomy in rats

    DEFF Research Database (Denmark)

    Olsen, Peter Skov; Boesby, S.; Kirkegaard, P.;

    2013-01-01

    growth factor could be identified in portal venous blood after intestinal instillation of epidermal growth factor. Brunner's glands and the submandibular glands secrete epidermal growth factor. Extirpation of Brunner's glands decreased liver regeneration, whereas removal of the submandibular glands had......The role of epidermal growth factor on liver regeneration after partial hepatectomy in rats was investigated. After a 70% hepatectomy in rats, the concentration of epidermal growth factor in portal venous blood was unchanged compared with unoperated controls. However, small amounts of epidermal...

  17. Effect of Gadolinium Chloride on Liver Regeneration Following Thioacetamide-Induced Necrosis in Rats

    Directory of Open Access Journals (Sweden)

    María Isabel Sánchez-Reus

    2010-11-01

    Full Text Available Gadolinium chloride (GD attenuates drug-induced hepatotoxicity by selectively inactivating Kupffer cells. The effect of GD was studied in reference to postnecrotic liver regeneration induced in rats by thioacetamide (TA. Rats, intravenously pretreated with a single dose of GD (0.1 mmol/Kg, were intraperitoneally injected with TA (6.6 mmol/Kg. Hepatocytes were isolated from rats at 0, 12, 24, 48, 72 and 96 h following TA intoxication, and samples of blood and liver were obtained. Parameters related to liver damage were determined in blood. In order to evaluate the mechanisms involved in the post-necrotic regenerative state, the time course of DNA distribution and ploidy were assayed in isolated hepatocytes. The levels of circulating cytokine TNFα was assayed in serum samples. TNFα was also determined by RT-PCR in liver extracts. The results showed that GD significantly reduced the extent of necrosis. The effect of GD induced noticeable changes in the post-necrotic regeneration, causing an increased percentage of hepatocytes in S phase of the cell cycle. Hepatocytes increased their proliferation as a result of these changes. TNFα expression and serum level were diminished in rats pretreated with GD. Thus, GD pre-treatment reduced TA-induced liver injury and accelerated postnecrotic liver regeneration. No evidence of TNFα implication in this enhancement of hepatocyte proliferation and liver regeneration was found. These results demonstrate that Kupffer cells are involved in TA-induced liver damage, as well as and also in the postnecrotic proliferative liver states.

  18. Expression patterns and action analysis of genes associated with drug-induced liver diseases during rat liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Qian-Ji Ning; Shao-Wei Qin; Cun-Shuan Xu

    2006-01-01

    AIM: To study the action of the genes associated with drug-induced liver diseases at the gene transcriptional level during liver regeneration (LR) in rats.METHODS: The genes associated with drug-induced liver diseases were obtained by collecting the data from databases and literature, and the gene expression changes in the regenerating liver were checked by the Rat Genome 230 2.0 array.RESULTS: The initial and total expression numbers of genes occurring in phases of 0.5-4 h after partial hepatectomy (PH), 4-6 h after PH (G0/G1 transition),6-66 h after PH (cell proliferation), 66-168 h after PH (cell differentiation and structure-function reconstruction) were 21, 3, 9, 2 and 21, 9, 19, 18, respectively. It is illustrated that the associated genes were mainly triggered at the initial stage of LR and worked at different phases. According to their expression similarity,these genes were classified into 5 types: only upregulated (12 genes), predominantly up-regulated (4genes), only down-regulated (11 genes), predominantly down-regulated (3 genes), and approximately up-/down-regulated (2 genes). The total times of their upand down-expression were 130 and 79, respectively,demonstrating that expression of most of the genes was increased during LR, while a few decreased. The cell physiological and biochemical activities during LR were staggered according to the time relevance and were diverse and complicated in gene expression patterns.CONCLUSION: Drug metabolic capacity in regenerating liver was enhanced. Thirty-two genes play important roles during liver regeneration in rats.

  19. Animal models for the study of liver regeneration: role of nitric oxide and prostaglandins.

    Science.gov (United States)

    Hortelano, Sonsoles; Zeini, Miriam; Casado, Marta; Martín-Sanz, Paloma; Boscá, Lisardo

    2007-01-01

    The mechanisms that permit adult tissues to regenerate are the object of intense study. Liver regeneration is a research area of considerable interest both from pathological and from physiological perspectives. One of the best models of the regenerative process is the two-thirds partial hepatectomy (PH). After PH, the remnant liver starts a series of timed responses that first favor cell growth and then halts hepatocyte proliferation once liver function is fully restored. The mechanisms regulating this process are complex and involve many cellular events. Initiation of liver regeneration requires the injury-related cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6), and involves the activation of cytokine-regulated transcription factors such as NF-kappaB and STAT3. An important event that takes place in the hours immediately after PH is the induction of nitric oxide synthase 2 (NOS-2) and cyclooxygenase 2 (COX-2), and the consequent release of nitric oxide (NO) and prostaglandins (PGs). NO is involved in the vascular readaptation after PH, favoring a general permeability to growth factors throughout the organ. This review examines the mechanisms that regulate NO release during liver regeneration and the animal models used to identify these pathways.

  20. Overexpression of NK2 inhibits liver regeneration after partial hepatectomy in mice

    Institute of Scientific and Technical Information of China (English)

    Toshiyuki Otsuka; Hitoshi Takagi; Glenn Merlino; Masatomo Mori; Norio Horiguchi; Daisuke Kanda; Takashi Kosone; Yuichi Yamazaki; Kazuhisa Yuasa; Naondo Sohara; Satoru Kakizaki; Ken Sato

    2005-01-01

    AIM: To investigate the in vivo effects of NK2 on liver regeneration after partial hepatectomy (PH). METHODS: Survival after PH was observed with 21 NK2 transgenic mice and 23 wild-type (WT) mice over 10 d. Liver regeneration was analyzed using histology and immunohistochemistry. Expressions of genes were analyzed using Northern blot analysis, immunoprecipitation and immunoblotting, and reverse transcriptase polymerase chain reaction assay. KaplanMeier method and the log-rank test were used for ahalyzing the survival after PH. Differences in the resultsof immunohistochemistry and percentage of liver regeneration was determined by the Student's t-test. RESULTS: More than half of NK2 transgenic mice died within 48 h after PH. After PH, increased deposition of small lipid droplets in hepatocytes was evident and hepatic proliferation was inhibited in NK2 transgenic mice. The hepatic expression and kinase activity of HGF receptor, c-Met, were unchanged among WT mice and NK2 transgenic mice after PH. The expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in liver tissues were prolonged in NK2 transgenic mice that died after PH.CONCLUSION: Our findings indicate that overexpression of NK2 inhibits liver regeneration after PH.

  1. Gene and protein expressions of P28gank in rat with liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Jian-Min Qin; Xiao-Yong Fu; Shen-Jing Li; Shu-Qin Liu; Jin-Zhang Zeng; Xiu-Hua Qiu; Meng-Chao Wu; Hong-Yang Wang

    2003-01-01

    AIM: To observe the gene and protein expression changes of p28GANK in regenerating liver tissues, and to reveal the biological function of p28GANK on the regulation of liver regeneration.METHODS: One hundred and thirty two adult male Sprague-Dawley rats were selected, weighing 200-250 g,and divided randomly into sham operation (SO) group and partial hepatectomy (PH) group. Each group had eleven time points: 0, 2, 6, 12, 24, 30, 48, 72, 120, 168 and 240 h,six rats were in each time point. The rats were undergone 70 % PH under methoxyflurane anesthesia by resection of the anterior and left lateral lobes of the liver. SO was conducted by laparotomy plus slight mobilization of the liver without resection. Liver specimens were collected at the indicated time points after PH or SO. The expression level of p28GANK mRNA was determined by Northern blot as well as at protein level via immunohistochemical staining.The expressions of p28GANK mRNA in these tissues were analyzed by imaging analysis system of FLA-2000 FUJIFILM and one way analysis of variance. The protein expressions of p28GANK in these tissues were analyzed with Fromowitz'method and Rank sum test.RESULTS: The expression of p28GANK mRNA in bhe regenerating liver tissues possessed two transcripts, which were 1.5 kb and 1.0 kb. There was a significantly different expression patterns of p28GANK mRNA between SO and PH groups (P<0.01). The expression of p28GANK mRNA increased 2 h after PH, the peak time was 72 h (SO group: 163.83±1.4720; PH group: 510.5±17.0499, P<0.01). There was a significant difference in the 1.5 kb transcript, which decreased gradually after 72 hours. The protein expression of p28GANK was mainly in the cytoplasm of regenerating hepatocytes, and increased near the central region 24 h after PH, and became strongly positive at 48 h (+++, vs the other time points P<0.05),but decreased 72 h after PH.CONCLUSION: The expression of p28GANK mRNA increases in the early stage of rat liver regeneration, the

  2. In vivo liver regeneration potential of human induced pluripotent stem cells from diverse origins.

    Science.gov (United States)

    Liu, Hua; Kim, Yonghak; Sharkis, Saul; Marchionni, Luigi; Jang, Yoon-Young

    2011-05-11

    Human induced pluripotent stem cells (iPSCs) are a potential source of hepatocytes for liver transplantation to treat end-stage liver disease. In vitro differentiation of human iPSCs into hepatic cells has been achieved using a multistage differentiation protocol, but whether these cells are functional and capable of engrafting and regenerating diseased liver tissue is not clear. We show that human iPSC-derived hepatic cells at various differentiation stages can engraft the liver in a mouse transplantation model. Using the same differentiation and transplantation protocols, we also assessed the ability of human iPSCs derived from each of the three developmental germ layer tissues (that is, ectoderm, mesoderm, and endoderm) to regenerate mouse liver. These iPSC lines, with similar but distinct global DNA methylation patterns, differentiated into multistage hepatic cells with an efficiency similar to that of human embryonic stem cells. Human hepatic cells at various differentiation stages derived from iPSC lines of different origins successfully repopulated the liver tissue of mice with liver cirrhosis. They also secreted human-specific liver proteins into mouse blood at concentrations comparable to that of proteins secreted by human primary hepatocytes. Our results demonstrate the engraftment and liver regenerative capabilities of human iPSC-derived multistage hepatic cells in vivo and suggest that human iPSCs of distinct origins and regardless of their parental epigenetic memory can efficiently differentiate along the hepatic lineage.

  3. DNMT1 is a Required Genomic Regulator for Murine Liver Histogenesis and Regeneration

    DEFF Research Database (Denmark)

    Kaji, Kosuke; Factor, Valentina M; Andersen, Jesper B

    2016-01-01

    conditional knockout mice (Dnmt1(Δalb) ) by crossing Dnmt1(fl/fl) with Albumin-Cre (Alb-Cre) transgenic mice. Serum, liver tissues and primary hepatocytes were collected from 1-20 week old mice. The Dnmt1(Δalb) phenotype was assessed by histology, confocal and electron microscopy, biochemistry as well...... hepatocytes caused global hypomethylation, enhanced DNA damage response and initiated a senescence state causing a progressive inability to maintain tissue homeostasis and proliferate in response to injury. The liver regenerated via activation and repopulation from progenitors due to lineage...... hepatocytes did not affect liver homeostasis. CONCLUSION: These results establish the indispensable role of DNMT1-mediated epigenetic regulation in postnatal liver growth and regeneration. The Dnmt1(Δalb) mice provide a unique experimental model to study the role of senescence and contribution of progenitor...

  4. Expression of tumor necrosis factor-alpha converting enzyme in liver regeneration after partial hepatectomy

    Institute of Scientific and Technical Information of China (English)

    Xian-Ming Lin; Ying-Bin Liu; Fan Zhou; Yu-Lian Wu; Li Chen; He-Qing Fang

    2008-01-01

    AIM:To study the expression of tumor necrosis factor-alpha converting enzyme (TACE) and evaluate its significance in liver regeneration after partial hepatectomy in vivo.METHODS:Male SD rats underwent 70% partial hepatec-tomy.The remaining liver and spleen tissue samples were collected at indicated time points after hepatectomy.TACE expression was investigated by Western blotting,immunohistochemistry,and serial section immunostaining.RESULTS:Expression of TACE in liver and spleen tissues after partial hepatectomy was a time-dependent alteration,reaching a maximal level between 24 and 48 h and remaining elevated for more than 168 h.TACE protein was localized to mononuclear cells (MNC),which infiltrated the liver from the spleen after hepatectomy.The kinetics of TACE expression was in accordance with the number of TACE-staining MNCs and synchronized with those of transforming growth factor-α(TGFα).In addition,TACE-staining MNC partially overlapped with CD3+ T lymphocytes.CONCLUSION:TACE may be involved in liver regenera-tion by pathway mediated with TGFα-EGFR in the cell-cycle progressive phase in vivo.TACE production and effect by paracrine may be a pathway of involvement in liver regeneration for the activated CD3+ T lymphocytes.

  5. Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration.

    Science.gov (United States)

    Malato, Yann; Naqvi, Syed; Schürmann, Nina; Ng, Raymond; Wang, Bruce; Zape, Joan; Kay, Mark A; Grimm, Dirk; Willenbring, Holger

    2011-12-01

    Recent evidence has contradicted the prevailing view that homeostasis and regeneration of the adult liver are mediated by self duplication of lineage-restricted hepatocytes and biliary epithelial cells. These new data suggest that liver progenitor cells do not function solely as a backup system in chronic liver injury; rather, they also produce hepatocytes after acute injury and are in fact the main source of new hepatocytes during normal hepatocyte turnover. In addition, other evidence suggests that hepatocytes are capable of lineage conversion, acting as precursors of biliary epithelial cells during biliary injury. To test these concepts, we generated a hepatocyte fate-tracing model based on timed and specific Cre recombinase expression and marker gene activation in all hepatocytes of adult Rosa26 reporter mice with an adenoassociated viral vector. We found that newly formed hepatocytes derived from preexisting hepatocytes in the normal liver and that liver progenitor cells contributed minimally to acute hepatocyte regeneration. Further, we found no evidence that biliary injury induced conversion of hepatocytes into biliary epithelial cells. These results therefore restore the previously prevailing paradigms of liver homeostasis and regeneration. In addition, our new vector system will be a valuable tool for timed, efficient, and specific loop out of floxed sequences in hepatocytes.

  6. What is Known Regarding the Participation of Factor Nrf-2 in Liver Regeneration?

    Directory of Open Access Journals (Sweden)

    José A. Morales-González

    2015-05-01

    Full Text Available It has been known for years that, after chemical damage or surgical removal of its tissue, the liver initiates a series of changes that, taken together, are known as regeneration, which are focused on the recovery of lost or affected tissue in terms of the anatomical or functional aspect. The Nuclear factor-erythroid 2-related factor (Nrf-2 is a reduction-oxidation reaction (redox-sensitive transcriptional factor, with the basic leucine Zipper domain (bZIP motif, encoding the NFE2L2 gene. The Keap1-Nrf2-ARE pathway is transcendental in the regulation of various cellular processes, such as antioxidant defenses, redox equilibrium, the inflammatory process, the apoptotic processes, intermediate metabolism, detoxification, and cellular proliferation. Some reports have demonstrated the regulator role of Nrf-2 in the cellular cycle of the hepatocyte, as well as in the modulation of the antioxidant response and of apoptotic processes during liver regeneration. It has been reported that there is a delay in liver regeneration after Partial hepatectomy (PH in the absence of Nrf-2, and similarly as a regulator of hepatic cytoprotection due to diverse chemical or biological agents, and in diseases such as hepatitis, fibrosis, cirrhosis, and liver cancer. This regulator/protector capacity is due to the modulation of the Antioxidant response elements (ARE. It is postulated that oxidative stress (OS can participate in the initial stages of liver regeneration and that Nrf-2 can probably participate. Studies are lacking on the different initiation stages, maintenance, and the termination of liver regeneration alone or with ethanol.

  7. Angiotensin-converting enzyme inhibition by lisinopril enhances liver regeneration in rats

    Directory of Open Access Journals (Sweden)

    F.S. Ramalho

    2001-01-01

    Full Text Available Bradykinin has been reported to act as a growth factor for fibroblasts, mesangial cells and keratinocytes. Recently, we reported that bradykinin augments liver regeneration after partial hepatectomy in rats. Angiotensin-converting enzyme (ACE is also a powerful bradykinin-degrading enzyme. We have investigated the effect of ACE inhibition by lisinopril on liver regeneration after partial hepatectomy. Adult male Wistar rats underwent 70% partial hepatectomy (PH. The animals received lisinopril at a dose of 1 mg kg body weight-1 day-1, or saline solution, intraperitoneally, for 5 days before hepatectomy, and daily after surgery. Four to six animals from the lisinopril and saline groups were sacrificed at 12, 24, 36, 48, 72, and 120 h after PH. Liver regeneration was evaluated by immunohistochemical staining for proliferating cell nuclear antigen using the PC-10 monoclonal antibody. The value for the lisinopril-treated group was three-fold above the corresponding control at 12 h after PH (P<0.001, remaining elevated at approximately two-fold above control values at 24, 36, 48 (P<0.001, and at 72 h (P<0.01 after PH, but values did not reach statistical difference at 120 h after PH. Plasma ACE activity measured by radioenzymatic assay was significantly higher in the saline group than in the lisinopril-treated group (P<0.001, with 81% ACE inhibition. The present study shows that plasma ACE inhibition enhances liver regeneration after PH in rats. Since it was reported that bradykinin also augments liver regeneration after PH, this may explain the liver growth stimulating effect of ACE inhibitors.

  8. Can hyperbaric oxygenation decrease doxorubicin hepatotoxicity and improve regeneration in the injured liver?

    Science.gov (United States)

    Firat, Ozgur; Kirdok, Ozgur; Makay, Ozer; Caliskan, Cemil; Yilmaz, Funda; Ilgezdi, Savas; Karabulut, Bulent; Coker, Ahmet; Zeytunlu, Murat

    2009-01-01

    Portal vein embolization is used in the treatment of hepatocellular cancer, with the purpose of enhancing resectability. However, regeneration is restricted due to hepatocellular injury following chemotherapeutics (e.g. doxorubicin). The aim of this study was to investigate whether hyperbaric oxygenation (HBO) can alleviate the hepatotoxicity of chemotherapy and improve regeneration in the injured liver. Rats were allocated to four experimental groups. Group I rats were subjected to right portal vein ligation (RPVL); rats in groups II and III were administered doxorubicin prior to RPVL, with group III rats being additionally exposed to HBO sessions postoperatively; group IV rats was sham-operated. All rats were sacrificed on postoperative day 7, and liver injury was assessed by measuring alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Protein synthetic ability was determined based albumin levels and liver regeneration by the mitotic index (MI). The AST and ALT values of group II rats were significantly higher than those of group I, but not those of group III. Rats treated with doxorubicin and HBO (groups II and III) showed slightly but not significant differences in albumin levels than those subjected to only RPVL or sham-operated. The MI was significantly increased in groups I, II, and III, with the MI of group III rats significantly higher than those of group I rats. Based on our results, we conclude that HBO treatment has the potential to diminish doxorubicin-related hepatotoxicity and improve regeneration in the injured liver.

  9. Purification and Characterization of Hepatocyte Regeneration Stimulatory Factor from Shark Liver

    Institute of Scientific and Technical Information of China (English)

    OUYu; LUZheng-bing; WUWu-tong; WANGQiu-juan

    2003-01-01

    Aim To purify hepatocyte regeneration stimulatory factor from shark liver and research its molecular feature and activity. Methods and Results Hepatocyte regeneration stimulatory factor (sHRSF) was isolated from healthy shark livers and separated by homogenization, freezing-melting, heat treating, centfifugation, and ultmfdwation. HRSF activity was found mainly in the subfraction of molecular weight less than 30 000 daltons. This crude ultrafihrate was further purified successively by DEAE-Sepharose fast flow chromatography, FPLC Resource 30Q, Resource Q and Mono Q chromatography.A single band was displayed on sodium dodecyl sulfate polyacrylamide gel electrophoresis, which corresponds to molecular weight of 14 600 daltons. The characteristic absorption was obtained at the wavelength 276 nm. The isoelectric point was about 5.1. It contained 18 amino acids and the 15 N-terminal amino acid residues were LVGPIGAVGPAGKDG. It had a significant activity in stimulating liver to regenerate. Condusion We obtained an unknown new active protein, that is hepatocyte regeneration stimulatory factor from shark liver ( sHRSF).

  10. Regeneration and outcome of dual grafts in living donor liver transplantation.

    Science.gov (United States)

    Lu, Chia-Hsun; Chen, Tai-Yi; Huang, Tung-Liang; Tsang, Leo Leung-Chit; Ou, Hsin-You; Yu, Chun-Yen; Chen, Chao-Long; Cheng, Yu-Fan

    2012-01-01

    In living donor liver transplantation (LDLT), the essential aims are to provide an adequate graft volume to the recipient and to keep a sufficient remnant liver volume in the donor. In some instances, these aims cannot be met by a single donor and LDLT using dual grafts from two donors is a good solution. From 2002 to 2009, five recipients in our hospital received dual graft LDLT. Two recipients received one right lobe and one left lobe grafts; the other three received two left lobe grafts. The mean final liver regeneration rate was 91.2%. Left lobe graft atrophy in the long term was observed in recipients who received a right and a left lobe grafts. The initial bigger volume graft in all recipients was noted to have better regeneration than the smaller volume grafts. Portal flow and bilateral grafts volume size discrepancy were considered as two major factors influencing graft regeneration in this study. We also noted that the initial graft volume correlated with portal flow in the separate grafts and finally contribute to individual graft regeneration. Because of compensatory hypertrophy of the other graft, recipients who experienced atrophy of one graft did not show signs of liver dysfunction.

  11. Bone morphogenetic protein-2 is a negative regulator of hepatocyte proliferation downregulated in the regenerating liver

    NARCIS (Netherlands)

    Xu, Cui-Ping; Ji, Wen-Min; van den Brink, Gijs R.; Peppelenbosch, Maikel P.

    2006-01-01

    AIM: To characterize the expression and dynamic changes of bone morphogenetic protein (BMP)-2 in hepatocytes in the regenerating liver in rats after partial hepatectomy (PH), and examine the effects of BMP-2 on proliferation of human Huh7 hepatoma cells. METHODS: Fifty-four adult male Wistar rats we

  12. TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy in mice.

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    Gamze Karaca

    Full Text Available BACKGROUND & AIMS: Pro-inflammatory cytokines are important for liver regeneration after partial hepatectomy (PH. Expression of Fibroblast growth factor-inducible 14 (Fn14, the receptor for TNF-like weak inducer of apoptosis (TWEAK, is induced rapidly after PH and remains elevated throughout the period of peak hepatocyte replication. The role of Fn14 in post-PH liver regeneration is uncertain because Fn14 is expressed by liver progenitors and TWEAK-Fn14 interactions stimulate progenitor growth, but replication of mature hepatocytes is thought to drive liver regeneration after PH. METHODS: To clarify the role of TWEAK-Fn14 after PH, we compared post-PH regenerative responses in wild type (WT mice, Fn14 knockout (KO mice, TWEAK KO mice, and WT mice treated with anti-TWEAK antibodies. RESULTS: In WT mice, rare Fn14(+ cells localized with other progenitor markers in peri-portal areas before PH. PH rapidly increased proliferation of Fn14(+ cells; hepatocytic cells that expressed Fn14 and other progenitor markers, such as Lgr5, progressively accumulated from 12-8 h post-PH and then declined to baseline by 96 h. When TWEAK/Fn14 signaling was disrupted, progenitor accumulation, induction of pro-regenerative cytokines, hepatocyte and cholangiocyte proliferation, and over-all survival were inhibited, while post-PH liver damage and bilirubin levels were increased. TWEAK stimulated proliferation and increased Lgr5 expression in cultured liver progenitors, but had no effect on either parameter in cultured primary hepatocytes. CONCLUSIONS: TWEAK-FN14 signaling is necessary for the healthy adult liver to regenerate normally after acute partial hepatectomy.

  13. Erythropoietin Promotes Hepatic Regeneration After Extended Liver Resection in Rats

    OpenAIRE

    Ariyakhagorn, Veeravorn

    2010-01-01

    Erythropoietin (EPO) hat sich in verschiedensten Gewebetypen als potenter Organ- Protektor und Regenerations-Stimulator erwiesen. Bis heute sind jedoch keinerlei Daten bezüglich des Einflusses von EPO auf die Leberregeration verfügbar. Wir haben daher in einem Rattenmodell den Einfluß von EPO auf die Leberregeneration nach 70%-iger Leberteilresektion untersucht. Hierbei wurden drei Studiengruppen gebildet: Gruppe 1 erhielt eine intraportalvenöse EPO-Gabe 30 Minuten vor Resektion (4000 U...

  14. Loss and recovery of liver regeneration in rats with fulminant hepatic failure.

    Science.gov (United States)

    Eguchi, S; Lilja, H; Hewitt, W R; Middleton, Y; Demetriou, A A; Rozga, J

    1997-10-01

    We earlier described a model of fulminant hepatic failure (FHF) in the rat where partial hepatectomy is combined with induction of right liver lobes necrosis. After this procedure, lack of regenerative response in the residual viable liver tissue (omental lobes) was associated with elevated plasma hepatocyte growth factor (HGF) and transforming growth factor beta (TGF-beta1) levels and delayed expression of HGF and c-met mRNA in the remnant liver. Here, we investigated whether syngeneic isolated hepatocytes transplanted in the spleen will prolong survival and facilitate liver regeneration in FHF rats. Inbred male Lewis rats were used. Group I rats (n = 46) received intrasplenic injection of 2 x 10(7) hepatocytes and 2 days later FHF was induced. Group II FHF rats (n = 46) received intrasplenic injection of saline. Rats undergoing partial hepatectomy of 68% (PH; n = 30) and a sham operation (SO; n = 30) served as controls. In 20 FHF rats (10 rats/group), survival time was determined. The remaining 72 FHF rats (36 rats/group) were used for physiologic studies (liver function and regeneration and plasma growth factor levels). In Group I rats survival was longer than that of Group II controls (73 +/- 22 hr vs. 33 +/- 9 hr; P ammonia, lactate, total bilirubin, PT, and PTT values, lower activity of liver enzymes, and higher monoethylglycinexylidide (MEGX) production than Group II rats. In Group I rats, livers increased in weight at a rate similar to that seen in PH controls and showed distinct mitotic and DNA synthetic activity (incorporation of bromodeoxyuridine and proliferation cell nuclear antigen expression). Plasma HGF and TGF-beta1 levels in these rats decreased and followed the pattern seen in PH rats; additionally, c-met expression in the remnant liver was accelerated. Hepatocyte transplantation prolonged survival in FHF rats and facilitated liver regeneration. Even though the remnant liver increased in weight four times reaching 30% of the original liver mass

  15. Interleukin-1 receptor antagonist modulates the early phase of liver regeneration after partial hepatectomy in mice.

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    Antonino Sgroi

    Full Text Available BACKGROUND: Cytokine administration is a potential therapy for acute liver failure by reducing inflammatory responses and favour hepatocyte regeneration. The aim of this study was to evaluate the role of interleukin-1 receptor antagonist (IL-1ra during liver regeneration and to study the effect of a recombinant human IL-1ra on liver regeneration. METHODS: We performed 70%-hepatectomy in wild type (WT mice, IL-1ra knock-out (KO mice and in WT mice treated by anakinra. We analyzed liver regeneration at regular intervals by measuring the blood levels of cytokines, the hepatocyte proliferation by bromodeoxyuridin (BrdU incorporation, proliferating cell nuclear antigen (PCNA and Cyclin D1 expression. The effect of anakinra on hepatocyte proliferation was also tested in vitro using human hepatocytes. RESULTS: At 24h and at 48 h after hepatectomy, IL-1ra KO mice had significantly higher levels of pro-inflammatory cytokines (IL-6, IL-1β and MCP-1 and a reduced and delayed hepatocyte proliferation measured by BrdU incorporation, PCNA and Cyclin D1 protein levels, when compared to WT mice. IGFBP-1 and C/EBPβ expression was significantly decreased in IL-1ra KO compared to WT mice. WT mice treated with anakinra showed significantly decreased levels of IL-6 and significantly higher hepatocyte proliferation at 24h compared to untreated WT mice. In vitro, primary human hepatocytes treated with anakinra showed significantly higher proliferation at 24h compared to hepatocytes without treatment. CONCLUSION: IL1ra modulates the early phase of liver regeneration by decreasing the inflammatory stress and accelerating the entry of hepatocytes in proliferation. IL1ra might be a therapeutic target to improve hepatocyte proliferation.

  16. Omega-3 polyunsaturated fatty acids promote liver regeneration after 90% hepatectomy in rats

    Institute of Scientific and Technical Information of China (English)

    Yu-Dong Qiu; Sheng Wang; Yue Yang; Xiao-Peng Yan

    2012-01-01

    AIM:To evaluate the effectiveness of omega-3 polyunsaturated fatty acid (ω-3 PUFA) administration on liver regeneration after 90% partial hepatectomy (PH) in METHODS:ω-3 PUFAs were intravenously injected in the ω-3 PUFA group before PH surgery.PH,sparing only the caudate lobe,was performed in both the control and the ω-3 PUFA group.Survival rates,liver weight/body weight ratios,liver weights,HE staining,transmission electron microscope imaging,nuclearassociated antigen Ki-67,enzyme-linked immunosorbent assay and signal transduction were evaluated to analyze liver regeneration.RESULTS:All rats in the control group died within 30 h after hepatectomy.Survival rates in the ω-3 PUFA group were 20/20 at 30 h and 4/20 1 wk after PH.Liver weight/body weight ratios and liver weights increased significantly in the ω-3 PUFA group.The structure of sinusoidal endothelial cells and space of Disse was greatly restored in the ω-3 PUFA group compared to the control group after PH.In the ω-3 PUFA group,interleukin (IL)-4 and IL-10 levels were significantly increased whereas IL-6 and tumor necrosis factor-α levels were dramatically decreased.In addition,activation of protein kinase B (Akt) and of signal transducer and activator of transcription 3 signaling pathway were identified at an earlier time after PH in the ω-3 PUFA group.CONCLUSION:Omega-3 polyunsaturated fatty acids may prevent acute liver failure and promote liver regeneration after 90% hepatectomy in rats.

  17. Impaired liver regeneration in Ldlr-/- mice is associated with an altered hepatic profile of cytokines, growth factors, and lipids.

    Science.gov (United States)

    Pauta, Montse; Rotllan, Noemi; Vales, Frances; Fernandez-Hernando, Ana; Allen, Ryan M; Ford, David A; Marí, Montserrat; Jiménez, Wladimiro; Baldán, Angel; Morales-Ruiz, Manuel; Fernández-Hernando, Carlos

    2013-10-01

    It is widely recognized that in the early stages of liver regeneration after partial hepatectomy, the hepatocytes accumulate a significant amount of lipids. The functional meaning of this transient steatosis and its effect on hepatocellular proliferation are not well defined. In addition, the basic mechanisms of this lipid accumulation are not well understood although some studies suggest the participation of the Low Density Lipoprotein Receptor (Ldlr). To address these questions, we studied the process of liver regeneration in Ldlr null mice and wild type mice following partial hepatectomy. Ldlr deficiency was associated with a significant decrease in serum albumin concentration, during early stages of liver regeneration, and a delayed hepatic regeneration. Remnant livers of Ldlr(-)(/)(-) showed a time-shifted expression of interleukin-6 (IL6) and a defective activation of tumor necrosis factor-α (TNFα) and hepatocyte growth factor (HGF) expression in early phases of liver regeneration. Unexpectedly, Ldlr(-)(/)(-) showed no significant differences in the content of lipid droplets after partial hepatectomy compared to wild type mice. However, lipidomic analysis of the regenerating liver from Ldlr(-)(/)(-) revealed a lipid profile compatible with liver quiescence: high content of cholesterol esters and ceramide, and low levels of phosphatidylcholine. Ldlr deficiency is associated with significant changes in the hepatic lipidome that affect cytokine-growth factor signaling and impair liver regeneration. These results suggest that the analysis of the hepatic lipidome may help predict the success of liver regeneration in the clinical environment, specifically in the context of pre-existing liver steatosis. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  18. Conditional genetic elimination of hepatocyte growth factor in mice compromises liver regeneration after partial hepatectomy.

    Directory of Open Access Journals (Sweden)

    Kari Nejak-Bowen

    Full Text Available Hepatocyte growth factor (HGF has been shown to be indispensable for liver regeneration because it serves as a main mitogenic stimulus driving hepatocytes toward proliferation. We hypothesized that ablating HGF in adult mice would have a negative effect on the ability of hepatocytes to regenerate. Deletion of the HGF gene was achieved by inducing systemic recombination in mice lacking exon 5 of HGF and carrying the Mx1-cre or Cre-ER(T transgene. Analysis of liver genomic DNA from animals 10 days after treatment showed that a majority (70-80% of alleles underwent cre-induced genetic recombination. Intriguingly, however, analysis by RT-PCR showed the continued presence of both unrecombined and recombined forms of HGF mRNA after treatment. Separation of liver cell populations into hepatocytes and non-parenchymal cells showed equal recombination of genomic HGF in both cell types. The presence of the unrecombined form of HGF mRNA persisted in the liver in significant amounts even after partial hepatectomy (PH, which correlated with insignificant changes in HGF protein and hepatocyte proliferation. The amount of HGF produced by stellate cells in culture was indirectly proportional to the concentration of HGF, suggesting that a decrease in HGF may induce de novo synthesis of HGF from cells with residual unrecombined alleles. Carbon tetrachloride (CCl4-induced regeneration resulted in a substantial decrease in preexisting HGF mRNA and protein, and subsequent PH led to a delayed regenerative response. Thus, HGF mRNA persists in the liver even after genetic recombination affecting most cells; however, PH subsequent to CCl4 treatment is associated with a decrease in both HGF mRNA and protein and results in compromised liver regeneration, validating an important role of this mitogen in hepatic growth.

  19. Bile acids are "homeotrophic" sensors of the functional hepatic capacity and regulate adaptive growth during liver regeneration.

    Science.gov (United States)

    Geier, Andreas; Trautwein, Christian

    2007-01-01

    Liver mass depends on one or more unidentified humoral signals that drive regeneration when liver functional capacity is diminished. Bile acids are important liver products, and their levels are tightly regulated. Here, we identify a role for nuclear receptor-dependent bile acid signaling in normal liver regeneration. Elevated bile acid levels accelerate regeneration, and decreased levels inhibit liver regrowth, as does the absence of the primary nuclear bile acid receptor FXR. We propose that FXR activation by increased bile acid flux is a signal of decreased functional capacity of the liver. FXR, and possibly other nuclear receptors, may promote homeostasis not only by regulating expression of appropriate metabolic target genes but also by driving homeotrophic liver growth.

  20. Demethylation of IGFBP5 by Histone Demethylase KDM6B Promotes Mesenchymal Stem Cell-Mediated Periodontal Tissue Regeneration by Enhancing Osteogenic Differentiation and Anti-Inflammation Potentials.

    Science.gov (United States)

    Liu, Dayong; Wang, Yuejun; Jia, Zhi; Wang, Liping; Wang, Jinsong; Yang, Dongmei; Song, Jianqiu; Wang, Songlin; Fan, Zhipeng

    2015-08-01

    Mesenchymal stem cell (MSC)-mediated periodontal tissue regeneration is considered a promising method for periodontitis treatment. The molecular mechanism underlying directed differentiation and anti-inflammatory actions remains unclear, thus limiting potential MSC application. We previously found that insulin-like growth factor binding protein 5 (IGFBP5) is highly expressed in dental tissue-derived MSCs compared with in non-dental tissue-derived MSCs. IGFBP5 is mainly involved in regulating biological activity of insulin-like growth factors, and its functions in human MSCs and tissue regeneration are unclear. In this study, we performed gain- and loss-of-function assays to test whether IGFBP5 could regulate the osteogenic differentiation and anti-inflammatory potential in MSCs. We found that IGFBP5 expression was upregulated upon osteogenic induction, and that IGFBP5 enhanced osteogenic differentiation in MSCs. We further showed that IGFBP5 prompted the anti-inflammation effect of MSCs via negative regulation of NFκB signaling. Depletion of the histone demethylase lysine (K)-specific demethylase 6B (KDM6B) downregulated IGFBP5 expression by increasing histone K27 methylation in the IGFBP5 promoter. Moreover, IGFBP5 expression in periodontal tissues was downregulated in individuals with periodontitis compared with in healthy people, and IGFBP5 enhanced MSC-mediated periodontal tissue regeneration and alleviated local inflammation in a swine model of periodontitis. In conclusion, our present results reveal a new function for IGFBP5, provide insight into the mechanism underlying the directed differentiation and anti-inflammation capacities of MSCs, and identify a potential target mediator for improving tissue regeneration.

  1. Recent Strategies Combining Biomaterials and Stem Cells for Bone, Liver and Skin Regeneration.

    Science.gov (United States)

    Morelli, Sabrina; Salerno, Simona; Ahmed, Haysam Mohamed Magdy; Piscioneri, Antonella; Bartolo, Loredana De

    2016-01-01

    This review is focused on the combination of biomaterials with stem cells as a promising strategy for bone, liver and skin regeneration. At first, we describe stem cell-based constructs for bone tissue engineering with special attention to recent advanced approaches based on the use of biomaterial scaffolds with renewable stem cells that have been used for bone regeneration. We illustrate the strategies to improve liver regeneration by using liver stem cells and biomaterials and/or devices as therapeutic approaches. In particular, examples of biomaterials in combination with other technologies are presented since they allow the differentiation of stem cells in hepatocytes. After a description of the role and the benefit of MSCs in wound repair and in skin substitutes we highlight the suitability of biomaterials in guiding stem cell differentiation for skin regeneration and cutaneous repair in both chronic and acute wounds. Finally, an overview of the types of bioreactors that have been developed for the differentiation of stem cells and are currently in use, is also provided. The examples of engineered microenvironments reported in this review indicate that a detailed understanding of the various factors and mechanisms that control the behavior of stem cells in vivo has provided useful information for the development of advanced bioartificial systems able to control cell fate.

  2. Designing the method for optical in vitro monitoring of the cell-mediated scaffold technology for bone regeneration based on laser-induced fluorescence spectroscopy

    Science.gov (United States)

    Larionov, P. M.; Maslov, N. A.; Papaeva, E. O.; Tereshchenko, V. P.; Khlestkin, V. K.; Bogachev, S. S.; Proskurina, A. S.; Titov, A. T.; Filipenko, M. L.; Pavlov, V. V.; Kudrov, G. A.; Orishich, A. M.

    2016-08-01

    One of the main unsolved problems in traumatology and orthopedics is reconstruction of critical-sized segmental bone defects. We believe that implementation of noninvasive monitoring of the bioengineering stages for cell-mediated bone scaffold by laser-induced fluorescence (LIF) can become a positive aspect in mastering this technique. An electrospun scaffold model (parameters: 10 wt. % polycaprolactone; 5% wt type A gelatin; mean fiber diameter 877.1 ± 169.1, and contact angle 45.3°) seeded with BHK IR cell culture (182 ± 38 cells/mm2) was used to show the principal possibility of differentiating between the scaffold seeded and unseeded with cells. First of all, the fluorescence spectra of the cell-seeded scaffold contain a peak at 305 nm for the excitation range of 230-290 nm, which can be used to differentiate between the samples. An increase in fluorescence intensity of the cell-seeded scaffold in the range of 400- 580 nm upon excitation at 230-340 nm is also noticeable. The wavelength of 250 nm is characterized by high signal intensity and is most suitable for differentiation between the samples.

  3. Nrf2 is involved in maintaining hepatocyte identity during liver regeneration.

    Directory of Open Access Journals (Sweden)

    Yuhong Zou

    Full Text Available Nrf2, a central regulator of the cellular defense against oxidative stress and inflammation, participates in modulating hepatocyte proliferation during liver regeneration. It is not clear, however, whether Nrf2 regulates hepatocyte growth, an important cellular mechanism to regain the lost liver mass after partial hepatectomy (PH. To determine this, various analyses were performed in wild-type and Nrf2-null mice following PH. We found that, at 60 h post-PH, the vast majority of hepatocytes lacking Nrf2 reduced their sizes, activated hepatic progenitor markers (CD133, TWEAK receptor, and trefoil factor family 3, depleted HNF4α protein, and downregulated the expression of a group of genes critical for their functions. Thus, the identity of hepatocytes deficient in Nrf2 was transiently but massively impaired in response to liver mass loss. This event was associated with the coupling of protein depletion of hepatic HNF4α, a master regulator of hepatocyte differentiation, and concomitant inactivation of hepatic Akt1 and p70S6K, critical hepatocyte growth signaling molecules. We conclude that Nrf2 participates in maintaining newly regenerated hepatocytes in a fully differentiated state by ensuring proper regulation of HNF4α, Akt1, and p70S6K during liver regeneration.

  4. Gene modulation associated with inhibition of liver regeneration in hepatitis B virus X transgenic mice

    Institute of Scientific and Technical Information of China (English)

    Malgorzata Sidorkiewicz; Jean-Philippe Jais; Guilherme Tralhao; Serban Morosan; Carlo Giannini; Nicolas Brezillon; Patrick Soussan; Oona Delpuech; Dina Kremsdorf

    2008-01-01

    AIM: To analyze the modulation of gene expression profile associated with inhibition of liver regeneration in hepatitis B X (HBx)-expressing transgenic mice.METHODS: Microarray technology was performed on liver tissue obtained from 4 control (LacZ) and 4 transgenic mice (HBx-LacZ), 48 h after partial hepatectomy. The significance of the normalized log-ratios was assessed for each gene, using robust Mests under an empirical Bayes approach. Microarray hybridization data was verified on selected genes by quantitative PCR.RESULTS: The comparison of gene expression patterns showed a consistent modulation of the expression of 26 genes, most of which are implicated in liver regeneration. Up-regulated genes included DNA repair proteins (Rad-52, MSH6) and transmembrane proteins (syndecan 4, tetraspanin), while down-regulated genes were connected to the regulation of transcription (histone deacetylase, Zfp90, MyoDl) and were involved in the cholesterol metabolic pathway and isoprenoidbiosynthesis (farnesyl diphosphate synthase, Cyp7b1, geranylgeranyl diphosphate synthase, SAA3).CONCLUSION: Our results provide a novel insight into the biological activities of HBx, implicated in the inhibition of liver regeneration.

  5. Extent of liver resection modulates the activation of transcription factors and the production of cytokines involved in liver regeneration

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    AIM: To investigate the molecular events involved in liver regeneration following subtotal hepatectomy (SH) as previous studies have largely focused on partial hepatectomy (PH).METHODS: Male Wistar rats were subjected to 70% PH or 90% SH, respectively, and sacrificed at different times after surgery. Untreated and sham-operated animals served as controls. Serum and liver samples were obtained to investigate liver function, apoptosis (TUNEL assay) and transcription factors (NF-κB, Stat3; ELISA) or cytokines (HGF, TNF-α, IL-6, TGF-α, TGF-β; quantitative RT-PCR) involved in liver regeneration. RESULTS: Serum levels of ALT and AST in animals with 70% PH differed significantly from sham-operated and control animals. We found that the peak concentration 12 h after surgery returned to control levels 7 d after surgery. LDH was increased only at 12 h after 70% PH compared to sham. Bilirubin showed no differences between the sham and 70% resection. After PH, early NF-κB activation was detected 12 h after surgery (313.21 ± 17.22 ng/mL), while there was no activation after SH (125.22 ± 44.36 ng/mL) compared to controls (111.43 ± 32.68 ng/mL) at this time point. In SH, however, NF-κB activation was delayed until 24 h (475.56 ± 144.29 ng/mL). Star3 activation was similar in both groups. These findings correlated with suppressed and delayed induction of regenerative genes after SH (i.e. TNF-α 24 h postoperatively: 2375 ± 1220 in 70% and 88±31 in 90%; IL-6 12 h postoperatively: 2547 ± 441 in 70% and 173 ± 82 in 90%). TUNEL staining revealed elevated apoptosis rates in SH (0.44% at 24 h; 0.63% at 7 d) compared to PH (0.27% at 24 h; 0.15% at 7 d). CONCLUSION: The molecular events involved in liver regeneration are significantly influenced by the extent of resection as SH leads to suppression and delay of liver regeneration compared to PH, which is associated with delayed activation of NF-κB and suppression of proregenerative cytokines.

  6. Participation of liver progenitor cells in liver regeneration: lack of evidence in the AAF/PH rat model.

    Science.gov (United States)

    Dusabineza, Ange-Clarisse; Van Hul, Noémi K; Abarca-Quinones, Jorge; Starkel, Peter; Najimi, Mustapha; Leclercq, Isabelle A

    2012-01-01

    When hepatocyte proliferation is impaired, liver progenitor cells (LPC) are activated to participate in liver regeneration. We used the 2-acetaminofluorene/partial hepatectomy (AAF/PH) model to evaluate the contribution of LPC to liver cell replacement and function restoration. Fischer rats subjected to AAF/PH (or PH alone) were investigated 7, 10 and 14 days post-hepatectomy. Liver mass recovery (LMR) was estimated, and the liver mass to body weight ratio calculated. We used serum albumin and bilirubin levels, and liver albumin mRNA levels to assess the liver function. LPC expansion was analyzed by cytokeratin 19 (CK19), glutathione S-transferase protein (GSTp) immunohistochemistry and by CK19, CD133, transforming growth factor-β1 and hepatocyte growth factor mRNA expression in livers. Cell proliferation was evaluated by Ki67 and BrdU immunostaining. Compared with PH alone where LMR was ∼100% 14 days post-PH, LMR was defective in AAF/PH rats (64.1±15.5%, P=0.0004). LPC expansion was scarce in PH livers (0.5±0.4% of CK19(+) area), but significant in AAF/PH livers (8.5±7.2% of CK19(+)), and inversely correlated to LMR (r(2)=0.63, PPH animals presented liver failure (low serum albumin and high serum bilirubin) 14 days post-PH. Compared with animals with preserved function, this was associated with a lower LMR (50±6.8 vs 74.6±9.4%, P=0.0005), a decreased liver to body weight ratio (2±0.3 vs 3.5±0.6%, P=0.001), and a larger LPC expansion such as proliferating Ki67(+) LPC covered 17.4±4.2% of the liver parenchyma vs 3.1±1.5%, (Plivers with preserved function. These observations suggest that, in this model, the efficient recovery of the liver function was ensured rather by the proliferation of mature hepatocytes than by the LPC expansion and differentiation into hepatocytes.

  7. Differentiation of human embryonic stem cells along a hepatocyte lineage and its application in liver regeneration

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Hepatocyte transplantation and bioartificial liver(BAL)as alternatives to liver transplantation offer the possibility of effective treatment for many inherited and acquired hepatic disorders.Unfortunately,the limited availability of donated livers and the variability of their derived hepatocytes make it difficult to obtain enough viable human hepatocytes for the hepatocyte-based therapies.Embryonic stem cells (ESCs),which could be isolated directly from the blastocyst inner cell mass,have permanent self-renewal capability and developmental pluripotency and therefore might be an ideal cell source in the treatment of hepatic discords.However,differentiation of hESCS into hepatocytes with significant numbers remains a challenge.This review updates our current understanding of differentiation of ESCs into hepatic lineage cells,their future therapeutic uses and problems in liver regeneration.

  8. Liver regeneration - The best kept secret: A model of tissue injury response

    Directory of Open Access Journals (Sweden)

    Javier A. Cienfuegos

    2014-03-01

    Full Text Available Liver regeneration (LR is one of the most amazing tissue injury response. Given its therapeutic significance has been deeply studied in the last decades. LR is an extraordinary complex process, strictly regulated, which accomplishes the characteristics of the most evolutionary biologic systems (robustness and explains the difficulties of reshaping it with therapeutic goals. TH reproduces the physiological tissue damage response pattern, with a first phase of priming of the hepatocytes -cell-cycle transition G0-G1-, and a second phase of proliferation -cell-cycle S/M phases- which ends with the liver mass recovering. This process has been related with the tissue injury response regulators as: complement system, platelets, inflammatory cytokines (TNF-α, IL-1β, IL-6, growth factors (HGF, EGF, VGF and anti-inflammatory factors (IL-10, TGF-β. Given its complexity and strict regulation, illustrates the unique alternative to liver failure is liver transplantation. The recent induced pluripotential cells (iPS description and the mesenchymal stem cell (CD133+ plastic capability have aroused new prospects in the cellular therapy field. Those works have assured the cooperation between mesenchymal and epithelial cells. Herein, we review the physiologic mechanisms of liver regeneration.

  9. Cross effects of resveratrol and mesenchymal stem cells on liver regeneration and homing in partially hepatectomized rats.

    Science.gov (United States)

    Okay, Erdem; Simsek, Turgay; Subasi, Cansu; Gunes, Abdullah; Duruksu, Gokhan; Gurbuz, Yesim; Gacar, Gulcin; Karaoz, Erdal

    2015-04-01

    In this study, we examined the effect of preoperatively administered resveratrol (RV) and mesenchymal stem cells (MSCs) on regeneration of partially hepatectomized rat liver. We also evaluated the effect of RV on homing of MSCs. MSCs were isolated from bone marrow and cultured in vitro. Wistar albino rats were randomly divided into four groups. In groups, rats received (1) no treatment, (2) single dose RV, (3) MSCs and (4) RV plus MSCs before partial hepatectomy (PH). Injected MSCs were traced by labeling them with green fluorescent protein, and liver regeneration was determined by comparison of liver weight gain, histological examination and immunohistochemical staining with proliferating cell nuclear antigen (PCNA) for mitotic cells. The expression levels of tumor necrosis factor -alpha (TNF-α), interleukin-6 (IL-6) and hepatocyte growth factor (HGF) were also determined in the parafin sections of liver specimens with immunohistochemical staining. Administration of RV and MSCs separately or together enhanced liver regeneration despite decreasing the TNF-α and IL-6 expression. This positive contribution was probably due to direct raising effect on HGF for RV and HGF expression for MSCs that we demonstrated with immunohistochemical staining. Additionally, RV increased the homing of MSCs in liver probably related to life prolonging effect on MSCs. These results indicate that preoperative RV as well as MSCs application enhances liver regeneration after partial hepatectomy in rats. Paying attention to RV about the effect on liver regeneration and homing of MSCs might be the goal of further investigations.

  10. Sustained Release of Bone Morphogenetic Protein 2 via Coacervate improves Muscle Derived Stem Cell Mediated Cartilage Regeneration in MIA-induced Osteoarthritis

    Science.gov (United States)

    Hicks, Justin James; Rocha, Jorge Luis; Li, Hongshuai; Huard, Johnny; Wang, Yadong; Hogan, MaCalus Vinson

    2016-01-01

    Objectives: Individuals who participate in sports have an increased risk of osteoarthritis (OA), characterized by articular cartilage degeneration. Currently, there is no cure for OA with treatment aimed at symptom relief and improved function. Muscle-derived stem cells (MDSCs) have been shown to exhibit long-term proliferation, high self-renewal, and multipotent differentiation capabilities in vitro. Previously, we have demonstrated that murine MDSCs retrovirally transduced to express chondrogenic proteins (BMPs) differentiate into chondrocytes and enhance cartilage repair in vivo. Direct injection of therapeutic proteins can promote cartilage healing; however, they have relatively short half-lives requiring muitiple injections of high dosages. This presents a challenge in terms of maintaining adequate local BMP levels and could negatively affect both injured and normal structures and lead to side effects such as osteophyte formation. Gene therapy is a promising approach that addresses this problem; however, its utilization in clinical applications is much further down the road. In order to circumvent viral transduction of cells for cartilage regeneration, we developed a unique growth factor delivery platform comprised of native heparin and a synthetic polycation, poly(ethylene argininylaspartate diglyceride) (PEAD) incorporated with BMP2 (BMP2 coacervate). In this study, we show that sustained delivery of BMP2 via a BMP2 coacervate can induce the differentiation of MDSCs to a chondrocyte lineage for in vivo cartilage regeneration and healing in a Monoiodoacetate (MIA)-induced osteoarthritis model. Methods: mMDSCs were isolated from muscle biopsies via a modified pre-plated technique. The BMP2 coacervates were prepared as previously described. The release profiles of BMP2 coacervate were tested by ELISA. The chondrogenic effects that delivery of BMP2 had on MDSCs were evaluated by RT-PCR. The efficacy of MDSC with BMP2 coacervate were evaluated in vivo in a MIA

  11. Identification and Characterization of 177 Unreported Genes Associated with Liver Regeneration

    Institute of Scientific and Technical Information of China (English)

    Cunshuan Xu; Salman Rahman; Jingbo Zhang; Cuifang Chang; Jinyun Yuan; Hongpeng Han; Kejin Yang; Lifeng Zhao; Wenqiang Li; Yuchang Li; Huiyong Zhang

    2004-01-01

    The mammalian liver has a very strong regeneration capacity after partial hepatectomy (PH). To further learn the genes participating in the liver regeneration (LR), 551 cDNAs selected from subtracted cDNA libraries of the regenerating rat liver were screened by microarray, and their expression profiles were studied by cluster and generalization analyses. Among them, 177 genes were identified unreported and up- or down-regulated more than twofold at one or more time points after PH, of which 62 genes were down-regulated to less than 0.5; 99 genes were up-regulated to 2-10 folds, and 16 genes were either up- or down-regulated at different time points during LR. By using BLAST and GENSCAN, these genes were located on responsible chromosomes with 131 genes on the long arms of the chromosomes. The cluster and generalization analyses showed that the gene expression profiles are similar in 2 and 4, 12 and 16, 96 and 144 h respectively after PH,suggesting that the actions of the genes expressed in the same profiles are similar,and those expressed in different profiles have less similarity. However, the types,characteristics and functions of the 177 genes remain to be further studied.

  12. Integrative proteomic and microRNA analysis of the priming phase during rat liver regeneration.

    Science.gov (United States)

    Geng, Xiaofang; Chang, Cuifang; Zang, Xiayan; Sun, Jingyan; Li, Pengfei; Guo, Jianli; Xu, Cunshuan

    2016-01-10

    The partial hepatectomy (PH) model provides an effective medium for study of liver regeneration (LR). Considering that LR is regulated by microRNAs (miRNAs), investigation of the regulatory role of miRNAs is critical for revealing how regenerative processes are initiated and controlled. Using high-throughput sequencing technology, we examined miRNA expression profiles of the regenerating rat liver after PH, and found that 23 miRNAs were related to rat LR. Among them, several miRNAs were significantly altered at 2h and 6h after PH, corresponding to the priming phase of LR. Furthermore, we examined the protein profiles in the regenerating rat liver at 2h and 6h after PH by iTRAQ coupled with LC-MS/MS, and found that 278 proteins were significantly changed. Subsequently, an integrative proteomic and microRNA analysis by Ingenuity Pathway Analysis 9.0 (IPA) software showed that miR-125a, miR-143, miR-150, miR-181c, miR-182, miR-183, miR-199a, miR-429 regulated the priming phase of rat LR by modulating the expression of proteins involved in networks critical for cell apoptosis, cell survival, cell cycle, inflammatory response, metabolism, etc. Thus, our studies provide novel evidence for a functional molecular network populated by the down-regulated targets of the up-regulated miRNAs in the priming phase of rat LR.

  13. Isolation of Mallory bodies and an attempt to demonstrate cell mediated immunity to Mallory body isolate in patients with alcoholic liver disease

    DEFF Research Database (Denmark)

    Gluud, C; Hardt, F; Aldershvile, J

    1981-01-01

    in haematoxylin-eosin stained smears. Electron microscopy confirmed the presence of Mallory bodies in the isolates. The Mallory body isolate was used as antigen in the agarose leucocyte migration inhibition test in order to test the cell-mediated immunity. No significant difference in leucocyte migration...

  14. Four waves of hepatocyte proliferation linked with three waves of hepatic fat accumulation during partial hepatectomy-induced liver regeneration.

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    Yuhong Zou

    Full Text Available Partial hepatectomy (PH triggers hepatocyte proliferation-mediated liver repair and is widely used to study the mechanisms governing liver regeneration in mice. However, the dynamics of the hepatocyte proliferative response to PH remain unclear. We found that PH-induced mouse liver regrowth was driven by four consecutive waves of hepatocyte replication. The first wave exhibited the highest magnitude followed by two moderate waves and one minor wave. Underlying this continuous hepatocyte replication was persistent activation of cell cycle components throughout the period of liver regeneration. Hepatocyte mitotic activity in the first three proliferative cycles showed a circadian rhythm manifested by three corresponding mitosis peaks, which were always observed at Zeitgeber time 0. The Bmal1-Clock/Wee1/Cdc2 pathway has been proposed by others to govern the circadian rhythm of hepatocyte mitosis during liver regeneration. However, we did not observe the correlations in the expression or phosphorylation of these proteins in regenerating livers. Notably, Bmal1 protein displayed frequent changes in hepatic distribution and cellular localization as the liver regrowth progressed. Further, three waves of hepatic fat accumulation occurred during hepatic regeneration. The first started before and lasted through the first round of hepatocyte proliferation, whereas the second and third occurred concomitantly with the second and third mitotic peaks, respectively.PH-induced liver regeneration consists of four continuous waves of hepatocyte proliferation coupled with three waves of hepatic fat accumulation. Bmal1, Wee1, and Cdc2 may not form a pathway regulating the circadian rhythm of hepatocyte mitosis during liver regeneration.

  15. Bone morphogenetic protein-2 is a negative regulator of hepatocyte proliferation downregulated in the regenerating liver

    Institute of Scientific and Technical Information of China (English)

    Cui-Ping Xu; Wen-Min Ji; Gijs R van den Brink; Maikel P Peppelenbosch

    2006-01-01

    AIM: To characterize the expression and dynamic changes of bone morphogenetic protein (BMP)-2 in hepatocytes in the regenerating liver in rats after partial hepatectomy (PH), and examine the effects of BMP-2 on proliferation of human Huh7 hepatoma cells.METHODS: Fifty-four adult male Wistar rats were randomly divided into three groups: A normal control (NC) group, a partial hepatectomized (PH) group and a sham operated (SO) group. To study the effect of liver regeneration on BMP-2 expression, rats were sacrificed before and at different time points after PH or the sham intervention (6, 12, 24 and 48 h). For each time point, six rats were used in parallel. Expression and distribution of BMP-2 protein were determined in regenerating liver tissue by Western blot analysis and immunohistochemistry. Effects of BMP-2 on cell proliferation of human Huh7 hepatoma cell line were assessed using an MTT assay.RESULTS: In the normal liver strong BMP-2 expression was observed around the central and portal veins. The expression of BMP-2 decreased rapidly as measured by both immunohistochemistry and Western blot analysis.This decrease was at a maximum of 3.22 fold after 12 h and returned to normal levels at 48 h after PH. No significant changes in BMP-2 immunoreactivity were observed in the SO group. BMP-2 inhibited serum induced Huh7 cell proliferation.CONCLUSION: BMP-2 is expressed in normal adult rat liver and negatively regulates hepatocyte proliferation.The observed down regulation of BMP-2 following partial hepatectomy suggests that such down regulation may be necessary for hepatocyte proliferation.

  16. Human Adipose Tissue Derived Stem Cells Promote Liver Regeneration in a Rat Model of Toxic Injury

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    Eva Koellensperger

    2013-01-01

    Full Text Available In the light of the persisting lack of donor organs and the risks of allotransplantations, the possibility of liver regeneration with autologous stem cells from adipose tissue (ADSC is an intriguing alternative. Using a model of a toxic liver damage in Sprague Dawley rats, generated by repetitive intraperitoneal application of retrorsine and allyl alcohol, the ability of human ADSC to support the restoration of liver function was investigated. A two-thirds hepatectomy was performed, and human ADSC were injected into one remaining liver lobe in group 1 (n = 20. Injection of cell culture medium performed in group 2 (n = 20 served as control. Cyclosporine was applied to achieve immunotolerance. Blood samples were drawn weekly after surgery to determine liver-correlated blood values. Six and twelve weeks after surgery, animals were sacrificed and histological sections were analyzed. ADSC significantly raised postoperative albumin (P < 0.017, total protein (P < 0.031, glutamic oxaloacetic transaminase (P < 0.001, and lactate dehydrogenase (P < 0.04 levels compared to injection of cell culture medium alone. Transplanted cells could be found up to twelve weeks after surgery in histological sections. This study points towards ADSC being a promising alternative to hepatocyte or liver organ transplantation in patients with severe liver failure.

  17. Hepatitis B virus HBx protein impairs liver regeneration through enhanced expression of IL-6 in transgenic mice.

    Science.gov (United States)

    Quétier, Ivan; Brezillon, Nicolas; Duriez, Marion; Massinet, Hélène; Giang, Eric; Ahodantin, James; Lamant, Céline; Brunelle, Marie-Noëlle; Soussan, Patrick; Kremsdorf, Dina

    2013-08-01

    Conflicting results have been reported regarding the impact of hepatitis B virus X protein (HBx) expression on liver regeneration triggered by partial hepatectomy (PH). In the present report we investigated the mechanisms by which HBx protein alters hepatocyte proliferation after PH. PH was performed on a transgenic mouse model in which HBx expression is under the control of viral regulatory elements and liver regeneration was monitored. LPS, IL-6 neutralizing antibody, and SB203580 were injected after PH to evaluate IL-6 participation during liver regeneration. Cell cycle progression of hepatocytes was delayed in HBx transgenic mice compared to WT animals. Moreover, HBx induced higher secretion of IL-6 soon after PH. Upregulation of IL-6 was associated with an elevation of STAT3 phosphorylation, SOCS3 transcript accumulation and a decrease in ERK1/2 phosphorylation in the livers of HBx transgenic mice. The involvement of IL-6 overexpression in cell cycle deregulation was confirmed by the inhibition of liver regeneration in control mice after the upregulation of IL-6 expression using LPS. In addition, IL-6 neutralization with antibodies was able to restore liver regeneration in HBx mice. Finally, the direct role of p38 in IL-6 secretion after PH was demonstrated using SB203580, a pharmacological inhibitor. HBx is able to induce delayed hepatocyte proliferation after PH, and HBx-induced IL-6 overexpression is involved in delayed liver regeneration. By modulating IL-6 expression during liver proliferation induced by stimulation of the cellular microenvironment, HBx may participate in cell cycle deregulation and progression of liver disease. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  18. The combined effect of erythropoietin and granulocyte macrophage colony stimulating factor on liver regeneration after major hepatectomy in rats

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    Frangou Matrona

    2010-07-01

    Full Text Available Abstract Background The liver presents a remarkable capacity for regeneration after hepatectomy but the exact mechanisms and mediators involved are not yet fully clarified. Erythropoietin (EPO and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF have been shown to promote liver regeneration after major hepatectomy. Aim of this experimental study is to compare the impact of exogenous administration of EPO, GM-CSF, as well as their combination on the promotion of liver regeneration after major hepatectomy. Methods Wistar rats were submitted to 70% major hepatectomy. The animals were assigned to 4 experimental groups: a control group (n = 21 that received normal saline, an EPO group (n = 21, that received EPO 500 IU/kg, a GM-CSF group (n = 21 that received 20 mcg/kg of GM-CSF and a EPO+GMCSF group (n = 21 which received a combination of the above. Seven animals of each group were killed on the 1st, 3rd and 7th postoperative day and their remnant liver was removed to evaluate liver regeneration by immunochemistry for PCNA and Ki 67. Results Our data suggest that EPO and GM-CSF increases liver regeneration following major hepatectomy when administered perioperatively. EPO has a more significant effect than GM-CSF (p Conclusion EPO, GM-CSF and their combination enhance liver regeneration after hepatectomy in rats when administered perioperatively. However their combination has a weaker effect on liver regeneration compared to EPO alone. Further investigation is needed to assess the exact mechanisms that mediate this finding.

  19. In vitro culture of isolated primary hepatocytes and stem cell-derived hepatocyte-like cells for liver regeneration.

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    Hu, Chenxia; Li, Lanjuan

    2015-08-01

    Various liver diseases result in terminal hepatic failure, and liver transplantation, cell transplantation and artificial liver support systems are emerging as effective therapies for severe hepatic disease. However, all of these treatments are limited by organ or cell resources, so developing a sufficient number of functional hepatocytes for liver regeneration is a priority. Liver regeneration is a complex process regulated by growth factors (GFs), cytokines, transcription factors (TFs), hormones, oxidative stress products, metabolic networks, and microRNA. It is well-known that the function of isolated primary hepatocytes is hard to maintain; when cultured in vitro, these cells readily undergo dedifferentiation, causing them to lose hepatocyte function. For this reason, most studies focus on inducing stem cells, such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), hepatic progenitor cells (HPCs), and mesenchymal stem cells (MSCs), to differentiate into hepatocyte-like cells (HLCs) in vitro. In this review, we mainly focus on the nature of the liver regeneration process and discuss how to maintain and enhance in vitro hepatic function of isolated primary hepatocytes or stem cell-derived HLCs for liver regeneration. In this way, hepatocytes or HLCs may be applied for clinical use for the treatment of terminal liver diseases and may prolong the survival time of patients in the near future.

  20. Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma.

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    Michele Vacca

    Full Text Available BACKGROUND & AIMS: Liver regeneration (LR is a valuable model for studying mechanisms modulating hepatocyte proliferation. Nuclear receptors (NRs are key players in the control of cellular functions, being ideal modulators of hepatic proliferation and carcinogenesis. METHODS & RESULTS: We used a previously validated RT-qPCR platform to profile modifications in the expression of all 49 members of the NR superfamily in mouse liver during LR. Twenty-nine NR transcripts were significantly modified in their expression during LR, including fatty acid (peroxisome proliferator-activated receptors, PPARs and oxysterol (liver X receptors, Lxrs sensors, circadian masters RevErbα and RevErbβ, glucocorticoid receptor (Gr and constitutive androxane receptor (Car. In order to detect the NRs that better characterize proliferative status vs. proliferating liver, we used the novel Random Forest (RF analysis to selected a trio of down-regulated NRs (thyroid receptor alpha, Trα; farsenoid X receptor beta, Fxrβ; Pparδ as best discriminators of the proliferating status. To validate our approach, we further studied PPARδ role in modulating hepatic proliferation. We first confirmed the suppression of PPARδ both in LR and human hepatocellular carcinoma at protein level, and then demonstrated that PPARδ agonist GW501516 reduces the proliferative potential of hepatoma cells. CONCLUSIONS: Our data suggest that NR transcriptome is modulated in proliferating liver and is a source of biomarkers and bona fide pharmacological targets for the management of liver disease affecting hepatocyte proliferation.

  1. Significance and mechanism of CYP7a1 gene regulation during the acute phase of liver regeneration.

    Science.gov (United States)

    Zhang, Lisheng; Huang, Xiongfei; Meng, Zhipeng; Dong, Bingning; Shiah, Steven; Moore, David D; Huang, Wendong

    2009-02-01

    Cholesterol 7alpha-hydroxylase (CYP7a1) is the rate-limiting enzyme in the classic pathway of bile acid synthesis. Expression of CYP7a1 is regulated by a negative feedback pathway of bile acid signaling. Previous studies have suggested that bile acid signaling is also required for normal liver regeneration, and CYP7a1 expression is strongly repressed after 70% partial hepatectomy (PH). Both the effect of CYP7a1 suppression on liver regrowth and the mechanism by which 70% PH suppresses CYP7a1 expression are unknown. Here we show that liver-specific overexpression of an exogenous CYP7a1 gene impaired liver regeneration after 70% PH, which was accompanied by increased hepatocyte apoptosis and liver injury. CYP7a1 expression was initially suppressed after 70% PH in an farnesoid X receptor/ small heterodimer partner-independent manner; however, both farnesoid X receptor and small heterodimer partner were required to regulate CYP7a1 expression at the later stage of liver regeneration. c-Jun N-terminus kinase and hepatocyte growth factor signaling pathways are activated during the acute phase of liver regeneration. We determined that hepatocyte growth factor and c-Jun N-terminus kinase pathways were involved in the suppressing of the CYP7a1 expression in the acute phase of live regeneration. Taken together, our results provide the significance that CYP7a1 suppression is required for liver protection after 70% PH and there are two distinct phases of CYP7a1 gene regulation during liver regeneration.

  2. MBSJ MCC Young Scientist Award 2012 Liver regeneration: a unique and flexible reaction depending on the type of injury.

    Science.gov (United States)

    Suzuki, Atsushi

    2015-02-01

    The liver can be thought of as a mysterious organ, because it has an elegant regenerative capability. This phenomenon has been well known since ancient times and is already applied to medical treatments for severe hepatic disorders by transplanting portions of liver received from living donors. However, it was not until quite recently that the mechanism underlying the principle of liver regeneration was investigated more deeply. Recent advances in the technologies for characterizing cell properties and examining the molecular nature of cells are enabling us to understand what occurs in the regenerating liver. After acute liver damage, hepatocytes actively proliferate in response to external stimulation by humoral factors. However, in the chronically injured liver, hepatocytes cannot proliferate well, but biliary cells appearing after chronic liver damage form primitive ductules around portal veins of the liver. These biliary cells may have a multiple origin, including hepatocytes, and contain progenitor cells giving rise to both hepatocytes and biliary cells, or represent cells that can be directly converted into hepatocytes. Although liver regeneration is more complicated than we had thought, unremitting efforts by researchers will certainly connect the numerous findings obtained in basic research with the development of new therapeutic strategies for liver diseases. © 2014 The Authors. Genes to Cells published by Wiley Publishing Asia Pty Ltd and the Molecular Biology Society of Japan.

  3. Comparative analysis of regulatory roles of P38 signaling pathway in 8 types liver cell during liver regeneration.

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    Yang, Xianguang; Zhu, Lin; Zhao, Weiming; Shi, Yaohuang; He, Chuncui; Xu, Cunshuan

    2016-12-05

    P38MAPK signaling pathway was closely related to cell proliferation, apoptosis, cell differentiation, cell survival, cell death, and so on. However, the regulatory mechanism of P38MAPK signaling pathway in liver regeneration (LR) was unclear. In order to further reveal the roles of P38MAPK signaling pathway in rat liver regeneration, Ingenuity Pathway Analysis (IPA) software and related data sites were used to construct P38MAPK signaling pathway, and the pathway was confirmed by relevant documents literature. The expression changes of P38MAPK signaling pathway-related gene in eight type cells were further analyzed by Rat Genome 230 2.0 Array, and the results showed that 95 genes in P38MAPK signaling pathway had significant changes. H-cluster analysis showed that hepatocyte cell (HC), pit cell (PC), oval cell (OC) and biliary epithelial cell (BEC) are clustered together; and the same as Kupffer cell (KC), sinusoidal endothelial cell (SEC), dendritic cell (DC) and hepatic stellate cell (HSC). IPA software and expression analysis systematic explorer (EASE) were applied to functional enrichment analysis, and the results showed that P38MAPK signaling pathway was mainly involved in apoptosis, cell death, cell proliferation, cell survival, cell viability, activation, cell cycle progression, necrosis, synthesis of DNA and other physical activity during LR. In conclusion, P38MAPK signaling pathway regulated various physiological activities of LR through multiple signaling pathways.

  4. Transcription Profiles of Marker Genes Predict The Transdifferentiation Relationship between Eight Types of Liver Cell during Rat Liver Regeneration

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    Xiaguang Chen

    2015-07-01

    Full Text Available Objective: To investigate the transdifferentiation relationship between eight types of liver cell during rat liver regeneration (LR. Materials and Methods: 114 healthy Sprague-Dawley (SD rats were used in this experimental study. Eight types of liver cell were isolated and purified with percoll density gradient centrifugation and immunomagentic bead methods. Marker genes for eight types of cell were obtained by retrieving the relevant references and databases. Expression changes of markers for each cell of the eight cell types were measured using microarray. The relationships between the expression profiles of marker genes and transdifferentiation among liver cells were analyzed using bioinformatics. Liver cell transdifferentiation was predicted by comparing expression profiles of marker genes in different liver cells. Results: During LR hepatocytes (HCs not only express hepatic oval cells (HOC markers (including PROM1, KRT14 and LY6E, but also express biliary epithelial cell (BEC markers (including KRT7 and KRT19; BECs express both HOC markers (including GABRP, PCNA and THY1 and HC markers such as CPS1, TAT, KRT8 and KRT18; both HC markers (KRT18, KRT8 and WT1 and BEC markers (KRT7 and KRT19 were detected in HOCs. Additionally, some HC markers were also significantly upregulated in hepatic stellate cells ( HSCs, sinusoidal endothelial cells (SECs , Kupffer cells (KCs and dendritic cells (DCs, mainly at 6-72 hours post partial hepatectomy (PH. Conclusion: Our findings indicate that there is a mutual transdifferentiation relationship between HC, BEC and HOC during LR, and a tendency for HSCs, SECs, KCs and DCs to transdifferentiate into HCs.

  5. Hepatocyte-specific deletion of Cdc42 results in delayed liver regeneration after partial hepatectomy in mice

    DEFF Research Database (Denmark)

    Yuan, Haixin; Zhang, Hong; Wu, Xunwei

    2009-01-01

    . Consistent with this, expression of cyclins D1, A, and E was markedly delayed or reduced in Cdc42LK livers during regeneration. As a potential effector of Cdc42, Rac1 activation was dramatically attenuated in Cdc42LK livers after partial hepatectomy, suggesting it is regulated in a Cdc42-dependent manner....... Activation of certain proliferative signaling pathways, such as extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p70S6 kinase pathways, was delayed in Cdc42LK livers. In addition, dilated bile canaliculi and excessive lipid accumulation were observed in mutant livers during liver...

  6. GH receptor plays a major role in liver regeneration through the control of EGFR and ERK1/2 activation.

    Science.gov (United States)

    Zerrad-Saadi, Amal; Lambert-Blot, Martine; Mitchell, Claudia; Bretes, Hugo; Collin de l'Hortet, Alexandra; Baud, Véronique; Chereau, Fanny; Sotiropoulos, Athanassia; Kopchick, John J; Liao, Lan; Xu, Jianming; Gilgenkrantz, Hélène; Guidotti, Jacques-Emmanuel

    2011-07-01

    GH is a pleiotropic hormone that plays a major role in proliferation, differentiation, and metabolism via its specific receptor. It has been previously suggested that GH signaling pathways are required for normal liver regeneration but the molecular mechanisms involved have yet to be determined. The aim of this study was to identify the mechanisms by which GH controls liver regeneration. We performed two thirds partial hepatectomies in GH receptor (GHR)-deficient mice and wild-type littermates and showed a blunted progression in the G(1)/S transition phase of the mutant hepatocytes. This impaired liver regeneration was not corrected by reestablishing IGF-1 expression. Although the initial response to partial hepatectomy at the priming phase appeared to be similar between mutant and wild-type mice, cell cycle progression was significantly blunted in mutant mice. The main defect in GHR-deficient mice was the deficiency of the epidermal growth factor receptor activation during the process of liver regeneration. Finally, among the pathways activated downstream of GHR during G(1) phase progression, namely Erk1/2, Akt, and signal transducer and activator of transcription 3, we only found a reduced Erk1/2 phosphorylation in mutant mice. In conclusion, our results demonstrate that GH signaling plays a major role in liver regeneration and strongly suggest that it acts through the activation of both epidermal growth factor receptor and Erk1/2 pathways.

  7. Expression of bcl-2 gene family during resection induced liver regeneration:Comparison between hepatectomized and sham groups

    Institute of Scientific and Technical Information of China (English)

    Kamil Can Akcali; Aydin Dalgic; Ahmet Ucar; Khemaeis Ben Haj; Dilek Guvenc

    2004-01-01

    AIM: During liver regeneration cellular proliferation and apoptosis result in tissue remodeling to restore normal hepatic mass and structure. Main regulators of the apoptotic machinery are the Bcl-2 family proteins but their roles are not well defined throughout the liver regeneration. We aimed to analyze the expression levels of bcl-2gene family members during resection induced liver regeneration.METHODS: We performed semi-quantitative RT-PCR to examine the expression level of bak, bax, bcl-2 and bcl-xL in 70% hepatectomized rat livers during the whole regeneration process and compared to that of the sham and normal groups.RESULTS: The expression of bakand baxwas decreased whereas that of bcl-2and bcl-XL was increased in hepatectomized animals compared to normal liver at most time points. We also reported for the first time that sham group of animals had statistically significant higher expression of bakand bax than hepatectomized animals. In addition, the area under the curve (AUC) values of these genes was larger in sham groups than the hepatectomized groups.CONCLUSION: The expression changes of bak, bax, bcl-2 and bcl-,XL genes are altered not only due to regeneration,but also due to effects of surgical operations.

  8. Expression patterns and action analysis of genes associated with hepatitis virus infection during rat liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Li-Juan Su; Guang-Wei Ding; Zhi-Li Yang; Shou-Bing Zhang; Yu-Xiu Yang; Cun-Shuan Xu

    2006-01-01

    AIM: To study the action of hepatitis virus infectionassociated genes at transcription level during liver regeneration (LR).METHODS: Hepatitis virus infection-associated genes were obtained by collecting the data from databases and retrieving the correlated articles, and their expression changes in the regenerating rat liver were detected with the rat genome 230 2.0 array.RESULTS: Eighty-eight genes were found to be associated with liver regeneration. The number of genes initially and totally expressed during initial LR [0.5-4 h after partial hepatectomy (PH)], transition from G0 to G1 (4-6 h after PH), cell proliferation (6-66 h after PH), cell differentiation and reorganization of structure-function (66-168 h after PH) was 37, 8, 48, 3 and 37,26, 80, 57, respectively, indicating that the genes were mainly triggered at the early stage of LR (0.5-4 h after PH), and worked at different phases. These genes were classified into 5 types according to their expression similarity, namely 37 up-regulated, 9 predominantly up-regulated, 34 down-regulated, 6 predominantly down-regulated and 2 up/down-regulated genes. Their total up- and down-regulation frequencies were 359 and 149 during LR, indicating that the expression of most genes was enhanced, while the expression of a small number of genes was attenuated during LR. According to time relevance, they were classified into 12 groups (0.5 and 1h, 2 and 4h, 6h, 8 and 12h, 16 and 96h, 18 and 24 h, 30 and 42 h, 36 and 48 h, 54 and 60 h, 66 and 72 h, 120 and 144 h, 168 h), demonstrating that the cellular physiological and biochemical activities during LR were fluctuated. According to expression changes of the genes, their expression patterns were classified into 23 types, suggesting that the cellular physiological and biochemical activities during LR were diverse and complicated.CONCLUSION: The anti-virus infection capacity of regenerating liver can be enhanced and 88 genes play an important role in LR.

  9. Redox state and energy metabolism during liver regeneration: alterations produced by acute ethanol administration.

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    Gutiérrez-Salinas, J; Miranda-Garduño, L; Trejo-Izquierdo, E; Díaz-Muñoz, M; Vidrio, S; Morales-González, J A; Hernández-Muñoz, R

    1999-12-01

    Ethanol metabolism can induce modifications in liver metabolic pathways that are tightly regulated through the availability of cellular energy and through the redox state. Since partial hepatectomy (PH)-induced liver proliferation requires an oversupply of energy for enhanced syntheses of DNA and proteins, the present study was aimed at evaluating the effect of acute ethanol administration on the PH-induced changes in cellular redox and energy potentials. Ethanol (5 g/kg body weight) was administered to control rats and to two-thirds hepatectomized rats. Quantitation of the liver content of lactate, pyruvate, beta-hydroxybutyrate, acetoacetate, and adenine nucleotides led us to estimate the cytosolic and mitochondrial redox potentials and energy parameters. Specific activities in the liver of alcohol-metabolizing enzymes also were measured in these animals. Liver regeneration had no effect on cellular energy availability, but induced a more reduced cytosolic redox state accompanied by an oxidized mitochondrial redox state during the first 48 hr of treatment; the redox state normalized thereafter. Administration of ethanol did not modify energy parameters in PH rats, but this hepatotoxin readily blocked the PH-induced changes in the cellular redox state. In addition, proliferating liver promoted decreases in the activity of alcohol dehydrogenase (ADH) and of cytochrome P4502E1 (CYP2E1); ethanol treatment prevented the PH-induced diminution of ADH activity. In summary, our data suggest that ethanol could minimize the PH-promoted metabolic adjustments mediated by redox reactions, probably leading to an ineffective preparatory event that culminates in compensatory liver growth after PH in the rat.

  10. Down-regulation of microRNA-26a promotes mouse hepatocyte proliferation during liver regeneration.

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    Jian Zhou

    Full Text Available BACKGROUND: Inadequate liver regeneration (LR is still an unsolved problem in major liver resection and small-for-size syndrome post-living donor liver transplantation. A number of microRNAs have been shown to play important roles in cell proliferation. Herein, we investigated the role of miR-26a as a pivotal regulator of hepatocyte proliferation in LR. METHODOLOGY/PRINCIPAL FINDINGS: Adult male C57BL/6J mice, undergoing 70% partial hepatectomy (PH, were treated with Ad5-anti-miR-26a-LUC or Ad5-miR-26a-LUC or Ad5-LUC vector via portal vein. The animals were subjected to in vivo bioluminescence imaging. Serum and liver samples were collected to test liver function, calculate liver-to-body weight ratio (LBWR, document hepatocyte proliferation (Ki-67 staining, and investigate potential targeted gene expression of miR-26a by quantitative real-time PCR and Western blot. The miR-26a level declined during LR after 70% PH. Down-regulation of miR-26a by anti-miR-26a expression led to enhanced proliferation of hepatocytes, and both LBWR and hepatocyte proliferation (Ki-67(+ cells % showed an increased tendency, while liver damage, indicated by aspartate aminotransferase (AST, alanine aminotransferase (ALT and total bilirubin (T-Bil, was reduced. Furthermore, CCND2 and CCNE2, as possible targeted genes of miR-26a, were up-regulated. In addition, miR-26a over-expression showed converse results. CONCLUSIONS/SIGNIFICANCE: MiR-26a plays crucial role in regulating the proliferative phase of LR, probably by repressing expressions of cell cycle proteins CCND2 and CCNE2. The current study reveals a novel miRNA-mediated regulation pattern during the proliferative phase of LR.

  11. Function and expression study uncovered hepatocyte plasma membrane ecto-ATP synthase as a novel player in liver regeneration.

    Science.gov (United States)

    Taurino, Federica; Giannoccaro, Caterina; Sardanelli, Anna Maria; Cavallo, Alessandro; De Luca, Elisa; Santacroce, Salvatore; Papa, Sergio; Zanotti, Franco; Gnoni, Antonio

    2016-08-15

    ATP synthase, canonically mitochondrially located, is reported to be ectopically expressed on the plasma membrane outer face of several cell types. We analysed, for the first time, the expression and catalytic activities of the ecto- and mitochondrial ATP synthase during liver regeneration. Liver regeneration was induced in rats by two-thirds partial hepatectomy. The protein level and the ATP synthase and/or hydrolase activities of the hepatocyte ecto- and mitochondrial ATP synthase were analysed on freshly isolated hepatocytes and mitochondria from control, sham-operated and partial hepatectomized rats. During the priming phase of liver regeneration, 3 h after partial hepatectomy, liver mitochondria showed a marked lowering of the ATP synthase protein level that was reflected in the impairment of both ATP synthesis and hydrolysis. The ecto-ATP synthase level, in 3 h partial hepatectomized hepatocytes, was decreased similarly to the level of the mitochondrial ATP synthase, associated with a lowering of the ecto-ATP hydrolase activity coupled to proton influx. Noteworthily, the ecto-ATP synthase activity coupled to proton efflux was completely inhibited in 3 h partial hepatectomized hepatocytes, even in the presence of a marked intracellular acidification that would sustain it as in control and sham-operated hepatocytes. At the end of the liver regeneration, 7 days after partial hepatectomy, the level and the catalytic activities of the ecto- and mitochondrial ATP synthase reached the control and sham-operated values. The specific modulation of hepatocyte ecto-ATP synthase catalytic activities during liver regeneration priming phase may modulate the extracellular ADP/ATP levels and/or proton influx/efflux trafficking, making hepatocyte ecto-ATP synthase a candidate for a novel player in the liver regeneration process. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  12. TRANEXAMIC ACID ACTION ON LIVER REGENERATION AFTER PARTIAL HEPATECTOMY: EXPERIMENTAL MODEL IN RATS.

    Science.gov (United States)

    Sobral, Felipe Antonio; Daga, Henrique; Rasera, Henrique Nogueira; Pinheiro, Matheus da Rocha; Cella, Igor Furlan; Morais, Igor Henrique; Marques, Luciana de Oliveira; Collaço, Luiz Martins

    2016-01-01

    Different lesions may affect the liver resulting in harmful stimuli. Some therapeutic procedures to treat those injuries depend on liver regeneration to increase functional capacity of this organ. Evaluate the effects of tranexamic acid on liver regeneration after partial hepatectomy in rats. 40 rats (Rattus norvegicus albinus, Rodentia mammalia) of Wistar-UP lineage were randomly divided into two groups named control (CT) and tranexamic acid (ATX), with 20 rats in each. Both groups were subdivided, according to liver regeneration time of 32 h or seven days after the rats had been operated. The organ regeneration was evaluated through weight and histology, stained with HE and PCNA. The average animal weight of ATX and CT 7 days groups before surgery were 411.2 g and 432.7 g, and 371.3 g and 392.9 g after the regeneration time, respectively. The average number of mitotic cells stained with HE for the ATX and CT 7 days groups were 33.7 and 32.6 mitosis, and 14.5 and 14.9 for the ATX and CT 32 h groups, respectively. When stained with proliferating cell nuclear antigen, the numbers of mitotic cells counted were 849.7 for the ATX 7 days, 301.8 for the CT 7 days groups, 814.2 for the ATX 32 hand 848.1 for the CT 32 h groups. Tranexamic acid was effective in liver regeneration, but in longer period after partial hepatectomy. Muitas são as injúrias que acometem o fígado e levam a estímulo lesivo. Alguns procedimentos terapêuticos para tratamento dessas lesões dependem da regeneração hepática para aumentar a sua capacidade funcional. Avaliar o efeito do ácido tranexâmico na regeneração hepática após hepatectomia parcial em ratos. Foram utilizados 40 ratos (Rattus norvegicus albinus, Rodentia mammalia) convencionais da linhagem Wistar-UP. Foram divididos aleatoriamente em dois grupos de 20: grupo controle (CT) e grupo ácido tranexâmico (ATX). Cada um deles foi divido em dois subgrupos para avaliar a regeneração hepática no tempo de 32 h e 7 dias do p

  13. The mitochondrial import gene tomm22 is specifically required for hepatocyte survival and provides a liver regeneration model

    Science.gov (United States)

    Curado, Silvia; Ober, Elke A.; Walsh, Susan; Cortes-Hernandez, Paulina; Verkade, Heather; Koehler, Carla M.; Stainier, Didier Y. R.

    2010-01-01

    SUMMARY Understanding liver development should lead to greater insights into liver diseases and improve therapeutic strategies. In a forward genetic screen for genes regulating liver development in zebrafish, we identified a mutant – oliver – that exhibits liver-specific defects. In oliver mutants, the liver is specified, bile ducts form and hepatocytes differentiate. However, the hepatocytes die shortly after their differentiation, and thus the resulting mutant liver consists mainly of biliary tissue. We identified a mutation in the gene encoding translocase of the outer mitochondrial membrane 22 (Tomm22) as responsible for this phenotype. Mutations in tomm genes have been associated with mitochondrial dysfunction, but most studies on the effect of defective mitochondrial protein translocation have been carried out in cultured cells or unicellular organisms. Therefore, the tomm22 mutant represents an important vertebrate genetic model to study mitochondrial biology and hepatic mitochondrial diseases. We further found that the temporary knockdown of Tomm22 levels by morpholino antisense oligonucleotides causes a specific hepatocyte degeneration phenotype that is reversible: new hepatocytes repopulate the liver as Tomm22 recovers to wild-type levels. The specificity and reversibility of hepatocyte ablation after temporary knockdown of Tomm22 provides an additional model to study liver regeneration, under conditions where most hepatocytes have died. We used this regeneration model to analyze the signaling commonalities between hepatocyte development and regeneration. PMID:20483998

  14. Study of MicroRNAs Related to the Liver Regeneration of the Whitespotted Bamboo Shark, Chiloscyllium plagiosum

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    Conger Lu

    2013-01-01

    Full Text Available To understand the mechanisms of liver regeneration better to promote research examining liver diseases and marine biology, normal and regenerative liver tissues of Chiloscyllium plagiosum were harvested 0 h and 24 h after partial hepatectomy (PH and used to isolate small RNAs for miRNA sequencing. In total, 91 known miRNAs and 166 putative candidate (PC miRNAs were identified for the first time in Chiloscyllium plagiosum. Through target prediction and GO analysis, 46 of 91 known miRNAs were screened specially for cellular proliferation and growth. Differential expression levels of three miRNAs (xtr-miR-125b, fru-miR-204, and hsa-miR-142-3p_R-1 related to cellular proliferation and apoptosis were measured in normal and regenerating liver tissues at 0 h, 6 h, 12 h, and 24 h using real-time PCR. The expression of these miRNAs showed a rising trend in regenerative liver tissues at 6 h and 12 h but exhibited a downward trend compared to normal levels at 24 h. Differentially expressed genes were screened in normal and regenerating liver tissues at 24 h by DDRT-PCR, and ten sequences were identified. This study provided information regarding the function of genes related to liver regeneration, deepened the understanding of mechanisms of liver regeneration, and resulted in the addition of a significant number of novel miRNAs sequences to GenBank.

  15. Down-regulation of MiR-127 facilitates hepatocyte proliferation during rat liver regeneration.

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    Chuanyong Pan

    Full Text Available Liver regeneration (LR after partial hepatectomy (PH involves the proliferation and apoptosis of hepatocytes, and microRNAs have been shown to post-transcriptionally regulate genes involved in the regulation of these processes. To explore the role of miR-127 during LR, the expression patterns of miR-127 and its related proteins were investigated. MiR-127 was introduced into a rat liver cell line to examine its effects on the potential target genes Bcl6 and Setd8, and functional studies were undertaken. We discovered that miR-127 was down-regulated and inversely correlated with the expression of Bcl6 and Setd8 at 24 hours after PH, a time at which hypermethylation of the promoter region of the miR-127 gene was detected. Furthermore, in BRL-3A rat liver cells, we observed that overexpression of miR-127 significantly suppressed cell growth and directly inhibited the expression of Bcl6 and Setd8. The results suggest that down-regulation of miR-127 may be due to the rapid methylation of its promoter during the first 24 h after PH, and this event facilitates hepatocyte proliferation by releasing Bcl6 and Setd8. These findings support a miRNA-mediated negative regulation pattern in LR and implicate an anti-proliferative role for miR-127 in liver cells.

  16. A20 modulates lipid metabolism and energy production to promote liver regeneration.

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    Scott M Damrauer

    Full Text Available BACKGROUND: Liver regeneration is clinically of major importance in the setting of liver injury, resection or transplantation. We have demonstrated that the NF-κB inhibitory protein A20 significantly improves recovery of liver function and mass following extended liver resection (LR in mice. In this study, we explored the Systems Biology modulated by A20 following extended LR in mice. METHODOLOGY AND PRINCIPAL FINDINGS: We performed transcriptional profiling using Affymetrix-Mouse 430.2 arrays on liver mRNA retrieved from recombinant adenovirus A20 (rAd.A20 and rAd.βgalactosidase treated livers, before and 24 hours after 78% LR. A20 overexpression impacted 1595 genes that were enriched for biological processes related to inflammatory and immune responses, cellular proliferation, energy production, oxidoreductase activity, and lipid and fatty acid metabolism. These pathways were modulated by A20 in a manner that favored decreased inflammation, heightened proliferation, and optimized metabolic control and energy production. Promoter analysis identified several transcriptional factors that implemented the effects of A20, including NF-κB, CEBPA, OCT-1, OCT-4 and EGR1. Interactive scale-free network analysis captured the key genes that delivered the specific functions of A20. Most of these genes were affected at basal level and after resection. We validated a number of A20's target genes by real-time PCR, including p21, the mitochondrial solute carriers SLC25a10 and SLC25a13, and the fatty acid metabolism regulator, peroxisome proliferator activated receptor alpha. This resulted in greater energy production in A20-expressing livers following LR, as demonstrated by increased enzymatic activity of cytochrome c oxidase, or mitochondrial complex IV. CONCLUSION: This Systems Biology-based analysis unravels novel mechanisms supporting the pro-regenerative function of A20 in the liver, by optimizing energy production through improved lipid/fatty acid

  17. The effect of Prometheus device on laboratory markers of inflammation and tissue regeneration in acute liver failure management.

    Science.gov (United States)

    Rocen, M; Kieslichova, E; Merta, D; Uchytilova, E; Pavlova, Y; Cap, J; Trunecka, P

    2010-11-01

    Prometheus, based on modified fractionated plasma separation and adsorption (FPSA) method, is used in the therapy of acute liver failure as a bridge to liver transplantation. As the therapeutic effect of Prometheus is caused not only by the elimination of terminal metabolites, the aim of the study was to identify the effect of FPSA on the levels of cytokines and markers of inflammation and liver regeneration. Previous studies assessing cytokine levels involved mostly acute-on-chronic liver failure patients. Data concerning markers of inflammation and liver regeneration are not published yet. Eleven patients (three males, eight females) with acute liver failure were investigated. These patients underwent 37 therapeutic sessions on Prometheus device. Before and after each treatment, the plasma levels of selected cytokines, tumor necrosis factor alpha (TNFα), C-reactive protein (CRP), procalcitonin (PCT), hepatocyte growth factor (HGF), and α(1) fetoprotein, were measured, and the kinetics of their plasma concentrations was evaluated. Before the therapy, elevated levels of interleukin (IL)-6, IL-8, IL-10, TNFα, CRP, and PCT were detected. The level of TNFα, CRP, PCT, and α(1) fetoprotein decreased significantly during the therapy. In contrast, an increase of HGF was detected. The decline of IL-6, IL-8, and IL-10 concentrations was not significant. Our results show that Prometheus is highly effective in clearing inflammatory mediators responsible for systemic inflammatory response syndrome and affects the serum levels of inflammatory and regeneration markers important for management of acute liver failure.

  18. An Oral Salmonella-Based Vaccine Inhibits Liver Metastases by Promoting Tumor-Specific T-Cell-Mediated Immunity in Celiac and Portal Lymph Nodes: A Preclinical Study.

    Science.gov (United States)

    Vendrell, Alejandrina; Mongini, Claudia; Gravisaco, María José; Canellada, Andrea; Tesone, Agustina Inés; Goin, Juan Carlos; Waldner, Claudia Inés

    2016-01-01

    Primary tumor excision is one of the most widely used therapies of cancer. However, the risk of metastases development still exists following tumor resection. The liver is a common site of metastatic disease for numerous cancers. Breast cancer is one of the most frequent sources of metastases to the liver. The aim of this work was to evaluate the efficacy of the orally administered Salmonella Typhi vaccine strain CVD 915 on the development of liver metastases in a mouse model of breast cancer. To this end, one group of BALB/c mice was orogastrically immunized with CVD 915, while another received PBS as a control. After 24 h, mice were injected with LM3 mammary adenocarcinoma cells into the spleen and subjected to splenectomy. This oral Salmonella-based vaccine produced an antitumor effect, leading to a decrease in the number and volume of liver metastases. Immunization with Salmonella induced an early cellular immune response in mice. This innate stimulation rendered a large production of IFN-γ by intrahepatic immune cells (IHIC) detected within 24 h. An antitumor adaptive immunity was found in the liver and celiac and portal lymph nodes (LDLN) 21 days after oral bacterial inoculation. The antitumor immune response inside the liver was associated with increased CD4(+) and dendritic cell populations as well as with an inflammatory infiltrate located around liver metastatic nodules. Enlarged levels of inflammatory cytokines (IFN-γ and TNF) were also detected in IHIC. Furthermore, a tumor-specific production of IFN-γ and TNF as well as tumor-specific IFN-γ-producing CD8 T cells (CD8(+)IFN-γ(+)) were found in the celiac and portal lymph nodes of Salmonella-treated mice. This study provides first evidence for the involvement of LDLN in the development of an efficient cellular immune response against hepatic tumors, which resulted in the elimination of liver metastases after oral Salmonella-based vaccination.

  19. An oral Salmonella-based vaccine inhibits liver metastases by promoting tumor-specific T cell-mediated immunity in celiac & portal lymph nodes. A preclinical study.

    Directory of Open Access Journals (Sweden)

    Alejandrina eVendrell

    2016-03-01

    Full Text Available Primary tumor excision is one of the therapies of cancer most widely used. However, the risk of metastases development still exists following tumor resection. The liver is a common site of metastatic disease for numerous cancers. Breast cancer is one of the most frequent source of metastases to the liver. The aim of this work was to evaluate the efficacy of the orally-administered Salmonella Typhi vaccine strain CVD 915 on the development of liver metastases in a mouse model of breast cancer. To this end, one group of BALB/c mice was immunized with CVD 915 via o.g. while another received PBS as a control. After 24 h, mice were injected with LM3 mammary adenocarcinoma cells into the spleen and subjected to splenectomy. This oral Salmonella-based vaccine produced an antitumor effect, leading to a decrease in the number and volume of liver metastases. Immunization with Salmonella induced an early cellular immune response in mice. This innate stimulation rendered a large production of IFN-γ by intrahepatic immune cells (IHIC detected within 24 h. An antitumor adaptive immunity was found in the liver and celiac & portal lymph nodes (LDLN 21 days after oral bacterial inoculation. The antitumor immune response inside the liver was associated with increased CD4+ and DC cell populations as well as with an inflammatory infiltrate located around liver metastatic nodules. Enlarged levels of inflammatory cytokines (IFN-γ and TNF were also detected in IHIC. Furthermore, a tumor-specific production of IFN-γ and TNF as well as tumor-specific IFN-γ-producing CD8 T cells (CD8+IFN-γ+ were found in the celiac & portal lymph nodes of Salmonella-treated mice. This study provides first evidence for the involvement of LDLN in the development of an efficient cellular immune response against hepatic tumors, which resulted in the elimination of liver metastases after oral Salmonella-based vaccination.

  20. Alleviation of Ischemia-Reperfusion Injury in Liver Steatosis by Augmenter of Liver Regeneration Is Attributed to Antioxidation and Preservation of Mitochondria.

    Science.gov (United States)

    Weng, Junhua; Li, Wen; Jia, Xiaowei; An, Wei

    2017-10-01

    Fatty liver is one of the major impediments to liver surgery and liver transplantation because steatotic hepatocytes are more susceptible to ischemia-reperfusion injury (IRI). In this study, the effects of augmenter of liver regeneration (ALR) on hepatic IRI in steatotic mice were investigated. In vivo, liver steatosis of mice was induced by feeding a methionine-choline-deficient diet for 2 weeks. Three days before hepatic partial warm IRI, mice were transfected with the ALR-containing adenovirus. In an in vitro study, the protective effect of ALR on steatotic HepG2 cells was analyzed after hypoxia/reoxygenation (HR) treatment. The transfection of the ALR gene into steatotic mice attenuated liver injury, inhibiting hepatic oxidative stress, increasing antioxidation capacities, promoting liver regeneration, and consequently suppressing cell apoptosis/death. Furthermore, resistance to HR injury was notably increased in ALR-transfected cells compared with the vector-transfected cells. The HR-induced rise in the mitochondrial reactive oxygen species was reduced, and cellular antioxidant activities were enhanced. The ALR transfection prevented cells from apoptosis, which can be attributed to the preservation of the mitochondrial membrane potential, enhancement of oxygen consumption rate and production of adenosine triphosphate. ALR protects steatotic hepatocytes from IRI by attenuating oxidative stress and mitochondrial dysfunction, as well as improving antioxidant effect. ALR may be used as a potential therapeutic agent when performing surgery and transplantation of steatotic liver.

  1. Cell-mediated mutagenesis by chemical carcinogens

    Energy Technology Data Exchange (ETDEWEB)

    Huberman, E.; Langenbach, R.

    1978-01-01

    The cell-mediated mutation system, with the proper choice of metabolizing cells, can be used to detect the mutagenic activities of different classes of chemical carcinogens. When fibroblastic cells were used as the metabolizing cells, a correlation between the in vivo carcinogenic activity and the in vitro mutagenic activity of 11 aromatic polycyclic hydrocarbons was observed. When primary liver cells were used as the metabolizing cells, three known liver carcinogens were demonstrated to be mutagenic by the cell-mediated assay, while two non-carcinogenic analogues were not mutagenic. These results from the cell-mediated system suggest that the reactive intermediates of the carcinogens are stable enough to be transferred from the metabolizing cells to the V79 cells. The cell-mediated mutagenesis system is a simple in vitro assay which may simulate the in vivo situation. It was concluded that this approach could be extended to the co-cultivation of cells from other organs or tissues with mutable mammalian cells.

  2. Effect of liver regeneration after partial hepatectomy and ischemia-reperfusion on expression of growth factor receptors

    Institute of Scientific and Technical Information of China (English)

    P Baier; G Wolf-Vorbeck; S Hempel; UT Hopt; E von Dobschuetz

    2006-01-01

    AIM: To investigate the effects of experimental partial hepatectomy and normothermic ischemia-reperfusion damage on the time course of the expression of four different growth factor receptors in liver regeneration.This is relevant due to the potential therapeutic use of growth factors in stimulating liver regeneration.METHODS: For partial hepatectomy (PH) 80% of the liver mass was resected in Sprague Dawley rats.Ischemia and reperfusion (I/R) were induced by occlusion of the portal vein and the hepatic artery for 15 min. The epidermal growth factor receptor, hepatic growth factor receptor, fibroblast growth factor receptor and tumour necrosis factor receptor-1 were analysed by immunohistochemistry up to 72 h after injury.Quantitative RT-PCR was performed at the time point of minimal receptor expression (24 h).RESULTS: In immunohistochemistry, EGFR, HGFR,FGFR and TNFR1 showed biphasic kinetics after partial hepatectomy with a peak up to 12 h, a nadir after 24 h and another weak increase up to 72 h. During liver regeneration, after ischemia and reperfusion, the receptor expression was lower; the nadir at 24 h after reperfusion was the same. To evaluate whether this nadir was caused by a lack of mRNA transcription, or due to a posttranslational regulation, RT-PCR was performed at 24 h and compared to resting liver. In every probe there was specific mRNA for the receptors. EGFR, FGFR and TNFR1 mRNA expression was equal or lower than in resting liver, HGFR expression after I/R was stronger than in the control.CONCLUSION: At least partially due to a post-transcriptional process, there is a nadir in the expression of the analysed receptors 24 h after liver injury. Therefore,a therapeutic use of growth factors to stimulate liver regeneration 24 h after the damage might be not successful.

  3. Low-dose steroid pretreatment ameliorates the transient impairment of liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Toshihito Shibata; Toru Mizuguchi; Yukio Nakamura; Masaki Kawamoto; Makoto Meguro; Shigenori Ota; Koichi Hirata; Hidekazu Ooe; Toshihiro Mitaka

    2012-01-01

    AIM:To determine if liver regeneration (LR) could be disturbed following radiofrequency (RF) ablation and whether modification of LR by steroid administration occurs.METHOIDS:Sham operation,partial hepatectomy (PH),and partial hepatectomy with radiofrequency ablation (PHA) were performed on adult Fisher 344 rats.We investigated the recovery of liver volume,DNA synthetic activities,serum cytokine/chemokine levels and signal transducers and activators of transcription 3 DNA-binding activities in the nucleus after the operations.Additionally,the effects of steroid (dexamethasone) pretreatment in the PH group (S-PH) and the PHA group (S-PHA) were compared.RESULTS:The LR after PHA was impaired,with high serum cytokine/chemokine induction compared to PH,although the ratio of the residual liver weight to body weight was not significantly different.Steroid pretreatment disturbed LR in the S-PH group.On the other hand,low-dose steroid pretreatment improved LR and suppressed tumor necrosis factor (TNF)-α elevation in the S-PHA group,with recovery of STAT3 DNA-binding activity.On the other hand,low-dose steroid pretreatment improved LR and suppressed TNF-α elevation in the S-PHA group,with recovery of STAT3 DNA-binding activity.CONCLUSION:LR is disturbed after RF ablation,with high serum cytokine/chemokine induction.Low-dose steroid administration can improve LR after RF ablation with TNF-α suppression.

  4. Liver remnant regeneration in donors after living donor liver transplantation. Long-term follow-up using CT and MR imaging

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    Klink, T. [INSELSPITAL - Bern University Hospital (Switzerland). Diagnostic, Interventional, and Pediatric Radiology; University Medical Center Hamburg-Eppendorf, Hamburg (Germany). Diagnostic and Interventional Radiology; Simon, P. [Merciful Brethren Hospital, Trier (Germany). Dept. of Radiology, Neuroradiology, Sonography and Nuclearmedicine; University Medical Center Hamburg-Eppendorf, Hamburg (Germany). Diagnostic and Interventional Radiology; Knopp, C.; Ittrich, H.; Adam, G.; Koops, A. [University Medical Center Hamburg-Eppendorf, Hamburg (Germany). Diagnostic and Interventional Radiology; Fischer, L. [University Medical Center Hamburg-Eppendorf, Hamburg (Germany). Dept. of Hepatobiliary Surgery and Transplant Surgery

    2014-06-15

    Purpose: To assess liver remnant volume regeneration and maintenance, and complications in the long-time follow-up of donors after living donor liver transplantation using CT and MRI. Materials and Methods: 47 donors with a mean age of 33.5 years who donated liver tissue for transplantation and who were available for follow-up imaging were included in this retrospective study. Contrast-enhanced CT and MR studies were acquired for routine follow-up. Two observers evaluated pre- and postoperative images regarding anatomy and pathological findings. Volumes were manually measured on contrast-enhanced images in the portal venous phase, and potential postoperative complications were documented. Pre- and postoperative liver volumes were compared for evaluating liver remnant regeneration. Results: 47 preoperative and 89 follow-up studies covered a period of 22.4 months (range: 1 - 84). After right liver lobe (RLL) donation, the mean liver remnant volume was 522.0 ml (± 144.0; 36.1%; n = 18), after left lateral section (LLS) donation 1,121.7 ml (± 212.8; 79.9%; n = 24), and after left liver lobe (LLL) donation 1,181.5 ml (± 279.5; 72.0%; n = 5). Twelve months after donation, the liver remnant volume were 87.3% (RLL; ± 11.8; n = 11), 95.0% (LS; ± 11.6; n = 18), and 80.1% (LLL; ± 2.0; n = 2 LLL) of the preoperative total liver volume. Rapid initial regeneration and maintenance at 80% of the preoperative liver volume were observed over the total follow-up period. Minor postoperative complications were found early in 4 patients. No severe or late complications or mortality occurred. Conclusion: Rapid regeneration of liver remnant volumes in all donors and volume maintenance over the long-term follow-up period of up to 84 months without severe or late complications are important observations for assessing the safety of LDLT donors. (orig.)

  5. Cloning and prokaryotic expression of rat homolog of Serpina3n and its expression change during liver regeneration.

    Science.gov (United States)

    Wang, G P; Zhang, X S; Li, Y H; Zheng, J L; Tang, C Z; Zhang, W X

    2012-09-03

    A strikingly upregulated expressed sequence tag was screened from regenerating rat liver at 8 h in a 0-4-8-12 h short-interval successive partial hepatectomy model from a previous study. In the present study, a full-length open reading frame (ORF) corresponding to this expressed sequence tag was predicted through electronic cloning and was subsequently cloned from an 8-h rat regenerating liver and deposited in GenBank (accession No. HM448398). Sequence analysis of HM448398 and the predicted ORF revealed that the two ORFs may be different transcripts of a gene. The sequence of HM448398 was highly homologous to that of rat Serpina3n, suggesting that it may be a homolog of Serpina3n. The pGEX-2TK prokaryotic expression vector for this ORF was constructed, and the result of sodium dodecyl sulfate polyacrylamide gel electrophoresis manifested that the recombinant expression vector could express the glutathione-S-transferase-fused rat homolog of Serpina3n in an insoluble form in BL21. The target fusion protein was purified with affinity chromatography and was used as antigen to immunize rabbits for the production of polyclonal antibodies. Immunohistochemistry and real-time reverse transcription polymerase chain reaction analysis revealed that the gene was highly expressed in the priming and termination phases of liver regeneration. These findings lay a solid foundation for further study of roles of HM448398 using knock-in and RNA interference methods during liver regeneration.

  6. Gene Expression Profiles in Living Donors Immediately After Partial Hepatectomy—The Initial Response of Liver Regeneration

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    Cheng-Maw Ho

    2007-01-01

    Conclusion: Gene expression profiles immediately after partial hepatectomy were reported first in humans with the techniques of oligo DNA microarray, which were compatible with the initial gene expression patterns of liver regeneration in rats. [J Formos Med Assoc 2007;106(4:288-294

  7. Kupffer cell depletion by CI2MDP-liposomes alters hepatic cytokine expression and delays liver regeneration after partial hepatectomy.

    Science.gov (United States)

    Meijer, C; Wiezer, M J; Diehl, A M; Schouten, H J; Schouten, H J; Meijer, S; van Rooijen, N; van Lambalgen, A A; Dijkstra, C D; van Leeuwen, P A

    2000-02-01

    Although Kupffer cells (KCs) are capable of producing important growth-stimulating cytokines, their role in liver regeneration following partial hepatectomy (PH) remains poorly understood. In the present study liver regeneration was studied after KC-depletion by intravenous administration of liposome-encapsulated dichloromethylene-diphosphonate (C12MDP), a method known to physically eliminate KCs. Furthermore, splenectomy was performed one week prior to PH to exclude the effect of C12MDP-liposomes on macrophage populations in the spleen. KC-depletion was confirmed in cryostat liver sections stained with the monoclonal antibody ED2, a marker for resident tissue macrophages. Forty-eight hours after PH, the cumulative hepatocyte DNA synthesis, as determined in liver sections by the hepatocyte bromodeoxyuridine labeling index, was significantly decreased in KC-depleted rats when compared to control-rats. The weight of the remnant liver, expressed as a percentage of the initial liver weight, was significantly less at 96 h after PH in KC-depleted rats. KC-depletion abolished the hepatic interleukin-6 (IL-6) and interleukin-10 (IL-10) mRNA synthesis and decreased hepatic expression of tumor necrosis factor-alpha (TNF-alpha), hepatocyte growth factor (HGF) and transforming growth factor-beta1(TGF-beta1) mRNA after PH, as was assessed by reverse-transcriptase polymerase chain reaction (RT-PCR). Moreover, at 4 h after PH the systemic release of IL-6 was significantly decreased in KC-depleted rats. We conclude that KCs are important for hepatocyte regeneration after PH. Delayed liver regeneration in KC-depleted rats can be explained, at least in part, by an imbalanced hepatic cytokine expression, thereby suppressing important growth-stimulating cytokines.

  8. CLONING AND ANALYSIS OF THE GENOMIC DNA SEQUENCE OF AUGMENTER OF LIVER REGENERATION FROM RAT

    Institute of Scientific and Technical Information of China (English)

    董菁; 成军; 王勤环; 施双双; 王刚; 斯崇文

    2002-01-01

    Objective.To search for genomic DNA sequence of the augmenter of liver regeneration (ALR) of rat.Methods.Polymerase chain reaction (PCR) with specific primers was used to amplify the sequence from the rat genome.Results.A piece of genomic DNA sequence and a piece of pseudogene of rat ALR were identified.The lengths of the gene and pseudogene are 1508 bp and 442 bp,respectively.The ALR gene of rat includes 3 exons and 2 introns.The 442 bp DNA sequence may represent a pseudogene or a ALR related peptide.Predicted amino acid sequence analysis showed that there were 14 different amino acid residues between the gene and pseudogene.ALR related peptide is 84 amino acid residues in length and relates closely to ALR protein.Conclusion.There might be a multigene family of ALR in rat.

  9. Kinetics of Phosphatase of Regenerating Liver-3 (PRL-3) Inhibition by Small-molecular Inhibitors

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Phosphatase of Regenerating Liver-3 (PRL-3) is a newly identified colorectal cancer metastasis-related protein,which isa 22 kDa non-classical protein tyrosine phosphatase with a C-terminal prenylation motif. In this study, the inhibition kinetics of protein tyrosine phosphatases (PTPs) by a fluorescent substrate, 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) was evaluated. PRL-3 exhibits classical Michaelis-Menten kinetics with a vmax value of the inhibitor magnolol can cause Km to increase, but does not alter the vmax value, which suggests the competitive inhibition of PRL-3. At the same time, it was found that DiFMUP is a more sensitive substrate for PRL-3 than para-nitrophenyl phosphate(pNPP) that is more frequently used at present. Furthermore, the method of screening for PTPs by the use of DiFMUP was developed, which studied the acceptance of DiFMUP by other PTPs.

  10. Multiple Doses of Erythropoietin Impair Liver Regeneration by Increasing TNF-α, the Bax to Bcl-xL Ratio and Apoptotic Cell Death

    OpenAIRE

    Katja Klemm; Christian Eipel; Daniel Cantré; Kerstin Abshagen; Menger, Michael D.; Brigitte Vollmar

    2008-01-01

    BACKGROUND: Liver resection and the use of small-for-size grafts are restricted by the necessity to provide a sufficient amount of functional liver mass. Only few promising strategies to maximize liver regeneration are available. Apart from its erythropoiesis-stimulating effect, erythropoietin (EPO) has meanwhile been recognized as mitogenic, tissue-protective, and anti-apoptotic pleiotropic cytokine. Thus, EPO may support regeneration of hepatic tissue. METHODOLOGY: Rats undergoing 68% hepat...

  11. Gene expression differences of regenerating rat liver in a short interval successive partial hepatectomy

    Institute of Scientific and Technical Information of China (English)

    Cun-Shuan Xu; Hui-Yong Zhang; Salman Rahman; Jing-Bo Zhang; An-Shi Zhang; Hong-Peng Han; Jin-Yun Yuan; Cui-Fang Chang; Wen-Qiang Li; Ke-Jin Yang; Li-Feng Zhao; Yu-Chang Li

    2004-01-01

    AIM: To identify the genes expressed differentially in the regenerating rat liver in a short interval successive partial hepatectomy (SISPH), and to analyze their expression profiles. METHODS: Five hundred and fifty-one elements selected from subtractive cDNA libraries were conformed to a cDNAmicroarray (cDNA chip). An extensive gene expressionanalysis following 0-36-72-96-144 h SISPH was performed by microarray.RESETS: Two hundred and sixteen elements were identified either up- or down-regulated more than 2-fold at one or more time points of SISPH. By cluster analysis and generalization analysis, 8 kinds of ramose gene expression clusters were generated in the SISPH. Of the 216 elements, 111 were up-regulated and 105 down-regulated. Except 99 unreported genes, 117 reported genes were categorized into 22 groups based on their biological functions. Comparison of the gene expression in SISPH with that after partial hepatectomy (PH) disclosed that 56 genes were specially altered in SISPH, and 160 genes were simultaneously up regulated or down-regulated in SISPH and after PH, but in various amount and at different time points.CONCLUSION: Genes expressed consistently are far less than that intermittently; the genes strikingly increased are much less than that increased only 2-5 fold; the expression trends of most genes in SISPH and in PH are similar, but the expression of 56 genes is specifically altered in SISPH.Microarray combined with suppressive subtractive hybridization can in a large scale effectively identify the genes related to liver regeneration.

  12. Expression pattern and action analysis of genes associated with the responses to chemical stimuli during rat liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Shao-Wei Qin; Li-Feng Zhao; Xiao-Guang Chen; Cun-Shuan Xu

    2006-01-01

    AIM: To study the genes associated with the responses to chemokines, nutrients, inorganic substances, organic substances and xenobiotics after rat partial hepatectomy (PH) at transcriptional level.METHODS: The associated genes involved in the five kinds of responses were obtained from database and literature, and the gene expression changes during liver regeneration in rats were checked by the Rat Genome 230 2.0 array.RESULTS: It was found that 60, 10, 9, 6, 26 genes respectively participating in the above five kinds of responses were associated with liver regeneration. The numbers of initially and totally expressed genes occurring in the initial phase of liver regeneration (0.5-4 h after PH), G0/G1 transition (4-6 h after PH), cell proliferation (6-66 h after PH), cell differentiation and structure-functional reconstruction (66-168 h after PH) were 51,19, 52, 6 and 51, 43, 98, 68 respectively, illustrating that the associated genes were mainly triggered in the initiation and transition stages, and functioned at different phases. According to their expression similarity,these genes were classified into 5 groups: only upregulated (47), predominantly up-regulated (18), only down-regulated (24), predominantly down-regulated (10), and up- and down-regulated (8). The total times of their up-regulated and down-regulated expression were 441 and 221, demonstrating that the number of up-regulated genes is more than that of the down-regulated genes. Their time relevance and gene expression patterns were classified into 14 and 26 groups, showing that the cell physiological and biochemical activities were staggered, diversified and complicated during liver regeneration in rats.CONCLUSION: The chemotaxis was enhanced mainly in the forepart and metaphase of LR. The response of regenerating liver to nutrients and chemical substances was increased, whereas that to xenobiotics was not strong. One hundred and seven genes associated with LR play important roles in the responses to

  13. The Balance between CD8(+) T Cell-Mediated Clearance of AAV-Encoded Antigen in the Liver and Tolerance Is Dependent on the Vector Dose.

    Science.gov (United States)

    Kumar, Sandeep R P; Hoffman, Brad E; Terhorst, Cox; de Jong, Ype P; Herzog, Roland W

    2017-04-05

    The liver continuously receives antigens from circulation and the gastrointestinal tract. A complex immune regulatory system has evolved in order to both limit inflammation and promote tolerance in the liver. Although in situ immune tolerance mechanisms enable successful gene therapy and liver transplantation, at the same time they facilitate chronic infections by pathogens such as hepatitis viruses. It is, however, poorly understood why hepatocytes infected with hepatitis viruses or transduced with adeno-associated virus (AAV)-based vectors may be rejected by CD8(+) T cells several months later. We found that hepatic transfer of limited doses of an AAV-ovalbumin vector rapidly induced antigen-specific CD8(+) T cells that only became functionally competent after >2 months. At this time, CD8(+) T cells had downregulated negative checkpoint markers, e.g., the programmed death 1 [PD-1] receptor, and upregulated expression of relevant cytokines. At further reduced vector dose, only intrahepatic rather than systemic CD8(+) T cell responses occurred, showing identical delay in antigen clearance. In contrast, PD-1-deficient mice rapidly cleared ovalbumin. Interestingly, higher vector dose directed sustained transgene expression without CD8(+) T cell responses. Regulatory T cells, IL-10 expression, and Fas-L contributed to high-dose tolerance. Thus, viral vector doses profoundly impact CD8(+) T cell responses.

  14. Impact of allyl disulfide on oxidative damage and liver regeneration in an experimental hepatectomy model.

    Science.gov (United States)

    Battal, M; Kartal, A; Citgez, B; Yilmaz, B; Akcakaya, A; Karatepe, O

    2015-01-01

    We investigated the effects of allyl disulfide (agarlic extract) on tissue damage, regeneration, proliferation and oxidative damage in an experimental liver resection model. In the study, 24 female Wistar albinorats weighing approximately 200-250 g were used. Group 1:The rats in the experimental group all received a 70%hepatectomy and were fed an Allyl disulfide (30 μg kg day,Allyl disulfide, Sigma-Aldrich, formula: C6H10S2, CASNumber: 2179-57-9, formula weight: 146.27 g mol) in supplement to a regular diet for 1 week both preoperatively and postoperatively. Group 2: The rats in the control group also underwent a 70% hepatectomy and were given regular food and water for 1 week both preop and postop. Group 3: In the sham group, all rats were sacrificed 7 days after surgery. Forbiochemical evaluation, SGOT, SGPT, bilirubin, CRP and MDA were studied. In a histopathological examination, the fattening of the liver tissue, existence of (macro-micro vesicular),fibrosis, pleomorphism at hepatocyte nuclei, portal inflammation, existence of intralobular inflammatory cells,dilation at sinusoids, congestion, congestion at the central vein, regeneration, existence of Kupffer cells in the sinu soidallumen and ki-67 proliferation index at hepatocytes were examined. A significant difference between group 1 and group2 was observed regarding the existence of regeneration,(p:0.06), the occurrence of nuclear pleomorphisms (p:0,001)and the fibroblast activity status (p:0.001). Significant differences were found between the experimental groups in regard to Kupffer cell increase and dilation and the hyperemiastatus in the sinusoid lumens (p:0.013 and p:0.001,respectively). In the Allyl disulfide group, the proliferation index was significantly higher than that of the other groups(p:0,001), while the average plasma MDA value was lower than that of the other groups (p: 0,042). No significant differences were found among the groups with respect to tissue MDA values (p:0,720). No

  15. Establishment and primary clinical application of competitive inhibition for measurement of augmenter of liver regeneration.

    Science.gov (United States)

    Wang, Na; Sun, Hang; Tang, Lin; Deng, Jianchuan; Luo, Ya; Guo, Hui; Liu, Qi

    2014-01-01

    The aim of the present study was to establish a quantitative method for the measurement of serum human augmenter of liver regeneration (hALR) using competitive inhibition that is applicable in the clinic. A monoclonal antibody to hALR was used as the primary antibody and the pure hALR protein was used as a standard for competition with Eu(3+)-labeled hALR (Eu(3+)-hALR) to plot a standard curve. Serum samples from 90 patients with various liver diseases due to hepatitis B virus (HBV) infection were used for a competitive reaction with Eu(3+)-hALR. A regression analysis of the results was performed using the standard curve to calculate the serum concentration of hALR. The minimum detectable value using direct competitive measurement established by Eu(3+)-hALR was 1 ng/ml, with a positive linear correlation within the range of 200 ng/ml. In the sera of the 90 patients, the hALR level in the severe hepatitis group was the highest, followed by that in the acute hepatitis group. The serum hALR levels in the cirrhosis and chronic hepatitis groups were significantly higher compared with those in the normal control groups (Pcompetitive measurement method of serum hALR established in the present study has high sensitivity, specificity, stability and reliability, meets clinical requirements and may be used as potential index in clinical tests.

  16. Effects of augmentation of liver regeneration recombinant plasmid on rat hepatic fibrosis

    Institute of Scientific and Technical Information of China (English)

    Qing Li; Dian-Wu Liu; Li-Mei Zhang; Bing Zhu; Yu-Tong He; Yong-Hong Xiao

    2005-01-01

    AIM: To investigate the effects of eukaryotic expression of plasmid on augmentation of liver regeneration (ALR) in rat hepatic fibrosis and to explore their mechanisms. METHODS: Ten rats were randomly selected from 50Wistar rats as normal control group. The rest were administered intraperitoneally with porcine serum twice weekly. After 8 wk, they were randomly divided into:model control group, colchicine group (Col), first ALR group (ALR1), second ALR group (ALR2). Then colchicine ALR recombinant plasmid were used to treat them respectively. At the end of the 4th wk, rats were killed.Serum indicators were detected and histopathological changes were graded. Expression of type Ⅰ, Ⅲ, collagen and TIMP-1 were detected by immunohisto-chemistry and expression of TIMP-1 mRNA was detected by semiquantified RT-PCR.RESULTS: The histologic examination showed that the degree of the rat hepatic fibrosis in two ALR groups was lower than those in model control group. Compared with model group, ALR significantly reduced the serum levels of ALT,AST, HA, LN, PCⅢ and Ⅳ (P<0.05). Immunohistochemical staining showed that expression of type Ⅰ, Ⅲ, collagen and TIMP-1 in two ALR groups was ameliorated dramatically compared with model group (Ⅰ collagen: 6.94±1.42, 5.80±1.66and 10.83±3.58 in ALR1, ALR2 and model groups, respectively;Ⅲ collagen: 7.18±1.95, 4.50±1.67 and 10.25±2.61,respectively; TIMP-1: 0.39±0.05, 0.20±0.06 and 0.53±0.12,respectively, P<0.05 or P<0.01). The expression level of TIMP-1 mRNA in the liver tissues was markedly decreased in two ALR groups compared with model group (TIMP-1mRNA/β-actin: 0.89±0.08, 0.65±0.11 and 1.36±0.11 in ALR1, ALR2 and model groups respectively, P<0.01).CONCLUSION: ALR recombinant plasmid has beneficial effects on rat hepatic fibrosis by enhancing regeneration of injured liver cells and inhibiting TIMP-1 expressions.

  17. WNT5A inhibits hepatocyte proliferation and concludes β-catenin signaling in liver regeneration.

    Science.gov (United States)

    Yang, Jing; Cusimano, Antonella; Monga, Jappmann K; Preziosi, Morgan E; Pullara, Filippo; Calero, Guillermo; Lang, Richard; Yamaguchi, Terry P; Nejak-Bowen, Kari N; Monga, Satdarshan P

    2015-08-01

    Activation of Wnt/β-catenin signaling during liver regeneration (LR) after partial hepatectomy (PH) is observed in several species. However, how this pathway is turned off when hepatocyte proliferation is no longer required is unknown. We assessed LR in liver-specific knockouts of Wntless (Wls-LKO), a protein required for Wnt secretion from a cell. When subjected to PH, Wls-LKO showed prolongation of hepatocyte proliferation for up to 4 days compared with littermate controls. This coincided with increased β-catenin-T-cell factor 4 interaction and cyclin-D1 expression. Wls-LKO showed decreased expression and secretion of inhibitory Wnt5a during LR. Wnt5a expression increased between 24 and 48 hours, and Frizzled-2 between 24 and 72 hours, after PH in normal mice. Treatment of primary mouse hepatocytes and liver tumor cells with Wnt5a led to a notable decrease in β-catenin-T-cell factor activity, cyclin-D1 expression, and cell proliferation. Intriguingly, Wnt5a-LKO did not display any prolongation of LR because of compensation by other cells. In addition, Wnt5a-LKO hepatocytes failed to respond to exogenous Wnt5a treatment in culture because of a compensatory decrease in Frizzled-2 expression. In conclusion, we demonstrate Wnt5a to be, by default, a negative regulator of β-catenin signaling and hepatocyte proliferation, both in vitro and in vivo. We also provide evidence that the Wnt5a/Frizzled-2 axis suppresses β-catenin signaling in hepatocytes in an autocrine manner, thereby contributing to timely conclusion of the LR process.

  18. Impaired liver regeneration in Ldlr−/− mice is associated with an altered hepatic profile of cytokines, growth factors and lipids

    Science.gov (United States)

    Pauta, Montse; Rotllan, Noemi; Vales, Frances; Allen, Ryan M.; Ford, David A.; Marí, Montserrat; Jiménez, Wladimiro; Baldán, Ángel

    2014-01-01

    Background & Aims It is widely recognized that in the early stages of liver regeneration after partial hepatectomy the hepatocytes accumulate a significant amount of lipids. The functional meaning of this transient steatosis and its effect on hepatocellular proliferation are not well defined. In addition, the basic mechanisms of this lipid accumulation are not well understood although some studies suggest the participation of the Low Density Lipoprotein Receptor (Ldlr). Methods To address these questions we studied the process of liver regeneration in Ldlr null mice and wild-type mice following 75% partial hepatectomy. Results Ldlr deficiency was associated with a significant decrease in serum albumin concentration, during early stages of liver regeneration, and a delayed hepatic regeneration. Remnant livers of Ldlr−/− showed a time-shifted expression of interleukin-6 (IL-6) and a defective activation of tumor necrosis factor-α (TNFα) and hepatocyte growth factor (HGF) expression in early phases of liver regeneration. Unexpectedly, Ldlr−/− showed no significant differences in the content of lipid droplets after partial hepatectomy compared to wild-type mice. However, lipidomic analysis of the regenerating liver from Ldlr−/− revealed a lipid profile compatible with liver quiescence: high content of cholesterol esters and ceramide, and low levels of phosphatidylcholine. Conclusion Ldlr deficiency is associated with significant changes in the hepatic lipidome that affect cytokine-growth factor signaling and impair liver regeneration. These results suggest that the analysis of the hepatic lipidome may help to predict the success of liver regeneration in the clinical environment, specifically in the context of pre-existing liver steatosis. PMID:23712050

  19. CCR5 and CXCR3 are dispensable for liver infiltration, but CCR5 protects against virus-induced T-cell-mediated hepatic steatosis

    DEFF Research Database (Denmark)

    Holst, P J; Orskov, C; Qvortrup, K;

    2007-01-01

    CCR5 and CXCR3 are important molecules in regulating the migration of activated lymphocytes. Thus, the majority of tissue-infiltrating T cells found in the context of autoimmune conditions and viral infections express CCR5 and CXCR3, and the principal chemokine ligands are expressed within inflamed...... tissues. Accordingly, intervention studies have pointed to nonredundant roles of these receptors in models of allograft rejection, viral infection, and autoimmunity. In spite of this, considerable controversy exists, with many studies failing to support a role for CCR5 or CXCR3 in disease pathogenesis....... One possible explanation is that different chemokine receptors may take over in the absence of any individual receptor, thus rendering individual receptors redundant. We have attempted to address this issue by analyzing CCR5(-/-), CXCR3(-/-), and CCR5/CXCR3(-/-) mice with regard to virus-induced liver...

  20. Liver regeneration after partial hepatectomy in rat is more impaired in a steatotic liver induced by dietary fructose compared to dietary fat

    Energy Technology Data Exchange (ETDEWEB)

    Tanoue, Shirou [Department of Digestive and Lifestyle-Related Diseases, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima (Japan); Uto, Hirofumi, E-mail: hirouto@m2.kufm.kagoshima-u.ac.jp [Department of Digestive and Lifestyle-Related Diseases, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima (Japan); Kumamoto, Ryo; Arima, Shiho; Hashimoto, Shinichi; Nasu, Yuichiro; Takami, Yoichiro; Moriuchi, Akihiro; Sakiyama, Toshio; Oketani, Makoto; Ido, Akio; Tsubouchi, Hirohito [Department of Digestive and Lifestyle-Related Diseases, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima (Japan)

    2011-04-01

    Highlights: {yields} Hepatic steatosis in rats fed a high fructose diet was less severe than that in rats fed a high fat diet. {yields} Liver regeneration was more impaired in rats fed a high fructose diet than in rats fed a high fat diet. {yields} Dysregulation of genes associated with metabolism may contribute to impairment of liver regeneration. {yields} Regulation of the TGF-{beta}1 level after partial hepatectomy may be impaired in rats fed a high fructose diet. -- Abstract: Hepatic steatosis (HS) has a negative effect on liver regeneration, but different pathophysiologies of HS may lead to different outcomes. Male Sprague-Dawley rats were fed a high fructose (66% fructose; H-fruc), high fat (54% fat; H-fat), or control chow diet for 4 weeks. Based on hepatic triglyceride content and oil red O staining, HS developed in the H-fruc group, but was less severe compared to the H-fat group. Hepatic mRNA expression levels of fatty acid synthase and fructokinase were increased and those of carnitine palmitoyltransferase-1 and peroxisome proliferator-activated receptor-{alpha} were decreased in the H-fruc group compared to the H-fat group. Liver regeneration after 70% partial hepatectomy (PHx) was evaluated by measuring the increase in postoperative liver mass and PCNA-positive hepatocytes, and was impaired in the H-fruc group compared to the H-fat and control groups on days 3 and 7. Serum levels of tumor necrosis factor-{alpha}, interleukin-6 and hepatocyte growth factor did not change significantly after PHx. In contrast, serum TGF-{beta}1 levels were slightly but significantly lower in the control group on day 1 and in the H-fat group on day 3 compared to the level in each group on day 0, and then gradually increased. However, the serum TGF-{beta}1 level did not change after PHx in the H-fruc group. These results indicate that impairment of liver regeneration after PHx in HS is related to the cause, rather than the degree, of steatosis. This difference may result

  1. Human augmenter of liver regeneration: probing the catalytic mechanism of a flavin-dependent sulfhydryl oxidase.

    Science.gov (United States)

    Schaefer-Ramadan, Stephanie; Gannon, Shawn A; Thorpe, Colin

    2013-11-19

    Augmenter of liver regeneration is a member of the ERV family of small flavin-dependent sulfhydryl oxidases that contain a redox-active CxxC disulfide bond in redox communication with the isoalloxazine ring of bound FAD. These enzymes catalyze the oxidation of thiol substrates with the reduction of molecular oxygen to hydrogen peroxide. This work studies the catalytic mechanism of the short, cytokine form of augmenter of liver regeneration (sfALR) using model thiol substrates of the enzyme. The redox potential of the proximal disulfide in sfALR was found to be approximately 57 mV more reducing than the flavin chromophore, in agreement with titration experiments. Rapid reaction studies show that dithiothreitol (DTT) generates a transient mixed disulfide intermediate with sfALR signaled by a weak charge-transfer interaction between the thiolate of C145 and the oxidized flavin. The subsequent transfer of reducing equivalents to the flavin ring is relatively slow, with a limiting apparent rate constant of 12.4 s(-1). However, reoxidation of the reduced flavin by molecular oxygen is even slower (2.3 s(-1) at air saturation) and thus largely limits turnover at 5 mM DTT. The nature of the charge-transfer complexes observed with DTT was explored using a range of simple monothiols to mimic the initial nucleophilic attack on the proximal disulfide. While β-mercaptoethanol is a very poor substrate of sfALR (∼0.3 min(-1) at 100 mM thiol), it rapidly generates a mixed disulfide intermediate allowing the thiolate of C145 to form a strong charge-transfer complex with the flavin. Unlike the other monothiols tested, glutathione is unable to form charge-transfer complexes and is an undetectable substrate of the oxidase. These data are rationalized on the basis of the stringent steric requirements for thiol-disulfide exchange reactions. The inability of the relatively bulky glutathione to attain the in-line geometry required for efficient disulfide exchange in sfALR may be

  2. A novel glucagon-like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice.

    Science.gov (United States)

    Valdecantos, M Pilar; Pardo, Virginia; Ruiz, Laura; Castro-Sánchez, Luis; Lanzón, Borja; Fernández-Millán, Elisa; García-Monzón, Carmelo; Arroba, Ana I; González-Rodríguez, Águeda; Escrivá, Fernando; Álvarez, Carmen; Rupérez, Francisco J; Barbas, Coral; Konkar, Anish; Naylor, Jacqui; Hornigold, David; Santos, Ana Dos; Bednarek, Maria; Grimsby, Joseph; Rondinone, Cristina M; Valverde, Ángela M

    2017-03-01

    Because nonalcoholic steatohepatitis (NASH) is associated with impaired liver regeneration, we investigated the effects of G49, a dual glucagon-like peptide-1/glucagon receptor agonist, on NASH and hepatic regeneration. C57Bl/6 mice fed chow or a methionine and choline-deficient (MCD) diet for 1 week were divided into 4 groups: control (chow diet), MCD diet, chow diet plus G49, and M+G49 (MCD diet plus G49). Mice fed a high-fat diet (HFD) for 10 weeks were divided into groups: HFD and H+G49 (HFD plus G49). Following 2 (MCD groups) or 3 (HFD groups) weeks of treatment with G49, partial hepatectomy (PH) was performed, and all mice were maintained on the same treatment schedule for 2 additional weeks. Analysis of liver function, hepatic regeneration, and comprehensive genomic and metabolic profiling were conducted. NASH was ameliorated in the M+G49 group, manifested by reduced inflammation, steatosis, oxidative stress, and apoptosis and increased mitochondrial biogenesis. G49 treatment was also associated with replenishment of intrahepatic glucose due to enhanced gluconeogenesis and reduced glucose use through the pentose phosphate cycle and oxidative metabolism. Following PH, G49 treatment increased survival, restored the cytokine-mediated priming phase, and enhanced the proliferative capacity and hepatic regeneration ratio in mice on the MCD diet. NASH markers remained decreased in M+G49 mice after PH, and glucose use was shifted to the pentose phosphate cycle and oxidative metabolism. G49 administered immediately after PH was also effective at alleviating the pathological changes induced by the MCD diet. Benefits in terms of liver regeneration were also found in mice fed HFD and treated with G49.

  3. Significance and Mechanism of CYP7a1 Gene Regulation during the Acute Phase of Liver Regeneration

    OpenAIRE

    Zhang, Lisheng; Huang, Xiongfei; Meng, Zhipeng; Dong, Bingning; Shiah, Steven; Moore, David D.; Huang, Wendong

    2008-01-01

    Cholesterol 7α-hydroxylase (CYP7a1) is the rate-limiting enzyme in the classic pathway of bile acid synthesis. Expression of CYP7a1 is regulated by a negative feedback pathway of bile acid signaling. Previous studies have suggested that bile acid signaling is also required for normal liver regeneration, and CYP7a1 expression is strongly repressed after 70% partial hepatectomy (PH). Both the effect of CYP7a1 suppression on liver regrowth and the mechanism by which 70% PH suppresses CYP7a1 expr...

  4. Effects of platelet-rich plasma on liver regeneration in CCl4-induced hepatotoxicity model.

    Science.gov (United States)

    Mafi, Afsaneh; Dehghani, Farzaneh; Moghadam, Abbas; Noorafshan, Ali; Vojdani, Zahra; Talaei-Khozani, Tahereh

    2016-12-01

    Numerous bioactive growth factors and cytokines in platelet-rich plasma (PRP) have recently made it an attractive biomaterial for therapeutic purposes. These growth factors have the potential to regenerate the injured tissues. The aim of this study was to investigate the therapeutic effects of PRP in hepatotoxic animal model. Hepatotoxicity was induced in rats by oral administration of 4 mL/kg/week of CCl4 diluted 1:1 in corn oil for 10 weeks. To confirm the hepatotoxicity, 24 h after the last CCl4 administration, blood samples were collected via cardiac puncture to assess the serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, total protein, and total bilirubin. Twenty-four hours after blood collection, the experimental animals received a single injection of PRP (1 mL) via the anterior mesenteric vein. One week later, all biochemical tests were performed again, and the rats were scarified and their livers were removed, prepared histologically, and stained. The stereological analyses were performed to evaluate the effects of PRP on histopathological features of CCl4-treated livers. The results were compared statistically with the corresponding control and CCl4+normal saline (NS)-treated animals. A significant decrease in the number and volume of hepatocytes (p = 0.01), and also a reduction in the volume of sinusoids (p = 0.001) and connective tissue (p = 0.04), were observed in the PRP-treated animals compared with the CCl4+NS-treated ones. Our findings demonstrated that application of PRP had beneficial effects on CCl4-induced fibrosis; however, it had detrimental effects on the total number of hepatocytes and the volume of hepatocytes and sinusoidal spaces.

  5. Inhibiting effect of a hepatoma extract on the mitotic rate of regenerating liver.

    Science.gov (United States)

    Echave Llanos, J M; Badrán, A F; Moreno, F R

    1986-01-01

    Aqueous tumor extracts were prepared by the homogenization of a fast-growing, undifferentiated, transplantable malignant murine hepatoma in distilled water. After centrifugation, an aliquot of 0.01 ml of the supernatant g body weight was injected intraperitoneally into partially hepatectomized mice. Control animals were injected with saline. Groups of mice were killed at various times in relation to the hepatectomy. Four h before killing the animals were given Colcemid (1 microgram/g body weight). The number of Colcemid-arrested mitoses in the hepatocytes and in the littoral cells, respectively, were counted in 140 microscopic fields. The extract significantly inhibited the mitotic rate in hepatocytes when the injection was given between 22 h before, and up to 26 h after hepatectomy. In the littoral cells, a slight initial stimulation was followed by a slight but significant inhibition which occurred when the injection was given at hepatectomy or until 18 h after hepatectomy. The effect was not modified by exposing the extracts to temperatures of 47 degrees C for 30 min or 22 degrees C for 24 h, but 10 min of boiling destroyed their inhibitory effect. Lyophilization and storing at -18 degrees C for up to 4 weeks did not modify the effect. The mitosis-inhibiting effect was also measurable when the extract was injected subcutaneously. There was an almost linear dose-response curve. The results are discussed in relation to circadian rhythms, the pattern of liver cell proliferation after hepatectomy, and recent similar reports from the literature. The conclusion is drawn that extracts of a hepatoma contain one or more growth-inhibitory factors significantly active on regenerating liver cells, and less significantly on littoral cells.

  6. Expression and localization of augmenter of liver regeneration in human muscle tissue.

    Science.gov (United States)

    Polimeno, Lorenzo; Pesetti, Barbara; Giorgio, Floriana; Moretti, Biagio; Resta, Leonardo; Rossi, Roberta; Annoscia, Emanuele; Patella, Vittorio; Notarnicola, Angela; Mallamaci, Rosanna; Francavilla, Antonio

    2009-08-01

    Mitochondrial DNA (mt-DNA) disorders and abnormal regulation of nuclear-derived proteins devoted to the cross-talk between the two cellular genomes have recently interested researchers in the field of neuromuscular diseases. We have identified, isolated and sequenced a new gene, augmenter of liver regeneration (ALR) that stimulates in vivo hepatocyte proliferation and up-regulates mt-DNA expression and ATP production. ALR protein (Alrp) is mainly located, in rat, in the mitochondrial inter-membrane space and its mRNA is particularly abundant in brain, muscle, testis and liver, tissues whose activity is mostly dependent on mitochondrial metabolism. Studies on rat Alrp sequence revealed the presence of homologous amino-acid sections into proteins derived from mouse, human, Drosophyla, plants and even DNA viruses. In this article, we evaluated ALR expression in normal human muscular tissues, both as protein and as mRNA. The data, obtained by molecular biology, immunohistochemistry and electron microscopy, demonstrated that: (i) Alrp and ALR mRNA are present in human muscular tissue; (ii) Alrp is particularly expressed in muscular fibres rich in mitochondria; (iii) Alrp is localized in the mitochondrial inter-membrane space or associated to mitochondrial cristae; and (iv) in subjects younger then 35 years of age, ALR mRNA expression is different between male and female subjects. In conclusion, the present data set Alrp, as a factor associated with mitochondria also in human tissue, call for future studies aimed at establishing Alrp as an important factor involved in the molecular events that trigger neuromuscular diseases.

  7. Med1 subunit of the mediator complex in nuclear receptor-regulated energy metabolism, liver regeneration, and hepatocarcinogenesis.

    Science.gov (United States)

    Jia, Yuzhi; Viswakarma, Navin; Reddy, Janardan K

    2014-01-01

    Several nuclear receptors regulate diverse metabolic functions that impact on critical biological processes, such as development, differentiation, cellular regeneration, and neoplastic conversion. In the liver, some members of the nuclear receptor family, such as peroxisome proliferator-activated receptors (PPARs), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), liver X receptor (LXR), pregnane X receptor (PXR), glucocorticoid receptor (GR), and others, regulate energy homeostasis, the formation and excretion of bile acids, and detoxification of xenobiotics. Excess energy burning resulting from increases in fatty acid oxidation systems in liver generates reactive oxygen species, and the resulting oxidative damage influences liver regeneration and liver tumor development. These nuclear receptors are important sensors of exogenous activators as well as receptor-specific endogenous ligands. In this regard, gene knockout mouse models revealed that some lipid-metabolizing enzymes generate PPARα-activating ligands, while others such as ACOX1 (fatty acyl-CoA oxidase1) inactivate these endogenous PPARα activators. In the absence of ACOX1, the unmetabolized ACOX1 substrates cause sustained activation of PPARα, and the resulting increase in energy burning leads to hepatocarcinogenesis. Ligand-activated nuclear receptors recruit the multisubunit Mediator complex for RNA polymerase II-dependent gene transcription. Evidence indicates that the Med1 subunit of the Mediator is essential for PPARα, PPARγ, CAR, and GR signaling in liver. Med1 null hepatocytes fail to respond to PPARα activators in that these cells do not show induction of peroxisome proliferation and increases in fatty acid oxidation enzymes. Med1-deficient hepatocytes show no increase in cell proliferation and do not give rise to liver tumors. Identification of nuclear receptor-specific coactivators and Mediator subunits should further our understanding of the complexities of metabolic

  8. Autologous adipose tissue-derived mesenchymal stem cells are involved in rat liver regeneration following repeat partial hepatectomy

    OpenAIRE

    Liu, Tao; MU, HONG; Shen, Zhongyang; SONG, ZHUOLUN; Chen, Xiaobo; Wang, Yuliang

    2016-01-01

    Adipose tissue-derived mesenchymal stem cells (ADSCs) have been considered to be attractive and readily available adult mesenchymal stem cells, and they are becoming increasingly popular for use in regenerative cell therapy, as they are readily accessible through minimally invasive techniques. The present study investigated whether autologous ADSC transplantation promoted liver regeneration following a repeat partial hepatectomy in rats. The rats were divided into three groups as follows: 70%...

  9. HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver

    DEFF Research Database (Denmark)

    Ding, Bi-Sen; Liu, Catherine H; Sun, Yue

    2016-01-01

    Regeneration of hepatic sinusoidal vasculature is essential for non-fibrotic liver regrowth and restoration of its metabolic capacity. However, little is known about how this specialized vascular niche is regenerated. Here we show that activation of endothelial sphingosine-1-phosphate receptor-1 ...

  10. Large scale of identification of differentially expressed genes in the regenerating rat liver after SISPH

    Institute of Scientific and Technical Information of China (English)

    XU Cunshuan; RAHMAN Salman; YUAN Jinyun; HAN Hongpeng; CHANG Cuifang; LI Wenqiang; YANG Kejin; ZHAO Lifeng; LI Yuchang; ZHANG Huiyong

    2005-01-01

    Extensive gene expression analysis was carried out after a 0, 4, 36, 72, 96 h short interval successive partial hepatectomy (SISPH) was performed. A total of 185 elements were identified as differing by more than two-fold in their expression levels at one or more time points. Of these 185 elements, 103 were up-regulated, 82 were down-regulated and 86 elements were unreported genes. Quite a few genes were previously unknown to be involved in liver regeneration (LR). Using cluster and general analysis, we found that the genes at five time points of the SISPH share eight different types of different expression profiles and eight distinct temporal induction or suppression patterns. A comparison of the gene expression in SISPH with that after PH found that 41 genes were specifically altered in SISPH, and 144 genes were simultaneously up-regulated or down-regulated in SISPH and after PH, but they were present in different amounts at the different time points. The conclusions are that (i) microarrays combined with suppressive subtractive hybridization (SSH) can effectively identify genes involved in LR on a large scale; (ii) more genes were up-regulated than down-regulated; (iii) there are fewer abundantly expressed genes than those with increased levels of 2-5 fold.

  11. Suppression of breast tumor growth by DNA vaccination against phosphatase of regenerating liver 3.

    Science.gov (United States)

    Lv, J; Liu, C; Huang, H; Meng, L; Jiang, B; Cao, Y; Zhou, Z; She, T; Qu, L; Wei Song, S; Shou, C

    2013-08-01

    Phosphatase of regenerating liver (PRL)-3 is highly expressed in multiple cancers and has important roles in cancer development. Some small-molecule inhibitors and antibodies targeting PRL-3 have been recently reported to inhibit tumor growth effectively. To determine whether PRL-3-targeted DNA vaccination can induce immune response to prevent or inhibit the tumor growth, we established mouse D2F2 breast cancer cells expressing PRL-3 (D2F2/PRL-3) and control cells (D2F2/NC) with lentivirus, and constructed pVAX1-Igκ-PRL-3 plasmid (named as K-P3) as DNA vaccine to immunize BALB/c mice. We found that the K-P3 vaccine delivered by gene gun significantly prevented the growth of D2F2/PRL-3 compared with pVAX1-vector (Padjuvants, such as Mycobacterium tuberculosis heat-shock protein, CTL antigen 4 and M. tuberculosis T-cell stimulatory epitope (MT), into K-P3 vaccine for expressing the fusion proteins. We found that these adjuvant molecules did not significantly improve the antitumor activity of PRL-3 vaccine, but enhanced the production of PRL-3 antibodies in immunized mice. Summarily, our findings demonstrate that PRL-3-targeted DNA vaccine can generate significantly preventive and therapeutic effects on the growth of breast cancer expressing PRL-3 through the induction of cellular immune responses to PRL-3.

  12. Expression and clinical role of protein of regenerating liver (PRL) phosphatases in ovarian carcinoma.

    Science.gov (United States)

    Reich, Reuven; Hadar, Shany; Davidson, Ben

    2011-02-11

    The present study analyzed the expression and clinical role of the protein of regenerating liver (PRL) phosphatase family in ovarian carcinoma. PRL1-3 mRNA expression was studied in 184 tumors (100 effusions, 57 primary carcinomas, 27 solid metastases) using RT-PCR. PRL-3 protein expression was analyzed in 157 tumors by Western blotting. PRL-1 mRNA levels were significantly higher in effusions compared to solid tumors (p PRL-1 and PRL-2 were overexpressed in pleural compared to peritoneal effusions (p = 0.001). PRL-3 protein expression was significantly higher in primary diagnosis pre-chemotherapy compared to post-chemotherapy disease recurrence effusions (p = 0.003). PRL-1 mRNA expression in effusions correlated with longer overall survival (p = 0.032), and higher levels of both PRL-1 and PRL-2 mRNA correlated with longer overall survival for patients with pre-chemotherapy effusions (p = 0.022 and p = 0.02, respectively). Analysis of the effect of laminin on PRL-3 expression in ovarian carcinoma cells in vitro showed dose-dependent PRL-3 expression in response to exogenous laminin, mediated by Phospholipase D. In contrast to previous studies associating PRL-3 with poor outcome, our data show that PRL-3 expression has no clinical role in ovarian carcinoma, whereas PRL-1 and PRL-2 expression is associated with longer survival, suggesting that PRL phosphatases may be markers of improved outcome in this cancer.

  13. Partial hepatectomy induces delayed hepatocyte proliferation and normal liver regeneration in ovariectomized mice

    Directory of Open Access Journals (Sweden)

    Umeda M

    2015-07-01

    Full Text Available Makoto Umeda,1 Masaki Hiramoto,1,2 Takeshi Imai1 1Department of Aging Intervention, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; 2Department of Biochemistry, Tokyo Medical University, Tokyo, Japan Abstract: Estrogens play central roles in sexual development, reproduction, and hepatocyte proliferation. The ovaries are one of the main organs for estradiol (E2 production. Ovariectomies (OVXs were performed on the female mice, and hepatocyte proliferation was analyzed. The ovariectomized mice exhibited delayed hepatocyte proliferation after partial hepatectomy (PH and also exhibited delayed and reduced E2 induction. Both E2 administration and PH induced the gene expression of estrogen receptor α (ERα. The transcripts of ERα were detected specifically in periportal hepatocytes after E2 administration and PH. Moreover, the E2 concentrations and hepatocyte proliferation rates were highest in the proestrus period of the estrous cycle. Taken together, these findings indicate that E2 accelerated ERα expression in periportal hepatocytes and hepatocyte proliferation in the female mice.Keywords: estrogen, ER, estrous cycle, hepatocyte proliferation, liver regeneration

  14. Regenerating the liver: not so simple after all? [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Malcolm R. Alison

    2016-07-01

    Full Text Available Under normal homeostatic conditions, hepatocyte renewal is a slow process and complete turnover likely takes at least a year. Studies of hepatocyte regeneration after a two-thirds partial hepatectomy (2/3 PH have strongly suggested that periportal hepatocytes are the driving force behind regenerative re-population, but recent murine studies have brought greater complexity to the issue. Although periportal hepatocytes are still considered pre-eminent in the response to 2/3 PH, new studies suggest that normal homeostatic renewal is driven by pericentral hepatocytes under the control of Wnts, while pericentral injury provokes the clonal expansion of a subpopulation of periportal hepatocytes expressing low levels of biliary duct genes such as Sox9 and osteopontin. Furthermore, some clarity has been given to the debate on the ability of biliary-derived hepatic progenitor cells to generate physiologically meaningful numbers of hepatocytes in injury models, demonstrating that under appropriate circumstances these cells can re-populate the whole liver.

  15. Cellular Origins of Regenerating Nodules and Malignancy in the FAH Model of Liver Injury after Bone Marrow Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Pei-Rong Wang

    2016-01-01

    Full Text Available In previous reports, we and other groups have shown that proliferating hepatocytes are formed by the fusion of donor hematopoietic cells with host hepatocytes in the Fah−/− model. Thus, it would be interesting to determine whether cell fusion occurs during malignancy. However, it is difficult to demonstrate such processes using this model. Therefore, we established a new strain to study the processes of regenerating nodules and malignancy and their origins. The FAH−/− mouse model was crossed with the ROSAnZ strain and their offspring was genotyped for FAH−/− and ROSAnZ mutations to create a new strain (Fah−/−-ROSAnZ. Using this strain as recipients, we performed bone marrow transplantation experiments. As a result, we could not demonstrate the presence of any epithelial cells except hepatocytes that were of donor origin in regenerating tissue, and no evidence of cell fusion was found in tumors. The hepatic malignancy was of host origin in these mice. There was higher expression of extracellular matrix proteins and more inflammatory cells in liver tumor nodules than in regenerating normal liver nodules. Hepatocytes generated by fusion with bone marrow cells did not form malignant tumors. Extracellular matrix and inflammatory cells had significantly accumulated in liver tumors.

  16. Vitamin K2-enhanced liver regeneration is associated with oval cell expansion and up-regulation of matrilin-2 expression in 2-AAF/PH rat model.

    Science.gov (United States)

    Lin, M; Sun, P; Zhang, G; Xu, X; Liu, G; Miao, H; Yang, Y; Xu, H; Zhang, L; Wu, P; Li, M

    2014-03-01

    Normal liver has a great potential of regenerative capacity after partial hepatectomy. In clinic, however, most patients receiving partial hepatectomy are usually suffering from chronic liver diseases with severely damaged hepatocyte population. Under these conditions, activation of hepatic progenitor cell (oval cell in rodents) population might be considered as an alternative mean to enhance liver functional recovery. Vitamin K2 has been shown to promote liver functional recovery in patients with liver cirrhosis. In this study, we explored the possibility of vitamin K2 treatment in activating hepatic oval cell for liver regeneration with the classic 2-acetamido-fluorene/partial hepatectomy (2-AAF/PH) model in Sprague-Dawley rats. In 2-AAF/PH animals, vitamin K2 treatment induced a dose-dependent increase of liver regeneration as assessed by the weight ratio of remnant liver versus whole body and by measuring serum albumin level. In parallel, a drastic expansion of oval cell population as assessed by anti-OV6 and anti-CK19 immunostaining was noticed in the periportal zone of the remnant liver. Since matrilin-2 was linked to oval cell proliferation and liver regeneration after partial hepatectomy, we assessed its expression at both the mRNA and protein levels. The results revealed a significant increase after vitamin K2 treatment in parallel with the expansion of oval cell population. Consistently, knocking down matrilin-2 expression in vivo largely reduced vitamin K2-induced liver regeneration and oval cell proliferation in 2-AAF/PH animals. In conclusion, these data suggest that vitamin K2 treatment enhances liver regeneration after partial hepatectomy, which is associated with oval cell expansion and matrilin-2 up-regulation.

  17. 血流力学信号与肝再生的研究进展%Research progress of hemodynamic signal and liver regeneration

    Institute of Scientific and Technical Information of China (English)

    马心逸; 刘巧云; 喻智勇

    2014-01-01

    肝脏再生能力强,外科手术预后与肝再生能力密切相关.肝再生的机制主要包括生化学说和流体力学学说.适度门静脉血流高压灌注是启动肝再生的必要因素.肝动脉缓冲反应、流体切应力的变化、气体信号分子均在肝再生过程中起着重要作用.研究肝再生的血流力学信号机制对肝脏疾病的治疗具有重要意义.%Liver has great ability in regeneration,and liver regeneration is closely related to the prognosis of patients who received liver surgeries.The mechanisms of liver regeneration include biochemical theory and hemodynamic theory.Portal perfusion with moderate pressure is an important factor for starting liver regeneration.Hepatic artery buffer response,fluid shear stress and gasotransmitter play important roles in the liver regeneration.Learning the mechanisms of hemodynamic signal is of great importance for the treatment of liver diseases.

  18. Methods of Liver Stem Cell Therapy in Rodents as Models of Human Liver Regeneration in Hepatic Failure.

    Science.gov (United States)

    Hashemi Goradel, Nasser; Darabi, Masoud; Shamsasenjan, Karim; Ejtehadifar, Mostafa; Zahedi, Sarah

    2015-09-01

    Cell therapy is a promising intervention for treating liver diseases and liver failure. Different animal models of human liver cell therapy have been developed in recent years. Rats and mice are the most commonly used liver failure models. In fact, rodent models of hepatic failure have shown significant improvement in liver function after cell infusion. With the advent of stem-cell technologies, it is now possible to re-programme adult somatic cells such as skin or hair-follicle cells from individual patients to stem-like cells and differentiate them into liver cells. Such regenerative stem cells are highly promising in the personalization of cell therapy. The present review article will summarize current approaches to liver stem cell therapy with rodent models. In addition, we discuss common cell tracking techniques and how tracking data help to direct liver cell therapy research in animal models of hepatic failure.

  19. Eight paths of ERK1/2 signalling pathway regulating hepatocyte proliferation in rat liver regeneration

    Indian Academy of Sciences (India)

    J. W. Li; G. P. Wang; J. Y. Fan; C. F. Chang; C. S. Xu

    2011-12-01

    Although it is known that hormones, growth factors and integrin promote hepatocyte proliferation in liver regeneration (LR) through ERK1/2 signalling pathway, reports about regulating processes of its intracellular paths in hepatocytes of LR are limited. This study aims at exploring which paths of ERK1/2 signalling pathway participate in the regulation of rat LR, especially in hepatocyte proliferation, and how they do so. In all, 14 paths and 165 genes are known to be involved in ERK1/2 signalling pathway. Of them, 161 genes are included in Rat Genome 230 2.0 Array. This array was used to detect expression changes of genes related to ERK1/2 signalling pathway in isolated hepatocytes of rat LR, showing that 60 genes were related to hepatocytes of LR. In addition, bioinformatics and systems biology methods were used to analyse the roles of 14 above paths in regenerating hepatocytes. We found that three paths, RTK → SHC → GRB2/SOS → RAS → RAF, Integrin → FAK → RAC → PAK → RAF and G → PI3K → RAC → PAK → RAF, promoted the G1 phase progression of hepatocytes by activating ERK1/2. A further four paths, Gq → PLC → PKC → SRC/PYK2 → GRB2/SOS → RAS → RAF, RTK → PLC → PKC → SRC/PYK2 → GRB2/SOS → RAS → RAF, Integrin → FAK/SRC → GRB2/SOS → RAS → RAF and Integrin → FAK → RAC → PAK → RAF, advanced the cell progression of S phase and G2/M checkpoint by activating ERK1/2, and so did PP1/2 → Mek1/2 by decreasing the negative influence on ERK1/2. At the late phase of LR, Gs → AC → EPAC → Rap1 → Raf blocked hepatocyte proliferation by decreasing the activity of ERK1/2 and so did PP1/2 → Mek1/2. In summary, 60 genes and 8 paths of ERK1/2 signalling pathway regulated hepatocyte proliferation in rat LR.

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

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    AIM:To investigate the effects of vitamins(A,C and F)on liver injury induced by ethanol administration during liver regeneration in rats.METHODS:Male Wistar rats subjected to 70% partial hepatectomy were divided into five groups (groups 1-5).During the experiment,animals of Group 1 drank only water.The other four groups(2-5)drank 30 mL of ethanol/L of water.Group 3 additionally received vitamin A,those of group 4 vitamin C and those of group 5 received vitamin E.Subsequently serum alanine aminotTansferase (ALT),aspartate aminotransferase (AST),albumin and bilirubin were measured colorimetrically.Lipid peroxidation (thiobarbituric-acid reactive substances,TBARS) both in plasma and liver was measured,as well as liver mass gain assessment and total DNA.RESULTS;Compared with sham group,serum AST and ALT increased significantly under ethanol treatment (43% and 93%,respectively,with P<0.05).Vitamin C and vitamin E treatment attenuated the ethanol-induced increases in ALT and AST activity.Ethanol treatment also decreased serum albumin concentration compared to sham group (3.1 ± 0.4 g/dL vs 4.5 ± 0.2 g/dL;P < 0.05).During liver regeneration vitamins C and E significantly ameliorated liver injury for ethanol administration in hepatic lipid peroxidation (4.92 nmol/mg and 4.25 nmol/mg vs 14.78 nmol/mg,respectively,with P < 0.05).In association with hepatic injury,ethanol administration caused a significant increase in both hepatic and plasma lipid peroxidation.Vitamins (C and E) treatment attenuated hepatic and plasma lipid peroxidation.CONCLUSION:Vitamins C and E protect against liver injury and dysfunction,attenuate lipid peroxidation,and thus appear to be significantly more effective than vitamin A against ethanol-mediated toxic effects during liver regeneration.

  1. Innate immune responses involving natural killer and natural killer T cells promote liver regeneration after partial hepatectomy in mice.

    Science.gov (United States)

    Hosoya, Satoko; Ikejima, Kenichi; Takeda, Kazuyoshi; Arai, Kumiko; Ishikawa, Sachiko; Yamagata, Hisafumi; Aoyama, Tomonori; Kon, Kazuyoshi; Yamashina, Shunhei; Watanabe, Sumio

    2013-02-01

    To clarify the roles of innate immune cells in liver regeneration, here, we investigated the alteration in regenerative responses after partial hepatectomy (PH) under selective depletion of natural killer (NK) and/or NKT cells. Male, wild-type (WT; C57Bl/6), and CD1d-knockout (KO) mice were injected with anti-NK1.1 or anti-asialo ganglio-N-tetraosylceramide (GM1) antibody and then underwent the 70% PH. Regenerative responses after PH were evaluated, and hepatic expression levels of cytokines and growth factors were measured by real-time RT-PCR and ELISA. Phosphorylation of STAT3 was detected by Western blotting. Depletion of both NK and NKT cells with an anti-NK1.1 antibody in WT mice caused drastic decreases in bromodeoxyuridine uptake, expression of proliferating cell nuclear antigen, and cyclin D1, 48 h after PH. In mice given NK1.1 antibody, increases in hepatic TNF-α, IL-6/phospho-STAT3, and hepatocyte growth factor (HGF) levels following PH were also blunted significantly, whereas IFN-γ mRNA levels were not different. CD1d-KO mice per se showed normal liver regeneration; however, pretreatment with an antiasialo GM1 antibody to CD1d-KO mice, resulting in depletion of both NK and NKT cells, also blunted regenerative responses. Collectively, these observations clearly indicated that depletion of both NK and NKT cells by two different ways results in impaired liver regeneration. NK and NKT cells most likely upregulate TNF-α, IL-6/STAT3, and HGF in a coordinate fashion, thus promoting normal regenerative responses in the liver.

  2. Expression of phosphatase of regenerating liver-3 is associated with prognosis of Wilms’ tumor

    Directory of Open Access Journals (Sweden)

    Sun F

    2017-01-01

    Full Text Available Fengyin Sun,1 Wenyi Li,2,3 Lie Wang,2 Changfeng Jiao3 1Department of Pediatric Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 2Department of General Surgery, Fuzhou General Hospital of Nanjing Command, PLA, Fuzhou, Fujian Province, 3Department of Vascular Surgery, Xinzhou City People’s Hospital, Xinzhou, Shanxi Province, People’s Republic of China Objective: The current study was undertaken to explore the clinical and prognostic value of phosphatase of regenerating liver-3 (PRL-3 expression in Wilms’ tumor. Methods: Seventy-six patients with Wilms’ tumor in Qilu Hospital from January 2003 to July 2009 were enrolled in the study. Protein expression level of PRL-3 was examined by immunohistochemical staining, and the correlation between PRL-3 expression and histopathological parameters, clinical variables, and outcome of patients with Wilms’ tumor were analyzed. Results: We found that 19% of patients with unfavorable histology had tumor recurrence and 16% of patients died following the operation. PRL-3 was expressed in 15 out of 76 tumors (19% and expressed highly in unfavorable histology Wilms’ tumor (P=0.04. PRL-3 protein expression level was correlated to 2.5-fold increase in recurrence rate of Wilms’ tumor (P=0.06 without any statistically significant difference. However, in favorable histology Wilms’ tumor, PRL-3 expression was correlated to an increase of 3.4-fold in recurrence rate (P=0.03. Conclusion: The expression of PRL-3 protein was correlated with an increased recurrence rate of favorable histology Wilms’ tumor. PRL-3 may serve as a promising biomarker for predicting patients with high risk of Wilms’ tumor. Further investigations are warranted to investigate the clinical function of PRL-3 in Wilms’ tumor. Keywords: Wilms’ tumor, prognosis, tumorigenesis, recurrence

  3. Procyanidins Negatively Affect the Activity of the Phosphatases of Regenerating Liver.

    Directory of Open Access Journals (Sweden)

    Sven Stadlbauer

    Full Text Available Natural polyphenols like oligomeric catechins (procyanidins derived from green tea and herbal medicines are interesting compounds for pharmaceutical research due to their ability to protect against carcinogenesis in animal models. It is nevertheless still unclear how intracellular pathways are modulated by polyphenols. Monomeric polyphenols were shown to affect the activity of some protein phosphatases (PPs. The three phosphatases of regenerating liver (PRLs are close relatives and promising therapeutic targets in cancer. In the present study we show that several procyanidins inhibit the activity of all three members of the PRL family in the low micromolar range, whereas monomeric epicatechins show weak inhibitory activity. Increasing the number of catechin units in procyanidins to more than three does not further enhance the potency. Remarkably, the tested procyanidins showed selectivity in vitro when compared to other PPs, and over 10-fold selectivity toward PRL-1 over PRL-2 and PRL-3. As PRL overexpression induces cell migration compared to control cells, the effect of procyanidins on this phenotype was studied. Treatment with procyanidin C2 led to a decrease in cell migration of PRL-1- and PRL-3-overexpressing cells, suggesting the compound-dependent inhibition of PRL-promoted cell migration. Treatment with procyanidin B3 led to selective suppression of PRL-1 overexpressing cells, thereby corroborating the selectivity toward PRL-1- over PRL-3 in vitro. Together, our results show that procyanidins negatively affect PRL activity, suggesting that PRLs could be targets in the polypharmacology of natural polyphenols. Furthermore, they are interesting candidates for the development of PRL-1 inhibitors due to their low cellular toxicity and the selectivity within the PRL family.

  4. ZBTB20 is involved in liver regeneration after partial hepatectomy in mouse

    Institute of Scientific and Technical Information of China (English)

    Ming-Zhe Weng; Peng-Yuan Zhuang; Zhen-Yu Hei; Pei-Yi Lin; Zhi-Sheng Chen; Ying-Bin Liu; Zhi-Wei Quan and Zhao-Hui Tang

    2014-01-01

    BACKGROUND: A  better  understanding  of  the  molecular mechanisms in liver regeneration holds promise for exploring the new potential therapy for liver failure. The present study was to investigate the role of zinc ifnger and BTB domain-containing protein 20 (ZBTB20), a potential factor associated with liver regeneration, in a model of 70% hepatectomy in mice. METHODS: Parameters for liver proliferation such as liver/body ratio and BrdU positivity were obtained via direct measurement and  immunohistochemistry.  The  levels  of  zinc  ifngers  and homeoboxes 2 (ZHX2), ZBTB20, alpha-fetoprotein (AFP) and glypican 3 (GPC3) transcripts in the regenerating liver tissue of a 70% hepatectomy rodent model were monitored by real-time PCR analysis at different time points. Knockdown of ZBTB20 was performed to characterize its regulatory function. RESULTS: A negatively regulating relationship between ZHX2, ZBTB20 and AFP, GPC3 was revealed from 24 to 72 hours after 70% hepatectomy. ZBTB20 appears to negatively regulate AFP and GPC3 transcription since the knockdown of ZBTB20 promoted the proliferation of hepatocytes and the expression of AFP and GPC3. CONCLUSION: In addition to AFP, GPC3 and ZHX2, ZBTB20 is a new regulator in liver regeneration and the decrease of ZBTB20 expression following 70% hepatectomy promotes AFP and GPC3 expression.

  5. Transcriptome atlas of aromatic amino acid family metabolism-related genes in eight liver cell types uncovers the corresponding metabolic pathways in rat liver regeneration.

    Science.gov (United States)

    Chang, Cuifang; Xu, CunShuan

    2010-10-01

    To explore gene expression of aromatic amino acid family metabolism and their metabolic pathways of eight liver cell types in rat liver regeneration, eight kinds of rat regenerating liver cells were isolated by using the combination of percoll density gradient centrifugation and immunomagnetic bead methods. Rat Genome 230 2.0 Array was used to detect the expression changes of genes associated with aromatic amino acid family metabolism. The transcriptome atlas showed that the metabolic pathway of phenylalanine was mainly catalyzed into tyrosine in hepatic stellate cells in the initiation stage, tyrosine was oxidized into dopa and norepinephrine in biliary epithelia cells and dendritic cells, and norepinephrine was finally catalyzed into adrenaline in biliary epithelia cells and pit cells in the progress stage. Thyroid hormone of tyrosine catabolites was synthesized from tyrosine in almost all cells in different stage of LR, among which genes of T3 biosynthesis were increased in HCs, BECs, SECs and DCs in the progress stage. Tryptophan was decarboxylated to 5-hydroxytryptamine in dendritic cells in the progress stage. Based on the results as above, we concluded that phenylalanine is the major source of tyrosine, proliferation of biliary epithelia cells and dendritic cells maybe promote by tyrosine catabolites-dopa and norepinephrine, biliary epithelia cells and pit cells maybe promote by adrenaline. T3 maybe play a major role on proliferation of HCs, BECs, SECs and DCs in the progress stage. The proliferation of dendritic cells maybe promote by tryptophan catabolites-5-hydroxytryptamine. Copyright 2010. Published by Elsevier Ltd.

  6. Effects of Zuogui Wan on neurocyte apoptosis and down-regulation of TGF-β1 expression in nuclei of arcuate hypothalamus of monosodium glutamate -liver regeneration rats

    Institute of Scientific and Technical Information of China (English)

    Han-Min Li; Xiang Gao; Mu-Lan Yang; Jia-Jun Mei; Liu-Tong Zhang; Xing-Fan Qiu

    2004-01-01

    AIM: To inquire into the effects and mechanism of Zuogui Wan (Pills for Kidney Yin) on neurocyte apoptosis in nuclei of arcuate hypothalamus (ARN) of monosodium glutamate(MSG)-liver regeneration rats, and the mechanism of liver regeneration by using optic microscope, electron microscope and in situ end labeling technology to adjust nerve-endocrineimmunity network.METHODS: Neurocyte apoptosis in ARN of the experiment rats was observed by using optic microscope, electron microscope andin situ end labeling technology. Expression of TGF-β1 in ARN was observed by using immunohistochemistry method.RESULTS: The expression of TGF-β1 in rats of model group was increased with the increase of ARN neurocyte apoptosis index (AI) (t = 8.3097, 12.9884, P<0.01). As compared with the rats of model group, the expression of TGF-β1 in rats of Zuogui Wan treatment group was decreased with the significant decrease of ARN neurocyte apoptosis (t = 4.5624,11.1420, P<0.01).CONCLUSION: Brain neurocyte calcium ion overexertion and TGF-β1 protein participate in the adjustment and control of ARN neurocyte apoptosis in MSG-liver regeneration-rats. Zuogui Wan can prevent ARN neurocyte apoptosis of MSG-liver regeneration in rats by downregulating the expression of TGF-β1, and influence liver regeneration through adjusting nerve-endocrine-immune network.

  7. Signaling factors in stem cell-mediated repair of infarcted myocardium

    NARCIS (Netherlands)

    Vandervelde, S; van Luyn, MJA; Tio, RA; Harmsen, MC

    2005-01-01

    Myocardial infarction leads to scar formation and subsequent reduced cardiac performance. The ultimate therapy after myocardial infarction would pursue stem cell-based regeneration. The aim of stem cell-mediated cardiac repair embodies restoration of cardiac function by regeneration of healthy myoca

  8. Liver fibrosis and regeneration in dogs and cats: An immunohistochemical approach

    NARCIS (Netherlands)

    IJzer, J.

    2008-01-01

    In this thesis we focus on liver tissue repair processes in canine and feline hepatitis, on formalin fixed paraffin embedded archival liver specimens. Hepatitis was diagnosed using histological standard criteria, and always includes hepatocellular cell death and an inflammatory infiltrate.

  9. Suppression of graft regeneration, not ischemia/reperfusion injury, is the primary cause of small-for-size syndrome after partial liver transplantation in mice.

    Directory of Open Access Journals (Sweden)

    Ning Pan

    Full Text Available BACKGROUND: Ischemia/reperfusion injury (IRI is commonly considered to play a crucial role in the pathogenesis of small-for-size syndrome (SFSS after liver transplantation. Rapid regeneration is also considered essential for the survival of SFS grafts. METHODS: Mouse models of full-size orthotopic liver transplantation, 50% partial liver transplantation and 30% partial liver transplantation were established. Survival rate and serum alanine aminotransferase were observed. IRI was assessed by hepatic pathologic alterations, apoptosis and necrosis. Regeneration response was detected by mitotic index, BrdU incorporation and PCNA, Cyclin D1 and Cyclin E expression. The expression of mTOR, AKT, ERK, JNK2 and p70S6K, also involved in regeneration signaling pathways, were analyzed as well. RESULTS: 30% partial liver graft resulted in a significantly low 7-day survival rate (P = 0.002 with no marked difference in tissue injury compared with the 50% partial graft group. Serum alanine aminotransferase levels were not significantly different between partial transplantation and full-size transplantation. Western blot analysis of caspase-3 and TUNEL staining also indicated no significant difference in apoptosis response between 30% partial transplantation and half-size or full-size transplantation (P = 0.436, P = 0.113, respectively. However, liver regeneration response indicators, mitotic index (P<0.0001 and BrdU (P = 0.0022, were markedly lower in 30% LTx compared with 50% LTx. Suppressed expression of PCNA, cyclin D1, cyclin E, mTOR, JNK2, AKT, ERK and p70S6K was also detected by western blot. CONCLUSIONS: Liver regeneration is markedly suppressed in SFSS, and is more likely the primary cause of SFSS, rather than ischemia/reperfusion injury. Therapy for recovering graft regeneration could be a potentially important strategy to reduce the incidence of SFSS.

  10. Loss of α1,6-fucosyltransferase suppressed liver regeneration: implication of core fucose in the regulation of growth factor receptor-mediated cellular signaling.

    Science.gov (United States)

    Wang, Yuqin; Fukuda, Tomohiko; Isaji, Tomoya; Lu, Jishun; Gu, Wei; Lee, Ho-Hsun; Ohkubo, Yasuhito; Kamada, Yoshihiro; Taniguchi, Naoyuki; Miyoshi, Eiji; Gu, Jianguo

    2015-02-05

    Core fucosylation is an important post-translational modification, which is catalyzed by α1,6-fucosyltransferase (Fut8). Increased expression of Fut8 has been shown in diverse carcinomas including hepatocarcinoma. In this study, we investigated the role of Fut8 expression in liver regeneration by using the 70% partial hepatectomy (PH) model, and found that Fut8 is also critical for the regeneration of liver. Interestingly, we show that the Fut8 activities were significantly increased in the beginning of PH (~4d), but returned to the basal level in the late stage of PH. Lacking Fut8 led to delayed liver recovery in mice. This retardation mainly resulted from suppressed hepatocyte proliferation, as supported not only by a decreased phosphorylation level of epidermal growth factor (EGF) receptor and hepatocyte growth factor (HGF) receptor in the liver of Fut8(-/-) mice in vivo, but by the reduced response to exogenous EGF and HGF of the primary hepatocytes isolated from the Fut8(-/-) mice. Furthermore, an administration of L-fucose, which can increase GDP-fucose synthesis through a salvage pathway, significantly rescued the delayed liver regeneration of Fut8(+/-) mice. Overall, our study provides the first direct evidence for the involvement of Fut8 in liver regeneration.

  11. Identification of expressed genes in regenerating rat liver in 0-4-8-12 h short interval successive partial hepatectomy

    Institute of Scientific and Technical Information of China (English)

    Cun-Shuan Xu; Salman Rahman; Jing-Bo Zhang; Jin-Yun Yuan; Wen-Qiang Li; Hong-Peng Han; Ke-Jin Yang; Cui-Fang Chang; Li-Feng Zhao; Yu-Chang Li; Hui-Yong Zhang

    2005-01-01

    AIM: To identify the genes differentially expressed in the regenerating rat liver of 0-4-8-12 h short interval successive partial hepatectomy (SISPH) and to analyze their expression profiles.METHODS: Five hundred and fifty-one elements screened from subtractive cDNA libraries were made into a cDNA microarray (cDNA chip). Extensive gene expression analysis following 0-4-8-12 h SISPH was conducted by microarray.RESULTS: One hundred and eighty-three elements were selected, which were either up- or down-regulated more than 2-fold at one or more time points after SISPH. Cluster analysis and generalization analysis showed that there were five distinct temporal patterns of gene expression.Eighty-six genes were unreported, associated with liver regeneration (LR).CONCLUSION: Microarray analysis shows that the down regulated genes are much more than the up-regulated ones in SISPH; the numbers of genes expressed consistently are fewer than that expressed immediately; the genes expressed in high abundance are much fewer than that increased 2-5-fold. The comparison of SISPH with partial hepatectomy (PH) shows that the expression trends of most genes in SISPH and in PH are similar,but the expression of 43 genes is specifically altered in SISPH.

  12. Anandamide drives cell cycle progression through CB1 receptors in a rat model of synchronized liver regeneration.

    Science.gov (United States)

    Pisanti, Simona; Picardi, Paola; Pallottini, Valentina; Martini, Chiara; Petrosino, Stefania; Proto, Maria Chiara; Vitale, Mario; Laezza, Chiara; Gazzerro, Patrizia; Di Marzo, Vincenzo; Bifulco, Maurizio

    2015-12-01

    The endocannabinoid system, through cannabinoid receptor signaling by endocannabinoids, is involved in a wide range of functions and physiopathological conditions. To date, very little is known concerning the role of the endocannabinoids in the control and regulation of cell proliferation. An anti-proliferative action of CB1 signaling blockade in neurogenesis and angiogenesis argues in favor of proliferation-promoting functions of endocannabinoids through CB1 receptors when pro-growth signals are present. Furthermore, liver regeneration, a useful in vivo model of synchronized cell proliferation, is characterized by a peak of anandamide that elicits through CB1 receptor, the expression of critical mitosis genes. The aim of this study was to focus on the timing of endocannabinoid signaling changes during the different phases of the cell cycle, exploiting the rat liver regeneration model following partial hepatectomy, the most useful to study synchronized cell cycle in vivo. Hepatic regeneration led to increased levels of anandamide and endocannabinoid-like molecules oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in the G1 phase of the cell cycle, with a concomitant increase in CB1 mRNA levels, whose protein expression peaked later during the S phase. Blocking of CB1 receptor with a low dose of the selective antagonist/inverse agonist SR141716 (0.7 mg/kg/dose) affected cell cycle progression reducing the expression of PCNA, and through the inhibition of pERK and pSTAT3 pathways. These results support the notion that the signaling mediated by anandamide through CB1 receptor may be important for the entry and progression of cells into the cell cycle and hence for their proliferation under mitogenic signals.

  13. Reduction in Bile Acid Pool Causes Delayed Liver Regeneration Accompanied by Down-regulated Expression of FXR and C-Jun mRNA in Rats

    Institute of Scientific and Technical Information of China (English)

    董秀山; 赵浩亮; 马晓明; 王世明

    2010-01-01

    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),...

  14. Transplantation of Porcine Hepatocytes Cultured with Polylactic Acid-O-Carboxymethylated Chitosan Nanoparticles Promotes Liver Regeneration in Acute Liver Failure Rats

    Directory of Open Access Journals (Sweden)

    Zhong Chen

    2011-01-01

    Full Text Available In this study, free porcine hepatocytes suspension (Group A, porcine hepatocytes embedded in collagen gel (Group B, porcine hepatocytes cultured with PLA-O-CMC nanoparticles and embedded in collagen gel (Group C, and PLA-O-CMC nanoparticles alone (Group D were transplanted into peritoneal cavity of ALF rats, respectively. The result showed that plasma HGF levels were elevated post-transplantation with a peak at 12 hr. The rats in Group C showed highest plasma HGF levels at 2, 6, 12, 24 and 36 hr post-transplantation and lowest HGF level at 48 hr. Plasma VEGF levels were elevated at 48 hr post-transplantation with a peak at 72 hr. The rats in Group C showed highest plasma HGF levels at 48, 72, and 96 hr post-transplantation. The liver functions in Group C were recovered most rapidly. Compared with Group B, Group C had significant high liver Kiel 67 antigen labeling index (Ki-67 LI at day 1 post-HTx (P<.05. Ki-67 LI in groups B and C was higher than that in groups A and D at days 5 and 7 post-HTx. In conclusion, intraperitoneal transplantation of porcine hepatocytes cultured with PLA-O-CMC nanoparticles and embedded in collagen gel can promote significantly liver regeneration in ALF rats.

  15. Expression profiles of the genes associated with metabolism and transport of amino acids and their derivatives in rat liver regeneration.

    Science.gov (United States)

    Xu, C S; Chang, C F

    2008-01-01

    Amino acids (AA) are components of protein and precursors of many important biological molecules. To address effects of the genes associated with metabolism and transport of AA and their derivatives during rat liver regeneration (LR), we firstly obtained the above genes by collecting databases data and retrieving related thesis, and then analyzed their expression profiles during LR using Rat Genome 230 2.0 array. The LR-associated genes were identified by comparing the gene expression difference between partial hepatectomy (PH) and sham-operation (SO) rat livers. It was approved that 134 genes associated with metabolism of AA and their derivatives and 26 genes involved in transport of them were LR-associated. The initially and totally expressing number of these genes occurring in initial phase of LR (0.5-4 h after PH), G0/G1 (4-6 h after PH), cell proliferation (6-66 h after PH), cell differentiation and structure-function reconstruction of liver tissue (72-168 h after PH) were respectively 76, 17, 79, 5 and 162, 89, 564, 195, illustrating that these LR-associated genes were initially expressed mainly in initial stage, and functioned in different phases. Frequencies of up-regulation and down-regulation of them being separately 564 and 357 demonstrated that genes up-regulated outnumbered those down-regulated. Categorization of their expression patterns into 22 types implied the diversity of cell physiological and biochemical activities. According to expression changes and patterns of the above-mentioned genes in LR, it was presumed that histidine biosynthesis in the metaphase and anaphase, valine metabolism in the anaphase, and metabolism of glutamate, glutamine, asparate, asparagine, methionine, alanine, leucine and aromatic amino acid almost were enhanced in the whole LR; as for amino acid derivatives, transport of neutral amino acids, urea, gamma-aminobutyric acid, betaine and taurine, metabolism of dopamine, heme, S-adenosylmethionine, thyroxine, and

  16. Construction of High Expression Plasmid of Human Augmenter of Liver Regeneration( hALR), Expression and Purification of hALR

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Experimental evidence has been presented to suggest that the human augmenter of liver regeneration (hALR)serves as a hepatotrophic growth factor during liver regeneration and as a generalized growth factor during pancreas transplant/regeneration. A prokaryotic expression plasmid, pRSET/6his-c-myc-hALR was constructed, by cloning synthesized hALR cDNA into pRSET/6his-c-myc that was improved on the basis of pRSET B by the group. As a result, the protein was highly expressed in E. coli BL21. The recombinant hALR was over 60% of the total protein in E. coli. Its validity was confirmed by meansof Western Blotting. The protein was purified by Ni-NTA affinity chromatography and this FAD-dependent sulfhydryl oxidase activity was measured.

  17. HEDGEHOG SIGNALING IS CRITICAL FOR NORMAL LIVER REGENERATION AFTER PARTIAL HEPATECTOMY IN MICE

    OpenAIRE

    Ochoa, Begoña; Syn, Wing-Kin; Delgado, Igotz; Karaca, Gamze F.; Jung, Youngmi; Wang, Jiangbo; Zubiaga, Ana M.; Fresnedo, Olatz; Omenetti, Alessia; Zdanowicz, Marzena; Choi, Steve S.; Diehl, Anna Mae

    2010-01-01

    Distinct mechanisms are believed to regulate growth of the liver during fetal development and after injury in adults because the former relies on progenitors while the latter generally involves replication of mature hepatocytes. However, chronic liver injury in adults increases production of Hedgehog (Hh) ligands, developmental morphogens that control progenitor cell fate and orchestrate various aspects of tissue construction during embryogenesis. This raises the possibility that similar Hh-d...

  18. Dicer-dependent production of microRNA221 in hepatocytes inhibits p27 and is required for liver regeneration in mice.

    Science.gov (United States)

    Oya, Yuki; Masuzaki, Ryota; Tsugawa, Daisuke; Ray, Kevin C; Dou, Yongchao; Karp, Seth J

    2017-05-01

    Dicer processes microRNAs (miRs) into active forms in a wide variety of tissues, including the liver. To determine the role of Dicer in liver regeneration, we performed a series of in vivo and in vitro studies in a murine 2/3 hepatectomy model. Dicer was downregulated after 2/3 hepatectomy, and loss of Dicer inhibited liver regeneration associated with decreased cyclin A2 and miR-221, as well as increased levels of the cell cycle inhibitor p27. In vitro, miR-221 inhibited p27 production in primary hepatocytes and increased hepatocyte proliferation. Specific reconstitution of miR-221 in hepatocyte-specific Dicer-null mice inhibited p27 and restored liver regeneration. In wild type mice, targeted inhibition of miR-221 using a cholesterol-conjugated miR-221 inhibited hepatocyte proliferation after 2/3 hepatectomy. These results identify Dicer production of miR-221 as an essential component of a miRNA-dependent mechanism for suppression of p27 that controls the rate of hepatocyte proliferation after partial hepatectomy.NEW & NOTEWORTHY Our findings demonstrate a direct role for microRNAs in controlling the rate of liver regeneration after injury. By deleting Dicer, an enzyme responsible for processing microRNAs into mature forms, we determined miR-221 is a critical microRNA in the physiological process of restoration of liver mass after injury. miR-221 suppresses p27, releasing its inhibitory effects on hepatocyte proliferation. Pharmaceuticals based on miR-221 may be useful to modulate hepatocyte proliferation in the setting of liver injury. Copyright © 2017 the American Physiological Society.

  19. Multiple doses of erythropoietin impair liver regeneration by increasing TNF-alpha, the Bax to Bcl-xL ratio and apoptotic cell death.

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    Katja Klemm

    Full Text Available BACKGROUND: Liver resection and the use of small-for-size grafts are restricted by the necessity to provide a sufficient amount of functional liver mass. Only few promising strategies to maximize liver regeneration are available. Apart from its erythropoiesis-stimulating effect, erythropoietin (EPO has meanwhile been recognized as mitogenic, tissue-protective, and anti-apoptotic pleiotropic cytokine. Thus, EPO may support regeneration of hepatic tissue. METHODOLOGY: Rats undergoing 68% hepatectomy received daily either high dose (5000 IU/kg bw i.v. or low dose (500 IU/kg bw i.v. recombinant human EPO or equal amounts of physiologic saline. Parameters of liver regeneration and hepatocellular apoptosis were assessed at 24 h, 48 h and 5 d after resection. In addition, red blood cell count, hematocrit and serum EPO levels as well as plasma concentrations of TNF-alpha and IL-6 were evaluated. Further, hepatic Bcl-x(L and Bax protein expression were analyzed by Western blot. PRINCIPAL FINDINGS: Administration of EPO significantly reduced the expression of PCNA at 24 h followed by a significant decrease in restitution of liver mass at day 5 after partial hepatectomy. EPO increased TNF-alpha levels and shifted the Bcl-x(L to Bax ratio towards the pro-apoptotic Bax resulting in significantly increased hepatocellular apoptosis. CONCLUSIONS: Multiple doses of EPO after partial hepatectomy increase hepatocellular apoptosis and impair liver regeneration in rats. Thus, careful consideration should be made in pre- and post-operative recombinant human EPO administration in the setting of liver resection and transplantation.

  20. Integrative and comparative genomics analysis of early hepatocellular carcinoma differentiated from liver regeneration in young and old

    Directory of Open Access Journals (Sweden)

    Ozand Pinar T

    2010-06-01

    Full Text Available Abstract Background Hepatocellular carcinoma (HCC is the third-leading cause of cancer-related deaths worldwide. It is often diagnosed at an advanced stage, and hence typically has a poor prognosis. To identify distinct molecular mechanisms for early HCC we developed a rat model of liver regeneration post-hepatectomy, as well as liver cells undergoing malignant transformation and compared them to normal liver using a microarray approach. Subsequently, we performed cross-species comparative analysis coupled with copy number alterations (CNA of independent early human HCC microarray studies to facilitate the identification of critical regulatory modules conserved across species. Results We identified 35 signature genes conserved across species, and shared among different types of early human HCCs. Over 70% of signature genes were cancer-related, and more than 50% of the conserved genes were mapped to human genomic CNA regions. Functional annotation revealed genes already implicated in HCC, as well as novel genes which were not previously reported in liver tumors. A subset of differentially expressed genes was validated using quantitative RT-PCR. Concordance was also confirmed for a significant number of genes and pathways in five independent validation microarray datasets. Our results indicated alterations in a number of cancer related pathways, including p53, p38 MAPK, ERK/MAPK, PI3K/AKT, and TGF-β signaling pathways, and potential critical regulatory role of MYC, ERBB2, HNF4A, and SMAD3 for early HCC transformation. Conclusions The integrative analysis of transcriptional deregulation, genomic CNA and comparative cross species analysis brings new insights into the molecular profile of early hepatoma formation. This approach may lead to robust biomarkers for the detection of early human HCC.

  1. Cell-mediated immune response

    DEFF Research Database (Denmark)

    Meyer, Sonja Izquierdo; Fuglsang, Katrine; Blaakaer, Jan

    2014-01-01

    OBJECTIVE: This clinical review aims to assess the efficacy of human papillomavirus 16/18 (HPV16/18) vaccination on the cell-mediated immune response in women with existing cervical intraepithelial neoplasia or cervical cancer induced by HPV16 or HPV18. DATA SOURCES AND STUDY SELECTION: A focused...... and thorough literature search conducted in five different databases found 996 publications. Six relevant articles were chosen for further review. In total, 154 patients (>18 years of age) were enrolled in prospective study trials with 3-15 months of follow up. The vaccine applications were administered two...... triggered a detectable cell-mediated immune response, some of which were statistically significant. Correlations between immunological response and clinical outcome (histopathology) were not significant, so neoplasms may not be susceptible to vaccine-generated cytotoxic T cells (CD8(+)). CONCLUSIONS...

  2. [Krezatsin--a stimulant of the activity of regenerating liver cells].

    Science.gov (United States)

    Rasulov, M M; Kuznetsov, I G; Belousov, A A; Zabozlaev, A G; Khvylia, S I; Voronkov, M G

    1993-01-01

    In experiments with partial hepatectomy in rats, the application of cresacin was shown to potentiate processes of hepatocyte regeneration, to increase high-energy compounds therein, and to accelerate some phases of mitotic cycle. These processes occur along with an inhibition of lipid peroxidation in hepatocytes, a decrease in the rate of transmembrane oxygen transport in mitochondria, and a reduction of cytochrome oxidase amount. It was concluded that cresacin directly stimulates diverse links of metabolic pathway.

  3. Expression patterns and action analysis of genes associated with physiological responses during rat liver regeneration: Innate immune response

    Institute of Scientific and Technical Information of China (English)

    Guang-Wen Chen; Ming-Zhen Zhang; Li-Feng Zhao; Cun-Shuan Xu

    2006-01-01

    AIM: To study the relationship between innate immune response and liver regeneration (LR) at transcriptional level.METHODS: Genes associated with innate immunity response were obtained by collecting the data from databases and retrieving articles. Gene expression changes in rat regenerating liver were detected by rat genome 230 2.0 array.RESULTS: A total of 85 genes were found to be associated with LR. The initially and totally expressed number of genes at the phases of initiation [0.5-4 h after partial hepatectomy (PH)], transition from Go to G1 (4-6 h after PH), cell proliferation (6-66 h after PH),cell differentiation and structure-function reconstruction (66-168 h after PH) was 36, 9, 47, 4 and 36, 26, 78,50, respectively, illustrating that the associated genes were mainly triggered at the initial phase of LR and worked at different phases. According to their expression similarity, these genes were classified into 5 types: 41 up-regulated, 4 predominantly up-regulated, 26 downregulated, 6 predominantly down-regulated, and 8 approximately up/down-regulated genes, respectively.The expression of these genes was up-regulated 350 times and down-regulated 129 times respectively,demonstrating that the expression of most genes was enhanced while the expression of a small number of genes was decreased during LR. Their time relevance was classified into 14 groups, showing that the cellular physiological and biochemical activities during LR were staggered. According to the gene expression patterns,they were classified into 28 types, indicating that the cellular physiological and biochemical activities were diverse and complicated during LR.CONCLUSION: Congenital cellular immunity is enhanced mainly in the forepart, prophase and anaphase of LR while congenital molecular immunity is increased dominantly in the forepart and anaphase of LR. A total of 85 genes associated with LR play an important role in innate immunity.

  4. Hyperbaric oxygenation after portal vein emobilization for regeneration of the predicted remnant liver.

    Science.gov (United States)

    Uwagawa, T; Unemura, Y; Yamazaki, Y

    2001-09-01

    Liver failure often develops after extensive liver resection. Preoperative portal vein embolization to induce compensatory hypertrophy in the predicted remnant liver decreases clinical complications after hepatectomy. The aim of this study was to examine whether hyperbaric oxygenation (HBO) after portal vein embolization increases compensatory hypertrophy of the predicted liver remnant. We performed portal vein ligation and HBO in rats to investigate whether HBO after portal vein embolization increases compensatory hypertrophy of the predicted remnant liver. Rats were divided into four groups that underwent (1) laparotomy only (control group); (2) right portal vein ligation (RPL group); (3) RPL followed by HBO at 2 atm (HBO-2 atm group; 1 h/day, 5 days/week for 2 weeks); or (4) RPL followed by HBO at 3 atm (HBO-3 atm group). Laparotomy was repeated after 2 weeks in each group; serum levels of albumin and hepatocyte growth factor (HGF) were measured, and the ratio of the weights of nonligated to ligated hepatic segments and the percentage of hepatocytes expressing proliferating cell nuclear antigen (PCNA) in ligated hepatic segments were determined. In rats that had received HBO after RPL, serum levels of HGF, weight ratios of nonligated to ligated hepatic segments, and the percentage of PCNA-positive hepatocytes in nonligated liver were significantly higher than those in the control group. Furthermore, rats that had undergone 3-atm HBO after RPL had significantly higher serum levels of HGF and percentages of PCNA-positive hepatocytes in nonligated hepatic segments. Preoperative HBO after portal vein embolization may be useful for inducing compensatory hypertrophy of the predicted remnant liver. Copyright 2001 Academic Press.

  5. The NF-κB subunit RelA/p65 is dispensable for successful liver regeneration after partial hepatectomy in mice.

    Directory of Open Access Journals (Sweden)

    Marc Ringelhan

    Full Text Available BACKGROUND: The transcription factor NF-κB consisting of the subunits RelA/p65 and p50 is known to be quickly activated after partial hepatectomy (PH, the functional relevance of which is still a matter of debate. Current concepts suggest that activation of NF-κB is especially critical in non-parenchymal cells to produce cytokines (TNF, IL-6 to adequately prime hepatocytes to proliferate after PH, while NF-κB within hepatocytes mainly bears cytoprotective functions. METHODS: To study the role of the NF-κB pathway in different liver cell compartments, we generated conditional knockout mice in which the transactivating NF-κB subunit RelA/p65 can be inactivated specifically in hepatocytes (Rela(F/FAlbCre or both in hepatocytes plus non-parenchymal cells including Kupffer cells (Rela(F/FMxCre. 2/3 and 80% PH were performed in controls (Rela(F/F and conditional knockout mice (Rela(F/FAlbCre and Rela(F/FMxCre and analyzed for regeneration. RESULTS: Hepatocyte-specific deletion of RelA/p65 in Rela(F/FAlbCre mice resulted in an accelerated cell cycle progression without altering liver mass regeneration after 2/3 PH. Surprisingly, hepatocyte apoptosis or liver damage were not enhanced in Rela(F/FAlbCre mice, even when performing 80% PH. The additional inactivation of RelA/p65 in non-parenchymal cells in Rela(F/FMxCre mice reversed the small proliferative advantage observed after hepatocyte-specific deletion of RelA/p65 so that Rela(F/FMxCre mice displayed normal cell cycle progression, DNA-synthesis and liver mass regeneration. CONCLUSION: The NF-κB subunit RelA/p65 fulfills opposite functions in different liver cell compartments in liver regeneration after PH. However, the effects observed after conditional deletion of RelA/p65 are small and do not alter liver mass regeneration after PH. We therefore do not consider RelA/p65-containing canonical NF-κB signalling to be essential for successful liver regeneration after PH.

  6. The Herbal Compound “Diwu Yanggan” Modulates Liver Regeneration by Affecting the Hepatic Stem Cell Microenvironment in 2-Acetylaminofluorene/Partial Hepatectomy Rats

    Directory of Open Access Journals (Sweden)

    Bin-Bin Zhao

    2015-01-01

    Full Text Available Ethnopharmacological Relevance. “Diwu Yanggan” (DWYG has been reported to regulate liver regeneration, modulate the immune response, ameliorate liver injury, kill virus, ameliorate liver fibrosis, and suppress hepatic cancer. However, its mechanisms are still unknown. Objectives. To investigate the effects of DWYG on oval cell proliferation in 2-AAF/PH rats and determine its mechanism. Methods. Wistar rats were randomly distributed into normal group, sham group, vehicle group, and DWYG group. Hepatic pathological changes were examined by H&E staining. The oval cell markers CD34, AFP, CK-19 and hematopoietic cell markers CD45, Thy1.1, and hepatocyte marker ALB were examined with immunohistochemistry. The percentage of CD34/CD45 double-positive cells in bone marrow was detected by flow cytometry. Cytokine levels were measured with the Bio-plex suspension array system. Results. DWYG significantly increased the survival rates of 2-AAF/PH rats and promoted liver regeneration. Furthermore, DWYG increased the ratio of CD34/CD45 double-positive cells on days 10 and 14. In addition, DWYG gradually restored IL-1, GRO/KC, and VEGF levels to those of the normal group. Conclusions. DWYG increases 2-AAF/PH rat survival rates, suppresses hepatic precarcinoma changes, and restores hepatic tissue structure and function. DWYG may act by modulating the hepatic microenvironment to support liver regeneration.

  7. Assessment of a dual regulatory role for NO in liver regeneration after partial hepatectomy: protection against apoptosis and retardation of hepatocyte proliferation.

    Science.gov (United States)

    Zeini, Miriam; Hortelano, Sonsoles; Través, Paqui G; Gómez-Valadés, Alicia G; Pujol, Anna; Perales, José C; Bartrons, Ramón; Boscá, Lisardo

    2005-06-01

    The role of hepatic nitric oxide (NO) in liver regeneration after partial hepatectomy (PH) was studied in animals carrying a nitric oxide synthase-2 transgene under the control of the phospho(enol)pyruvate carboxykinase promoter. These mice expressed NOS-2 in liver cells under fasting conditions. Liver mass recovery and molecular parameters related to cell proliferation were determined after PH. Preexisting hepatic NO synthesis, as well as NO delivery by NO-donors, impaired early signaling (for example, attenuated NF-kappaB activation and TNF-alpha and IL-6 release). The regenerative process was also impaired as a result of an insufficient proliferative response, but mouse survival after surgery was not compromised. However, NO exerted a protective role against apoptosis in transgenic hepatectomized mice. Local production of NO in liver cells, achieved by hydrodynamic-based transfection with a NOS-2-encoding plasmid, also resulted in delayed liver recovery after PH and also protected against Fas-mediated apoptosis. These data show that sustained presence of NO after PH exerts a dual role: attenuating liver regeneration while efficiently protecting against liver apoptosis.

  8. Autophagy in anti-apoptotic effect of augmenter of liver regeneration in HepG2 cells.

    Science.gov (United States)

    Shi, Hong-Bo; Sun, Hai-Qing; Shi, Hong-Lin; Ren, Feng; Chen, Yu; Chen, De-Xi; Lou, Jin-Li; Duan, Zhong-Ping

    2015-05-07

    To investigate the role of autophagy in the anti-apoptotic effect of augmenter of liver regeneration (ALR). Autophagy was induced through serum deprivation. An ALR-expressing plasmid was transfected into HepG2 cells, and autophagic flux was determined using fluorescence microscopy, electron microscopy, Western blot and quantitative polymerase chain reaction (qPCR) assays. After ALR-expressing plasmid transfection, an autophagy inhibitor [3-methyladenine (3-MA)] was added to HepG2 cells, and apoptosis was observed using fluorescence microscopy and flow cytometry. Autophagy was activated in HepG2 cells, peaking at 24 h after serum deprivation. Microtubule-associated protein light chain three-II levels were higher in HepG2 cells treated with ALR than in control cells, fluorescence microscopy, electron microscopy and qPCR studies showed the similar trend, and p62 levels showed the opposite trend, which indicated that ALR may play an important role in increasing autophagy flux. The numbers of apoptotic cells were substantially higher in HepG2 cells treated with both ALR and 3-MA than in cells treated with ALR alone. Therefore, the protective effect of ALR was significantly attenuated or abolished when autophagy was inhibited, indicating that the anti-apoptotic effect of ALR may be related to autophagy. ALR protects cells from apoptosis partly through increased autophagy in HepG2 cells and may be valuable as a new therapeutic treatment for liver disease.

  9. Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration.

    NARCIS (Netherlands)

    Matondo, R.B.; Punt, C.; Homberg, J.R.; Toussaint, M.J.; Kisjes, R.; Korporaal, S.J.; Akkerman, J.W.; Cuppen, E.; Bruin, A. de

    2009-01-01

    The serotonin transporter is implicated in the uptake of the vasoconstrictor serotonin from the circulation into the platelets, where 95% of all blood serotonin is stored and released in response to vascular injury. In vivo studies indicated that platelet-derived serotonin mediates liver regeneratio

  10. Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration

    NARCIS (Netherlands)

    Matondo, R.B.; Punt, C.; Homberg, J.R.; Toussaint, M.J.; Kisjes, R.; Korporaal, S.J.; Akkerman, J.W.; Cuppen, E.; de Bruin, A.

    2009-01-01

    The serotonin transporter is implicated in the uptake of the vasoconstrictor serotonin from the circulation into the platelets, where 95% of all blood serotonin is stored and released in response to vascular injury. In vivo studies indicated that platelet-derived serotonin mediates liver regeneratio

  11. Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration.

    NARCIS (Netherlands)

    Matondo, R.B.; Punt, C.; Homberg, J.R.; Toussaint, M.J.; Kisjes, R.; Korporaal, S.J.; Akkerman, J.W.; Cuppen, E.; Bruin, A. de

    2009-01-01

    The serotonin transporter is implicated in the uptake of the vasoconstrictor serotonin from the circulation into the platelets, where 95% of all blood serotonin is stored and released in response to vascular injury. In vivo studies indicated that platelet-derived serotonin mediates liver regeneratio

  12. Application of quantitative targeted absolute proteomics to profile protein expression changes of hepatic transporters and metabolizing enzymes during cholic acid-promoted liver regeneration.

    Science.gov (United States)

    Miura, Takayuki; Tachikawa, Masanori; Ohtsuka, Hideo; Fukase, Koji; Nakayama, Shun; Sakata, Naoaki; Motoi, Fuyuhiko; Naitoh, Takeshi; Katayose, Yu; Uchida, Yasuo; Ohtsuki, Sumio; Terasaki, Tetsuya; Unno, Michiaki

    2017-02-26

    Preoperative administration of cholic acid (CA) may be an option to increase the liver volume before elective liver resection surgery, so it is important to understand its effects on liver functionality for drug transport and metabolism. The purpose of this study was to clarify the absolute protein expression dynamics of transporters and metabolizing enzymes in the liver of mice fed CA-containing diet for 5 days (CA1) and mice fed CA-containing diet for 5 days followed by diet without CA for 7 days (CA2), in comparison with non CA-fed control mice. The CA1 group showed the increased liver weight, cell proliferation index, and oxidative stress, but no increase of apoptosis. Quantitative targeted absolute proteomics revealed (i) decreases in basolateral bile acid transporters ntcp, oatp1a1, oatp1b2, bile acid synthesis-related enzymes cyp7a1 and cyp8b1, and drug transporters bcrp, mrp6, ent1, oatp2b1, and (ii) increases in glutathione biosynthetic enzymes and drug-metabolizing enzyme cyp3a11. Liver concentrations of reduced and oxidized glutathione were both increased. In the CA2 group, the increased liver weight was maintained, while the biochemical features and protein profiles were restored to the non-CA-fed control levels. These findings suggest that CA administration alters liver functionality per body during liver regeneration and restoration.

  13. Postnatal liver growth and regeneration are independent of c-myc in a mouse model of conditional hepatic c-myc deletion

    Directory of Open Access Journals (Sweden)

    Sanders Jennifer A

    2012-03-01

    Full Text Available Abstract Background The transcription factor c-myc regulates genes involved in hepatocyte growth, proliferation, metabolism, and differentiation. It has also been assigned roles in liver development and regeneration. In previous studies, we made the unexpected observation that c-Myc protein levels were similar in proliferating fetal liver and quiescent adult liver with c-Myc displaying nucleolar localization in the latter. In order to investigate the functional role of c-Myc in adult liver, we have developed a hepatocyte-specific c-myc knockout mouse, c-mycfl/fl;Alb-Cre. Results Liver weight to body weight ratios were similar in control and c-myc deficient mice. Liver architecture was unaffected. Conditional c-myc deletion did not result in compensatory induction of other myc family members or in c-Myc's binding partner Max. Floxed c-myc did have a negative effect on Alb-Cre expression at 4 weeks of age. To explore this relationship further, we used the Rosa26 reporter line to assay Cre activity in the c-myc floxed mice. No significant difference in Alb-Cre activity was found between control and c-mycfl/fl mice. c-myc deficient mice were studied in a nonproliferative model of liver growth, fasting for 48 hr followed by a 24 hr refeeding period. Fasting resulted in a decrease in liver mass and liver protein, both of which recovered upon 24 h of refeeding in the c-mycfl/fl;Alb-Cre animals. There was also no effect of reducing c-myc on recovery of liver mass following 2/3 partial hepatectomy. Conclusions c-Myc appears to be dispensable for normal liver growth during the postnatal period, restoration of liver mass following partial hepatectomy and recovery from fasting.

  14. Oval cell response is attenuated by depletion of liver resident macrophages in the 2-AAF/partial hepatectomy rat.

    Directory of Open Access Journals (Sweden)

    Shuai Xiang

    Full Text Available BACKGROUND/AIMS: Macrophages are known to play an important role in hepatocyte mediated liver regeneration by secreting inflammatory mediators. However, there is little information available on the role of resident macrophages in oval cell mediated liver regeneration. In the present study we aimed to investigate the role of macrophages in oval cell expansion induced by 2-acetylaminofluorene/partial hepatectomy (2-AAF/PH in rats. METHODOLOGY/PRINCIPAL FINDINGS: We depleted macrophages in the liver of 2-AAF/PH treated rats by injecting liposome encapsulated clodronate 48 hours before PH. Regeneration of remnant liver mass, as well as proliferation and differentiation of oval cells were measured. We found that macrophage-depleted rats suffered higher mortality and liver transaminase levels. We also showed that depletion of macrophages yielded a significant decrease of EPCAM and PCK positive oval cells in immunohistochemical stained liver sections 9 days after PH. Meanwhile, oval cell differentiation was also attenuated as a result of macrophage depletion, as large foci of small basophilic hepatocytes were observed by day 9 following hepatectomy in control rats whereas they were almost absent in macrophage depleted rats. Accordingly, real-time polymerase chain reaction analysis showed lower expression of albumin mRNA in macrophage depleted livers. Then we assessed whether macrophage depletion may affect hepatic production of stimulating cytokines for liver regeneration. We showed that macrophage-depletion significantly inhibited hepatic expression of tumor necrosis factor-α and interleukin-6, along with a lack of signal transducer and activator of transcription 3 phosphorylation during the early period following hepatectomy. CONCLUSIONS: These data indicate that macrophages play an important role in oval cell mediated liver regeneration in the 2-AAF/PH model.

  15. Concurrent Deletion of Cyclin E1 and Cyclin-Dependent Kinase 2 in Hepatocytes Inhibits DNA Replication and Liver Regeneration in Mice

    OpenAIRE

    Hu W; Nevzorova YA; Haas U; Moro N.; Sicinski P; Geng Y; Barbacid M; Trautwein C; Liedtke C.

    2014-01-01

    The liver has a strong regenerative capacity. After injury, quiescent hepatocytes can reenter the mitotic cell cycle to restore tissue homeostasis. This G0/G1-S cell-cycle transition of primed hepatocytes is regulated by complexes of cyclin-dependent kinase 2 (Cdk2) with E-type cyclins (CcnE1 or CcnE2). However, single genetic ablation of either E-cyclin or Cdk2 does not affect overall liver regeneration. Here, we systematically investigated the contribution of CcnE1, CcnE2, and Cdk2 for live...

  16. Beneficial effects of splenectomy on liver regeneration in a rat model of massive hepatectomy

    Institute of Scientific and Technical Information of China (English)

    Yan-Shun Ren; Nian-Song Qian; Yu Tang; Yong-Hui Liao; Wei-Hui Liu; Vikram Raut; Kai-Shan Tao; Ke-Feng Dou

    2012-01-01

    BACKGROUND: Small-for-size syndrome is a widely recognized clinical  complication  after  living  donor  liver  transplantation or  extended  hepatectomy  due  to  inadequate  liver  mass.  The purpose of this study was to investigate the role of splenectomy in rats after massive hepatectomy, a surrogate model of small-for-size graft. METHODS: Rats  were  divided  into  eight  groups, each with 20  animals:  50% hepatectomy (50% Hx), 50% hepatectomy+splenectomy (50% Hx+Sp), 60% Hx, 60% Hx+Sp, 70% Hx, 70% Hx+Sp,  90%  Hx  and  90%  Hx+Sp.  The  following  parameters were evaluated: liver function tests (ALT, AST and TBIL), liver regeneration  ratio,  DNA  synthesis,  proliferation  cell  nuclear antigen,  hepatic  oxygen  delivery  (HDO2)  and  hepatic  oxygen consumption (HVO2). RESULTS: The  liver  regeneration  ratio  was  enhanced  in  the Hx+Sp  groups  (P CONCLUSIONS: Splenectomy  significantly  improved  liver function,  and  enhanced  DNA  synthesis  and  proliferation cell  nuclear  antigen  after  massive  hepatectomy  in  rats.  This operation  could  be  mediated  through  increased  HDO2  and HVO2, which facilitate liver regeneration.

  17. Downregulation of IL6 Targeted MiR-376b May Contribute to a Positive IL6 Feedback Loop During Early Liver Regeneration in Mice

    Directory of Open Access Journals (Sweden)

    Shan Lu

    2015-08-01

    Full Text Available Background/Aims: MicroRNAs (miRNAs are a group of endogenous, small, noncoding RNAs implicated in a variety of biological processes, including cell proliferation, apoptosis, differentiation and metabolism. The present study aims to explore the potential role and molecular mechanism of miR-376b during the early phase of liver regeneration. Methods: MiRNA profiling microarrays were used to assess the changes in miRNA expression. For functional analysis, cell proliferation, apoptosis assays, real time quantitative PCR and westernblot analysis were performed. Results: The comprehensive miRNA expression profiling assays on regenerating liver tissues 4 h after partial hepatectomy (PH showed that three miRNAs (miR-127, miR-376b and miR-494 located in the Dlk1-Gtl2 miRNA cluster were significantly downregulated. In vitro functional studies demonstrated that high-level interleukin 6 (IL6 inhibited the expression of miR-376b, and miR-376b mimics treatment decreased cell proliferation and increased apoptosis. Further target analysis showed that miR-376b reduced the mRNA and protein expression levels of NF-kappa-B inhibitor zeta (NFKBIZ and signal transducers and transcription activators 3 (STAT3. Additionally, IL6-induced miR-376b downregulation would, in turn, increase the expression of IL-6 possibly via a feedback loop involving NFKBIZ or/and STAT3. Conclusion: During the early phase of liver regeneration, miR-376b expression was significantly decreased. Our findings reveal that a regulatory circuitry between miR-376b and IL-6 may exist, which trigger the initiation of liver regeneration.

  18. Site-specific insertion of selenium into the redox-active disulfide of the flavoprotein augmenter of liver regeneration.

    Science.gov (United States)

    Schaefer-Ramadan, Stephanie; Thorpe, Colin; Rozovsky, Sharon

    2014-04-15

    Augmenter of liver regeneration (sfALR) is a small disulfide-bridged homodimeric flavoprotein with sulfhydryl oxidase activity. Here, we investigate the catalytic and spectroscopic consequences of selectively replacing C145 by a selenocysteine to complement earlier studies in which random substitution of ∼90% of the 6 cysteine residues per sfALR monomer was achieved growing Escherichia coli on selenite. A selenocysteine insertion sequence (SECIS) element was installed within the gene for human sfALR. SecALR2 showed a spectrum comparable to that of wild-type sfALR. The catalytic efficiency of SecALR2 towards dithiothreitol was 6.8-fold lower than a corresponding construct in which position 145 was returned to a cysteine residue while retaining the additional mutations introduced with the SECIS element. This all-cysteine control enzyme formed a mixed disulfide between C142 and β-mercaptoethanol releasing C145 to form a thiolate-flavin charge transfer absorbance band at ∼530nm. In contrast, SecALR2 showed a prominent long-wavelength absorbance at 585 nm consistent with the expectation that a selenolate would be a better charge-transfer donor to the isoalloxazine ring. These data show the robustness of the ALR protein fold towards the multiple mutations required to insert the SECIS element and provide the first example of a selenolate to flavin charge-transfer complex. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Phosphatase of regenerating liver-3 directly interacts with integrin β1 and regulates its phosphorylation at tyrosine 783

    Directory of Open Access Journals (Sweden)

    Tian Wei

    2012-10-01

    Full Text Available Abstract Background Phosphatase of regenerating liver-3 (PRL-3 or PTP4A3 has been implicated in controlling cancer cell proliferation, motility, metastasis, and angiogenesis. Deregulated expression of PRL-3 is highly correlated with cancer progression and predicts poor survival. Although PRL-3 was categorized as a tyrosine phosphatase, its cellular substrates remain largely unknown. Results We demonstrated that PRL-3 interacts with integrin β1 in cancer cells. Recombinant PRL-3 associates with the intracellular domain of integrin β1 in vitro. Silencing of integrin α1 enhances PRL-3-integrin β1 interaction. Furthermore, PRL-3 diminishes tyrosine phosphorylation of integrin β1 in vitro and in vivo. With site-specific anti-phosphotyrosine antibodies against residues in the intracellular domain of integrin β1, tyrosine-783, but not tyrosine-795, is shown to be dephosphorylated by PRL-3 in a catalytic activity-dependant manner. Phosphorylation of Y783 is potentiated by ablation of PRL-3 or by treatment with a chemical inhibitor of PRL-3. Conversely, depletion of integrin α1 decreases the phosphorylation of this site. Conclusions Our results revealed a direct interaction between PRL-3 and integrin β1 and characterized Y783 of integrin β1 as a bona fide substrate of PRL-3, which is negatively regulated by integrin α1.

  20. Determination of the distance between the two neutral flavin radicals in augmenter of liver regeneration by pulsed ELDOR.

    Science.gov (United States)

    Kay, Christopher W M; Elsässer, Celine; Bittl, Robert; Farrell, Scott R; Thorpe, Colin

    2006-01-11

    Pulsed electron-electron double resonance (ELDOR) has been used to obtain structural information from a FAD-dependent sulfhydryl oxidase, Augmenter of Liver Regeneration (ALR). ALR is a homodimer with each subunit containing a noncovalently bound FAD cofactor. Both FADs may be converted into the blue neutral radical form by aerobic treatment with DTT. From three-pulse and four-pulse ELDOR experiments, a distance of 26.1 +/- 0.8 A could be determined between the FAD cofactors in human ALR. Taking into account the electron spin density distribution in a neutral flavin radical obtained from density functional theory calculations, a distance of 26.9 A could be estimated for the separation of the spin centers in the X-ray structure of rat ALR. The good agreement confirms that rat ALR may be used as a model for mechanistic discussions of human ALR. The experiments also demonstrate that neutral flavin radicals have the appropriate properties to be used as intrinsic spin labels for distance determinations in proteins.

  1. The essential role of FKBP38 in regulating phosphatase of regenerating liver 3 (PRL-3) protein stability.

    Science.gov (United States)

    Choi, Myung-Suk; Min, Sang-Hyun; Jung, Haiyoung; Lee, Ju Dong; Lee, Tae Ho; Lee, Heung Kyu; Yoo, Ook-Joon

    2011-03-11

    The phosphatase of regenerating liver-3 (PRL-3) is a member of protein tyrosine phosphatases and whose deregulation is implicated in tumorigenesis and metastasis of many cancers. However, the underlying mechanism by which PRL-3 is regulated is not known. In this study, we identified the peptidyl prolyl cis/trans isomerase FK506-binding protein 38 (FKBP38) as an interacting protein of PRL-3 using a yeast two-hybrid system. FKBP38 specifically binds to PRL-3 in vivo, and that the N-terminal region of FKBP38 is crucial for binding with PRL-3. FKBP38 overexpression reduces endogenous PRL-3 expression levels, whereas the depletion of FKBP38 by siRNA increases the level of PRL-3 protein. Moreover, FKBP38 promotes degradation of endogenous PRL-3 protein via protein-proteasome pathway. Furthermore, FKBP38 suppresses PRL-3-mediated p53 activity and cell proliferation. These results demonstrate that FKBP38 is a novel regulator of the oncogenic protein PRL-3 abundance and that alteration in the stability of PRL-3 can have a dramatic impact on cell proliferation. Thus, FKBP38 may play a critical role in tumorigenesis.

  2. Radiofrequency Ablation: Inflammatory Changes in the Periablative Zone Can Induce Global Organ Effects, including Liver Regeneration.

    Science.gov (United States)

    Rozenblum, Nir; Zeira, Evelyne; Bulvik, Baruch; Gourevitch, Svetlana; Yotvat, Hagit; Galun, Eithan; Goldberg, S Nahum

    2015-08-01

    To determine the kinetics of innate immune and hepatic response to the coagulation necrosis area that remains in situ after radiofrequency (RF) ablation, the cytokine profile of this response, and its local and global effect on the whole organ in a small-animal model. A standardized RF ablation dose (70°C for 5 minutes) was used to ablate more than 7% of the liver in 91 C57BL6 mice (wild type) according to a protocol approved by the animal care committee. The dynamic cellular response in the border zone surrounding ablation-induced coagulation and in the ablated lobe and an untreated lobe were characterized with immunohistochemistry 24 hours, 72 hours, 7 days, and 14 days after ablation (the time points at which cells migrate to necrotic tissues). After characterization of the cellular populations that reacted to the RF treatment, cytokines secreted by these cells were blocked, either by using interleukin-6 knockout mice (n = 24) or c-met inhibitor PHA 665752 (n = 15), to elucidate the key factors facilitating the wound healing response to RF ablation. Statistical significance was assessed with nonparametric analysis of variance. RF ablation induces a strong time-dependent immunologic response at the perimeter of the necrotic zone. This includes massive accumulation of neutrophils, activated myofibroblasts, and macrophages peaking at 24 hours, 7 days, and 14 days after ablation, respectively. In correlation with myofibroblast accumulation, RF ablation induced hepatocyte proliferation in both the ablated lobe and an untreated lobe (mean, 165.15 and 230.4 cyclin-dependent kinase 47-positive cells per ×20 field, respectively, at day 7; P RF ablation induces not only a local periablational inflammatory zone but also more global proliferative effects on the liver. These IL-6- and/or c-met-mediated changes could potentially account for some of the local and distant tumor recurrence observed after treatment. © RSNA, 2015 Online supplemental material is available for

  3. The effects of protaglandin E sub 2 and cyclooxygenase inhibition on ornithine decarboxylase activation and DNA synthesis during carbon tetrachloride-induced liver regeneration

    Energy Technology Data Exchange (ETDEWEB)

    Shilstone, J.J.

    1989-01-01

    Increases in prostaglandin E{sub 2} (PGE{sub 2}) and ornithine decarboxylase (ODC) activity are necessary for liver regeneration following surgical partial hepatectomy (SPH). The purpose of this study was to examine liver regeneration induced by carbon tetrachloride (CCl{sub 4}) to determine whether DNA synthesis initiation mechanisms involving PGE{sub 2} and ODC operated in a similar manner to that seen in SPH. The rat chemical partial hepatectomy (CPH) model was established in our laboratory as a method to examine regenerative processes. A characteristic time course of {sup 3}H thymidine incorporation into DNA was demonstrated which peaked 48 hours following CPH. Increases in liver specific serum sorbitol dehydrogenase (sSDH) and glutamate-pyruvate transaminase (sGPT) indicated that significant necrotic damage had occurred in the liver as a result of CCl{sub 4} toxicity. Increased DNA synthesis and necrotic damage in the liver satisfied criteria for use of this procedure as a model of regeneration. Hepatic PGE{sub 2} synthesis was measured using radioimmunoassay (RIA) during the 12 hr period following CPH. Increases in PGE{sub 2} concentration were seen at 2, 4, 6, and 8 hrs. Indomethacin (50 mg/kg) administered intraperitoneally 90 minutes prior to CPH inhibited increases in PGE{sub 2}. Therefore, increased PGE{sub 2} seen during this time is due to cyclooxygenase. Indomethacin administration did not inhibit DNA synthesis measured by {sup 3}H thymidine incorporation into DNA at 24, 48, 72, and 96 hrs. Thus the increased PGE{sub 2} concentrations seen in the period immediately following CPH are not required for DNA synthesis. Therefore, different mechanisms of DNA synthesis initiation are operative in CPH and SPH.

  4. Four and a Half LIM Domains 1b (Fhl1b) Is Essential for Regulating the Liver versus Pancreas Fate Decision and for β-Cell Regeneration

    Science.gov (United States)

    Xu, Jin; Cui, Jiaxi; Del Campo, Aranzazu; Shin, Chong Hyun

    2016-01-01

    The liver and pancreas originate from overlapping embryonic regions, and single-cell lineage tracing in zebrafish has shown that Bone morphogenetic protein 2b (Bmp2b) signaling is essential for determining the fate of bipotential hepatopancreatic progenitors towards the liver or pancreas. Despite its pivotal role, the gene regulatory networks functioning downstream of Bmp2b signaling in this process are poorly understood. We have identified four and a half LIM domains 1b (fhl1b), which is primarily expressed in the prospective liver anlage, as a novel target of Bmp2b signaling. fhl1b depletion compromised liver specification and enhanced induction of pancreatic cells from endodermal progenitors. Conversely, overexpression of fhl1b favored liver specification and inhibited induction of pancreatic cells. By single-cell lineage tracing, we showed that fhl1b depletion led lateral endodermal cells, destined to become liver cells, to become pancreatic cells. Reversely, when fhl1b was overexpressed, medially located endodermal cells, fated to differentiate into pancreatic and intestinal cells, contributed to the liver by directly or indirectly modulating the discrete levels of pdx1 expression in endodermal progenitors. Moreover, loss of fhl1b increased the regenerative capacity of β-cells by increasing pdx1 and neurod expression in the hepatopancreatic ductal system. Altogether, these data reveal novel and critical functions of Fhl1b in the hepatic versus pancreatic fate decision and in β-cell regeneration. PMID:26845333

  5. Four and a Half LIM Domains 1b (Fhl1b Is Essential for Regulating the Liver versus Pancreas Fate Decision and for β-Cell Regeneration.

    Directory of Open Access Journals (Sweden)

    Jin Xu

    2016-02-01

    Full Text Available The liver and pancreas originate from overlapping embryonic regions, and single-cell lineage tracing in zebrafish has shown that Bone morphogenetic protein 2b (Bmp2b signaling is essential for determining the fate of bipotential hepatopancreatic progenitors towards the liver or pancreas. Despite its pivotal role, the gene regulatory networks functioning downstream of Bmp2b signaling in this process are poorly understood. We have identified four and a half LIM domains 1b (fhl1b, which is primarily expressed in the prospective liver anlage, as a novel target of Bmp2b signaling. fhl1b depletion compromised liver specification and enhanced induction of pancreatic cells from endodermal progenitors. Conversely, overexpression of fhl1b favored liver specification and inhibited induction of pancreatic cells. By single-cell lineage tracing, we showed that fhl1b depletion led lateral endodermal cells, destined to become liver cells, to become pancreatic cells. Reversely, when fhl1b was overexpressed, medially located endodermal cells, fated to differentiate into pancreatic and intestinal cells, contributed to the liver by directly or indirectly modulating the discrete levels of pdx1 expression in endodermal progenitors. Moreover, loss of fhl1b increased the regenerative capacity of β-cells by increasing pdx1 and neurod expression in the hepatopancreatic ductal system. Altogether, these data reveal novel and critical functions of Fhl1b in the hepatic versus pancreatic fate decision and in β-cell regeneration.

  6. A novel cell-free strategy for promoting mouse liver regeneration: utilization of a conditioned medium from adipose-derived stem cells.

    Science.gov (United States)

    Lee, Sang Kuon; Lee, Sang Chul; Kim, Say-June

    2015-04-01

    Although stem cells have beneficial effects, their clinical application faces many issues, including high cost and safety. Because stem cell plasty is largely based on their paracrine activity, this study aimed to test the hypothesis that utilization of the stem-cell secretome instead of actual cells would not only overcome these limitations, but also have similar effects as stem cell-based therapy. Partial hepatectomized mice were divided into four groups according to the material administered via the tail vein: normal saline (saline group); 1.0 × 10(6) human adipose tissue-derived stem cells (ASCs) in 0.1 mL saline (ASC group); 25-fold concentrated conditioned medium from ASCs (ASC-secretome group); and concentrated medium (media group). Specimens were obtained postoperatively. Liver regeneration was estimated by bromodeoxyuridine incorporation, Lgr5 RT-PCR, proliferating cell nuclear antigen western blot, and liver weights, and liver function was estimated by albumin immunohistochemistry and liver function tests. The liver regenerative capacities of the ASC and ASC-secretome groups were not statistically different from each other, but were higher than their respective control groups. Moreover, the ASC and ASC-secretome groups promoted the phosphorylation of Akt, STAT3, and Erk1/2, and expressed higher levels of mouse albumin in immunohistochemistry. ASCs and ASC-secretome infusions to the partially hepatectomized mice produced similar outcomes in terms of liver regeneration and mouse albumin expression. Therefore, cell-free therapy, which is based on the paracrine properties of stem cells, is expected to overcome the limitations of cell-based methods and to provide a novel treatment for liver diseases.

  7. Cellular aspects of liver regeneration Aspectos celulares da regeneração hepática

    Directory of Open Access Journals (Sweden)

    Marissa Rabelo Tarlá

    2006-01-01

    Full Text Available This paper has the objective to analyze the cellular aspects of liver regeneration (LR. Upon damage in this organ, the regenerative capacity of hepatocyte is sufficiently able to reestablish the parenchyma as a whole. Taking into account the regenerative capacity of hepatocyte, the need of a progenitor or a liver trunk cell was not obvious. Nowadays it is well-established that precursor cells take part in the liver regenerative process. The liver trunk cell, oval cell, acts as a bypotential precursor, contributing for the liver restoration, mainly when the hepatocytes are unable to proliferate. Another precursor, trunk cell of hematopoetic origin (HSC, takes part in the regenerative process, originating cells of the hepatocitic lineage and colangiocytes, as well as the oval cell. The way the trans-differentiation takes place is not established yet. A number of studies must be undertaken in order to clarify questions, such as the possible occurrence of cellular fusion process between the HSC and the hepatic cells and the possibility of application as a new therapeutic procedure in the treatment of diseases associated with insufficiency of this noble organ.Este artigo tem como objetivo analisar aspectos da regeneração hepática (RH sob a óptica celular. Em vigência de uma lesão neste órgão a capacidade regenerativa do hepatócito é suficientemente capaz de restabelecer o parênquima como um todo. Levando em conta a elevada capacidade regenerativa do hepatócito, a necessidade de um progenitor ou uma célula tronco hepática não era óbvia. Hoje esta bem estabelecido que células precursoras participam do processo regenerativo hepático. A célula tronco hepática, célula oval, atua como um precursor bipotencial, contribuindo para o restauro do fígado principalmente quando os hepatócitos se encontram impossibilitados de proliferar. Um outro precursor, a célula tronco de origem hematopoética (HSC, participa do processo regenerativo

  8. Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches

    National Research Council Canada - National Science Library

    Akram, Khondoker M; Patel, Neil; Spiteri, Monica A; Forsyth, Nicholas R

    2016-01-01

    ...) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development...

  9. Expression patterns and action analysis of genes associated with physiological responses during rat liver regeneration: Cellular immune response

    Institute of Scientific and Technical Information of China (English)

    Lian-Xing Zhang; Li-Feng Zhao; An-Shi Zhang; Xiao-Guang Chen; Cun-Shuan Xu

    2006-01-01

    AIM: To study the cellular immune response during rat liver regeneration (LR) at a transcriptional level.METHODS: Genes associated with the cellular immune response were obtained by collecting the data from databases and retrieving articles. Gene expression changes during LR were detected by rat genome 230 2.0 array.RESULTS: A total of 127 genes were found to be associated with LR. The number of initially and totally expressing genes in the initial phase of LR [0.5-4 h after partial hepatectomy (PH)], transition from G0-G1(4-6 h after PH), cell proliferation (6-66 h after PH),cell differentiation and structure-function reconstruction (66-168 h after PH) was 54, 11, 34, 3 and 54, 49, 70, 49 respectively, illustrating that the associated genes were mainly triggered at the initiation of LR, and worked at different phases. According to their expression similarity,these genes were classified into 41 up-regulated, 21 predominantly up-regulated, 41 down-regulated, 14 predominantly down-regulated, 10 similarly up-regulated and down-regulated genes, respectively. The total upand down-regulated expression times were 419 and 274,respectively, demonstrating that the expression of most genes was increased while the expression of a small number of genes was decreased. Their time relevance was classified into 14 groups, showing that the cellular physiological and biochemical activities were staggered during LR. According to the gene expression patterns,they were classified into 21 types, showing the activities were diverse and complicated during LR.CONCLUSION: Antigen processing and presentation are enhanced mainly in the forepart, prophase and anaphase of LR. T-cell activation and antigen elimination are enhanced mainly in the forepart and prophase of LR. A total of 127 genes associated with LR play an important role in cellular immunity.

  10. A novel upregulation of glutathione peroxidase 1 by knockout of liver-regenerating protein Reg3β aggravates acetaminophen-induced hepatic protein nitration.

    Science.gov (United States)

    Yun, Jun-Won; Lum, Krystal; Lei, Xin Gen

    2013-12-01

    Murine regenerating islet-derived 3β (Reg3β) represents a homologue of human hepatocarcinoma-intestine-pancreas/pancreatic-associated protein and enhances mouse susceptibility to acetaminophen (APAP)-induced hepatotoxicity. Our objective was to determine if and how knockout of Reg3β (KO) affects APAP (300 mg/kg, ip)-mediated protein nitration in mouse liver. APAP injection produced greater levels of hepatic protein nitration in the KO than in the wild-type mice. Their elevated protein nitration was alleviated by a prior injection of recombinant mouse Reg3β protein and was associated with an accelerated depletion of the peroxynitrite (ONOO(-)) scavenger glutathione by an upregulated hepatic glutathione peroxidase-1 (GPX1) activity. The enhanced GPX1 production in the KO mice was mediated by an 85% rise (pnitration and a new biosynthesis control of GPX1 by a completely "unrelated" regenerating protein, Reg3β, via transcriptional activation of Scly in coping with hepatic protein nitration. Linking selenoproteins to tissue regeneration will have profound implications in understanding the mechanism of Se functions and physiological coordination of tissue regeneration with intracellular redox control. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Disruptive cell cycle regulation involving epigenetic downregulation of Cdkn2a (p16(Ink4a)) in early-stage liver tumor-promotion facilitating liver cell regeneration in rats.

    Science.gov (United States)

    Tsuchiya, Takuma; Wang, Liyun; Yafune, Atsunori; Kimura, Masayuki; Ohishi, Takumi; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

    2012-09-28

    Cell cycle aberration was immunohistochemically examined in relation to preneoplastic liver cell foci expressing glutathione S-transferase placental form (GST-P) at early stages of tumor-promotion in rats with thioacetamide (TAA), a hepatocarcinogen facilitating liver cell regeneration. Immunoexpression of p16(Ink4a) following exposure to other hepatocarcinogens/promoters and its DNA methylation status were also analyzed during early and late tumor-promotion stages. GST-P(+) liver cell foci increased cell proliferation and decreased apoptosis when compared with surrounding liver cells. In concordance with GST-P(+) foci, checkpoint proteins at G(1)/S (p21(Cip1), p27(Kip1) and p16(Ink4a)) and G(2)/M (phospho-checkpoint kinase 1, Cdc25c and phospho-Wee1) were either up- or downregulated. Cellular distribution within GST-P(+) foci was either increased or decreased with proteins related to G(2)-M phase or DNA damage (topoisomerase IIα, phospho-histone H2AX, phospho-histone H3 and Cdc2). In particular, p16(Ink4a) typically downregulated in GST-P(+) foci and regenerative nodules at early tumor-promotion stage with hepatocarcinogens facilitating liver cell regeneration and in neoplastic lesions at late tumor-promotion stage with hepatocarcinogens/promoters irrespective of regenerating potential. Hypermethylation at exon 2 of Cdkn2a was detected at both early- and late-stages. Thus, diverse disruptive expression of G(1)/S and G(2)/M proteins, which allows for clonal selection of GST-P(+) foci, results in the acquisition of multiple aberrant phenotypes to disrupt checkpoint function. Moreover, increased DNA-damage responses within GST-P(+) foci may be the signature of genetic alterations. Intraexonic hypermethylation may be responsible for p16(Ink4a)-downregulation, which facilitates cell cycle progression in early preneoplastic lesions produced by repeated cell regeneration and late-stage neoplastic lesions irrespective of the carcinogenic mechanism. Copyright © 2012

  12. A molecular view of liver regeneration Uma visão molecular da regeneração hepática

    Directory of Open Access Journals (Sweden)

    Marissa Rabelo Tarlá

    2006-01-01

    Full Text Available The purpose of this review was to carry out an analysis of the liver regenerative process focusing on the molecular interactions involved in this process. The authors undertook a review of scientific publications with a focus on the liver regeneration.The cellular processes involved in liver regeneration require multiple systematic actions related to cytokines and growth factors. These interactions result in the initiation of mitogenic potential of the hepatocytes. The action of these modulators in the regenerative process require a processing in the extra-cellular matrix. Serines and metal proteins are responsible for the bio availability of cytokines and growth factors so that they can interact as receptors in the cellular membrane generating signaling events for the beginning and end of the liver regenerative process. The exact mechanism of interaction between cells, cytokines and growth factors is not well established yet. A series of ordered events that result in the hepatic tissue regeneration has been described. The better understanding of these interactions should provide a new approach of the treatment for liver diseases, aiming at inducing the regenerative process.O objetivo desta revisão foi desenvolver uma análise do processo regenerativo do fígado, focando as interações moleculares envolvidas neste processo.Os processos celulares envolvidos na regeneração hepática requerem múltiplas ações sistemáticas relacionadas com citoquinas e fatores de crescimento. Estas interações resultam na iniciação do potencial mitogênico dos hepatócitos. A ação destes moduladores do processo regenerativo necessita de processamento no meio extra celular. As serinas e metaloproteínas são responsáveis pela biodisponibilização de citoquinas e fatores de crescimento, para que então possam interagir com receptores na membrana celular gerando os eventos sinalizadores para o inicio e o término do processo regenerativo hepático.O exato

  13. Comparison of stem-cell-mediated osteogenesis and dentinogenesis.

    Science.gov (United States)

    Batouli, S; Miura, M; Brahim, J; Tsutsui, T W; Fisher, L W; Gronthos, S; Robey, P Gehron; Shi, S

    2003-12-01

    The difference between stem-cell-mediated bone and dentin regeneration is not yet well-understood. Here we use an in vivo stem cell transplantation system to investigate differential regulation mechanisms of bone marrow stromal stem cells (BMSSCs) and dental pulp stem cells (DPSCs). Elevated expression of basic fibroblast growth factor (bFGF) and matrix metalloproteinase 9 (MMP-9, gelatinase B) was found to be associated with the formation of hematopoietic marrow in BMSSC transplants, but not in the connective tissue of DPSC transplants. The expression of dentin sialoprotein (DSP) specifically marked dentin synthesis in DPSC transplants. Moreover, DPSCs were found to be able to generate reparative dentin-like tissue on the surface of human dentin in vivo. This study provided direct evidence to suggest that osteogenesis and dentinogenesis mediated by BMSSCs and DPSCs, respectively, may be regulated by distinct mechanisms, leading to the different organization of the mineralized and non-mineralized tissues.

  14. A Switch in the Dynamics of Intra-Platelet VEGF-A from Cancer to the Later Phase of Liver Regeneration after Partial Hepatectomy in Humans.

    Directory of Open Access Journals (Sweden)

    Bibek Aryal

    Full Text Available Liver regeneration (LR involves an early inductive phase characterized by the proliferation of hepatocytes, and a delayed angiogenic phase distinguished by the expansion of non-parenchymal compartment. The interest in understanding the mechanism of LR has lately shifted from the proliferation and growth of parenchymal cells to vascular remodeling during LR. Angiogenesis accompanied by LR exerts a pivotal role to accomplish the process. Vascular endothelial growth factor (VEGF has been elucidated as the most dynamic regulator of angiogenesis. From this perspective, platelet derived/Intra-platelet (IP VEGF-A should be associated with LR.Thirty-seven patients diagnosed with hepatocellular carcinoma and undergoing partial hepatectomy (PH were enrolled in the study. Serum and IP VEGF-A was monitored preoperatively and at four weeks of PH. Liver volumetry was determined on computer models derived from computed tomography (CT scan.Serum and IP VEGF-A was significantly elevated at four weeks of PH. Preoperative IP VEGF-A was higher in patients with advanced cancer and vascular invasion. Postoperative IP VEGF-A was higher after major liver resection. There was a statistically significant correlation between postoperative IP VEGF-A and the future remnant liver volume. Moreover, the soluble vascular endothelial growth factor receptor-1 (sVEGFR1 was distinctly down-regulated suggesting a fine-tuned angiogenesis at the later phase of LR.IP VEGF-A is overexpressed during later phase of LR suggesting its implications in inducing angiogenesis during LR.

  15. Comparative Study of Compensatory Liver Regeneration in a Rat Model: Portal Vein Ligation Only versus Sequential Ligation of the Portal Vein and Hepatic Artery

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Soo Young [Dept. of Pathology, Dongnam Institute of Radiological and Medical Sciences, Busan (Korea, Republic of); Jeon, Gyeong Sik [Dept. of Radiology, CHA Bundang Medical Center, College of Medicine, CHA University, Seongnam (Korea, Republic of); Lee, Byung Mo [Dept. of Surgery, Seoul Paik Hospital, Inje University College of Medicine, Seoul (Korea, Republic of)

    2013-04-15

    To compare the volume change and the regenerative capacity between portal vein ligation (embolization) (PVL) and heterochronous PVL with hepatic artery ligation (HAL) in a rodent model. The animals were separated into three groups: group I, ligation of the left lateral and median portal vein branches; group II, completion of PVL, followed by ligation of the same branches of the hepatic artery after 48 h; control group, laparotomy without ligation was performed. Five rats from each group were sacrificed on 1, 3, 5, and 7 days after the operation. Volume change measurement, liver function tests and immunohistochemical analysis were performed. The volume of the nonligated lobe between groups I and II was not significantly different by day 5 and day 7. Mean alanine aminotransferase and total bilirubin levels were significantly higher in group II, while the albumin level was higher in group I. Both c-kit- and MIB-5-positive cells used in the activity detection of regeneration were more prevalent in group I on day 1, 3, and 5, with statistical significance. There was no operation related mortality. PVL alone is safe and effective in compensatory liver regeneration. Performing both PVL and HAL does not confer any additional benefits.

  16. Phosphatase of regenerating liver-3 localizes to cyto-membrane and is required for B16F1 melanoma cell metastasis in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Ran Song

    Full Text Available BACKGROUND: Phosphatase of regenerating liver-3 (PRL-3 is a member of the novel phosphatases of regenerating liver family, characterized by one protein tyrosine phosphatase active domain and a C-terminal prenylation (CCVM motif. Though widely proposed to facilitate metastasis in many cancer types, PRL-3's cellular localization and the function of its CCVM motif in metastatic process remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, a series of Myc tagged PRL-3 wild type or mutant plasmids were expressed in B16F1 melanoma cells to investigate the relationship between PRL-3's cellular localization and metastasis. With immuno-fluorescence microcopy and cell adhesion/migration assay in vitro, and an experimental passive metastasis model in vivo, we found that CCVM motif is critical for the localization of PRL-3 on cell plasma membrane and the lung metastasis of melanoma. In particular, Cystine170 is the key site for prenylation in this process. CONCLUSIONS/SIGNIFICANCE: These results suggest that cellular localization of PRL-3 is highly correlated with its function in tumor metastasis, and inhibition of PRL-3 prenylation might be a new approach to cancer therapy.

  17. Insulin promotes sinusoidal endothelial cell proliferation mediated by upregulation of vascular endothelial growth factor in regenerating rat liver after partial hepatectomy

    Institute of Scientific and Technical Information of China (English)

    Jian-Guo Qiao; Long Wu; Dao-Xiong Lei; Lu Wang

    2005-01-01

    AIM: To determine whether insulin could promote sinusoidal endothelial cell (SEC) proliferation mediated by upregulation of vascular endothelial growth factor (VEGF) in regenerating rat liver after partial hepatectomy (PHx).METHODS: Adult male Sprague-Dawley rats undergoing 70% PHx were injected with insulin (300 MU/kg) or saline via the tail veins every 8 h after surgery for 7 d and killed at 0, 24, 48, 72, 96, 120, 144, and 168 h after surgery.Proliferation of both hepatocytes and SECs was monitored by evaluating the proliferating cell nuclear antigen (PCNA)labeling index (LI). The expression of VEGF protein was evaluated by immunohistochemistry. The mRNA expressions of VEGF and its receptors Fit-1 and Flk-1 were evaluated by semi-quantitative reverse transcription-PCR.RESULTS: Insulin markedly increased the expression of VEGF mRNA between 24 and 120 h after hepatectomy compared to controls. Similarly, insulin significantly increased the expression of Fit-1 between 24 and 96 h.However, insulin had no significant effect on Flk-1.Furthermore, the immunohistochemical staining revealed that expression of VEGF protein increased in the insulin groups. Insulin significantly increased the PCNA LI of hepatocytes and SECs compared to controls.CONCLUSION: Exogenous insulin may promote SEC proliferation with an enhanced expression of VEGF and its receptor Fit-1 in regenerating rat liver after PHx.

  18. Mesenchymal stem cells promote liver regeneration and prolong survival in small-for-size liver grafts: involvement of C-Jun N-terminal kinase, cyclin D1, and NF-κB.

    Directory of Open Access Journals (Sweden)

    Weijie Wang

    Full Text Available BACKGROUND: The therapeutic potential of mesenchymal stem cells (MSCs has been highlighted recently for treatment of acute or chronic liver injury, by possibly differentiating into hepatocyte-like cells, reducing inflammation, and enhancing tissue repair. Despite recent progress, exact mechanisms of action are not clearly elucidated. In this study, we attempted to explore whether and how MSCs protected hepatocytes and stimulated allograft regeneration in small-for-size liver transplantation (SFSLT. METHODS: SFSLT model was established with a 30% partial liver transplantation (30PLT in rats. The differentiation potential and characteristics of bone marrow derived MSCs were explored in vitro. MSCs were infused transvenously immediately after graft implantation in therapy group. Expressions of apoptosis-, inflammatory-, anti-inflammatory-, and growth factor-related genes were measured by RT-PCR, activities of transcription factors AP-1 and NF-κB were analyzed by EMSA, and proliferative responses of the hepatic graft were evaluated by immunohistochemistry and western blot. RESULTS: MSCs were successfully induced into hepatocyte-like cells, osteoblasts and adipocytes in vitro. MSCs therapy could not only alleviate ischemia reperfusion injury and acute inflammation to promote liver regeneration, but also profoundly improve one week survival rate. It markedly up-regulated the mRNA expressions of HGF, Bcl-2, Bcl-XL, IL-6, IL-10, IP-10, and CXCR2, however, down-regulated TNF-α. Increased activities of AP-1 and NF-κB, as well as elevated expressions of p-c-Jun, cyclin D1, and proliferating cell nuclear antigen (PCNA, were also found in MSCs therapy group. CONCLUSION: These data suggest that MSCs therapy promotes hepatocyte proliferation and prolongs survival in SFSLT by reducing ischemia reperfusion injury and acute inflammation, and sustaining early increased expressions of c-Jun N-terminal Kinase, Cyclin D1, and NF-κB.

  19. Effect of aging on liver regeneration in rats Efeitos do envelhecimento na regeneração hepática em ratos

    Directory of Open Access Journals (Sweden)

    Maria de Lourdes Pessole Biondo-Simões

    2006-08-01

    Full Text Available PURPOSE: Regeneration and/or healing of tissues is believed to be more difficult in elderly people. The liver is one of the most complex organs in the human body, and is involved in a variety of functions. Liver regeneration is the body's protection mechanism against loss of functional liver tissue. The aim of this study is to identify the regenerative capacity of the liver in older animals and to compare it with that of young adult animals. METHODS: Thirty-four Wistar rats were used, of which 17 were 90 days old (young animals and 17 were 460 days old (old animals. Approximately 70% of the liver was surgically removed. Examinations were carried out after 24 hours and on day 7, using 3 methods: KWON et al.'s formula to identify increase in volume; mitotic figure count in 5 fields; and the percentage of PCNA-positive nuclei in 5 fields. RESULTS: The increase in volume of the remaining liver was greater in the young animals after both 24 hours (p=0.0006 and on day 7 (p=0.0000. Histological cuts showed a greater mitotic figure count in young animals evaluated after 24 hours (p=0.0000. Upon evaluation on day 7, recovery was observed in the old animals. This recovery was similar to that of the young ones (p=0.2851. The PCNA-positive nucleus count was greater in the young animals' liver cuts after 24 hours (p=0.0310, and, while it had decreased in young animals by day 7, recovery was observed in the older animals (p=0.0298. CONCLUSION: The data confirm that age is related to delay in liver regeneration in rats.OBJETIVO: Acredita-se que idosos tenham maior dificuldade de regenerar e/ou cicatrizar tecidos. O fígado é um dos mais complexos órgãos do corpo humano, e está envolvido em diversas funções. A regeneração hepática representa um mecanismo de proteção orgânica contra a perda de tecido hepático funcionante. O objetivo do presente estudo é reconhecer a capacidade regenerativa do fígado de animais velhos e compará-la com a de animais

  20. Glutathione transferases P1/P2 regulate the timing of signaling pathway activations and cell cycle progression during mouse liver regeneration.

    Science.gov (United States)

    Pajaud, J; Ribault, C; Ben Mosbah, I; Rauch, C; Henderson, C; Bellaud, P; Aninat, C; Loyer, P; Morel, F; Corlu, A

    2015-01-15

    Glutathione transferases (GST) are phase II enzymes catalyzing the detoxification of endogenous noxious compounds and xenobiotics. They also regulate phosphorylation activities of MAPKinases in a catalytic-independent manner. Previous studies have demonstrated the regulation of JNK-dependent pathway by GSTP1/2. Considering the crucial role of JNK in the early steps of the hepatocyte cell cycle, we sought to determine whether GSTP1/2 were essential for hepatocyte proliferation following partial hepatectomy (PH). Using a conventional double knockout mouse model for the Gstp1 and Gstp2 genes, we found that the lack of GSTP1/P2 reduced the rate of DNA replication and mitotic index during the first wave of hepatocyte proliferation. The lowered proliferation was associated with the decrease in TNFalpha and IL-6 plasma concentrations, reduced hepatic HGF expression and delayed and/or altered activation of STAT3, JNK and ERK1/2 signaling pathways. In addition, the expression and/or activation of cell cycle regulators such as Cyclin D1, CDK4, E2F1 and MCM7 was postponed demonstrating that the absence of GSTP1/2 delayed the entry into and progression through the G1 phase of the cell cycle and impaired the synchrony of proliferation in hepatocytes following PH. Furthermore, while JNK and its downstream targets c-Jun and ATF2 were activated during the early steps of the liver regeneration in wild-type animals, the constitutively active JNK found in the quiescent liver of Gstp1/2 knockout mice underwent a decrease in its activity after PH. Transient induction of antioxidant enzymes and nitric oxide synthase were also delayed or repressed during the regenerative response. Altogether our results demonstrate that GSTP1/2 are a critical regulators of hepatocyte proliferation in the initial phases of liver regeneration.

  1. Involvement of extracellular matrix protein matrilin-2 in oval cell-mediated rat liver regeneration%胞外基质Matrilin-2在肝再生中与大鼠卵圆细胞的关系

    Institute of Scientific and Technical Information of China (English)

    陈中; 黄亮; 晏建军; 严以群

    2010-01-01

    目的:探讨肝脏胞外基质Matrilin-2在肝再生中与卵圆细胞的关系及作用.方法:采用改良的Soft-Farber建立大鼠肝脏卵圆细胞增殖模型,对照组灌喂生理盐水.分别取术后2、4、6、9、12、15 d大鼠肝组织,采用免疫组织化学以及Western blot的方法动态观察大鼠卵圆细胞增殖模型中肝脏胞外基质成分Matrilin-2的变化与卵圆细胞的关系.结果:肝脏部分切除术(partial hepatectomy,PH)后第2天,卵圆细胞开始向门静脉周围区域增殖,Matrilin-2主要出现在门静脉周围的肝窦状隙内;术后第9天,卵圆细胞进一步向肝实质内增殖,Matrilin-2表达增加;术后第12天,随着卵圆细胞分化为小肝细胞结节,大多数Matrilin-2位于结节周边,少数出现在结节内.Matrilin-2的含量自肝切除后第2天开始升高,第9天达到高峰,第12天后逐步恢复生理水平.结论:肝脏胞外基质成分Matrilin-2与卵圆细胞介导的肝脏再生存在紧密联系并发挥重要的调控作用.

  2. Effect of lacking intestinal bile acid on liver regeneration in rats%肠道缺乏胆汁酸对大鼠肝再生的影响

    Institute of Scientific and Technical Information of China (English)

    董秀山; 赵浩亮

    2010-01-01

    Objective To investigate the effect of the lack of intestinal bile on liver regeneration after hepatectomy.Methods The model of interference with intestinal bile acid metabolism in rats was established by feeding rats with 0.2% cholic acid(cholic acid loading group), 2% cholestyramine resin(lack of bile group)and feeding the standard diet as the control group.Liver regeneration was compared among the 3 groups at 0, 1, 2, 3, and 7 d after 70% partial hepatectomy(PH)in rats and mRNA expression of the rate-limiting enzyme of bile acid biosynthesis(CYP7a1)and farnesoid X receptor (FXR)were detected.Results The rate of liver regeneration was significantly lower on days 3 and 7after PH in the lack of bile group than in the other groups(P<0.05).On day 1, the labeling indices of PCNA and Ki-67 in the lack of bile group(22.21% ±2.31%、 17.25 % ± 6.50 %)were lower than those in the cholic acid loading group(44.4%±4.92%、 30.83% ± 3.91%)and control group (38.74% ±6.42% 、27.04% ±7.22%)and the peaking of labeling indices was delayed.After PH, the mRNA expression of FXR was significantly lower in the lack of bile group than in other groups.However, CYP7al mRNA had a trend towards increase after PH and was higher than that in other groups.Conclusion Lack of intestinal bile results in delayed liver regeneration of normal rat liver accompanied by decreased expression of FXR mRNA after hepatectomy.%目的 探索肠道缺乏胆汁酸对肝再生的影响.方法 通过喂养大鼠0.2%胆酸(胆酸负荷组)、2%考来烯胺(胆酸缺乏组)建立干扰肠道胆汁酸代谢的动物模型,以喂养标准饲料作为对照组,所有大鼠均行70%肝部分切除术(PH).比较PH后0、1、2、3、7 d三组大鼠的肝脏再生情况,并检测法尼酯衍生物X受体FXR及其靶基因胆汁酸合成限速酶CYP7a1的mRNA表达.结果 胆酸缺乏组的肝再生率在PH后3、7 d显著低于胆酸负荷组和对照组(P<0.05),1 d时PCNA和Ki-67标记指数(22.21%±2.31%、17

  3. The role of interleukin-22 in liver regeneration after partial hepatectomy with concanavalin A-mediated liver injury in mice%白细胞介素-22对刀豆蛋白A介导肝损伤小鼠部分肝切除后肝再生的作用

    Institute of Scientific and Technical Information of China (English)

    刘子荣; 张雅敏; 杨超; 杨龙; 崔子林; 沈中阳

    2016-01-01

    Objective To study the therapeutic effects and mechanisms of interleukin-22 (IL-22) in liver regeneration after partial hepatectomy with concanavalin A (ConA)-mediated liver injury in mice.Methods C57/BL6 were divided into four groups with 25 mice per group:Partial hepatectomy (PH) group,ConA group,PH + ConA group,and PH + CouA + IL-22 group.The liver tissue at 32,40,48 h,1 w and 2 w after resection were obtained.Before sampling liver were weighted and calculated liver regeneration rate.Pathological changes were observed by hematoxylin-eosin staining.The expression and index of proliferating cell nuclear antigen (PCNA) in liver tissue were tested by immunohistochemical method.The levels of Cyclin D1 and signal transducer and activator of transcription 3 (STAT3) signaling pathway detected by Western blotting analysis.Results With administration of exogenous IL-22,the liver weight/body increased significantly,compared with ConA + PH group (2.95 ± 0.14,3.09 ± 0.14,3.78±0.10,4.89 ±0.12),ConA + PH + IL-22 group (3.16 ±0.17,3.34 ± 0.13,4.19 ± 0.14,5.14 ± 0.16) increased and reached statistical significance at 40,48 h,1 w or 2 w.Histopathology indicated that liver injury in mice of the treatment group was markedly alleviated.Furthermore,Western blotting revealed that in the four groups,STAT3 and Cyclin D1 level are the most significantly increased in the ConA + PH + IL-22 group as well as the least significantly increased in the ConA + PH group at all the time points.Conclusion IL-22 acts as a protective cytokine to attenuate liver injury in the model of hepatectomy in T cell-mediated hepatitis induced by concanavalin A.This effect of IL-22 might be mediated by enhancing pro-growth pathways via STAT3 activation and then inducing the expression of genes important for cell cycle progression (such as Cyclin D1).%目的 探讨刀豆蛋白A介导的肝损伤小鼠行部分肝切除术后白细胞介素-22(IL-22)对其肝脏再生的治疗作用及其机制.方法 100

  4. Temporal mapping of CEBPA and CEBPB binding during liver regeneration reveals dynamic occupancy and specific regulatory codes for homeostatic and cell cycle gene batteries

    DEFF Research Database (Denmark)

    Jakobsen, Janus Schou; Waage, Johannes; Rapin, Nicolas

    2013-01-01

    quantified the genome-wide binding patterns of two key hepatocyte transcription factors, CEBPA and CEBPB (also known as C/EBPalpha and C/EBPbeta), at multiple time points during the highly dynamic process of liver regeneration elicited by partial hepatectomy in mouse. Combining these profiles with RNA...... polymerase II binding data, we find three temporal classes of transcription factor binding to be associated with distinct sets of regulated genes involved in the acute phase response, metabolic/homeostatic functions, or cell cycle progression. Moreover, we demonstrate a previously unrecognized early phase......-renewal of differentiated cells. Taken together, our work emphasizes the power of global temporal analyses of transcription factor occupancy to elucidate mechanisms regulating dynamic biological processes in complex higher organisms....

  5. Hypothyroidism Induces a Moderate Steatohepatitis Accompanied by Liver Regeneration, Mast Cells Infiltration, and Changes in the Expression of the Farnesoid X Receptor.

    Science.gov (United States)

    Rodríguez-Castelán, J; Corona-Pérez, A; Nicolás-Toledo, L; Martínez-Gómez, M; Castelán, F; Cuevas-Romero, E

    2017-03-01

    Hypothyroidism is associated with the development of non-alcoholic steatohepatitis, but cellular mechanisms have been scarcely analyzed. Thyroid hormones regulate the synthesis and secretion of bile acids that are endogenous ligands of the farnesoid receptor (FXRα), which have been involved in the development of non-alcoholic steatohepatitis. However, the relationship between thyroid hormones and FXRα expression in the liver is yet unknown. Control (n=6) and methimazole-induced hypothyroid (n=6) female rabbits were used to evaluate the amount of lipids and glycogen, vascularization, hepatocytes proliferation, immune cells infiltration, and expression of FXRα. Student-t or Mann-Whitney U tests were carried out to determine significant differences. Hypothyroidism induced steatosis, glycogen loss, fibrosis, and a minor vascularization in the liver. In contrast, hypothyroidism increased the proliferation of hepatocytes and the infiltration of mast cells, but did not modify the number of immune cells into sinusoids. These changes were associated with a minor anti-FXRα immunoreactivity of periportal hepatocytes and pericentral immune cells. Our results suggest that hypothyroidism induces a moderate non-alcoholic steatohepatitis, alllowing the hepatic regeneration. The FXRα may be involved in the development of non-alcoholic steatohepatitis in hypothyroid subjects.

  6. Ageing and cell-mediated immunity.

    Science.gov (United States)

    Fixa, B; Komárková, O; Chmelar, V

    1975-01-01

    The lymphocyte transformation test with phytohemagglutinin as mitogen estimated according to the incorporation of 2-(14)C-thymidine in DNA was used as an indicator of cell-mediated reactivity in 53 healthy subjects. Three age groups were examined: up to 20 years (21 subjects), 21-40 years (10 subjects) and over 70 years (22 subjects). The responsiveness of lymphocytes decreased significantly with age. In the highest age group 12 pathologically low values were found.

  7. Cloning and analysizing the up-regulated expression of transthyretin-related gene(LR1) in rat liver regeneration following short interval successive partial hepatectomy

    Institute of Scientific and Technical Information of China (English)

    Cun-Shuan Xu; Yu-Chang Li; Jun-Tang Lin; Hui-Yong Zhang; Yun-Han Zhang

    2003-01-01

    AIM: Cloning and analysizing the up-regulated expressionof transthyretin-related gene following short intervalsuccessive partial hepatectomy (SISPH) to elucidate themechanism of differentiation, division, dedifferentiation andredifferentiation in rat liver regeneration (LR).METHODS: Lobus external sinister and lobus centralissinister, lobus centralis, lobus dexter, lobus candatus wereremoved one by one from rat liver at four different time points4, 36, 36 and 36 hr (total time: 4 hr, 40 hr, 76 hr, 112 hr)respectively. Suppression subtractive hybridization (SSH) wascarried out by using normal rat liver tissue as driver and thetissue following short interval successive partial hepatectomy(SISPH) as tester to construct a highly efficient forward-subtractive cDNA library. After screening, an interested ESTfragment was selected by SSH and primers were designedaccording to the sequence of the EST to clone the full-lengthcDNA fragment using RACE (rapid amplification of cDNAend). Homologous detection was performed between thefull-lenth cDNA and Genbank.RESULTS: Forward suppression subtractive hybridization(FSSH) library between 0 h and 112 h following SISPH wasconstructed and an up-regulated full-length cDNA (namedLR1), which was related with the transthyretin gene, wascloned by rapid amplification of cDNA end. It was suggestedthat the gene is involved in the cellular dedifferentiation inLR following SISPH.CONCLUSION: Some genes were up-regulated in 112 hfollowing SISPH in rat. LR1 is one of these up-regulatedexpression genes which may play an important role in rat LR.

  8. Early hepatic regeneration index and completeness of regeneration at 6 months after partial hepatectomy

    NARCIS (Netherlands)

    Kele, P. G.; de Boer, M.; van der Jagt, E. J.; Lisman, T.; Porte, R. J.

    2012-01-01

    Background: The liver is known to regenerate following partial hepatectomy (PH), but little is known about the timing and completeness of regeneration relative to the resected volume. This study examined whether liver volume regeneration following PH and its completeness 6 months after surgery is re

  9. Effect of sorafenib on liver regeneration after partial hepatoectomy in liver cirrhotic rats%索拉菲尼对肝硬化大鼠部分肝切除术后肝脏再生的影响

    Institute of Scientific and Technical Information of China (English)

    周小虎; 张红卫; 万云乐

    2012-01-01

    AIM:To sludy lhe effecl of sorafenib on lhe liver regeneration afler parlial hepaleclomy (PH) in cirrholic rals. METHODS: Thirly Wislar rals wilh liver cirrhosis induced successfully wilh dielhylnilrosamine (DEN) un-derwenl 30% PH and lhen were randomly divided inlo 2 groups ( n = 15 ). The rals in experimental group were fed wilh sorafenib al dose of 30 mg ? Kg-1·d-1 from lhe lsl day lo lhe l0th day afler PH, while ihose in conlrol group were fed wilh vehicle by gavage. The blood and liver lissues of lhe rals were collected afler PH and al lhe end of lhe experimenl. Liver regeneralion rale (LRR) and proliferating cell nuclear anligen (PCNA) expression were assessed for determining lhe hepatocyle proliferation. The conlent of alanine Iransaminase (ALT) , albumin (ALB) , tolal bilirubin (TBIL) , direct bili-rubin (DBIL) , angiogenesis relaled factors including vascular endolhelial growth faclor ( VEGF) , vascular endothelial growlh factor receplor 2 ( VEGFR - 2) , platelel - derived growth faclor receptor (3 ( PDGFR - (3 ) and micro - vessel densily ( MVD) were measured in both groups. RESULTS: LRRs on day 10 afler PH were 45.43% ±3.36% and 44.21% ±2.77% in experimental group and conlrol group, respectively (P>0. 05) , and lhe expression of PCNA in hepatic lissues of the rals was not found by lhe method of immunohislochemistry in bolh groups. Liver function index had no significant difference between lhe 2 groups (P >0. 05) . However, other lhan VEGF, sorafenib resulted in inhibilion of VEGFR -2 and PDGFR - (3 expression and reduction of MVD in experimenl group, and significant difference belween the 2 groups was observed (P0.05);(2)免疫组织化学(IHC)没有检测到PCNA;(3)2组的生化指标无显著差异(P>0.05);(4)实验组VEGFR-2和PDGFR-β的表达受到抑制,MVD降低,并且实验组与对照组差异有统计学意义(P<0.01).结论:索拉菲尼虽然对肝硬化血管再生相关因子有抑制作用,但是对肝细胞再生和肝功能没有明显影响.

  10. Expression Profile Changes of Genes Involved in Lipid Metabolism Pathway During Liver Regeneration in Mice%小鼠肝再生过程中脂质代谢相关通路中基因的表达谱变化

    Institute of Scientific and Technical Information of China (English)

    袁运生; 张夕原; 严德珺; 杨婷旭; 郜尽; 俞雁

    2009-01-01

    [Objective] The aim of the research was to study the expression profile changes of genes involved in lipid metabolism pathway during liver regeneration in mice. [Method] The CCl4 induced mouse model of liver regeneration was established and the total RNA was isolated from liver tissue of mouse. Then the changes of genes involved in lipid metabolism pathway during different stages of liver regeneration were detected through micro-array chip gene technique and their specific functions were also analyzed. [Result] During the process of liver regeneration, the expression level of 98 genes involved in lipid metabolism pathway changed, which were divided into eight groups according to change trend. In the mass, the expression of genes was inhibited in the early stage and up-regulated in the late phase. And the gene expression associated with fatty acid synthesis pathway was mainly up-regulated while the catabolic pathway did not change significantly. Most of genes involved in bile acid synthesis pathway were suppressed before 4.5 d and up-regulated after 4.5 d or 7 d. [Conclusion] During the process of liver regeneration, the genes associated with lipid metabolism are expressed in different trends, and this data should provide a specific range of genes for further studying the regulation effect of lipid metabolism related pathway on liver regeneration.

  11. Evolution Analysis of Rat Liver Regeneration Associated Gene MafF%大鼠肝再生相关基因MafF的分子进化研究

    Institute of Scientific and Technical Information of China (English)

    范念斯; 杨献光

    2011-01-01

    Maf family proteins are so named because of their structural similarity to the founding member, the oncoprotein v-Maf. The small Maf proteins (MafF, MafG and MafK), as all family members, include a characteristic basic region linked to a leucine zipper (b-Zip) domain which mediates DNA binding and subunit dimerization respectively. cDNA Microarray result displays that MafF mRNA express level rises rapidly after partial hepatectomy (PH) of rat. MafF may be involved in rat liver regeneration. The length polymorphism, stop codon polymorphism, ORF diversity and the high homology of different mammals' MafF genes are analyzed. Then, the polygenetic tree of MafF among different mammalian is established. It is hoped to understand the evolutionary relationship among the mammals' MafF gene and to provide materials for the research to reveal its role during rat liver regeneration.%Maf家族是碱性亮氨酸拉链(the basic leucine zipper,bZip)转录因子的一个亚群,是v-maf癌蛋白类似物.它可以通过结合不同的底物来调节下游基因的表达.cDNA Microarray结果显示,小Maf家族成员MafF在大鼠部分肝切除后表达水平迅速升高.为了详细研究该基因的特性,我们采用生物信息学手段来分析在不同动物中MafF基因的长度多态性、终止密码子多态性、ORF多态性以及氨基酸序列的同源性,建立不同动物MafF基因上的进化关系图谱,为了解MafF基因的演化关系,研究该基因参与大鼠肝再生的作用机理提供资料.

  12. [A case of multiple liver metastases from colon cancer treated with complete resection via two-stage hepatectomy after regeneration of the liver].

    Science.gov (United States)

    Sugishita, Toshiya; Ganno, Hideaki; Hataji, Kenichiro; Ami, Katunori; Nagahama, Takeo; Fukuda, Akira; Ando, Masayuki; Arai, Kuniyoshi

    2015-01-01

    A 55-year-old woman underwent low anterior resection for sigmoid colon cancer with multiple bilobar metastases. She then received 23 courses of Leucovorin, fluorouracil, and oxaliplatin (mFOLFOX) plus bevacizumab and 13 courses of Leucovorin, fluorouracil, and irinotecan (FOLFIRI) plus bevacizumab as down staging chemotherapy. A two-stage hepatectomy was planned to avoid the risk of hepatic failure due to radial resection of bilobar metastases. Therefore, a right lobectomy was performed, and curative resection was achieved 54 days after the first hepatectomy. Two-stage hepatectomy as well as a combination of induction chemotherapy and portal vein embolization may have contributed to the improved prognosis of the initially unresectable multiple bilobar liver metastases.

  13. Augmenter of liver regeneration, a protective factor against ROS-induced oxidative damage in muscle tissue of mitochondrial myopathy affected patients.

    Science.gov (United States)

    Polimeno, Lorenzo; Rossi, Roberta; Mastrodonato, Maria; Montagnani, Monica; Piscitelli, Domenico; Pesetti, Barbara; De Benedictis, Leonarda; Girardi, Bruna; Resta, Leonardo; Napoli, Anna; Francavilla, Antonio

    2013-11-01

    Mitochondria-related myopathies (MM) are a group of different diseases defined by a varying degree of dysfunctions of the mitochondrial respiratory chain which leads to reactive oxygen species (ROS) generation followed by oxidative stress and cellular damage. In mitochondrial myopathy muscle tissue an overexpression of antioxidant enzymes has been documented probably as an attempt to counteract the free radical generation. We previously documented, in human non-pathological muscle fibres, the expression of the augmenter of liver regeneration (ALR), a sulfhydryl oxidase enzyme, whose presence is related to the mitochondria; indeed it has been demonstrated that ALR mainly localizes in the mitochondrial inter-membrane space. Furthermore we reported, in different experimental models, in vivo and in vitro, the anti-apoptotic and anti-oxidative capacities of ALR, achieved by up-regulating Bcl-2 anti-apoptotic family factors and the anti-apoptotic/anti-oxidative secretory isoform of clusterin (sClu). With the present study we aimed to determine ALR, Bcl-2 protein, clusterin and ROS expression in muscle tissue biopsies from MM-affected patients. Non-pathological muscle tissue was used as control. Enzymatic, histochemical, immunohistochemical and immune electron microscopy techniques were performed. The data obtained revealed in MM-derived muscle tissue, compared to non-pathological tissue, the over-expression of ROS, ALR and Bcl-2 and the induction of the nuclear, pro-apoptotic, isoform of clusterin (nCLU).

  14. Augmenter of liver regeneration inhibits TGF-β1-induced renal tubular epithelial-to-mesenchymal transition via suppressing TβR II expression in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Liao, Xiao-hui [Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010 (China); Zhang, Ling, E-mail: lindazhang8508@hotmail.com [Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010 (China); Chen, Guo-tao; Yan, Ru-yu [Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010 (China); Sun, Hang; Guo, Hui [Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010 (China); Liu, Qi, E-mail: txzzliuqi@163.com [Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010 (China)

    2014-10-01

    Tubular epithelial-to-mesenchymal transition (EMT) plays a crucial role in the progression of renal tubular interstitial fibrosis (TIF), which subsequently leads to chronic kidney disease (CKD) and eventually, end-stage renal disease (ESRD). We propose that augmenter of liver regeneration (ALR), a member of the newly discovered ALR/Erv1 protein family shown to ameliorate hepatic fibrosis, plays a similar protective role in renal tubular cells and has potential as a new treatment option for CKD. Here, we showed that recombinant human ALR (rhALR) inhibits EMT in renal tubular cells by antagonizing activation of the transforming growth factor-β1 (TGF-β1) signaling pathway. Further investigation revealed that rhALR suppresses the expression of TGF-β receptor type II (TβR II) and significantly alleviates TGF-β1-induced phosphorylation of Smad2 and nuclear factor-κB (NF-κB). No apparent adverse effects were observed upon the addition of rhALR alone to cells. These findings collectively suggest that ALR plays a role in inhibiting progression of renal tubular EMT, supporting its potential utility as an effective antifibrotic strategy to reverse TIF in CKD. - Highlights: • ALR is involved in the pathological progression of renal EMT in NRK-52E cells. • ALR suppresses the expression of TβRII and the phosphorylation of Smad2 and NF-κB. • ALR plays a role in inhibiting progression of renal tubular EMT.

  15. The phosphatase of regenerating liver 3 (PRL-3) promotes cell migration through Arf-activity-dependent stimulation of integrin α5 recycling.

    Science.gov (United States)

    Krndija, Denis; Münzberg, Christin; Maass, Ulrike; Hafner, Margit; Adler, Guido; Kestler, Hans A; Seufferlein, Thomas; Oswald, Franz; von Wichert, Götz

    2012-08-15

    The formation of metastasis is one of the most critical problems in oncology. The phosphatase of regenerating liver 3 (PRL-3) is a new target in colorectal cancer, mediating metastatic behavior through a promigratory function. However, detailed explanations for this effect have remained elusive. Here we show that PRL-3 interacts with the ADP-ribosylation factor 1 (Arf1). PRL-3 colocalizes with Arf1 in an endosomal compartment and associates with transmembrane proteins such as the transferrin receptor and α5 integrins. PRL-3 interacts with Arf1 through a distinct motif and regulates activation of Arf1. PRL-3-mediated migration depends on expression and activation of Arf1 and is sensitive to treatment with Brefeldin A. We also demonstrate that PRL-3 modulates recycling of α5 integrins and that its phosphatase activity as well as Arf activation and compartmentalization with Arf1 are required for this effect. In summary our data identify a new function for PRL-3 and show that Arf1 is a new PRL-3-dependent mediator of enhanced migration of cancer cells through enhanced recycling of matrix receptors.

  16. Effect of naked eukaryotic expression plasmid encoding rat augmenter of liver regeneration on acute hepatic injury and hepatic failure in rats

    Institute of Scientific and Technical Information of China (English)

    Li-Mei Zhang; Dian-Wu Liu; Jian-Bo Liu; Xiao-Lin Zhang; Xiao-Bo Wang; Long-Mei Tang; Li-Qin Wang

    2005-01-01

    AIM: To study the protective effect of eukaryotic expression plasmid encoding augmenter of liver regeneration (ALR) on acute hepatic injury and hepatic failure in rats. METHODS: The PCR-amplified ALR gene was recombined with pcDNA3 plasmid, and used to treat rats with acute hepatic injury. The rats with acute hepatic injury induced by intraperitoneal injection of 2 mL/kg 50% carbon tetrachloride (CCl4) were randomly divided into saline control group and recombinant pcDNA3-ALR plasmid treatment groups. Recombinant pcDNA3-ALR plasmid DNA (50 or 200 μg/kg) was injected into the rats with acute hepatic injury intravenously, intraperitoneally, or intravenously and intraperitoneally in combination 4 h after CCl4 administration, respectively. The recombinant plasmid was injected once per 12 h into all treatment groups four times, and the rats were decapitated 12 h after the last injection. Hepatic histopathological alterations were observed after HE staining, the expression of proliferating cell nuclear antigen (PCNA) in liver tissue was detected by immunohistochemical staining, and the level of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) was determined by biochemical method. The recombinant plasmid DNA (200 μg/kg) and saline were intraperitoneally injected into the rats with acute hepatic failure induced by intraperitoneal injection of 4 mL/kg 50% CCl4 after 4 h of CCl4 administration, respectively. Rats living over 96 h were considered as survivals.RESULTS: The sequence of ALR cDNA of recombinant pcDNA3-ALR plasmid was accordant with the reported sequence of rat ALR cDNA. After the rats with acute hepatic injury were treated with recombinant pcDNA3-ALR plasmid, the degree of liver histopathological injury markedly decreased. The pathologic liver tissues, in which hepatic degeneration and necrosis of a small amount of hepatocytes and a large amount of infiltrating inflammatory cells were observed, and they became basically normal in the

  17. Mast Cell-Mediated Mechanisms of Nociception.

    Science.gov (United States)

    Aich, Anupam; Afrin, Lawrence B; Gupta, Kalpna

    2015-12-04

    Mast cells are tissue-resident immune cells that release immuno-modulators, chemo-attractants, vasoactive compounds, neuropeptides and growth factors in response to allergens and pathogens constituting a first line of host defense. The neuroimmune interface of immune cells modulating synaptic responses has been of increasing interest, and mast cells have been proposed as key players in orchestrating inflammation-associated pain pathobiology due to their proximity to both vasculature and nerve fibers. Molecular underpinnings of mast cell-mediated pain can be disease-specific. Understanding such mechanisms is critical for developing disease-specific targeted therapeutics to improve analgesic outcomes. We review molecular mechanisms that may contribute to nociception in a disease-specific manner.

  18. Do phosphatase of regenerating liver-3, matrix metalloproteinases-2, matrix metalloproteinases-9, and epidermal growth factor receptor-1 predict response to therapy and survival in glioblastoma multiforme?

    Directory of Open Access Journals (Sweden)

    Priyanka Soni

    2016-01-01

    Full Text Available Context: Poor survival of the glioblastoma multiforme (GBM has been attributed in part to the invasive nature of the lesion making complete surgical removal near impossible. Phosphatase of regenerating liver-3 (PRL-3, matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9, and epidermal growth factor receptor (EGFR-1 play a role in invasive nature of tumor cells. Aims: This study was conducted to evaluate PRL-3, MMP-2, MMP-9, and EGFR-1 (markers expression in cases to GBM and to correlate their expression with therapy response and survival. Settings and Design: GBM cases (n = 62 underwent surgery followed by radiation (n = 34 and chemoradiation (n = 28. Using WHO Response Evaluation Criteria in Solid Tumors criteria response to therapy was assessed at 3 months and cases followed up for survival. Subjects and Methods: Expression of markers was assessed by immunohistochemistry as a percentage of positive tumor cells in hot spots. Statistical Analysis Used: Kaplan–Meier, ANOVA, Chi-square test, univariate, and multivariate Cox-regression analysis was done. Results: Response to therapy was evident in 54.8% cases of responders with the mean survival of 494.03 ± 201.13 days and 45.2% cases of non responders (278.32 ± 121.66 days with P = 0.001. Mean survival for the patient's opted chemoradiation was 457.43 ± 222.48 days which was approximately 3 months greater than those who opted radiation alone (P = 0.029. We found PRL-3 overexpression was an independent, significant, poor prognostic factor for survival by multivariate analysis (P = 0.044. Cases negative for MMP's and EGFR showed increased survival, but the difference was insignificant. Conclusion: PRL-3 expression appears to be related to an adverse disease outcome.

  19. 人肝再生增强因子CXXC活性结构的研究%Study on the CXXC Activity Motif of Human Augmenter of Liver Regeneration

    Institute of Scientific and Technical Information of China (English)

    潘艳; 佟明华; 鞠桂芝; 孔祥平

    2006-01-01

    人肝再生增强因子(human augmenter of liver regeneration,hALR)蛋白序列中有一段保守的Cys-Xaa-Xaa-Cys(CXXC)氨基酸序列,针对hALRp的CXXC结构,对hALR分别进行C65A和Q88C突变,表达、纯化突变体蛋白.体外检测hALRp和突变体的黄素腺嘌呤二核苷酸(flavin adenine dinucleotide,FAD)辅助的巯基氧化酶活性,hALR-FAD和hALRQ88C-FAD组与对照组比较有显著差异(P<0.05),hALR-FAD和hALRQ88C-FAD组之间无差异;hALRC65A-FAD组与对照组比较无差异.结果显示,通过C65A突变将CXXC结构破坏后,该突变体的巯基氧化酶活性完全丧失;通过Q88C突变增加一个CXXC序列后,该突变体的巯基氧化酶活性较hALR-FAD未见明显增加;同时,FAD不仅是hALRp发挥巯基氧化酶活性必须的辅助因子,而且有助于hALRp突变体蛋白的复性.

  20. 软骨细胞发生和分化基因与大鼠肝再生的相关性%Relevance of Rat Liver Regeneration with the Genes of Chondrocyte Genesis and Differentiation

    Institute of Scientific and Technical Information of China (English)

    赵利峰; 李鹏鸽; 徐存拴

    2007-01-01

    肝脏由多种细胞构成,肝再生与细胞分化密切相关,细胞分化受基因转录水平调控.为在基因转录水平了解软骨细胞的发生和分化相关基因在大鼠肝再生中作用,通过搜集网站资料和查阅相关论文等方法获得参与软骨细胞发生和分化的基因,用Rat Genome 230 2.0芯片检测它们在大鼠肝再生(liver regeneration,LR)中表达情况,用比较真、假手术中基因表达差异确定肝再生相关基因.初步证实上述基因中23个基因与肝再生相关.肝再生启动(PH后0.5~4 h)、G0/G1过渡(PH后4~6 h)、细胞增殖(PH后6~66 h)、细胞分化和组织结构功能重建(PH后72~168 h)等四个阶段起始表达的基因数为15、4、8和0;基因的总表达次数为15、10、22和17.表明相关基因主要在肝再生启动阶段起始表达,在不同阶段发挥作用.它们共表达上调100次、下调77次,分为17种表达方式,表明肝再生中软骨细胞发生和分化相关基因活动多样和复杂.根据本文研究结果推测,上述基因不仅调节软骨细胞发生和分化,而且参与肝再生的生理生化活动.%Liver contains many cell types. Liver regeneration is closely related to cell differentiation, which is regulated by some genes. To investigate the actions of the genes participating in chondrocyte genesis and differentiation on rat liver regeneration at transcriptional level, the aforementioned genes were screened out via collecting database data and retrieving the related thesis. The Rat Genome 230 2.0 array was applied to the measurement of expression changes of them in rat regenerating liver. The liver regeneration-associated genes were determined by comparing differences in gene expression between partial hepatectomy (PH) and sham operation (SO). It was 23 among the above genes that were related to liver regeneration. In initiation phase of liver regeneration (0.5~4 h after PH), G0/G1 (4~6 h after PH), cell proliferation (6~66 h

  1. Resolution of cell-mediated airways diseases

    Science.gov (United States)

    2010-01-01

    "Inflammation resolution" has of late become a topical research area. Activation of resolution phase mechanisms, involving select post-transcriptional regulons, transcription factors, 'autacoids', and cell phenotypes, is now considered to resolve inflammatory diseases. Critical to this discourse on resolution is the elimination of inflammatory cells through apoptosis and phagocytosis. For major inflammatory diseases such as asthma and COPD we propose an alternative path to apoptosis for cell elimination. We argue that transepithelial migration of airway wall leukocytes, followed by mucociliary clearance, efficiently and non-injuriously eliminates pro-inflammatory cells from diseased airway tissues. First, it seems clear that numerous infiltrated granulocytes and lymphocytes can be speedily transmitted into the airway lumen without harming the epithelial barrier. Then there are a wide range of 'unexpected' findings demonstrating that clinical improvement of asthma and COPD is not only associated with decreasing numbers of airway wall inflammatory cells but also with increasing numbers of these cells in the airway lumen. Finally, effects of inhibition of transepithelial migration support the present hypothesis. Airway inflammatory processes have thus been much aggravated when transepithelial exit of leukocytes has been inhibited. In conclusion, the present hypothesis highlights risks involved in drug-induced inhibition of transepithelial migration of airway wall leukocytes. It helps interpretation of common airway lumen data, and suggests approaches to treat cell-mediated airway inflammation. PMID:20540713

  2. Early effects of liver regeneration on endocrine pancreas: in vivo change in islet morphology and in vitro assessment of systemic effects on β-cell function and viability in the rat model of two-thirds hepatectomy.

    Science.gov (United States)

    Moreau, F; Seyfritz, E; Toti, F; Sigrist, S; Bietigier, W; Pinget, M; Kessler, L

    2014-12-01

    Liver and pancreas share key roles in glucose homeostasis. Liver regeneration is associated with systemic modifications and depends especially on pancreatic hormones. The aim of the study was to investigate the role of systemic factors released after two-thirds hepatectomy (2/3H) on early possible consequences of liver regeneration on endocrine pancreas structure and function. The pancreas and serum were harvested 1, 2, or 3 days after 2/3H or sham operation in Lewis rats. The HGF and VEGF serum concentrations and plasma microparticles levels were measured. The fate of endocrine pancreas was examined through islets histomorphometry and function in sham and 2/3H rats. β-Cell line RIN-m5F viability was assessed after 24 h of growth in media supplemented with 10% serum from 2/3H or sham rats instead of FCS. Three days after surgery, the pancreas was heavier in 2/3H compared to sham rats (0.56 vs. 0.40% of body weight, p viability of RIN-m5F cells (99 vs. 67%, p concentration and a significant increase in microparticles levels, were observed in 2/3H vs. sham rats (9.8 vs. 6.5 nM Phtd Ser Eq., p influence β-cell viability and function by systemic effect.

  3. 脂肪细胞分化相关基因在大鼠再生肝中表达变化%EXPRESSION PROFILES OF THE GENES RELATED TO ADIPOCYTE DIFFERENTIATION IN THE RAT REGENERATING LIVER

    Institute of Scientific and Technical Information of China (English)

    赵利峰; 邵恒熠; 徐存拴

    2007-01-01

    To investigate the action of adipocyte differentiation-related genes during rat liver regeneration at transcriptional level,these genes were obtained by means of collection of the database data and retrieval of the related theses.The Rat Genome 230 2.0 array was used to inspect the expression changes of them in rat regenerating livers. Identification of the liver regeneration-associated genes was through performing three independent chip analyses,showing a greater than double change in gene expression at least at one time point during liver regeneration,and comparing differences in gene expression between partial hepatectomy (PH) and sham operation (SO).75 of the above genes were found to be liver regeneration-related.In initiation phase of liver regeneration(0.5-4 h after PH),G0/G1 (4-6 h after PH),cell proliferation(6-66 h after PH),cell differentiation and liver tissue structure-function reconstruction(72-168 h after PH),the number of the initially expressed genes was 44,13,30 and 1 respectively,and the total expression times of the genes were in a sequence of 88.58.302 and 90.illustrating that the initially expressed genes were advantaged in initial phase (0.5-4 h), and yielded function in each phases.The genes were totally up-regulated 313 times and down-regulated 167 times.43 expression patterns of them conferred multiformity and complication on the cellular physiological and biochem-ical activities liver regeneration involving.The results indicated that the above genes not only can regulate the adipocyte differentiation,but also can participate in the physiological and biochemical activities during liver regeneration.%肝脏由多种细胞构成,肝再生与细胞分化密切相关,细胞分化受基因转录水平调控.为在基因转录水平了解脂肪细胞分化基因在大鼠肝再生中作用,本文用搜集网站资料和查阅相关论文等方法获得上述基因,用Rat Genome 230 2.0芯片检测它们在大鼠肝再生(liver regeneration,LR)

  4. Expression of CK19 and PCNA in fibrosis rat regenerating liver after partial hepatectomy%CK19和PCNA在肝纤维化大鼠部分肝切除后再生肝中的表达

    Institute of Scientific and Technical Information of China (English)

    方方; 刘前进; 岳学强; 李娜娜; 刘恒兴

    2012-01-01

    Objective To detect the expressions of CK19 and PCNA in fibrosis rat regenerating liver after partial hepatectomy (PH) at the different time phase, for evaluating the bile duct regeneration in fibrotic liver. Methods Male SD rats were divided into two groups: the control group (42 rats) and the experimental group (42 rats). The rats of experimental group were injected CCL, to establish the hepatic fibrosis model, and then the two groups was endured PH operation. HE, immunohistochemical and double-label immunofluorescence were used to detect and analyze expressions of CK19 and PCNA in regenerating liver. Results The expression of CK19 increased gradually after PH in both groups, however, expression intensity in experimental animals was significantly higher than control ones at the same time point. As well, the expression of PCNA increased gradually after PH in both groups, however, expression level in experimental groups rose slowly, extended and the peak appeared later than the control. Conclusions (1) PH process of fibrotic rat liver can stimulate proliferation of Ocs and the differentiation to BECs, which mainly originate from compensatory hyperplasia in normal rats regenerating liver. (2) Before PH, liver cells in fibrosis rats have already proliferated, after PH, the effective regenerating cells are lower than the other liver injury.%目的 检测肝纤维化大鼠部分肝切除后不同时点CK19及PCNA的表达,了解胆管再生情况.方法 雄性SD大鼠,对照组和实验组各42只,实验组腹腔注射CC14制备肝纤维化模型,两组均进行部分肝切除术,在不同时点取材后利用HE、免疫组化及免疫荧光双标染色等方法检测CK19和PCNA的表达情况.结果 实验组和对照组术后随时间延长CK19表达均呈增强趋势,且实验组术后各时间点CK19的表达均高于对照组同时间点.两组PCNA的表达量都随时间推移逐步升高,但实验组大鼠明显上升缓慢,持续时间延长,表达高峰

  5. Possible neuroimmunomodulation therapy in T-cell-mediated oral diseases

    Directory of Open Access Journals (Sweden)

    Tsuyoshi Sato

    2015-01-01

    Full Text Available Introduction: Recurrent aphthous stomatitis and oral lichen planus are local chronic inflammatory diseases which are implicated in T cell-mediated immunity. According to the systematic review, there is insufficient evidence to support any specific treatment for T-cell mediated oral diseases. The hypothesis: In this paper, we propose a hypothesis that recurrent aphthous stomatitis and oral lichen planus can be treated with selective α7 subunit of nicotinic acetylcholine receptor (α7 -nAChR agonists. Our hypothesis is supported by the following two facts. First, the pathophysiological conditions, T h 1/T h 17 cell activation and autonomic nervous system dysfunction, are observed in T-cell mediated oral diseases as well as in T-cell mediated systemic diseases such as rheumatoid arthritis. Second, the cholinergic anti-inflammatory pathway is inhibited in systemic T-cell mediated chronic inflammatory diseases. On the other hand, treatment with α7 -nAChR agonists which activate the cholinergic anti-inflammatory pathway suppresses neuroinflammation via inhibition of T h 1/T h 17 responses in animal model of systemic T-cell mediated chronic inflammatory diseases. We thus expect that selective α7 -nAChR agonists will be effective for the treatment of T-cell mediated oral diseases. Evaluation of the hypothesis: To test our hypothesis, we need to develop in vivo mouse model of T-cell mediated oral diseases. To evaluate the therapeutic effect of a selective α7 -nAChR agonist, we choose ABT-107 because of its safety and tolerability. We believe that the selective α7 -nAChR agonist, especially ABT-107, may be a therapeutic drug to treat T-cell mediated oral diseases.

  6. Some principles of regeneration in mammalian systems.

    Science.gov (United States)

    Carlson, Bruce M

    2005-11-01

    This article presents some general principles underlying regenerative phenomena in vertebrates, starting with the epimorphic regeneration of the amphibian limb and continuing with tissue and organ regeneration in mammals. Epimorphic regeneration following limb amputation involves wound healing, followed shortly by a phase of dedifferentiation that leads to the formation of a regeneration blastema. Up to the point of blastema formation, dedifferentiation is guided by unique regenerative pathways, but the overall developmental controls underlying limb formation from the blastema generally recapitulate those of embryonic limb development. Damaged mammalian tissues do not form a blastema. At the cellular level, differentiation follows a pattern close to that seen in the embryo, but at the level of the tissue and organ, regeneration is strongly influenced by conditions inherent in the local environment. In some mammalian systems, such as the liver, parenchymal cells contribute progeny to the regenerate. In others, e.g., skeletal muscle and bone, tissue-specific progenitor cells constitute the main source of regenerating cells. The substrate on which regeneration occurs plays a very important role in determining the course of regeneration. Epimorphic regeneration usually produces an exact replica of the structure that was lost, but in mammalian tissue regeneration the form of the regenerate is largely determined by the mechanical environment acting on the regenerating tissue, and it is normally an imperfect replica of the original. In organ hypertophy, such as that occurring after hepatic resection, the remaining liver mass enlarges, but there is no attempt to restore the original form.

  7. BNIP3 involves in the process of erythropoietin promoting liver regeneration after partial hepatectomy in rat%BNIP3在rhEPO促进大鼠部分肝切除后肝再生中的作用

    Institute of Scientific and Technical Information of China (English)

    钟克波; 赖彦华; 毕民平

    2013-01-01

    目的 由BNIP3介导的线粒体动态平衡在肝脏的脂肪代谢及糖代谢中起重要作用,而肝再生与线粒体代谢密切相关.有研究表明EPO可促进肝脏再生,但具体机制不明.本文研究重组人促红细胞生成素(rhEPO)对大鼠部分肝切除后肝功能及肝再生的影响,以及BNIP3和TNF-αmRNA在再生肝组织中的表达.方法 36只Wistar大鼠随机分为rhEPO组和空白组,建立大鼠70%肝切除,肝切除后经门静脉注射3000IU/kg rhEPO,空白组注射等剂量生理盐水.术后1d、3d、5d各处死6只大鼠采集血清及肝脏标本,全自动生化分析仪测定血清谷丙转氨酶(ALT),免疫组织化学染色法检测Ki-67表达,ELISA法检测血清TNF-α、IL-6,荧光定量PCR检测肝组织BNIP3和TNF-α mRNA.结果 肝切除术后1d rhEPO组的谷丙转氨酶(ALT)显著低于空白组(P<0.05).肝切除术后1、5d rhEPO组Ki-67标记率显著高于空白组(P<0.05).肝切除术后1d rhEPO组TNF-α显著高于空白组(P<0.05),肝切除术后1d 3d rhEPO组IL-6显著高于空白组.肝切除术后1d 3d rhEPO组BNIP3和TNF-αmRNA显著高于空白组(P<0.05).结论 门静脉注射rhEPO具有肝保护和明显的促肝再生作用,其机制可能与BNIP3和TNF-α有关.%Objective BNIP3 mediate mitochondrial dynamic equilibrium in liver fat metabolism and glucose metabolism.Mitochondrial metabolism plays an important role in liver regeneration.Some studies have shown that EPO may promote liver regeneration,but the exact mechanism is remained to be elucidate.We study the effect of recombinant human erythropoietin (rhEPO) on liver function and liver regeneration after partial hepatectomy in rats,as well as the expression of BNIP3 and TNF-αmRNA in regenerating liver tissue.Methods 36 Wistar rats were randomly divided into the rhEPO group and blank group,and were submitted to 70% hepatectomy.The rhEPO group received 3000IU/kg of rhEPO throught portal vein injection and the blank control group

  8. Cell-mediated mutagenesis and cell transformation of mammalian cells by chemical carcinogens. [Rats, hamsters

    Energy Technology Data Exchange (ETDEWEB)

    Huberman, E.; Langenbach, R.

    1977-01-01

    We have developed a cell-mediated mutagenesis assay in which cells with the appropriate markers for mutagenesis are co-cultivated with either lethally irradiated rodent embryonic cells that can metabolize carcinogenic hydrocarbons or with primary rat liver cells that can metabolize chemicals carcinogenic to the liver. During co-cultivation, the reactive metabolites of the procarcinogen appear to be transmitted to the mutable cells and induce mutations in them. Assays of this type make it possible to demonstrate a relationship between carcinogenic potency of the chemicals and their ability to induce mutations in mammalian cells. In addition, by simultaneously comparing the frequencies of transformation and mutation induced in normal diploid hamster cells by benzo(a)pyrene (BP) and one of its metabolites, it is possible to estimate the genetic target size for cell transformation in vitro.

  9. Omega-3 polyunsaturated fatty acids prevent progression of liver fibrosis and promote liver regeneration after partial hepatectomy in cirrhotic rats%ω-3多不饱和脂肪酸对肝硬化大鼠肝切除术后肝细胞再生及肝纤维化程度的影响

    Institute of Scientific and Technical Information of China (English)

    杨跃; 段飞; 蔡浩; 陈靓; 林建宇; 仇毓东

    2013-01-01

    Objective:To evaluate the effect of omega-3 polyunsaturated fatty acids (ω-3 PUFA) on liver regeneration after hepatectomy and antifibrosis under the condition of liver cirrhosis in rats. Methods:Seventy precent hepatectomy was carried out in rats,which were subsequently divided into 4 groups: ①normal and hepatectomy group(PH) ,②liver cirrhosis and hepatectomy group(LC + PH) , ③liver cirrhosis,n-3 PUFA (1 ml/kg) and hepatectomy group (LC +n-3 PUFA[S] +PH) ,④liver cirrhosis , n-3 PUFA (2 ml/kg) and hepatectomy group (LC + n-3PUFA[ L] + PH). Body/liver weight ratios , Serum parameters, histopathological examination, immunostaining and quantification of mRNA expression were also investigated. Results:Liver regeneration in LC + PH group was significantly delayed compared with PH group 7 days after hepatectomy. On the other hand,liver regeneration in LC + n-3 PUFA[L] +PH group increased significantly. The liver fibrosis was significantly lower in the groups with use of n-3 PUFA. Conclusion: The n-3 PUFA can reduce liver fibrosis and promote liver regeneration, even under cirrhotic conditions.%目的:观察ω-3多不饱和脂肪酸(ω-3PUFA)对肝硬化大鼠70%肝切除术后肝细胞再生及肝纤维化程度的影响. 方法:将96只大鼠随机分为四组,即正常对照组(仅行70%肝切除);肝硬化对照组(肝硬化大鼠行70%肝切除);肝硬化小剂量组(肝硬化大鼠行70%肝切除后静脉注射ω-3PUFA 1 ml/kg);肝硬化大剂量组(肝硬化大鼠行70%肝切除后静脉注射ω-3PUFA 2 ml/kg).观察大鼠术后第1、3、5和7天肝细胞再生的情况,肝功能指标,残肝肝纤维化程度的变化等. 结果:与肝硬化对照组比,肝硬化大剂量组大鼠术后肝有明显的再生(P<0.05);术后第1和第3天ALT和AST有明显降低(P<0.05).术后第7天,肝硬化小剂量组和肝硬化大剂量组肝纤维化程度有明显减轻(P<0.05). 结论:ω-3PUFA不仅能促进肝硬化大鼠术后肝细胞再

  10. Long-Term GABA Administration Induces Alpha Cell-Mediated Beta-like Cell Neogenesis

    DEFF Research Database (Denmark)

    Ben-Othman, Nouha; Vieira, Andhira; Courtney, Monica

    2017-01-01

    The recent discovery that genetically modified α cells can regenerate and convert into β-like cells in vivo holds great promise for diabetes research. However, to eventually translate these findings to human, it is crucial to discover compounds with similar activities. Herein, we report...... also in humans. This newly discovered GABA-induced α cell-mediated β-like cell neogenesis could therefore represent an unprecedented hope toward improved therapies for diabetes......., these neo-generated β-like cells are functional and can repeatedly reverse chemically induced diabetes in vivo. Similarly, the treatment of transplanted human islets with GABA results in a loss of α cells and a concomitant increase in β-like cell counts, suggestive of α-to-β-like cell conversion processes...

  11. Liver diseases and aging : friends or foes?

    NARCIS (Netherlands)

    Sheedfar, Fareeba; Di Biase, Stefano; Koonen, Debby; Vinciguerra, Manlio

    2013-01-01

    The liver is the only internal human organ capable of natural regeneration of lost tissue, as little as 25% of a liver can regenerate into a whole liver. The process of aging predisposes to hepatic functional and structural impairment and metabolic risk. Therefore, understanding how aging could affe

  12. Liver diseases and aging : friends or foes?

    NARCIS (Netherlands)

    Sheedfar, Fareeba; Di Biase, Stefano; Koonen, Debby; Vinciguerra, Manlio

    2013-01-01

    The liver is the only internal human organ capable of natural regeneration of lost tissue, as little as 25% of a liver can regenerate into a whole liver. The process of aging predisposes to hepatic functional and structural impairment and metabolic risk. Therefore, understanding how aging could affe

  13. ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell-dependent release of TNF-alpha/IL-6 in mice.

    NARCIS (Netherlands)

    Selzner, N; Selzner, M; Odermatt, B; Tian, Y; Rooijen, van N.; Clavien, PA

    2003-01-01

    AIMS: Tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 mediate hepatocyte proliferation in vivo, suggesting that local and systemic inflammatory reactions may trigger hepatic regeneration after major tissue loss. METHODS: Wild-type, intercellular adhesion molecule (ICAM)-1-/-, and neutropeni

  14. 间断低氧预适应对大鼠肝切除术后残余肝脏再生的影响%Effects of intermittent hypoxic preconditioning on the residual liver regeneration after parital hepatectomy in rats

    Institute of Scientific and Technical Information of China (English)

    李广; 王健; 李鹏飞; 韩效帆; 朱世春; 李俊; 张培建

    2014-01-01

    Objective To investigate the effects of intermittent hypoxic preconditioning on residual liver regeneration after parital hepatectomy in rats.Methods Fifty-four Sprague-Dawley rats were randomly divided into 3 groups (each group contained eighteen animals):sham operation group (SO group),parital hepatectomy group (PH group)and intermittent hypoxic preconditioning group (IHP group).The rats in PH group underwent the left and middle lobectomy of liver(70% hepatectomy).The rats in IHP group were exposed to hypoxic environment of 10% oxygen for 1 h/d.And after a week,the rats underwent parital hepatectomy.Six rats in each group were sacrificed respectively on postoperative day 1,3 and 5 (POD 1,3 and 5).The resected liver and the regenerated liver were weighed to calculate liver regeneration degree and regeneration index.The values of alaninea minotransferase (ALT) and aspartate aminotransferase (AST) in the inferior vena venous blood were examined by automatic biochemical analyzer.The positive ratio of hepatocellular proliferating cell nuclear antigen (PCNA) in the residual liver was investigated immunohistochemically.Results The degree and index of liver regeneration in IHP group were respectively higher than those in PH group on POD 1 and 3(P <0.05),but there were no statistical differences between the two groups on POD 5.The levels of ALT and AST in PH and IHP group began to decline after surgery,but they remined higher than those in SO group.Moreover,the ALT and AST levels in IHP group were significantly lower than those in PH group on POD 1 (P <0.05).The positive ratios of hepatocellular PCNA were respectively higher than those in SO and PH group on POD 1,3 and 5 (P < 0.05).Conclusions To some extent,preoperative intermittent hypoxic preconditioning could prevent hepatocellular damage after parital hepatectomy,what is more,it also could promote the remnant liver regeneration.But the mechanism still needs to be studied furter.%目的 研究间断低氧

  15. Endogenous n-3 polyunsaturated fatty acids attenuate T cell-mediated hepatitis via autophagy activation

    Directory of Open Access Journals (Sweden)

    Yanli Li

    2016-09-01

    Full Text Available Omega-3 polyunsaturated fatty acids (n-3 PUFAs exert anti-inflammatory effects in several liver disorders, including cirrhosis, acute liver failure, and fatty liver disease. To date, little is known about their role in immune-mediated liver diseases. In this study, we used fat-1 transgenic mice rich in endogenous n-3 PUFAs to examine the role of n-3 PUFAs in immune-mediated liver injury. Concanavalin A (Con A was administered intravenously to wild-type (WT and fat-1 transgenic mice to induce T cell-mediated hepatitis. Reduced liver damage was shown in Con A-administrated fat-1 transgenic mice, as evidenced by decreased mortality, attenuated hepatic necrosis, lessened serum alanine aminotransferase (ALT activity, and inhibited production of pro-inflammatory cytokines (e.g. TNF-α, IL-6, IL-17A and IFN-γ. In vivo and in vitro studies demonstrated that n-3 PUFAs significantly inhibited the activation of hepatic T cells and the differentiation of Th1 cells after Con A challenge. Further studies showed that n-3 PUFAs markedly increased autophagy level in Con A-treated fat-1 T cells compared with the WT counterparts. Blocking hepatic autophagy activity with chloroquine diminished the differences in T cell activation and liver injury between Con A-injected WT and fat-1 transgenic mice. We conclude that n-3 PUFAs limit Con A-induced hepatitis via an autophagy-dependent mechanism, and could be exploited as a new therapeutic approach for autoimmune hepatitis.

  16. Endogenous n-3 Polyunsaturated Fatty Acids Attenuate T Cell-Mediated Hepatitis via Autophagy Activation

    Science.gov (United States)

    Li, Yanli; Tang, Yuan; Wang, Shoujie; Zhou, Jing; Zhou, Jia; Lu, Xiao; Bai, Xiaochun; Wang, Xiang-Yang; Chen, Zhengliang; Zuo, Daming

    2016-01-01

    Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert anti-inflammatory effects in several liver disorders, including cirrhosis, acute liver failure, and fatty liver disease. To date, little is known about their role in immune-mediated liver diseases. In this study, we used fat-1 transgenic mice rich in endogenous n-3 PUFAs to examine the role of n-3 PUFAs in immune-mediated liver injury. Concanavalin A (Con A) was administered intravenously to wild-type (WT) and fat-1 transgenic mice to induce T cell-mediated hepatitis. Reduced liver damage was shown in Con A-administrated fat-1 transgenic mice, as evidenced by decreased mortality, attenuated hepatic necrosis, lessened serum alanine aminotransferase activity, and inhibited production of pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-17A, and IFN-γ). In vivo and in vitro studies demonstrated that n-3 PUFAs significantly inhibited the activation of hepatic T cells and the differentiation of Th1 cells after Con A challenge. Further studies showed that n-3 PUFAs markedly increased autophagy level in Con A-treated fat-1 T cells compared with the WT counterparts. Blocking hepatic autophagy activity with chloroquine diminished the differences in T cell activation and liver injury between Con A-injected WT and fat-1 transgenic mice. We conclude that n-3 PUFAs limit Con A-induced hepatitis via an autophagy-dependent mechanism and could be exploited as a new therapeutic approach for autoimmune hepatitis. PMID:27679638

  17. Increased Whole-Body and Sustained Liver Cortisol Regeneration by 11β-Hydroxysteroid Dehydrogenase Type 1 in Obese Men With Type 2 Diabetes Provides a Target for Enzyme Inhibition

    Science.gov (United States)

    Stimson, Roland H.; Andrew, Ruth; McAvoy, Norma C.; Tripathi, Dhiraj; Hayes, Peter C.; Walker, Brian R.

    2011-01-01

    OBJECTIVE The cortisol-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies glucocorticoid levels in liver and adipose tissue. 11β-HSD1 inhibitors are being developed to treat type 2 diabetes. In obesity, 11β-HSD1 is increased in adipose tissue but decreased in liver. The benefits of pharmacological inhibition may be reduced if hepatic 11β-HSD1 is similarly decreased in obese patients with type 2 diabetes. To examine this, we quantified in vivo whole-body, splanchnic, and hepatic 11β-HSD1 activity in obese type 2 diabetic subjects. RESEARCH DESIGN AND METHODS Ten obese men with type 2 diabetes and seven normal-weight control subjects were infused with 9,11,12,12-[2H]4cortisol (40%) and cortisol (60%) at 1.74 mg/h. Adrenal cortisol secretion was suppressed with dexamethasone. Samples were obtained from the hepatic vein and an arterialized hand vein at steady state and after oral administration of cortisone (5 mg) to estimate whole-body and liver 11β-HSD1 activity using tracer dilution. RESULTS In obese type 2 diabetic subjects, the appearance rate of 9,12,12-[2H]3cortisol in arterialized blood was increased (35 ± 2 vs. 29 ± 1 nmol/min, P cortisol production was not reduced (29 ± 6 vs. 29 ± 6 nmol/min), and cortisol appearance in the hepatic vein after oral cortisone was unchanged. CONCLUSIONS Whole-body 11β-HSD1 activity is increased in obese men with type 2 diabetes, whereas liver 11β-HSD1 activity is sustained, unlike in euglycemic obesity. This supports the concept that inhibitors of 11β-HSD1 are likely to be most effective in obese type 2 diabetic subjects. PMID:21266326

  18. Innate immune recognition and regulation in liver injury: A brief report from a series of studies

    Institute of Scientific and Technical Information of China (English)

    TIAN ZhiGang

    2009-01-01

    The discovery of innate immune receptors and the emergence of liver Immunology (high content of NK and NKT cells in liver) led to the second research summit in innate immunity since the finding of NK cells in the middle 1970s. Liver disease is one of the most dangerous threats to humans, and the pro-gress in innate immunology and liver immunology made it possible to re-explain the cellular end too-lecular immune mechanisms of liver disease. In the past ten years, we have found that innate recogni-tion of hepatic NK and NKT subsets were involved in murine liver injury. We established a novel NK cell-dependent acute murine hepatitis model by activating Toll-like receptor-3 (TLR-3) with an injection of poly I:C, which may mimic mild viral hepatitis (such as Chronic Hepatitis B). We observed that a network of innate immune cells including NK, NKT and Kupffer cells is involved in liver immune injury in our established NK cell-dependent murine model. We noted that TLR-3 on Kupffer ceils activated by pretreatment with poly I:C might protect against bacterial toxin (LPS)-induced fuIminant hepatitis by down-regulating TLR-4 function, while TLR-3 pre-activation of NK cells might reduce Con A-induced NKT cell-mediated fulminant hepatitis by blocking NKT cell recruitment to the liver. We also found that the oversensitivity to injury by immune stimulation in HBV (hepatitis B virus) transgenic mice (full HBV gene-tg or HBs-tg) correlated to the over-expression of Real, an NKG2D (natural killer cell group 2D) ligand of NK cells or CDld, a ligand of TCR-V14 of NKT cells, on HBV+ hepatocytes, which leads to an innate immune response against hepatocytes and is critical in liver immune injury and regeneration.

  19. Establishing Same Kind Extraction Method to Find the Hepatocyte Key Genes in Rat Liver Regeneration from the Data of Gene Microarray%建立同类提取法从基因芯片检测数据中挖掘大鼠肝细胞的肝再生关键基因

    Institute of Scientific and Technical Information of China (English)

    2013-01-01

    To highlight the biological significance of gene microarray data,Rat Genome 230 2.0 Arrays were used to detect expression abundance of the hepatocyte genes in rat liver regeneration,F-test to test the gene expression differences and to identify the liver regeneration associated-genes in rat two-thirds hepatectomy(PH) and sham operation(SO),same kind extraction method to select the hepatocyte feature genes in rat liver regeneration,which came from the differential genes evaluated by Filter method,then the liver regeneration key genes of rat hepatocytes were identified according to their connectivities,physiological activities and research results. The research shows that Ccne1,Eg f,Met,etc 57 feature genes played key roles in the rat liver regeneration.%  为解析基因芯片检测数据的生物学意义,用 Rat Genome 2302.0芯片检测大鼠肝再生中肝细胞的基因表达丰度,用 F 检验大鼠2/3肝切除组(PH)与假手术组(SO)的基因表达差异性和获得大鼠肝细胞的肝再生相关基因,用同类提取法从过滤法计算的差异基因中筛选特征基因,根据特征基因的关联度、参与的生理活动和他人研究结果确认其中的关键基因.结果表明,Ccne1、Eg f、Met 等57个特征基因在大鼠肝再生中起关键作用.

  20. 液压转基因技术应用于大鼠再生肝转基因实验%Hydrodynamics-based transgene directively into rat regenerating liver in vivo

    Institute of Scientific and Technical Information of China (English)

    徐存拴; 邢雪琨; 杨献光; 朱秋实; 窦磊; 刘帅帅; 李幼; 张富春

    2009-01-01

    目的 探讨液压转基因技术(HDT)应用于大鼠再生肝转基因的条件和方法 . 方法 以2ml/s的速度将浓度为30mg/L的含目的 基因的质粒注射入大鼠尾静脉,于注射前/后不同时间进行大鼠2/3肝切除(PH),于PH后不同恢复时间称量大鼠体重(g)和再生肝重(g),计算肝系数(Lc),并从Lc±Lc*0%、*5%、*10%、*15%、*20%、*25%、*30%、*35%等15组中找出最佳组,作为计算不同恢复时间再生肝最适注射质粒溶液量的校正系数(Trc);取大鼠肝右叶中部组织制备冷冻切片,在波长488nm的荧光显微镜下观察、计数1万个细胞中的绿色荧光蛋白阳性细胞百分率. 结果 PH后注射生理盐水和注射空质粒对肝再生的影响与对照(只进行PH)相比无显著差异.PH前液压转基因的合适时间是PH前≥12h;PH后所有时间均可进行液压转基因.PH后对肝再生大鼠进行液压转基因的转基因溶液体积为大鼠体重(g)×9%×1/3×相应的校正系数(Trc).转入基因在体内的表达时间和丰度既受载体影响,又受插入的目的 基因影响. 结论 液压转基因技术亦可有效地应用于大鼠再生肝转基因研究.%Objective To study the conditions and methods of hydrodynamics-based transgene into rat regenerating liver in vivo. Methods The solution with concentration 30mg/L gene-containing plasmid was injected into rat tail veins at a speed of 2ml/s, then partial hepatectomy (PH) was performed at different times before/after injection, finally the rat (g) and regenerating liver (g) were weighed, and the liver coefficient (Lc) was calculated. Out of 15 groups which are Lc±Lc*0%, *5%, *10%, *15%, *20%, *25%, *30%, *35%, the most suitable group was chosen as correction coefficient to calculate the most appropriate volume of plasmid solution which was injected into the regenerating liver at different recovery times, and at the same time, right lobe of liver was gathered to make frozen section

  1. Expression of TCTP mRNA and its biological significance in liver regeneration%TCTP mRNA在肝再生中的表达及其生物学意义

    Institute of Scientific and Technical Information of China (English)

    朱武凌; 程海霞; 张伟丽; 张会勇; 林俊堂; 刘涌涛; 井长勤

    2009-01-01

    AIM: To investigate the expression of TCTP mRNA and its biological significance in liver regeneration. METHODS: Liver regeneration model was established by a two-thirds partial hepatectomy(PH) in healthy adult male SD rats. The regenerative liver tissues were harvested at different time-points after PH. The mitotic index(MI) was evaluated under microscope and the distri-bution in G0/G1-, S- and G2/M-phase subpopulation was deter-mined by flow cytometry. The expression of TCTP mRNA was measured by semi-quantitative RT-PCR. RESULTS: After PH, the MI of hepatocytes increased significantly at 3 to 12 h. Cell cycle analysis showed a G0/G1- to S-phase transition at 1 h and an increased proportion of G2/M-phase cells at 3 h, followed by the most significant increase at 6 h. The mRNA expression of TCTP was up-regulated slightly at 1 h, markedly increased at 3 to 12 h and then declined to the original level. CONCLUSION: The dynamic changes of TCTP mRNA expression may be related to the mitosis and cell proliferation in liver regeneration.%目的:探讨翻译控制肿瘤蛋白(TCTP)mRNA在肝再生中的表达情况和生物学意义.方法:对健康成年雄性SD大鼠进行2/3部分肝切除以建立肝再生模型,分别于肝切除术后不同时间点收集再生肝组织,在显微镜下进行有丝分裂指数评价,利用流式细胞术分析细胞周期分布变化;半定量RT-PCR法检测TCTP mRNA的表达.结果:肝细胞有丝分裂指数在术后3~12 h明显升高.细胞周期分析显示,肝切除术后1 h呈现G0/G1向s期迁移,G2/M期细胞比例在3 h呈现升高,6 h升高最为显著.TCTP mRNA的表达在肝切除术后1 h时轻微上调,在3~12 h呈显著升高,之后下降至初始水平.结论:在肝再生组织中TcTP mRNA表达呈动态变化,可能与有丝分裂和细胞增殖密切相关.

  2. Human Muse cells, non-tumorigenic pluripotent-like stem cells, have the capacity for liver regeneration by specific homing and replenishment of new hepatocytes in liver fibrosis mouse model.

    Science.gov (United States)

    Iseki, Masahiro; Kushida, Yoshihiro; Wakao, Shohei; Akimoto, Takahiro; Mizuma, Masamichi; Motoi, Fuyuhiko; Asada, Ryuta; Shimizu, Shinobu; Unno, Michiaki; Chazenbalk, Gregorio; Dezawa, Mari

    2016-11-02

    Muse cells, a novel type of non-tumorigenic pluripotent-like stem cells reside in the bone marrow, skin and adipose tissue, are collectable as cells positive for pluripotent surface marker SSEA-3. They are able to differentiate into cells representative of all three germ layers. The capacity of intravenously injected human bone marrow-Muse cells to repair the liver fibrosis model of immunodeficient mice was evaluated in this study. They exhibited the ability for differentiation spontaneously into hepatoblast/hepatocyte-lineage cells and high migration toward the serum and liver tissue of carbon tetrachloride-treated mice in vitro. In vivo, they specifically accumulated into the liver, but not into other organs except the lower rate in the lung at 2 weeks after intravenous injection into the liver fibrosis model. After homing, Muse cells spontaneously differentiated in vivo into HepPar-1 (71.1±15.2%), human albumin (54.3±8.2%) and anti-trypsin (47.9±4.6%)-positive cells without fusing with host hepatocytes, and expressed mature functional markers such as human-CYP1A2, and human-Glc-6-Pase, at 8 weeks. Recovery in serum total bilirubin and albumin, and significant attenuation of fibrosis were recognized with statistical differences between the Muse group and control groups which received the vehicle or the same number of non-Muse cells, namely cells other than Muse cells in bone marrow mesenchymal stem cells. Thus, unlike ES and iPS cells, Muse cells are unique in their efficient migration and integration into damaged liver only by intravenous injection, nontumorigenicity, and spontaneous differentiation into hepatocytes, rendering induction into hepatocytes prior to transplantation unnecessary. They are suggested to repair liver fibrosis in two simple steps; expansion after collection from the bone marrow and intravenous injection. Such feasible strategy might provide impressive regenerative performance to liver disease patients.

  3. Pancreatic islet regeneration and some liver biochemical parameters of leaf extracts of Vitex doniana in normal and streptozotocin-induced diabetic albino rats

    Institute of Scientific and Technical Information of China (English)

    Okpe Oche; Ibrahim Sani; Njoku Godwin Chilaka; Ndidi Uche Samuel; Atabo Samuel

    2014-01-01

    Objective: To test two water soluble extracts (aqueous and ethanolic) obtained from the leaves ofVitex doniana in normal and streptozotocin-induced diabetic rats for their effects on pancreatic endocrine tissues and serum marker enzymes for a period of 21 d. Methods: A total of 55 rats divided into 11 groups of 5 rats each were assigned into diabetic and non-diabetic groups and followed by a daily administration of ethanolic and aqueous extracts for 21 d. Group 1 was the normal control while group 7 was treated with standard drug.Results:The histopathological studies of the diabetic rats indicated increase in the volume density of islets, percent of β-cells and size of islet in the groups that received the plant extracts, which suggested regeneration of β-cells along with β-cells repairs, as compared with the non-treated diabetic control which showed complete degeneration of the islet cells. There was significant reduction (P0.01) in the serum activities of marker enzymes was observed for non-diabetic treated rats. Results of total bilirubin, direct bilirubin and unconjugated bilirubin showed that diabetic control group was significantly higher (P0.01) in total bilirubin and direct bilirubin compared with the normal control.Conclusion:This herbal therapy appears to bring about repair/regeneration of the endocrine pancreas and hepatic cells protection in the diabetic rat.

  4. Challenges and Opportunities for T-Cell-Mediated Strategies to Eliminate HIV Reservoirs

    National Research Council Canada - National Science Library

    Brockman, Mark A; Jones, R Brad; Brumme, Zabrina L

    2015-01-01

    ...(+) T-cell-mediated mechanisms. In this perspective, we highlight challenges to T-cell-mediated elimination of HIV reservoirs, including characteristics of responding T cells, aspects of the cellular reservoirs, and properties...

  5. Expression patterns and action analysis of steroid metabolismasso ciated genes during rat liver regeneration%类固醇代谢相关基因在大鼠肝再生中表达模式和作用分析

    Institute of Scientific and Technical Information of China (English)

    蔺芳; 王书丽; 徐存拴

    2011-01-01

    To study the action of the genes associated with steroid metabolism during liver regeneration (LR) at transcriptional level. The associated genes mentioned above were obtained by collecting the data of databases and referring to these, and the gene expression changes in the rat regenerating liver were checked by the gene chips. It was found that 83 genes were associated with liver regeneration. The initial and total expressing gene numbers in initiation phase of liver regeneration (0.5-4 h after PH), G0/G1 transition (4-6 h after PH), cell proliferation (6-66 h after PH), cell differentiation and structure-function reconstruction (72-168 h after PH) were 48, 11, 33, 3 and 48, 41, 80, 54, respectively, illustrating that the associated genes mainly were triggered in initiation phase of LR, and worked in different phases. Frequencies of both up-regulation and down-regulation being 286as well as classification of expression patterns into 12 types showed the diversification and complication of genes expression. It was inferred from the above gene expression changes and patterns that estrogen biosynthesis at prophase and biosynthesis of cholesterol and bile acid at anaphase were augmented; the increases in biosynthesis of androgen, glucocorticoid and progesterone almost during the whole LR; catabolism of progesterone and estrogen at forepart, prophase and anaphase, androgen catabolism at metaphase, and cholesterol catabolism at anaphase were all enhanced; and the catabolism of bile acid and mineralocorticoid remained almost during the whole LR.%为在基因转录水平了解类固醇代谢相关基因在大鼠肝再生(Liver regeneration,LR)中作用,文章通过搜集网站资料和查阅相关论文等方法获得了参与上述代谢活动的基因,用基因芯片检测了它们在大鼠再生肝中表达情况,初步证实上述基因中83个基因与肝再生相关.肝再生启动(PH后0.5~4 h)、G0/GI过渡(PH后4~6 h)、细胞增殖(PH后6~66h)、细胞分

  6. Suppression of cell-mediated immunity by misonidazole

    Energy Technology Data Exchange (ETDEWEB)

    Rockwell, S.; Neaderland, M.H. (Yale Univ., New Haven, CT (USA). School of Medicine)

    1982-08-01

    The data presented in this report demonstrate that single treatments with large doses of misonidazole (l mg/g) produce significant inhibition of delayed hypersensitivity to DNFB. Contact sensitivity to DNFB is generally considered to be a cell-mediated immune response (Asherson and Ptak 1968, Moorhead 1978, Phanuphak et al. 1974, Zembala and Asherson 1973). The authors' histological observations and the lack of ear swelling in the nude mice support this interpretation.

  7. Effect of antihypertensive agents on stellate cells during liver regeneration in rats Efeito de agentes anti-hipertensivos sobre as células estreladas durante a regeneração hepática em ratos

    Directory of Open Access Journals (Sweden)

    Leandra N. Z. Ramalho

    2003-03-01

    Full Text Available BACKGROUND: Although most studies have focused on the hepatocytes, all the hepatic cells participate in the regenerative process, among them the stellate cells. The stellate cells are mesenchymal cells involved in local neurotransmission and paracrine regulation of several liver functions. Acute hepatic tissue loss promotes the proliferation and activation of stellate cells from a quiescent state to myofibroblast-like cells. AIM: Investigate the effects of antihypertensive agents on the stellate cell population during the liver regenerative phenomenon in rats. METHODS: Adult male Wistar rats received lisinopril, losartan, bradykinin, or saline solution in a proportional volume, intraperitoneally, before and after 70% partial hepatectomy. Animals from the experimental and saline groups were sacrificed at 36 hours after partial hepatectomy. The alpha-smooth muscle actin labelled stellate cells population was counted in the periportal and pericentral zones of the liver specimen. RESULTS: The labelled stellate cells were more numerous in the control group both in the periportal and pericentral zones at 36 hours after partial hepatectomy than at the other times. The population of stellate cells was significantly lower in the losartan group and higher in the bradykinin and lisinopril groups than in the control group. CONCLUSIONS: These results suggest that losartan can inhibit and bradykinin and lisinopril can stimulate the stellate cell population during liver regeneration in rats. These cells synthesize several substances to stimulate liver regeneration.RACIONAL: Embora a maioria dos estudos focalize os hepatócitos, todas as células hepáticas participam do processo regenerativo, entre elas as células estreladas, que são células mesenquimais envolvidas na regulação de uma série de funções hepáticas. A perda aguda de parênquima hepático induz proliferação e ativação destas células, a partir de estado de quiescência para fen

  8. Flow cytometry evaluation of cell-mediated cytotoxicity.

    Science.gov (United States)

    Zarcone, D; Tilden, A B; Cloud, G; Friedman, H M; Landay, A; Grossi, C E

    1986-11-20

    A novel flow cytometry method for the evaluation of cell-mediated cytotoxicity is described. This method uses flow cytometry analysis to distinguish target cells from effector cells by differences in volume and light scatter characteristics. Non-viable target cells, following their interaction with effector cells, are determined via propidium iodide (PI) dye exclusion and then expressed as a percentage of the total target cell population. This assay is suitable both for analysis of systems which allow recycling of cytotoxic effector cells (total cell cytotoxicity assays, TCCA), and of systems in which recycling does not occur (single cell cytotoxicity assays, SCCA). Natural killer (NK) cell-mediated cytotoxicity evaluated by flow cytometry is significantly correlated with the standard 51Cr release assay. Flow cytometry can also be used to evaluate the competitive inhibition that certain cell types exert on the cell-mediated killing of NK-sensitive targets. A prerequisite for this assay is that competitor cells and target cells are distinguishable through their volume and light scatter characteristics. Advantages and pitfalls of the flow cytometry method are discussed, in comparison with the 51Cr-release assay.

  9. 带肝中静脉的活体右半肝移植供者Ⅳ段肝静脉分型对术后残肝淤血和再生的影响%The effect of segment Ⅳ hepatic vein's anatomy on remnant liver congestion and regeneration in right lobe liver graft donors with inclusion of the MHV

    Institute of Scientific and Technical Information of China (English)

    蒋文涛; 马楠; 王洪海; 张骊; 郭庆军; 潘澄; 邓永林; 郑虹; 朱志军

    2013-01-01

    Objective To investigate the effect of segment Ⅳ hepatic vein's type on the early remnant liver congestion and regeneration in right lobe living-related liver graft donors (LDLT) with the inclusion of middle hepatic vein (MHV).Methods Between October 2008 and April 2010,44 LDLT with MHV were performed.According to the type of Nakamura,we classified the segment Ⅳ hepatic vein by means of IQQA-MSCT and verified in operartion.We measured the volume of remnant liver by means of IQQA-MSCT and judged the congestion of segment Ⅳ through postoperative CT scan.Results IQQAMSCT was an effective method to construct and sort segment Ⅳ hepatic vein,which was verified by operartion.The ratio of serious segment Ⅳ congestion was 3.8% in type Ⅰ,40.0% in type Ⅱ,37.5% in type Ⅲ,and the difference was significant (x2 =9.004,P =0.007).Two weeks post operation,the volume of segments Ⅰ-Ⅲ in type Ⅰ was smaller than in type Ⅱ (F =7.977,P =0.01) and type Ⅲ (F =7.977,P =0.032),the volume of segment Ⅳ in type Ⅰ was bigger than in type Ⅱ (F =6.541,P =0.005) and type Ⅲ (F =6.541,P =0.014) conversely.The regeneration rate of segment Ⅳ in type Ⅰ was bigger than in type Ⅱ (F =4.14,P =0.027) and type Ⅲ (F =4.14,P =0.04),on the contrary,the regeneration rate of segments Ⅰ-Ⅲ in type Ⅰ was smaller than in in type Ⅱ (F =5.577,P =0.005) and type Ⅲ (F =5.577,P =0.047).But the regeneration rate of remnant liver was not different between the three groups (F =1.831,P =0.173).Conclusions IQQA-MSCT was an effective method to evaluate the donor in LDLT.The type of segment Ⅳ hepatic vein affected the remnant liver's congestion and regeneration.The segment Ⅳ hepatic vein's anatomy was significantly related with the postoperative congestion and regeneration of the remnant liver,which was compensated by the regeneration of segments Ⅰ-Ⅲ.%目的 了解带肝中静脉活体右半肝移植供者Ⅳ段肝静脉分型对术后残肝淤血

  10. My Regeneration:

    DEFF Research Database (Denmark)

    Carter, Dale

    2016-01-01

    and cultural referents shows that it offers an index to the album. Using its frontier setting and a variety of sacred and secular myths, symbols and icons, ‘Heroes and Villains,’ like Smile as a whole, offers historically-informed visions of national decline, crisis and regeneration that are at once critical...

  11. Parenteral Nutrition in Liver Resection

    Directory of Open Access Journals (Sweden)

    Carlo Chiarla

    2012-01-01

    Full Text Available Albeit a very large number of experiments have assessed the impact of various substrates on liver regeneration after partial hepatectomy, a limited number of clinical studies have evaluated artificial nutrition in liver resection patients. This is a peculiar topic because many patients do not need artificial nutrition, while several patients need it because of malnutrition and/or prolonged inability to feeding caused by complications. The optimal nutritional regimen to support liver regeneration, within other postoperative problems or complications, is not yet exactly defined. This short review addresses relevant aspects and potential developments in the issue of postoperative parenteral nutrition after liver resection.

  12. 扶正化瘀方对大鼠肝大部切除后肝再生的影响%Effect of Fuzheng huayu decoction on liver regeneration after partial hepatectomy in rats

    Institute of Scientific and Technical Information of China (English)

    张玉果; 赵素贤; 任伟光; 李亚; 南月敏

    2013-01-01

    目的 探讨扶正化瘀方对大鼠肝大部切除(PH)后肝再生的影响.方法 将28只正常雄性Wistar大鼠随机分为4组,分别为假手术组(对照组)、PH模型(PH)组、PH+扶正化瘀组和PH+促肝细胞生长素(pHGF)组,每组7只.扶正化瘀组和PH +pHGF组于实验前3天至实验结束,分别给予扶正化瘀方药液灌胃1 ml/l00 g和pHGF腹腔注射1 ml/100 g,每日1次.术后24 h心脏采血后处死大鼠,计算各组肝再生速度,血清标本检测ALT、AST、肿瘤坏死因子α(TNF-α)和白细胞介素6(IL-6)水平,免疫组织化学染色和荧光定量PCR检测肝组织cyclinD1的表达.结果 PH组、PH +pHGF组和PH+扶正化瘀组ALT、AST水平明显升高,白蛋白水平明显下降,与对照组比较差异均有统计学意义(均P <0.01).与对照组比较,PH组、PH +pHGF组和PH+扶正化瘀组血清TNF-α和IL-6水平均明显升高(均P<0.01).与对照组比较,PH组、PH+扶正化瘀组和PH +pHGF组大鼠有丝分裂指数、肝组织cyclin D1 mRNA和肝细胞核cyclin D1阳性率均明显升高(均P<0.01);PH+ PHGF组和PH+扶正化瘀组肝再生速度明显高于PH组[(22±4)%、(20±2)%比(13±1)%,P<0.01].与对照组比较,PH组、PH +pHGF组和PH+扶正化瘀组有丝分裂指数、肝组织cyclinD1 mRNA和肝细胞核cyclin D1阳性率均明显升高[有丝分裂指数:(25.90±0.95),(29.70±0.50),(30.30±0.96)%比(0.95±0.19)%;肝组织cyclin D1 mRNA:2.18±0.37,2.73±0.29,2.93±0.18比1.03±0.09;肝细胞核cyclin D1阳性率:(27.20±0.36)%,(28.30±0.16)%,(29.30±0.21)%比(0.95±0.19)%](P<0.01或P<0.05),而PH+扶正化瘀组和PH +pHGF组间差异无统计学意义(P>0.05).结论 扶正化瘀方可通过增强cyclinD1表达而促进大鼠肝大部切除术后的肝再生.%Objective To investigate the effect and possible mechanism of Fuzheng huayu decoction on liver regeneration in rats subsequent to partial hepatectomy.Methods Male Wistar rats were randomized into 4

  13. Effects of sympathetic denervation on liver regeneration after partial hepatic resection%去交感神经状态对肝部分切除后肝再生的影响

    Institute of Scientific and Technical Information of China (English)

    夏锋; 何振平; 段恒春; 李昆; 陈莉; 王小丽; 董家鸿

    2001-01-01

    目的 建立去交感神经状态动物模型并探讨去交感神经状态下对肝切除后肝再生的影响。方法 雄性Wistar大鼠共90只,用6-OHDA制作去交感神经状态动物模型。其中30只大鼠分为实验组和对照组各15例。按Higgins和Anderson方法加以改良,作肝左叶和肝中叶切除(约占全肝的68%)。实验组加做去交感神经模型。术后第7天全部动物经抽血处死,计算相对肝重(HMI)、肝再生率的指数(RLR)和有丝分裂指数(MI)。肝脏DNA合成率用3H标记胸腺嘧啶核苷(3H-TdR)掺入法测得。结果 注射6-OHDA后3~14 d,NE含量明显降低。行肝切除后两组大鼠术后7 d均无死亡,实验组大鼠HMI、RLR、MI和3H-TdR DNA掺入量较对照组均明显下降(P<0.01)。结论 6-OHDA可明显起到化学性去交感神经的效果。交感神经的存在与否对肝切除后肝再生具有明显影响,去交感神经状态可抑制肝再生的进程。%Objective To establish the animal model of denervation of sympathetic nerve and to explore the effects of denervation of the sympathetic nerve on liver regeneration after partial resection. Methods The animal model of denervation of sympathetic nerve was made with 6-OHDA. A total of thirty male Wistar rats were divided equally into experimental and control group. The left and middle lobe of liver were resected with improved Higgins and Anderson's method. Meanwhile, denervation was made in the experimental group. All the rats were killed by haemospasia on the 7 th day after operation. HMI, RLR and MI were measured. The rates of DNA synthesis were detected by 3H-TdR method. Results The concentration of NE decreased extremely on day 3 to day 14 after administration of 6-ONDA. No death happened in all the rats 7 days after liver resection. HMI, RLR, MI and 3H-TdR incorporation significantly decreased in experimental group compared with that in control (P<0.01). Conclusion The chemical

  14. The influence of hypothyroidism on liver regeneration: an experimental study in rats A influência do hipotireoidismo na regeneração hepatica: estudo experimental em ratos

    Directory of Open Access Journals (Sweden)

    Maria de Lourdes Pessole Biondo-Simões

    2007-01-01

    Full Text Available BACKGROUND: The influence of hypothyroidism in liver regeneration has been a controversial opinions. PURPOSE: The aim of this study is to identify the relationship between hypothyroidism and liver regeneration in rats. METHODS: Forty male Wistar rats divided into two groups of 20 specimens each. One group (C consisted of euthyroid rats, and the other (H of hypothyroid rats. All the animals were anesthetized with xylazine and ketamine and subjected to a longitudinal incision in the anterior cervical region. The thyroid was completely resected in group H and left intact in group C. Ten days after the first surgery, both groups of rats were weighed and submitted to partial hepatectomy, in which the left lateral and median lobes were resected and weighed. Examinations were carried out after 24 hours and, on day 7, using 3 methods: KWON et al.'s formula to identify increase in volume; mitotic figure count in five fields; and the percentage of PCNA-positive nuclei in five fields. RESULTS: Using KWON's formula, the regeneration rate for Group C after 24 hours was 58.49% whereas that for Group H was 50.42% (p=0.0165. After 7 days, the regeneration rate for Group C was 93.04% and Group H 93.74% (p=0.2165. The average number of mitotic figures after 24 hours was 14 ± 1.5 for Group C and 9.8 ± 2.2 for Group H (p=0,00016. After 7 days the corresponding figures were 5.4 ± 1.1 and 5.1 ± 1.2 (p=0,6343. The average number of PCNA-positive nuclei after 24 hours was 13.55 ± 3.84 in Group C and 7.7 ± 2.11 in Group H (p =0,0006. The corresponding figures after 7 days were 3.5 ± 2.39 for Group C and 4.11 ± 1.90 for Group H (p>0.05. CONCLUSION: We conclude that hypothyroidism in rats causes a delay in hepatic regeneration in the first 24 hours, but that after seven days the rate of regeneration is equal to that in euthyroid rats.BACKGROUND: A influência do hipotireoidismo na regeneração hepatica tem opiniões controvérsas. OBJETIVO: Identificar a rela

  15. Paper-based bioactive scaffolds for stem cell-mediated bone tissue engineering.

    Science.gov (United States)

    Park, Hyun-Ji; Yu, Seung Jung; Yang, Kisuk; Jin, Yoonhee; Cho, Ann-Na; Kim, Jin; Lee, Bora; Yang, Hee Seok; Im, Sung Gap; Cho, Seung-Woo

    2014-12-01

    Bioactive, functional scaffolds are required to improve the regenerative potential of stem cells for tissue reconstruction and functional recovery of damaged tissues. Here, we report a paper-based bioactive scaffold platform for stem cell culture and transplantation for bone reconstruction. The paper scaffolds are surface-engineered by an initiated chemical vapor deposition process for serial coating of a water-repellent and cell-adhesive polymer film, which ensures the long-term stability in cell culture medium and induces efficient cell attachment. The prepared paper scaffolds are compatible with general stem cell culture and manipulation techniques. An optimal paper type is found to provide structural, physical, and mechanical cues to enhance the osteogenic differentiation of human adipose-derived stem cells (hADSCs). A bioactive paper scaffold significantly enhances in vivo bone regeneration of hADSCs in a critical-sized calvarial bone defect. Stacking the paper scaffolds with osteogenically differentiated hADSCs and human endothelial cells resulted in vascularized bone formation in vivo. Our study suggests that paper possesses great potential as a bioactive, functional, and cost-effective scaffold platform for stem cell-mediated bone tissue engineering. To the best of our knowledge, this is the first study reporting the feasibility of a paper material for stem cell application to repair tissue defects. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Enhanced antioxidant capacity of dental pulp-derived iPSC-differentiated hepatocytes and liver regeneration by injectable HGF-releasing hydrogel in fulminant hepatic failure.

    Science.gov (United States)

    Chiang, Chih-Hung; Wu, Wai-Wah; Li, Hsin-Yang; Chien, Yueh; Sun, Cho-Chin; Peng, Chi-Hsien; Lin, Alex Tong-Long; Huang, Chi-Shuan; Lai, Ying-Hsiu; Chiou, Shih-Hwa; Hung, Shuen-Iu; Chang, Yuh-Lih; Lan, Yuan-Tzu; Liu, Dean-Mo; Chien, Chian-Shiu; Huo, Teh-Ia; Lee, Shou-Dong; Wang, Chien-Ying

    2015-01-01

    Acute hepatic failure (AHF) is a severe liver injury leading to sustained damage and complications. Induced pluripotent stem cells (iPSCs) may be an alternative option for the treatment of AHF. In this study, we reprogrammed human dental pulp-derived fibroblasts into iPSCs, which exhibited pluripotency and the capacity to differentiate into tridermal lineages, including hepatocyte-like cells (iPSC-Heps). These iPSC-Heps resembled human embryonic stem cell-derived hepatocyte-like cells in gene signature and hepatic markers/functions. To improve iPSC-Heps engraftment, we next developed an injectable carboxymethyl-hexanoyl chitosan hydrogel (CHC) with sustained hepatocyte growth factor (HGF) release (HGF-CHC) and investigated the hepatoprotective activity of HGF-CHC-delivered iPSC-Heps in vitro and in an immunocompromised AHF mouse model induced by thioacetamide (TAA). Intrahepatic delivery of HGF-CHC-iPSC-Heps reduced the TAA-induced hepatic necrotic area and rescued liver function and recipient viability. Compared with PBS-delivered iPSC-Heps, the HGF-CHC-delivered iPSC-Heps exhibited higher antioxidant and antiapoptotic activities that reduced hepatic necrotic area. Importantly, these HGF-CHC-mediated responses could be abolished by administering anti-HGF neutralizing antibodies. In conclusion, our findings demonstrated that HGF mediated the enhancement of iPSC-Hep antioxidant/antiapoptotic capacities and hepatoprotection and that HGF-CHC is as an excellent vehicle for iPSC-Hep engraftment in iPSC-based therapy against AHF.

  17. Advances in human placenta-derived stem cells for liver regeneration%胎盘源性干细胞在肝脏疾病中的研究进展

    Institute of Scientific and Technical Information of China (English)

    王建; 朱争艳; 杜智

    2013-01-01

    人类胎盘源性干细胞(hPDSCs)是干细胞的混合群.再生医学已将其用于某些功能衰竭和损伤器官的细胞再生、抗细胞凋亡、抗炎,抗肿瘤和细胞功能恢复研究.目前已有许多实验研究证明:胎盘间充质干细胞(PDMSCs)可以在体外分化为肝细胞样细胞,并于体内外促进干细胞增生和抗肝细胞凋亡,在动物肝损伤模型抑制肝纤维化.本文就胎盘干细胞的来源、分类、生物学特性以及胎盘干细胞在肝脏疾病中的治疗研究做一综述,以便为进一步探讨胎盘源性干细胞在肝脏疾病治疗中的应用提供新的思路.%Human placenta-derived stem cells (hPD-SCs) are a mixed group of stem cells.Stem cell medicine has applications for organ damage or failure through regenerative,anti-apoptotic,anti-inflammatory and anti-tumor properties in addition to cell function recovery.Presently,human placenta mesenchymal stem cells (hPMSCs) have similar characteristics to the differentiation of hepatocyte-like cells by promoting hepatocyte regeneration,anti-hepatocyte apoptosis and anti-liver fibrosis,in vitro or in animal models.To further our investigation,a summary of the origin,sorting and biological properties of hPDSCs along with a narration of hPDSCs for liver disease therapy was written.This leads to a discussion for new ideas to further explore cell treatment for liver disease.

  18. Periodontal regeneration.

    Science.gov (United States)

    Ivanovski, S

    2009-09-01

    The ultimate goal of periodontal therapy is the regeneration of the tissues destroyed as a result of periodontal disease. Currently, two clinical techniques, based on the principles of "guided tissue regeneration" (GTR) or utilization of the biologically active agent "enamel matrix derivative" (EMD), can be used for the regeneration of intrabony and Class II mandibular furcation periodontal defects. In cases where additional support and space-making requirements are necessary, both of these procedures can be combined with a bone replacement graft. There is no evidence that the combined use of GTR and EMD results in superior clinical results compared to the use of each material in isolation. Great variability in clinical outcomes has been reported in relation to the use of both EMD and GTR, and these procedures can be generally considered to be unpredictable. Careful case selection and treatment planning, including consideration of patient, tooth, site and surgical factors, is required in order to optimize the outcomes of treatment. There are limited data available for the clinical effectiveness of other biologically active molecules, such as growth factors and platelet concentrates, and although promising results have been reported, further clinical trials are required in order to confirm their effectiveness. Current active areas of research are centred on tissue engineering and gene therapy strategies which may result in more predictable regenerative outcomes in the future.

  19. INHIBITION OF GLUCOCORTICOID ON ORNITHINE DECARBOXYLASE DURING RAT LIVER REGENERATION%皮质酮对大鼠肝再生过程中鸟氨酸脱羧酶的抑制

    Institute of Scientific and Technical Information of China (English)

    马建敏; 和俊涛; 索世英; 宁黔冀; 徐存栓

    2008-01-01

    Objective The regulation of ornithine decarboxylase (ODC) gene expression and enzyme activity by corticosterone, the main glucocorticoid in rat, during rat liver regeneration induced by partial hepatectomy (PH) was evaluated.Methods Bilateral adrenaleetomies (ADX) and sham-ADX were performed on ether-anesthetized rats 3 days before PH.Corticosterone in sesame oil was injected subcutaneously to adrenalectomied rats. ODC mRNA, ODC protein and enzyme activity were detected by RT-PCR, Western blotting and high performance liquid chromatography (HPLC), respectively. Results The ODC mRNA levels, protein accumulation and enzyme activity were lower in the intact liver compared to the regenerating liver.After PH, mRNA levels were remarkably enhanced in all groups (n=6 in each group) and peaked at 5 hours post-PH. Till 7 hours, the contents in all groups from high to low were ADX group,control group (Sham-ADX group), ADX treated with 10mg/kg and 40mg/kg body weight corticosterone group, respectively. ODC protein accumulation in ADX rats was higher than that in control rats (n=13, the same below), but it decreasod in corticosterone-treated (10mg/kg) rats until 24 hours post-PH, with a strong decline seen in 40mg/kg corticosterone-treated rats. ODC activity was rapidly promoted, and the highest levels were observed at 6 hours after PH in all groups (n=6 in each group). After corticosterone treatment, the activities declined significantly at 6 hours post-PH, with the lowest value found in the 40mg/kg group. Conclusion Corticosterone treatment results in dose-dependent decreases in ODC mRNA and enzyme protein both in the intact liver and the regenerating liver. The change in ODC activity is partially related to alterations of ODC mRNA and protein accumulation.%目的 研究大鼠体内主要的糖皮质激素--皮质酮对部分肝切除(PH)诱导的再生肝鸟氨酸脱羧酶(ODC)基因表达及酶活性的影响.方法 乙醚麻醉大鼠,于PH前3d行双侧肾上腺切除术

  20. Experiment study of the effect of Fuzhenghuayu decoction on cyclinD1 during liver regeneration in rats%扶正化瘀方对大鼠肝再生过程中cyclinD1影响的实验研究

    Institute of Scientific and Technical Information of China (English)

    张玉果; 赵素贤; 李建梅; 任伟光; 李亚; 南月敏

    2013-01-01

    Objective To investigate the effect of Fuzhenghuayu decoction on cyclinD1 expression and liver regeneration rate during liver regeneration in rats 72 hours after partial hepatectomy. Methods Twenty-four male Wistar rats were randomized into 4 groups:sham-operation group (control group) ,partial hepatectomy group (PH group) ,partial hepatectomy + Fuzhenghuayu decoction group (PH + Fuzheng group) ,partial hepatectomy + pHGF group (PH +pHGF group) ,with 6 rats ineach group. The rats in PH group,PH + Fuzheng group and PH + pHGF group were hepatectomized (left lobe and median lobe, about 70% of liver total weight) , however, the rats in sham-operation group were performed with sham operation only . The rats in PH + Fuzheng group and in PH + pHGF group were given Fuzhenghuayu decoction 1 ml/100 g by gavage and intraperitoneal injection with pHGF 1 ml/ 100 g,once a day ,from 3 days before the experiment to end of the experiment. The rats were sacrificed 72 hours after the operation , and liver regeneration rate and mitotic indexes were calculated , and the expression levels of cyclinD1 were detected by immunohistostaining and fluorescent quantitation PCR . Resufl S As compared with those in sham-operation group, the mitotic indexes, expression levels of cyclin D1 mRNA of liver tissues and positive rate of cyclin D1 of hepatic nucleus in PH group ,PH + Fuzheng group ,PH + pHGF group were significantly increased ( P 0.05).结论 扶正化瘀方可上调正常大鼠肝大部切除术后72 h时肝细胞cyclinD1的表达,从而促进肝再生.

  1. Efeito do omeprazol e do pantoprazol sobre a regeneração hepática após hepatectomia parcial em ratos Effect of omeprazole and pantoprazole on liver regeneration after partial hepatectomy in rats

    Directory of Open Access Journals (Sweden)

    Gustavo Barreto de Melo

    2003-12-01

    Full Text Available OBJETIVO: Avaliar os efeitos do omeprazol e do pantoprazol sobre a regeneração hepática após hepatectomia parcial. MÉTODOS: Cinqüenta e oito ratos Wistar machos foram divididos em 4 grupos: Grupo SHAM, Grupo HP, Grupo PANTO e Grupo OMEP. Eles foram submetidos a hepatectomia parcial de 67% (Grupos HP, PANTO e OMEP ou laparotomia (Grupo SHAM. Os fígados foram removidos 32 e 56 horas após a operação. Depois, os animais foram sacrificados. Em todos os grupos, as substâncias (solução salina, omeprazol e pantoprazol foram aplicadas diariamente a partir do momento em que foram operados até o sacrifício. RESULTADOS: O índice de mitose no Grupo SHAM não foi significativo. Trinta e duas horas após a hepatectomia, a contagem de mitoses foi de 1,2 ± 1,09 para o Grupo HP, 1,2 ± 1,6 para o Grupo OMEP e 2,6 ± 3,2 para o Grupo PANTO. Na análise após 56 horas, os valores foram 1,6 ± 0,89 para o HP, 2 ± 1,8 para o OMEP e 2,6 ± 0,54 para o PANTO. Esses resultados não foram estatisticamente significativos. CONCLUSÃO: O omeprazol e o pantoprazol, agentes inibidores da bomba de prótons (H+, K+-ATPase, não interferem na regeneração hepática 32 e 56 horas após hepatectomia parcial a 67% em ratos.PURPOSE: To assess the effects of omeprazole and pantoprazole on liver regeneration after partial hepatectomy. METHODS: Fifty eight male Wistar rats were divided into 4 groups: SHAM, HP, PANTO and OMEP Groups. They were submitted to 67% partial hepatectomy (HP, PANTO and OMEP Groups or laparotomy (SHAM Group. Their livers were removed 32 and 56 hours after the operation. Then, the animals were sacrificed. In all groups, the substances (saline solution, omeprazole and pantoprazole were injected once daily from the moment they were operated on until the time of sacrifice. RESULTS: In SHAM Group the mitotic index was not significant. Thirty two hours after hepatectomy, the mitosis index was 1.2 ± 1.09 in HP Group, 1.2 ± 1.6 in OMEP Group and 2

  2. Reparative inflammation takes charge of tissue regeneration.

    Science.gov (United States)

    Karin, Michael; Clevers, Hans

    2016-01-21

    Inflammation underlies many chronic and degenerative diseases, but it also mitigates infections, clears damaged cells and initiates tissue repair. Many of the mechanisms that link inflammation to damage repair and regeneration in mammals are conserved in lower organisms, indicating that it is an evolutionarily important process. Recent insights have shed light on the cellular and molecular processes through which conventional inflammatory cytokines and Wnt factors control mammalian tissue repair and regeneration. This is particularly important for regeneration in the gastrointestinal system, especially for intestine and liver tissues in which aberrant and deregulated repair results in severe pathologies.

  3. Epoxyeicosanoids promote organ and tissue regeneration.

    Science.gov (United States)

    Panigrahy, Dipak; Kalish, Brian T; Huang, Sui; Bielenberg, Diane R; Le, Hau D; Yang, Jun; Edin, Matthew L; Lee, Craig R; Benny, Ofra; Mudge, Dayna K; Butterfield, Catherine E; Mammoto, Akiko; Mammoto, Tadanori; Inceoglu, Bora; Jenkins, Roger L; Simpson, Mary A; Akino, Tomoshige; Lih, Fred B; Tomer, Kenneth B; Ingber, Donald E; Hammock, Bruce D; Falck, John R; Manthati, Vijaya L; Kaipainen, Arja; D'Amore, Patricia A; Puder, Mark; Zeldin, Darryl C; Kieran, Mark W

    2013-08-13

    Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis.

  4. Liver bioengineering: current status and future perspectives.

    Science.gov (United States)

    Booth, Christopher; Soker, Tom; Baptista, Pedro; Ross, Christina L; Soker, Shay; Farooq, Umar; Stratta, Robert J; Orlando, Giuseppe

    2012-12-21

    The present review aims to illustrate the strategies that are being implemented to regenerate or bioengineer livers for clinical purposes. There are two general pathways to liver bioengineering and regeneration. The first consists of creating a supporting scaffold, either synthetically or by decellularization of human or animal organs, and seeding cells on the scaffold, where they will mature either in bioreactors or in vivo. This strategy seems to offer the quickest route to clinical translation, as demonstrated by the development of liver organoids from rodent livers which were repopulated with organ specific cells of animal and/or human origin. Liver bioengineering has potential for transplantation and for toxicity testing during preclinical drug development. The second possibility is to induce liver regeneration of dead or resected tissue by manipulating cell pathways. In fact, it is well known that the liver has peculiar regenerative potential which allows hepatocyte hyperplasia after amputation of liver volume. Infusion of autologous bone marrow cells, which aids in liver regeneration, into patients was shown to be safe and to improve their clinical condition, but the specific cells responsible for liver regeneration have not yet been determined and the underlying mechanisms remain largely unknown. A complete understanding of the cell pathways and dynamics and of the functioning of liver stem cell niche is necessary for the clinical translation of regenerative medicine strategies. As well, it will be crucial to elucidate the mechanisms through which cells interact with the extracellular matrix, and how this latter supports and drives cell fate.

  5. Liver transplant

    Science.gov (United States)

    Hepatic transplant; Transplant - liver; Orthotopic liver transplant; Liver failure - liver transplant; Cirrhosis - liver transplant ... The donated liver may be from: A donor who has recently died and has not had liver injury. This type of ...

  6. Regenerator seal

    Science.gov (United States)

    Davis, Leonard C.; Pacala, Theodore; Sippel, George R.

    1981-01-01

    A method for manufacturing a hot side regenerator cross arm seal assembly having a thermally stablilized wear coating with a substantially flat wear surface thereon to seal between low pressure and high pressure passages to and from the hot inboard side of a rotary regenerator matrix includes the steps of forming a flat cross arm substrate member of high nickel alloy steel; fixedly securing the side edges of the substrate member to a holding fixture with a concave surface thereacross to maintain the substrate member to a slightly bent configuration on the fixture surface between the opposite ends of the substrate member to produce prestress therein; applying coating layers on the substrate member including a wear coating of plasma sprayed nickel oxide/calcium flouride material to define a wear surface of slightly concave form across the restrained substrate member between the free ends thereon; and thereafter subjecting the substrate member and the coating thereon to a heat treatment of 1600.degree. F. for sixteen hours to produce heat stabilizing growth in the coating layers on the substrate member and to produce a thermally induced growth stress in the wear surface that substantially equalizes the prestress in the substrate whereby when the cross arm is removed from the fixture surface following the heat treatment step a wear face is formed on the cross arm assembly that will be substantially flat between the ends.

  7. Cell mediated immune response in human antirabies revaccination

    Directory of Open Access Journals (Sweden)

    Débora Regina Veiga

    1987-04-01

    Full Text Available The occurrence of secondary cell mediated immune response (CMI in human antirabies immunization was studied. The Puenzalida & Palácios vaccine was used because it is routinely used in Brazil. CMI was evaluated by lymphoblastic transformation indices obtained in whole blood culture in the presence of rabies and control (nervous tissue antigens. Eleven volunteers submitted to revaccination constituted the group under study, while three other volunteers submitted primo vaccination were utilized as control group. A clear secondary CMI to rabies antigen was detected in all the revaccinated volunteers who showed earlier and more intense response than the control group. Response to the control antigen, however, present in all the components of the first group was not detectable in two out of the three primovaccinated and very low in the third one.

  8. Molecular imaging of cell-mediated cancer immunotherapy.

    Science.gov (United States)

    Lucignani, Giovanni; Ottobrini, Luisa; Martelli, Cristina; Rescigno, Maria; Clerici, Mario

    2006-09-01

    New strategies based on the activation of a patient's immune response are being sought to complement present conventional exogenous cancer therapies. Elucidating the trafficking pathways of immune cells in vivo, together with their migratory properties in relation to their differentiation and activation status, is useful for understanding how the immune system interacts with cancer. Methods based on tissue sampling to monitor immune responses are inadequate for repeatedly characterizing the responses of the immune system in different organs. A solution to this problem might come from molecular and cellular imaging - a branch of biomedical sciences that combines biotechnology and imaging methods to characterize, in vivo, the molecular and cellular processes involved in normal and pathologic states. The general concepts of noninvasive imaging of targeted cells as well as the technology and probes applied to cell-mediated cancer immunotherapy imaging are outlined in this review.

  9. Influence of Liver regeneration after partial hepatectomy on the development of liver metastasis of colon cancer in rats%肝切除术后肝再生对大鼠结肠癌肝转移灶生长的影响

    Institute of Scientific and Technical Information of China (English)

    徐波; 蔡文松; 肖焕擎; 李书华; 夏金堂; 朱光辉; 翁杰锋

    2009-01-01

    目的 探讨肝再牛进程触发大鼠结肠痛肝转移残肝内隐性转移灶进展的发生机制.方法 采用肝包膜下种植建立结肠癌肝转移大鼠模型,随机分为假手术组、37%肝切除组和70%肝切除组;采用腹膜后注射建市结肠癌腹膜后转移模型,随机分为假手术组和70%肝切除组.手术后3周处死动物,测定肝内转移瘤量、再生肝重及腹膜后瘤结节重.在含有肝切除后24 h和14 d的门静脉血清培养基中进行结肠癌细胞Lovo体外培养,5.溴脱氧尿核苷(5-BrdU)DNA掺入法检测细胞增殖反应.结果 手术切除明显促进70%肝切除组肝内残留癌牛长(P0.05);肝切后24 h门静脉血清组5-BrdU DNA掺人率从第72小时开始增加,至第120小时呈持续增加趋势(P0.05).结论 结肠癌肝转移切除术后可诱发肝内微小残留灶的进展,并不通过血液循环全身性释放,对肝外转移瘤并不发挥作用.肝切除范围与诱发肿瘤生长有关,只有肝切除达到一定程度时,才足以刺激肿瘤生长.%Objective To investigate the stimulated effect of liver regeneration on colon cancer cells in remnant liver in rats. Methods Rat models with liver metastases or retro-peritoneal metastases of colon cancer were established: animals underwent 37% or 70% liver resection and were compared with a sham laparotomy( 15, 25, 15 cases, respectively). Metastases were performed two weeks before resection. Rats were killed 3 weeks after the resection. Total body weight, liver and tumor weights were recorded. The human colon adenocarcinoma cell line Lovo was cultured in the presence of portal serum withdrawn 24 hours and 14 days after partial hepatectomy(PH). DNA synthesis was assessed by flow cytometry analysis for 5-Bromodeoxyuridine (5-BrdU) incorporation. Results The tumor growth was accelerated in the remnant liver in 70% PH group, but the tumors in 37% PH group and retro-peritoneal site were not influenced by PH. Compared with the control group

  10. Regeneração hepática induzida por ressecção segmentar do fígado, em rato Hepatic regeneration induced by segmental liver resection, in rats

    Directory of Open Access Journals (Sweden)

    Andy Petroianu

    2004-02-01

    Full Text Available OBJETIVO: Avaliar a regeneração progressiva do parênquima hepatocitário, nos seus aspectos macro e microscópicos, em pós-operatório imediato e tardio de ressecção segmentar do fígado. MÉTODO: Foram estudados 10 ratos machos albinos da raça Wistar, pesando entre 250 e 300 gramas, submetidos à hepatectomia parcial de lobo esquerdo, com retirada de cerca de 20% da massa total do órgão. Os animais foram divididos aleatoriamente em dois grupos (n=5 para estudo no 7º (Grupo 1 e 21º (Grupo 2 dias pós-operatórios. Decorrido o tempo de acompanhamento, avaliou-se o aspecto macroscópico e microscópico do fígado. RESULTADOS: No Grupo 1, após sete dias, os animais apresentavam a cavidade abdominal com poucas aderências. O fígado mostrava reação cicatricial no local da ressecção, porém seu tamanho já era próximo ao normal. O exame histopatológico mostrou freqüentes sinais de poliploidia dos hepatócitos, além de tecido de granulação frouxo e desordenado, acompanhado de escasso infiltrado de células inflamatórias. O Grupo 2, após 21 dias, mostrava poucas aderências na cavidade abdominal, e o fígado com aspecto e dimensões próximos ao normal. A histologia mostrou tecido cicatricial mais denso, ordenado, sem sinais inflamatórios. Observou-se apenas pequeno grau de poliploidia hepatocitária. CONCLUSÃO: Após remoção cirúrgica de 20% do parênquima hepático houve aumento temporário da renovação celular verificado por poliploidia hepatocitária.BACKGROUND: To assess the progression of liver regeneration after partial hepatic resection. METHODS: Ten Wistar adult rats, of both sexes were studied. After anesthesia with ether, the animals were submitted to a left lobe parcial hepatectomy . Rats were randomly divided into two groups (n=5 according to the day macro and microscopic studies were carried out, 7th (Group 1 or 21st postoperative days. RESULTS: All rats survived throughout the experimental protocol. The

  11. TISSUE REGENERATION. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration.

    Science.gov (United States)

    Zhang, Yongyou; Desai, Amar; Yang, Sung Yeun; Bae, Ki Beom; Antczak, Monika I; Fink, Stephen P; Tiwari, Shruti; Willis, Joseph E; Williams, Noelle S; Dawson, Dawn M; Wald, David; Chen, Wei-Dong; Wang, Zhenghe; Kasturi, Lakshmi; Larusch, Gretchen A; He, Lucy; Cominelli, Fabio; Di Martino, Luca; Djuric, Zora; Milne, Ginger L; Chance, Mark; Sanabria, Juan; Dealwis, Chris; Mikkola, Debra; Naidoo, Jacinth; Wei, Shuguang; Tai, Hsin-Hsiung; Gerson, Stanton L; Ready, Joseph M; Posner, Bruce; Willson, James K V; Markowitz, Sanford D

    2015-06-12

    Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here, we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. The same compound also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. Thus, 15-PGDH inhibition may be a valuable therapeutic strategy for tissue regeneration in diverse clinical contexts.

  12. Cytokines and Liver Diseases

    Directory of Open Access Journals (Sweden)

    Herbert Tilg

    2001-01-01

    Full Text Available Cytokines are pleiotropic peptides produced by virtually every nucleated cell in the body. In most tissues, including the liver, constitutive production of cytokines is absent or minimal. There is increasing evidence that several cytokines mediate hepatic inflammation, apoptosis and necrosis of liver cells, cholestasis and fibrosis. Interestingly, the same mediators also mediate the regeneration of liver tissue after injury. Among the various cytokines, the proinflammatory cytokine tumour necrosis factor-alpha (TNF-a has emerged as a key factor in various aspects of liver disease, such as cachexia and/or cholestasis. Thus, antagonism of TNF-a and other injury-related cytokines in liver diseases merits evaluation as a treatment of these diseases. However, because the same cytokines are also necessary for the regeneration of the tissue after the liver has been injured, inhibition of these mediators might impair hepatic recovery. The near future will bring the exiting clinical challenge of testing new anticytokine strategies in various liver diseases.

  13. Studies of cell-mediated immune responses to influenza vaccination in systemic lupus erythematosus

    NARCIS (Netherlands)

    Holvast, Albert; Van Assen, Sander; De Haan, Aalzen; Huckriede, Anke; Benne, Cornelis A.; Westra, Johanna; Palache, Abraham; Wilschut, Jan; Kallenberg, Cornelis; Bijl, Marc

    2009-01-01

    Objective. Both antibody and cell-mediated responses are involved in the defense against influenza. In patients with systemic lupus erythematosus (SLE), a decreased antibody response to subunit influenza vaccine has been demonstrated, but cell-mediated responses have not yet been assessed. This stud

  14. 维生素K2促进大鼠肝再生模型肝切除术后肝功能恢复的研究%Positive effect of vitamin K2 on recovery of liver function in liver regeneration rats model after hepatectomy

    Institute of Scientific and Technical Information of China (English)

    张谷裕; 刘国华; 林满洲; 李明意; 杨永光; 许浩

    2013-01-01

    Objective To investigate the positive effect of the vitamin K2 on recovery of liver function in the rat liver regeneration process. Methods 180 SD rats were randomly divided into six groups including five experimental groups: (1) 2AAF+VLVK2/PH, (2) 2AAF+LVK/PH, (3) 2AAF+MVK/PH, (4) 2AAF+HVK/ PH, (5) 2AAF+VHVK/PH, and control group: 2AAF/PH. The 70% partial hepatectomy (PH) were performed on the day 4, 8, 12, 16 and 20. The levels of ALT, AST, ALB in blood serum were examined. Results Rats in 2AAF/PH group had significantly higher ALT, AST and a markedly lower level of ALB than other experimental groups on the day 4, 8(P 0.05 ). Conclusion Vitamin K2 can promote the recovery of rats liver function, and when dose were lower than 20 mg/ kg, the effect was dose dependent.%目的:通过建立大鼠肝卵圆细胞增殖肝再生模型.探讨维生素K2对大鼠肝再生模型部分肝切除术后肝再生过程中肝功能恢复的影响.方法:180只SD雄性大鼠随机分为6组,实验组5组:(1)2AAF+VLVK2/PH,(2)2AAF+LVK2/PH,(3)2AAF+MVK2/PH,(4)2AAF+HVK2/PH,(5)2AAF+VHVK2/PH;对照组:2AAF/PH.分别于术后第4、8、12、16、20天采血检测血清天门冬氨酸氨基转移酶(AST)、血清丙氨酸氨基转移酶(ALT)、白蛋白(ALB)的动态变化情况.结果:2AAF/PH组第4、8天ALT、AST与5组维生素K2不同剂量实验组相比较明显升高(P0.05).结论:维生素K2对大鼠肝再生模型术后肝功能恢复有明显的改善作用;当剂量低于20 mg/kg时,肝功能恢复呈剂量依赖性.

  15. A therapy for liver failure found in the JNK yard.

    Science.gov (United States)

    Willenbring, Holger; Grompe, Markus

    2013-04-11

    In the liver, the hepatocyte mass is kept stable through a tight balance between hepatocyte death and proliferation that is frequently lost upon acute or chronic liver injury. Wuestefeld et al. (2013) now identify a potentially druggable target that enhances hepatocyte proliferation and promotes liver regeneration, thereby preventing liver failure.

  16. Proliferative effect of the aqueous extract of Hyptis pectinata on liver regeneration after partial hepatectomy in rats Efeito do extrato aquoso da Hyptis pectinata na regeneração hepática após hepatectomia parcial em ratos

    Directory of Open Access Journals (Sweden)

    Gustavo Barreto Melo

    2006-01-01

    Full Text Available PURPOSE: This study was carried out to assess the effects of the aqueous extract of Hyptis pectinata leaves on liver regeneration and on serum enzymes (AST, ALT and gamma-GT after 67% partial hepatectomy in rats. METHODS: AST, ALT and gamma-GT, were determined by conventional procedures using a spectrophotometer (Model E2250-CELM. Liver regeneration was evaluated by immunohistochemical staining for proliferating cell nuclear antigen (PCNA. RESULTS:Oral pretreatment during 4 days at 100 mg/kg increased liver regeneration index. At 200 mg/kg, AST level was statistically decreased in comparison to the group submited to distilled water administration. The other enzymes assessed disclosed no difference when all groups were compared. CONCLUSION: The present study shows that the aqueous extract of Hyptis pectinata leaves contains some biological active principles that stimulate liver regeneration at 100 mg/kg and cause slight hepatic protection at 200 mg/kg.OBJETIVO: Este estudo foi realizado com o objetivo de verificar o efeito do extrato aquoso da Hyptis pectinata na regeneração hepática bem como nos níveis das enzimas séricas (AST, ALT e gama-GT após hepatectomia parcial de 67% em ratos. MÉTODOS: AST, ALT e gama-GT, foram determinadas pelo método cinético utilizando um espectrofotômetro (Modelo E2250-CELM. A regeneração hepática foi avaliada por imunohistoquímica (PCNA. RESULTADOS: O pré-tratamento oral de 100 mg/kg foi realizado durante 4 dias e causou aumento na regeneração hepática O pré-tratamento oral com 200 mg/kg diminuiu significativamente os níveis de AST quando comparado com o grupo submetido ao pré-tratamento com água destilada. As demais enzimas avaliadas não apresentaram diferenças quando comparadas entre os grupos estudados. CONCLUSÃO: O presente estudo mostra que o extrato aquoso da Hyptis pectinata, numa concentração de 100 mg/kg possui alguma atividade biológica estimulando a regeneração hepática e

  17. CXCR5+ T helper cells mediate protective immunity against tuberculosis

    Science.gov (United States)

    Slight, Samantha R.; Rangel-Moreno, Javier; Gopal, Radha; Lin, Yinyao; Fallert Junecko, Beth A.; Mehra, Smriti; Selman, Moises; Becerril-Villanueva, Enrique; Baquera-Heredia, Javier; Pavon, Lenin; Kaushal, Deepak; Reinhart, Todd A.; Randall, Troy D.; Khader, Shabaana A.

    2013-01-01

    One third of the world’s population is infected with Mycobacterium tuberculosis (Mtb). Although most infected people remain asymptomatic, they have a 10% lifetime risk of developing active tuberculosis (TB). Thus, the current challenge is to identify immune parameters that distinguish individuals with latent TB from those with active TB. Using human and experimental models of Mtb infection, we demonstrated that organized ectopic lymphoid structures containing CXCR5+ T cells were present in Mtb-infected lungs. In addition, we found that in experimental Mtb infection models, the presence of CXCR5+ T cells within ectopic lymphoid structures was associated with immune control. Furthermore, in a mouse model of Mtb infection, we showed that activated CD4+CXCR5+ T cells accumulated in Mtb-infected lungs and produced proinflammatory cytokines. Mice deficient in Cxcr5 had increased susceptibility to TB due to defective T cell localization within the lung parenchyma. We demonstrated that CXCR5 expression in T cells mediated correct T cell localization within TB granulomas, promoted efficient macrophage activation, protected against Mtb infection, and facilitated lymphoid follicle formation. These data demonstrate that CD4+CXCR5+ T cells play a protective role in the immune response against TB and highlight their potential use for future TB vaccine design and therapy. PMID:23281399

  18. Effects of chrysotherapy on cell mediated immune response.

    Science.gov (United States)

    Lorber, A; Jackson, W H; Simon, T M

    1982-01-01

    Auranofin (AF) differs significantly from gold sodium thiomalate (GSTM) in formulation, i.e., aurous gold is stabilized by dual sulfur and phosphorus ligands, hydrophobic rather than hydrophilic characteristics, and lack of ionic charge. These attributes facilitate: oral absorption of AF, plasma membrane penetration, increase in intracellular lymphocyte gold concentration; and perhaps thereby influence lymphocyte function. AF treated subjects recorded prompt and sharp declines in mitogen-induced lymphoproliferative response (LMR) greater than 80%; suppressed response to skin testing with dinitrochlorobenezene (DNCB) in 11 of 14 subjects; and blebbing of lymphocyte membranes by scanning electron microscopy. In contrast, lymphocytes from a matched group of GSTM treated subjects recorded later onset and less suppression of LMR; normal response to DNCB skin testing; and did not manifest membrane blebbing. Accordingly, the therapeutic action of AF on immune response was observed in the 16 subjects receiving 6 mg/d of an average of 45 weeks to effect primarily cell mediated rather than humoral immune response when compared with a matched group of GSTM treated patients.

  19. Mast cell mediators and peritoneal adhesion formation in the rat.

    Science.gov (United States)

    Langer, J C; Liebman, S M; Monk, P K; Pelletier, G J

    1995-09-01

    We have previously shown that mast cell stabilization attenuates peritoneal adhesion formation in the rat. The present study investigated the mechanism of this protection. Adhesions were created in weanling rats using cecal scraping and application of 95% ethanol. Rats received specific blockers for the mast cell products histamine, serotonin (5HT), leukotriene D4, and platelet activating factor intraperitoneally 30 min before laparotomy and at the time of abdominal closure. Control animals received saline. Adhesions were assessed blindly 1 week later using a standardized scale. Adhesion formation was not affected by histamine blockade using combined mepyramine and ranitidine, 5-HT1 blockade using methysergide, 5-HT3 blockade using ondansetron, leukotriene D4 blockade using MK-571, or platelet activating factor blockade using WEB-2086. However, blockade of the 5-HT2 receptor using ketanserin resulted in significant dose-dependent attenuation of adhesions compared to saline. These data suggest that mast cells mediate peritoneal adhesion formation in the rat through release of serotonin acting on 5HT2 receptors. Further understanding of this process may lead to new strategies for the prevention of postoperative adhesions.

  20. Natural killer cell mediated cytotoxic responses in the Tasmanian devil.

    Directory of Open Access Journals (Sweden)

    Gabriella K Brown

    Full Text Available The Tasmanian devil (Sarcophilus harrisii, the world's largest marsupial carnivore, is under threat of extinction following the emergence of an infectious cancer. Devil facial tumour disease (DFTD is spread between Tasmanian devils during biting. The disease is consistently fatal and devils succumb without developing a protective immune response. The aim of this study was to determine if Tasmanian devils were capable of forming cytotoxic antitumour responses and develop antibodies against DFTD cells and foreign tumour cells. The two Tasmanian devils immunised with irradiated DFTD cells did not form cytotoxic or humoral responses against DFTD cells, even after multiple immunisations. However, following immunisation with xenogenic K562 cells, devils did produce cytotoxic responses and antibodies against this foreign tumour cell line. The cytotoxicity appeared to occur through the activity of natural killer (NK cells in an antibody dependent manner. Classical NK cell responses, such as innate killing of DFTD and foreign cancer cells, were not observed. Cells with an NK-like phenotype comprised approximately 4 percent of peripheral blood mononuclear cells. The results of this study suggest that Tasmanian devils have NK cells with functional cytotoxic pathways. Although devil NK cells do not directly recognise DFTD cancer cells, the development of antibody dependent cell-mediated cytotoxicity presents a potential pathway to induce cytotoxic responses against the disease. These findings have positive implications for future DFTD vaccine research.

  1. Cell-mediated mutagenesis and cell transformation by chemical carcinogens

    Energy Technology Data Exchange (ETDEWEB)

    Huberman, E.; Langenbach, R.

    1977-01-01

    Results are reported from studies that showed that mutagenesis of mammalian cells can be achieved by carcinogenic polycyclic hydrocarbons, nitrosamines, and aflatoxins when tested in the presence of fibroblasts and hepatocytes which are able to metabolize these carcinogens. Further, we have found that there is a relationship between the degree of mutant induction and the degree of carcinogenicity of the different chemicals tested. By simultaneously measuring the frequency of cell transformation and the frequency of mutation at one locus (ouabain resistance) in the same cell system, it was possible to estimate the genetic target site for cell transformation. The results indicated that the target site for transformation is approximately 20 times larger than that determined for ouabain resistance. The results suggest that cell transformation may be due to a mutational event and the mutation can occur in one out of a small number of the same or different genes, and that the cell-mediated mutagenesis approach may be a valuable means of detecting tissue-specific carcinogens.

  2. Cytotoxic T cells mediate pathology and metastasis in cutaneous leishmaniasis.

    Directory of Open Access Journals (Sweden)

    Fernanda O Novais

    Full Text Available Disease progression in response to infection can be strongly influenced by both pathogen burden and infection-induced immunopathology. While current therapeutics focus on augmenting protective immune responses, identifying therapeutics that reduce infection-induced immunopathology are clearly warranted. Despite the apparent protective role for murine CD8⁺ T cells following infection with the intracellular parasite Leishmania, CD8⁺ T cells have been paradoxically linked to immunopathological responses in human cutaneous leishmaniasis. Transcriptome analysis of lesions from Leishmania braziliensis patients revealed that genes associated with the cytolytic pathway are highly expressed and CD8⁺ T cells from lesions exhibited a cytolytic phenotype. To determine if CD8⁺ T cells play a causal role in disease, we turned to a murine model. These studies revealed that disease progression and metastasis in L. braziliensis infected mice was independent of parasite burden and was instead directly associated with the presence of CD8⁺ T cells. In mice with severe pathology, we visualized CD8⁺ T cell degranulation and lysis of L. braziliensis infected cells. Finally, in contrast to wild-type CD8⁺ T cells, perforin-deficient cells failed to induce disease. Thus, we show for the first time that cytolytic CD8⁺ T cells mediate immunopathology and drive the development of metastatic lesions in cutaneous leishmaniasis.

  3. Stem cell  mediated liver regeneration:

    DEFF Research Database (Denmark)

    Jelnes, Peter

    Leversygdomme er et udbredt sundhedsproblem verden over. Kroniske leversygdomme er karakteriseret ved en kontinuerlig ødelæggelse af leverparenkymet samt fibrose. Den nuværende og foretrukne behandling af terminale leversygdomme er levertransplantation med efterfølgende immunsuppressiv behandling...

  4. Effects of urokinase type plasminogen activator gene transfected bone marrow-derived liver stem cells transplantation on hepatocyte regeneration in liver fibrosis rats%尿激酶型纤溶酶原激活物基因转染骨髓源性肝干细胞移植对肝纤维化大鼠肝细胞再生的影响

    Institute of Scientific and Technical Information of China (English)

    孙超; 李定国; 陈源文; 陈颖伟; 汪保灿

    2011-01-01

    目的 探讨尿激酶型纤溶酶原激活物(uPA)基因修饰骨髓源性肝干细胞(BDLSC)移植对四氯化碳(CCl4)诱导肝纤维化大鼠肝细胞再生的影响.方法 纯系Fisher 344雄性大鼠10只,为BDLSC供体大鼠.体外将AduPA转染雄性大鼠BDLSC.纯系Fisher 344雌性大鼠36只,均分为正常组(皮下注射橄榄油)、模型组(CCl4造模,尾静脉注射0.9%氯化钠)、BDLSC组(CCl4造模,尾静脉输入BDLSC)、转基因组(CCl4造模,尾静脉输入转基因BDLSC).检测大鼠肝功能和肝组织胶原面积.半定量RT-PCR方法检测大鼠肝组织肝细胞生长因子(HGF)及其受体c-met mRNA表达水平.免疫组织化学法检测大鼠肝组织增殖细胞核抗原(PCNA)蛋白表达.结果 正常组、模型组、BDLSC组、转基因组肝组织胶原染色面积分别为0.12%±0.03%、14.49%±1.40%、8.25%±0.82%、5.12%±0.40%,组间差异均有统计学意义(P值均<0.05).与模型组和BDLSC组相比,转基因组大鼠肝功能明显改善,血清透明质酸(HA)、血清Ⅲ型前胶原(PCⅢ)、肝组织羟脯氨酸含量明显降低,肝组织HGF和c-met mRNA水平均显著上调,PCNA蛋白表达显著增加.结论 uPA基因修饰BDLSC移植可能诱导肝细胞增殖,从而改善CCl4诱导肝纤维化大鼠的肝功能.%Objective To explore the effects of urokinase type plasminogen activator (uPA) gene-modified bone marrow-derived liver stem cells ( BDLSC) transplantation on hepatocyte regeneration in CCl4-induced liver fibrosis rats. Methods Ten male Fisher 344 rats were donor rats of BDLSC. The BDLSC of male rat was transfected with AduPA. Thirty-six female Fisher 344 rats were equally divided into normal group (injected subcutaneously with olive oil) , model group (CCl4 induced the model, injected through tail vein with 0. 9% sodium chloride), BDLSC group (CCl4 induced the model, injected through tail vein with BDLSC) and gene transfected group (CCl4 induced the model,injected through tail vein with gene transfected

  5. Active magnetic regenerator

    Science.gov (United States)

    Barclay, John A.; Steyert, William A.

    1982-01-01

    The disclosure is directed to an active magnetic regenerator apparatus and method. Brayton, Stirling, Ericsson, and Carnot cycles and the like may be utilized in an active magnetic regenerator to provide efficient refrigeration over relatively large temperature ranges.

  6. Helping the Retina Regenerate

    Science.gov (United States)

    ... Briefs > Helping the retina regenerate Helping the retina regenerate NEI Audacious Goals Initiative report outlines strategies to replace or reprogram neurons in the retina News Brief 03/30/17 ...

  7. Bioartificial Liver Support

    Directory of Open Access Journals (Sweden)

    Vincent G Bain

    2001-01-01

    Full Text Available Bioartificial liver support has been increasingly the focus of both basic and clinical research in an attempt to replicate the multiplicity of normal liver function. The concept is attractive because, if it is effective, patients with acute liver failure may be supported until native liver regeneration occurs or, by optimizing their condition, until liver transplantation is possible. Current bioartificial liver support systems utilize primary porcine hepatocytes or transformed human hepatocytes, which are housed within a bioreactor, through which the patient's blood or plasma is pumped in an extracorporeal circuit. The optimal source for the hepatocytes is an area of debate; however, a genetically engineered cell line may provide optimal function. Novel three-dimensional matrices that anchor the hepatocytes are being designed to mimic architectural features of the normal liver. Large multicentre, randomized, controlled trials are ongoing following several pilot studies. Serious side effects such as hemodynamic instability and immune reactions have been infrequent. Much controversy, however, surrounds the issue of possible transmission of pig endogenous retrovirus to humans, and current trials are being carefully monitored. Bioartificial liver support is a promising technology, and the results of current and planned studies are awaited with great interest.

  8. Fgf regulates dedifferentiation during skeletal muscle regeneration in adult zebrafish.

    Science.gov (United States)

    Saera-Vila, Alfonso; Kish, Phillip E; Kahana, Alon

    2016-09-01

    Fibroblast growth factors (Fgfs) regulate critical biological processes such as embryonic development, tissue homeostasis, wound healing, and tissue regeneration. In zebrafish, Fgf signaling plays an important role in the regeneration of the spinal cord, liver, heart, fin, and photoreceptors, although its exact mechanism of action is not fully understood. Utilizing an adult zebrafish extraocular muscle (EOM) regeneration model, we demonstrate that blocking Fgf receptor function using either a chemical inhibitor (SU5402) or a dominant-negative transgenic construct (dnFGFR1a:EGFP) impairs muscle regeneration. Adult zebrafish EOMs regenerate through a myocyte dedifferentiation process, which involves a muscle-to-mesenchyme transition and cell cycle reentry by differentiated myocytes. Blocking Fgf signaling reduced cell proliferation and active caspase 3 levels in the regenerating muscle with no detectable levels of apoptosis, supporting the hypothesis that Fgf signaling is involved in the early steps of dedifferentiation. Fgf signaling in regenerating myocytes involves the MAPK/ERK pathway: inhibition of MEK activity with U0126 mimicked the phenotype of the Fgf receptor inhibition on both muscle regeneration and cell proliferation, and activated ERK (p-ERK) was detected in injured muscles by immunofluorescence and western blot. Interestingly, following injury, ERK2 expression is specifically induced and activated by phosphorylation, suggesting a key role in muscle regeneration. We conclude that the critical early steps of myocyte dedifferentiation in EOM regeneration are dependent on Fgf signaling.

  9. Quantification of Hepatic Vascular and Parenchymal Regeneration in Mice

    Science.gov (United States)

    Xie, Chichi; Schwen, Lars Ole; Wei, Weiwei; Schenk, Andrea; Zafarnia, Sara; Gremse, Felix; Dahmen, Uta

    2016-01-01

    Background Liver regeneration consists of cellular proliferation leading to parenchymal and vascular growth. This study complements previous studies on cellular proliferation and weight recovery by (1) quantitatively describing parenchymal and vascular regeneration, and (2) determining their relationship. Both together are needed to (3) characterize the underlying growth pattern. Methods Specimens were created by injecting a polymerizing contrast agent in either portal or hepatic vein in normal or regenerating livers after 70% partial hepatectomy. 3D image data were obtained through micro-CT scanning. Parenchymal growth was assessed by determining weight and volume of the regenerating liver. Vascular growth was described by manually determined circumscribed parameters (maximal vessel length and radius of right inferior portal/hepatic vein), automatically determined cumulative parameters (total edge length and total vascular volume), and parameters describing vascular density (total edge length/volume, vascular volume fraction). The growth pattern was explored by comparing the relative increase of these parameters to the increase expected in case of isotropic expansion. Results Liver volume recovery paralleled weight recovery and reached 90% of the original liver volume within 7 days. Comparing radius-related vascular parameters immediately after surgical resection and after virtual resection in-silico revealed a slight increase, possibly reflecting the effect of resection-induced portal hyperperfusion. Comparing length-related parameters between post-operative day 7 and after virtual resection showed similar vascular growth in both vascular systems investigated. In contrast, radius-related parameters increased slightly more in the portal vein. Despite the seemingly homogeneous 3D growth, the observed vascular parameters were not compatible with the hypothesis of isotropic expansion of liver parenchyma and vascular structures. Conclusion We present an approach for

  10. Liver bioengineering: Current status and future perspectives

    Institute of Scientific and Technical Information of China (English)

    Christopher Booth; Tom Soker; Pedro Baptista; Christina L Ross; Shay Soker; Umar Farooq; Robert J Stratta

    2012-01-01

    The present review aims to illustrate the strategies that are being implemented to regenerate or bioengineer livers for clinical purposes.There are two general pathways to liver bioengineering and regeneration.The first consists of creating a supporting scaffold,either synthetically or by decellularization of human or animal organs,and seeding cells on the scaffold,where they will mature either in bioreactors or in vivo.This strategy seems to offer the quickest route to clinical translation,as demonstrated by the development of liver organoids from rodent livers which were repopulated with organ specific cells of animal and/or human origin.Liver bioengineering has potential for transplantation and for toxicity testing during preclinical drug development.The second possibility is to induce liver regeneration of dead or resected tissue by manipulating cell pathways.In fact,it is well known that the liver has peculiar regenerative potential which allows hepatocyte hyperplasia after amputation of liver volume.Infusion of autologous bone marrow cells,which aids in liver regeneration,into patients was shown to be safe and to improve their clinical condition,but the specific cells responsible for liver regeneration have not yet been determined and the underlying mechanisms remain largely unknown.A complete understanding of the cell pathways and dynamics and of the functioning of liver stem cell niche is necessary for the clinical translation of regenerative medicine strategies.As well,it will be crucial to elucidate the mechanisms through which cells interact with the extracellular matrix,and how this latter supports and drives cell fate.

  11. Regeneration of periodontal tissues: guided tissue regeneration.

    Science.gov (United States)

    Villar, Cristina C; Cochran, David L

    2010-01-01

    The concept that only fibroblasts from the periodontal ligament or undifferentiated mesenchymal cells have the potential to re-create the original periodontal attachment has been long recognized. Based on this concept, guided tissue regeneration has been applied with variable success to regenerate periodontal defects. Quantitative analysis of clinical outcomes after guided tissue regeneration suggests that this therapy is a successful and predictable procedure to treat narrow intrabony defects and class II mandibular furcations, but offers limited benefits in the treatment of other types of periodontal defects.

  12. Hepatic progenitors for liver disease: current position

    Directory of Open Access Journals (Sweden)

    Alice Conigliaro

    2010-02-01

    Full Text Available Alice Conigliaro1, David A Brenner2, Tatiana Kisseleva21University “La Sapienza”, Dipartimento di Biotecnologie Cellulari ed Ematologia Policlinico Umberto I, V Clinica Medica, Rome, Italy; 2Department of Medicine, University of California, San Diego, La Jolla, CA, USAAbstract: Liver regeneration restores the original functionality of hepatocytes and cholangiocytes in response to injury. It is regulated on several levels, with different cellular populations contributing to this process, eg, hepatocytes, liver precursor cells, intrahepatic stem cells. In response to injury, mature hepatocytes have the capability to proliferate and give rise to new hepatocytes and cholangiocytes. Meanwhile, liver precursor cells (oval cells have become the most recognized bipotential precursor cells in the damaged liver. They rapidly proliferate, change their cellular composition, and differentiate into hepatocytes and cholangiocytes to compensate for the cellular loss and maintain liver homeostasis. There is a growing body of evidence that oval cells originate from the intrahepatic stem cell(s, which in turn give(s rise to epithelial, including oval cells, and/or other hepatic cells of nonepithelial origin. Since there is a close relationship between the liver and hematopoiesis, bone marrow derived cells can also contribute to liver regeneration by the fusion of myeloid cells with damaged hepatocytes, or differentiation of mesenchymal stem cells into hepatocyte-like cells. The current review discusses the contribution of different cells to liver regeneration and their characteristics.Keywords: hepatic progenitor, liver disease, liver precursor cells, oval cells, hepatocytes, intrahepatic stem cells, cholangiocytes

  13. Liver Facts

    Science.gov (United States)

    ... Lung Kidney Pancreas Kidney/Pancreas Liver Intestine Liver Facts How the Liver Works The liver is one ... Camps for kids Contacting my donor family Data Facts about living donation Financing a transplant Matching organs ...

  14. Notch Signaling Inhibits Axon Regeneration

    OpenAIRE

    Bejjani, Rachid El; Hammarlund, Marc

    2012-01-01

    Many neurons have limited capacity to regenerate their axons after injury. Neurons in the mammalian CNS do not regenerate, and even neurons in the PNS often fail to regenerate to their former targets. This failure is likely due in part to pathways that actively restrict regeneration; however, only a few factors that limit regeneration are known. Here, using single-neuron analysis of regeneration in vivo, we show that Notch/lin-12 signaling inhibits the regeneration of mature C. elegans neuron...

  15. Effects of ursodeoxycholic acid on liver regeneration and Cyclin D1 expression in rats%熊去氧胆酸对大鼠肝再生和细胞周期蛋白D1表达的影响

    Institute of Scientific and Technical Information of China (English)

    张有福; 董秀山; 闫曙光; 赵浩亮

    2010-01-01

    目的 观察熊去氧胆酸对大鼠肝再生和细胞周期蛋白D1(Cyclin D1)表达的影响.方法 雄性Wistar大鼠分为对照组和熊去氧胆酸组(UDCA组),各32例.对照组给予标准饲料,UDCA组给予0.3%UDCA饲料,7d后行70%肝部分切除术(PH).于术后0、1、2、3 d四个时间点观察大鼠肝细胞增殖和Cyclin D1表达情况.结果 两组大鼠在0d时PCNA蛋白几乎不表达,在PH后1d,PCNA蛋白标记指数迅速上升达高峰,而UDCA组PCNA标记指数显著高于对照组(40.70±4.73比33.24±5.59,P0.05).UDCA组在PH术后1、2 d Cyclin D1表达明显高于对照组(P0.05).结论 熊去氧胆酸可促进肝细胞增殖,并且上调Cyclin D1表达.%Objective To investigate the effect of ursodeoxycholic acid(UDCA) on liver regeneration and Cyclin Dl expression in rats. Methods Male Wistar rats were randomly divided into two groups (re=32 in each group: the control group in which the rats were fed on standard diets, and the UDCA group in which rats were given 1% UDCA diets. Seven days later, 70% partial hepatectomy (PH) was performed. On the day 0,1,2 and 3 after PH, the rat liver regeneration and Cyclin Dl expression were examined. Results On the day 0, the PCNA was hardly expressed in all rats. On the day 1 after PH, the PC-NA labeling index reached a peak, and it was significantly higher in the UDCA group than in the control group (40.70±4.73 vs 33. 24 ± 5. 59, P0.05). On day 1, 2 after PH, the expression of Cyclin Dl in the UDCA group was significantly higher than in the control group (P0.05 ). Conclusion UDCA can promote liver regeneration, and increase the expression of Cyclin D1.

  16. Apoptosis, stem cells, and tissue regeneration.

    Science.gov (United States)

    Bergmann, Andreas; Steller, Hermann

    2010-10-26

    Most metazoans have at least some ability to regenerate damaged cells and tissues, although the regenerative capacity varies depending on the species, organ, or developmental stage. Cell replacement and regeneration occur in two contexts: renewal of spent cells during tissue homeostasis (homeostatic growth), and in response to external injury, wounding, or amputation (epimorphic regeneration). Model organisms that display remarkable regenerative capacity include amphibians, planarians, Hydra, and the vertebrate liver. In addition, several mammalian organs--including the skin, gut, kidney, muscle, and even the human nervous system--have some ability to replace spent or damaged cells. Although the regenerative response is complex, it typically involves the induction of new cell proliferation through formation of a blastema, followed by cell specification, differentiation, and patterning. Stem cells and undifferentiated progenitor cells play an important role in both tissue homeostasis and tissue regeneration. Stem cells are typically quiescent or passing slowly through the cell cycle in adult tissues, but they can be activated in response to cell loss and wounding. A series of studies, mostly performed in Drosophila as well as in Hydra, Xenopus, and mouse, has revealed an unexpected role of apoptotic caspases in the production of mitogenic signals that stimulate the proliferation of stem and progenitor cells to aid in tissue regeneration. This Review summarizes some of the key findings and discusses links to stem cell biology and cancer.

  17. Stirling convertor regenerators

    CERN Document Server

    Ibrahim, Mounir B

    2011-01-01

    Stirling Convertor Regenerators addresses the latest developments and future possibilities in the science and practical application of Stirling engine regenerators and technology. Written by experts in the vanguard of alternative energy, this invaluable resource presents integral scientific details and design concepts associated with Stirling converter regenerators. Content is reinforced with novel insights and remarkable firsthand experience that the authors and their colleagues acquired while working at the National Aeronautics and Space Administration (NASA) and other leading organizations.

  18. Tissue Remodelling following Resection of Porcine Liver

    Directory of Open Access Journals (Sweden)

    Ingvild Engdal Nygård

    2015-01-01

    Full Text Available Aim. To study genes regulating the extracellular matrix (ECM and investigate the tissue remodelling following liver resection in porcine. Methods. Four pigs with 60% partial hepatectomy- (PHx- induced liver regeneration were studied over six weeks. Four pigs underwent sham surgery and another four pigs were used as controls of the normal liver growth. Liver biopsies were taken upon laparotomy, after three and six weeks. Gene expression profiles were obtained using porcine-specific oligonucleotide microarrays. Immunohistochemical staining was performed and a proliferative index was assessed. Results. More differentially expressed genes were associated with the regulation of ECM in the resection group compared to the sham and control groups. Secreted protein acidic and rich in cysteine (SPARC and collagen 1, alpha 2 (COL1A2 were both upregulated in the early phase of liver regeneration, validated by immunopositive cells during the remodelling phase of liver regeneration. A broadened connective tissue was demonstrated by Masson’s Trichrome staining, and an immunohistochemical staining against pan-Cytokeratin (pan-CK demonstrated a distinct pattern of migrating cells, followed by proliferating cell nuclear antigen (PCNA positive nuclei. Conclusions. The present study demonstrates both a distinct pattern of PCNA positive nuclei and a deposition of ECM proteins in the remodelling phase of liver regeneration.

  19. Assessing humoral and cell-mediated immune response in Hawaiian green turtles, Chelonia mydas

    Science.gov (United States)

    Work, T.M.; Balazs, G.H.; Rameyer, R.A.; Chang, S.P.; Berestecky, J.

    2000-01-01

    Seven immature green turtles, Chelonia mydas, captured from Kaneohe Bay on the island of Oahu were used to evaluate methods for assessing their immune response. Two turtles each were immunized intramuscularly with egg white lysozyme (EWL) in Freunda??s complete adjuvant, Gerbu, or ISA-70; a seventh turtle was immunized with saline only and served as a control. Humoral immune response was measured with an indirect enzyme linked immunosorbent assay (ELISA). Cell-mediated immune response was measured using in vitro cell proliferation assays (CPA) using whole blood or peripheral blood mononuclear cells (PBM) cultured with concanavalin A (ConA), phytohaemagglutinin (PHA), or soluble egg EWL antigen. All turtles, except for one immunized with Gerbu and the control, produced a detectable humoral immune response by 6 weeks which persisted for at least 14 weeks after a single immunization. All turtles produced an anamnestic humoral immune response after secondary immunization. Antigen specific cell-mediated immune response in PBM was seen in all turtles either after primary or secondary immunization, but it was not as consistent as humoral immune response; antigen specific cell-mediated immune response in whole blood was rarely seen. Mononuclear cells had significantly higher stimulation indices than whole blood regardless of adjuvant, however, results with whole blood had lower variability. Both Gerbu and ISA-70 appeared to potentiate the cell-mediated immune response when PBM or whole blood were cultured with PHA. This is the first time cell proliferation assays have been compared between whole blood and PBM for reptiles. This is also the first demonstration of antigen specific cell-mediated response in reptiles. Cell proliferation assays allowed us to evaluate the cell-mediated immune response of green turtles. However, CPA may be less reliable than ELISA for detecting antigen specific immune response. Either of the three adjuvants appears suitable to safely elicit a

  20. Role of IL-33 and Its Receptor in T Cell-Mediated Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Qing Zhao

    2014-01-01

    Full Text Available Interleukin-33 (IL-33 is a new cytokine of interleukin-1 family, whose specific receptor is ST2. IL-33 exerts its functions via its target cells and plays different roles in diseases. ST2 deletion and exclusion of IL-33/ST2 axis are accompanied by enhanced susceptibility to dominantly T cell-mediated organ-specific autoimmune diseases. It has been reported that IL-33/ST2 pathway plays a key role in host defense and immune regulation in inflammatory and infectious diseases. This review focuses on new findings in the roles of IL-33 and ST2 in several kinds of T cell-mediated autoimmune diseases.

  1. Analysis of cell-mediated immune responses in support of dengue vaccine development efforts.

    Science.gov (United States)

    Rothman, Alan L; Currier, Jeffrey R; Friberg, Heather L; Mathew, Anuja

    2015-12-10

    Dengue vaccine development has made significant strides, but a better understanding of how vaccine-induced immune responses correlate with vaccine efficacy can greatly accelerate development, testing, and deployment as well as ameliorate potential risks and safety concerns. Advances in basic immunology knowledge and techniques have already improved our understanding of cell-mediated immunity of natural dengue virus infection and vaccination. We conclude that the evidence base is adequate to argue for inclusion of assessments of cell-mediated immunity as part of clinical trials of dengue vaccines, although further research to identify useful correlates of protective immunity is needed.

  2. Role of liver functions on liver cell mitosis

    Directory of Open Access Journals (Sweden)

    Takata,Tameyuki

    1974-06-01

    Full Text Available The control mechanism of mitosis in the regenerating rat liver was studied in relation to the cell functions. Partial hepatec· tomy induces a series of changes prior to the initiation of mitosis, i. e. decrease in serum glucose and albumin levels, loss of glycogen from liver cells, and increased lipid mobilization to liver cells. Massive supplies of glucose and fructose suppressed significantly hepatocellu. lar mitosis with suppression of lipid accumulation and preservation of glycogen in the liver cells and of blood sugar level. Homologous serum administration also suppressed the rate of liver cell mitosis after hepatectomy preventing the decrease in serum albumin level, but did not suppress the lipid accumulation in the liver. Starvation, which would relieve the liver cell from the work of detoxication of intesti. nal toxic products, did not show any suppressive effect on the mitotic rate of liver cells after partial hepatectomy in single animals. But starvation induced severe hypoglycemia, moderate hypoalbuminemia and loss of glycogen content in the liver. These changes in metabo. lism by starvation and partial hepatectomy were suppressed by con· jugating the animals with nonhepatectomized fed.partners by aortic anastomosis, and mitosis was suppressed in the residual liver of the fasting animals in this parabiosis. The results indicate that all the major functions of parenchymal live cells tested, sugar metabolism, serum albumin production, and detoxication, are closely related to the control of liver cell mitosis. Accumulation of lipids in the liver remnant after partial hepatectomy is thought to be for the compensa. tion of reduced glycogen storage and not concerned directly with the liver cell mitosis. Discussion was made briefly on the humoral factor and portal blood factor in relation to excess load of functions on resi. dual liver cells.

  3. Effect of internal and external biliary drainage on liver regeneration of the obstructive jaundice rats following PH%术前不同引流方式减黄对梗阻性黄疸大鼠部分肝切除术后肝功能和肝再生的影响

    Institute of Scientific and Technical Information of China (English)

    袁晟光; 梁科伟; 刘杰; 廖维甲; 覃理灵; 何松青

    2012-01-01

    目的 了解术前不同引流方式减黄对梗阻性黄疸(OJ) SD大鼠部分肝切除术(PH)术后肝功能和肝再生的影响.方法 建立OJ不同引流方式减黄70%部分肝切除SD大鼠动物模型.并在术后0、1、2、4、12、24、48和72h收集大鼠血液及肝脏组织标本,测定血清TBIL、ALB、ALT、AST水平,计算残肝重量、肝再生率,免疫组化法观察肝脏组织PCNA表达,ELISA法检测血清TNF-α水平.结果 PH术后各时段内引流(ID)组和外引流(ED)组TBIL、ALT、AST水平较OJ组均偏低.各时段ID组ALB水平较OJ组、ED组偏高.72 h肝再生率ID组高于ED组,ED组高于OJ组.3组PCNA水平均于12 h明显升高,ID组于24 h达高峰,OJ组、ED组高峰延迟至48 h且峰值偏低.PH术后各组血清TNF-α水平均呈上升趋势,ID组于12 h达高峰,OJ组、ED组均于24 h达高峰,各时段OJ组、ED组血清TNF-α水平较ID组均偏高.结论 内外引流术均可改善OJ所致的高胆红素血症和肝功能,并改善OJ大鼠残肝再生能力,但内引流效果更明显,且内引流术可以有效降低血清TNF-α水平.%Objective To evaluate the effect of internal and external biliary drainage on liver regeneration of the obstructive jaundice (OJ) rats following partial hepatectomy (PH) and to provide a theoretical basis for clinical application. Methods We established the model of OJ SD rats drainaged internally and externally following PH. At Oh, 1 h, 2 h, 4 h, 12 h, 24 h, 48 h and 72 h after PH, the rats were succumbed and the specimens of blood and liver were collected. The levels of TBIL, ALB, ALT, AST in serum and liver regeneration rates were determined. The expression of PCNA in residual liver tissues were analyzed by immunohistological technology. The levels of TNF-a in serum were measured by ELISA. Results After PH, the levels of TBIL, ALT and AST in OJ group were significantly higher than those in ID group and ED group at every moment. The level of ALB in ID group was significantly

  4. Participation of CD45, NKR-P1A and ANK61 antigen in rat hepatic NK cell (pit cell)-mediated target cell cytotoxicity

    Institute of Scientific and Technical Information of China (English)

    Dian Zhong Luo; David Vermijlen; B lent Ahishali; Vasilis Triantis; Eddie Wisse; Karin Vanderkerken; Peter J.K. Kuppen

    2000-01-01

    AIM Several triggering receptors have been described to be involved in natural killer (NK) cellmediated target cytotoxicity. In these studies, NK cells derived from blood or spleen were used. Pit cells are liver-specific NK cells that possess a higher level of natural cytotoxicity and a different morphology when compared to blood NK cells. The aim of this study was to characterize the role of the NK-triggering molecules NKR-P1A, ANK61 antigen, and CD45 in pit cell-mediated killing of target cells. METHODS 51 Cr-release and DNA fragmentation were used to quantify target cell lysis and apoptosis, respectively. RESULTS Flow cytometric analysis showed that pit cells expressed CD45, NKR-P1A, and ANK61 antigen. Treatment of pit cells with monoclonal antibody ( mAb ) to CD45 ( ANK74 ) not only inhibited CC531s or YAC-1 target lysis but also apoptosis induced by pit cells. The mAbs to NKRP1A (3.2.3) and ANK61 antigen (ANK61) had no effect on pit cell-mediated CC531s or YAC-1 target cytolysis or apoptosis, while they did increase the Fcγ receptor positive (FcγR+) P815 cytolysis and apoptosis. This enhanced cytotoxicity could he inhibited by 3,4-dichloroisocoumarin, an inhibitor of granzymes. CONCLUSION These results indicate that CD45 participates in pit cell-mediated CC531s and YAC-1 target cytolysis and apoptosis. NKR-P1A and ANK61 antigen on pit cells function as activation structures against FcγR+ P815 cells, which was mediated by the perforin/granzyme pathway.

  5. Coupled cellular therapy and magnetic targeting for airway regeneration.

    Science.gov (United States)

    Ordidge, Katherine L; Gregori, Maria; Kalber, Tammy L; Lythgoe, Mark F; Janes, Sam M; Giangreco, Adam

    2014-06-01

    Airway diseases including COPD (chronic obstructive pulmonary disease), cystic fibrosis and lung cancer are leading causes of worldwide morbidity and mortality, with annual healthcare costs of billions of pounds. True regeneration of damaged airways offers the possibility of restoring lung function and protecting against airway transformation. Recently, advances in tissue engineering have allowed the development of cadaveric and biosynthetic airway grafts. Although these have produced encouraging results, the ability to achieve long-term functional airway regeneration remains a major challenge. To promote regeneration, exogenously delivered stem and progenitor cells are being trialled as cellular therapies. Unfortunately, current evidence suggests that only small numbers of exogenously delivered stem cells engraft within lungs, thereby limiting their utility for airway repair. In other organ systems, magnetic targeting has shown promise for improving long-term robust cell engraftment. This technique involves in vitro cell expansion, magnetic actuation and magnetically guided cell engraftment to sites of tissue damage. In the present paper, we discuss the utility of coupling stem cell-mediated cellular therapy with magnetic targeting for improving airway regeneration.

  6. Liver macrophages in healthy and diseased liver.

    Science.gov (United States)

    Abdullah, Zeinab; Knolle, Percy A

    2017-04-01

    Kupffer cells, the largest tissue resident macrophage population, are key for the maintenance of liver integrity and its restoration after injury and infections, as well as the local initiation and resolution of innate and adaptive immunity. These important roles of Kupffer cells were recently identified in healthy and diseased liver revealing diverse functions and phenotypes of hepatic macrophages. High-level phenotypic and genomic analysis revealed that Kupffer cells are not a homogenous population and that the hepatic microenvironment actively shapes both phenotype and function of liver macrophages. Compared to macrophages from other organs, hepatic macrophages bear unique properties that are instrumental for their diverse roles in local immunity as well as liver regeneration. The diverse and, in part, contradictory roles of hepatic macrophages in anti-tumor and inflammatory immune responses as well as regulatory and regenerative processes have been obscured by the lack of appropriate technologies to specifically target or ablate Kupffer cells or monocyte-derived hepatic macrophages. Future studies will need to dissect the exact role of the hepatic macrophages with distinct functional properties linked to their differentiation status and thereby provide insight into the functional plasticity of hepatic macrophages.

  7. The Analysis of Activated Carbon Regeneration Technologies

    Institute of Scientific and Technical Information of China (English)

    姚芳

    2014-01-01

    A series of methods for activated carbon regeneration were briefly introduced.Such as thermal regeneration,chemical regeneration,biochemical regeneration,and newly supercritical fluid regeneration, electrochemical regeneration,light-catalyzed regeneration,and microwave radiation method,and the developing trend of activated carbon regeneration was predicted.

  8. Liver biopsy

    Science.gov (United States)

    Biopsy - liver; Percutaneous biopsy ... the biopsy needle to be inserted into the liver. This is often done by using ultrasound. The ... the chance of damage to the lung or liver. The needle is removed quickly. Pressure will be ...

  9. Liver Hemangioma

    Science.gov (United States)

    ... in your liver, even if it's a benign mass. There's no evidence that an untreated liver hemangioma can lead to liver ... of Nondiscrimination Advertising Mayo Clinic is a not-for-profit organization ...

  10. Prospects for tooth regeneration in the 21st century: a perspective.

    Science.gov (United States)

    Chai, Yang; Slavkin, Harold C

    2003-04-01

    The prospects for tooth regeneration in the 21st century are compelling. Using the foundations of experimental embryology, developmental and molecular biology, the principles of biomimetics (the mimicking of biological processes), tooth regeneration is becoming a realistic possibility within the next few decades. The cellular, molecular, and developmental "rules" for tooth morphogenesis are rapidly being discovered. The knowledge gained from adult stem cell biology, especially associated with dentin, cartilage, and bone tissue regeneration, provides additional opportunities for eventual tooth organogenesis. The centuries of tooth development using xenotransplantation, allotransplantation, and autotransplantation have resulted in many important insights that can enhance tooth regeneration. In considering the future, several lines of evidence need to be considered: (1) enamel organ epithelia and dental papilla mesenchyme tissues contain stem cells during postnatal stages of life; (2) late cap stage and bell stage tooth organs contain stem cells; (3) odontogenic adult stem cells respond to mechanical as well as chemical "signals"; (4) presumably adult bone marrow as well as dental pulp tissues contain "odontogenic" stem cells; and (5) epithelial-mesenchymal interactions are pre-requisite for tooth regeneration. The authors express "guarded enthusiasm," yet there should be little doubt that adult stem cell-mediated tooth regeneration will be realized in the not too distant future. The prospects for tooth regeneration could be realized in the next few decades and could be rapidly utilized to improve the quality of human life in many nations around the world.

  11. Crosslinked collagen/chitosan matrix for artificial livers

    NARCIS (Netherlands)

    Wang, X.H.; Li, D.P.; Wang, W.J.; Feng, Q.L.; Cui, F.Z.; Xu, Y.X.; Song, X.H.; van der Werf, Mark

    2003-01-01

    Matrices composed of collagen and chitosan may create an appropriate environment for the regeneration of livers. In this study, we have prepared, characterized and evaluated a new collagen/chitosan matrix (CCM). The CCM was made by using crosslinking agent

  12. A longitudinal study of cell-mediated immunity in pigs infected with porcine parvovirus

    DEFF Research Database (Denmark)

    Ladekjaer-Mikkelsen, A.S.; Nielsen, Jens

    2002-01-01

    Porcine parvovirus (PPV) is an ubiquitous pathogen causing reproductive failure in swine. Protection against reproductive failure caused by acute PPV infection has commonly been related to the presence of specific antibodies in the dam. However, the role of cell-mediated immunity during chronic PPV...

  13. Role of macrophage inflammatory protein-1alpha in T-cell-mediated immunity to viral infection

    DEFF Research Database (Denmark)

    Madsen, Andreas N; Nansen, Anneline; Christensen, Jan P

    2003-01-01

    The immune response to lymphocytic choriomeningitis virus in mice lacking macrophage inflammatory protein-1alpha (MIP-1alpha) was evaluated. Generation of virus-specific effector T cells is unimpaired in MIP-1alpha-deficient mice. Furthermore, MIP-1alpha is not required for T-cell-mediated virus...

  14. Stem cell-derived hepatocytes for functional liver replacement

    Directory of Open Access Journals (Sweden)

    Bruno eChrist

    2012-06-01

    Full Text Available Mesenchymal stem cells (MSC represent an alternate cell source to substitute for primary hepatocytes in hepatocyte transplantation because of their multiple differentiation potential and nearly unlimited availability. They may differentiate into hepatocyte-like cells in vitro and maintain specific hepatocyte functions also after transplantation into the regenerating livers of mice or rats both under injury and non-injury conditions. Depending on the underlying liver disease their mode of action is either to replace the diseased liver tissue or to support liver regeneration through their anti-inflammatory and anti-apoptotic as well as their pro-proliferative action.

  15. Schwann Cell-Mediated Preservation of Vision in Retinal Degenerative Diseases via the Reduction of Oxidative Stress: A Possible Mechanism

    Science.gov (United States)

    MAHMOUDZADEH, Raziyeh; HEIDARI-KESHEL, Saeed; LASHAY, Alireza

    2016-01-01

    After injury to the central nervous system (CNS), regeneration is often inadequate, except in the case of remyelination. This remyelination capacity of the CNS is a good example of a stem/precursor cell-mediated renewal process. Schwann cells have been found to act as remyelinating agents in the peripheral nervous system (PNS), but several studies have highlighted their potential role in remyelination in the CNS too. Schwann cells are able to protect and support retinal cells by secreting growth factors such as brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and basic fibroblast growth factor. Retinal degenerative diseases can be highly debilitating, and they are a major concern in countries with an ageing populations. One of the leading causes of permanent loss of vision in the West is a retinal degenerative disease known as age-related macular degeneration (AMD). In the United States, nearly 1.75 million people over the age of 40 have advanced AMD, and it is estimated that this number will increase to approximately 3 million people by 2020. One of the most common pathways involved in the initiation and development of retinal diseases is the oxidative stress pathway. In patients with diabetes, Schwann cells have been shown to be able to secrete large amounts of antioxidant enzymes that protect the PNS from the oxidative stress that results from fluctuations in blood glucose levels. This antioxidant ability may be involved in the mechanism by which Schwann cells are able to promote reconstruction in the CNS, especially in individuals with retinal injuries and degenerative diseases. PMID:28293647

  16. Regeneration and reprogramming compared

    Directory of Open Access Journals (Sweden)

    Robles Vanesa

    2010-01-01

    Full Text Available Abstract Background Dedifferentiation occurs naturally in mature cell types during epimorphic regeneration in fish and some amphibians. Dedifferentiation also occurs in the induction of pluripotent stem cells when a set of transcription factors (Oct4, Sox2, Klf4 and c-Myc is over expressed in mature cell types. Results We hypothesised that there are parallels between dedifferentiation or reprogramming of somatic cells to induced pluripotent stem cells and the natural process of dedifferentiation during epimorphic regeneration. We analysed expression levels of the most commonly used pluripotency associated factors in regenerating and non-regenerating tissue and compared them with levels in a pluripotent reference cell. We found that some of the pluripotency associated factors (oct4/pou5f1, sox2, c-myc, klf4, tert, sall4, zic3, dppa2/4 and fut1, a homologue of ssea1 were expressed before and during regeneration and that at least two of these factors (oct4, sox2 were also required for normal fin regeneration in the zebrafish. However these factors were not upregulated during regeneration as would be expected if blastema cells acquired pluripotency. Conclusions By comparing cells from the regeneration blastema with embryonic pluripotent reference cells we found that induced pluripotent stem and blastema cells do not share pluripotency. However, during blastema formation some of the key reprogramming factors are both expressed and are also required for regeneration to take place. We therefore propose a link between partially reprogrammed induced pluripotent stem cells and the half way state of blastema cells and suggest that a common mechanism might be regulating these two processes.

  17. Strategies for lung regeneration

    Directory of Open Access Journals (Sweden)

    Thomas H. Petersen

    2011-05-01

    Full Text Available Due to the limited ability of the adult lung to regenerate and the frequency of lung disease, the lung is a tissue that can especially benefit from regenerative medicine. Prospects for lung regeneration have made great strides in the past year. In this review, we summarize recent progress and key challenges for approaches in lung regenerative medicine. With a focus on the matrix components critical for the development of regenerative lung tissues, we discuss possible cell sources for lung regeneration, key matrix effects on cell repopulation, and physical stimuli that will aid in the growth of lung tissues in vitro.

  18. Tooth regeneration: Current status

    Directory of Open Access Journals (Sweden)

    Dadu Shifali

    2009-01-01

    Full Text Available Regeneration of a functional tooth has the potential to be a promising therapeutic strategy. Experiments have shown that with the use of principles of bioengineering along with adult stem cells, scaffold material, and signaling molecules, tooth regeneration is possible. Research work is in progress on creating a viable bioroot with all its support. A new culture needs to be created that can possibly provide all the nutrients to the stem cells. With the ongoing research, tissue engineering is likely to revolutionize dental health and well-being of people by regenerating teeth over the next decade.

  19. Tooth regeneration: current status.

    Science.gov (United States)

    Dadu, Shifali S

    2009-01-01

    Regeneration of a functional tooth has the potential to be a promising therapeutic strategy. Experiments have shown that with the use of principles of bioengineering along with adult stem cells, scaffold material, and signaling molecules, tooth regeneration is possible. Research work is in progress on creating a viable bioroot with all its support. A new culture needs to be created that can possibly provide all the nutrients to the stem cells. With the ongoing research, tissue engineering is likely to revolutionize dental health and well-being of people by regenerating teeth over the next decade.

  20. Regeneration Heat Exchange

    Energy Technology Data Exchange (ETDEWEB)

    J. Lin

    2003-07-30

    The original project goals were to establish the viability of the proposed gas turbine regenerator concept by performing the following tasks: (1) Perform detailed design of a working model of the regenerator concept. (2) Construct a ''bench-top'' model of the regenerator concept based upon the detail design. (3) Test the bench-top model and gather data to support the concept's viability. The project funding was used to acquire the tools and material to perform the aforementioned tasks.

  1. Chemical genetics and regeneration.

    Science.gov (United States)

    Sengupta, Sumitra; Zhang, Liyun; Mumm, Jeff S

    2015-01-01

    Regeneration involves interactions between multiple signaling pathways acting in a spatially and temporally complex manner. As signaling pathways are highly conserved, understanding how regeneration is controlled in animal models exhibiting robust regenerative capacities should aid efforts to stimulate repair in humans. One way to discover molecular regulators of regeneration is to alter gene/protein function and quantify effect(s) on the regenerative process: dedifferentiation/reprograming, stem/progenitor proliferation, migration/remodeling, progenitor cell differentiation and resolution. A powerful approach for applying this strategy to regenerative biology is chemical genetics, the use of small-molecule modulators of specific targets or signaling pathways. Here, we review advances that have been made using chemical genetics for hypothesis-focused and discovery-driven studies aimed at furthering understanding of how regeneration is controlled.

  2. Air regenerating and conditioning

    Science.gov (United States)

    Grishayenkov, B. G.

    1975-01-01

    Various physicochemical methods of regenerating and conditioning air for spacecraft are described with emphasis on conditions which affect efficiency of the system. Life support systems used in closed, hermetically sealed environments are discussed with references to actual application in the Soviet Soyuz and Voskhod manned spacecraft. Temperature and humidity control, removal of carbon dioxide, oxygen regeneration, and removal of bacteria and viruses are among the factors considered.

  3. Nanostructured Biomaterials for Regeneration**

    OpenAIRE

    Wei, Guobao; Ma, Peter X.

    2008-01-01

    Biomaterials play a pivotal role in regenerative medicine, which aims to regenerate and replace lost/dysfunctional tissues or organs. Biomaterials (scaffolds) serve as temporary 3D substrates to guide neo tissue formation and organization. It is often beneficial for a scaffolding material to mimic the characteristics of extracellular matrix (ECM) at the nanometer scale and to induce certain natural developmental or/and wound healing processes for tissue regeneration applications. This article...

  4. 肌浆网/内质网钙ATP酶在大鼠肝再生过程中的表达和活性分析%Expression Patterns and Activity Analysis of the Sarco (endo) Plasmic Reticulum Ca2+-ATPase in the Liver Regeneration of Rats

    Institute of Scientific and Technical Information of China (English)

    吴灿; 侯国俊; 支樑健; 王颖; 叶波平

    2012-01-01

    肌浆网/内质网钙ATP酶(SERCA)主要位于内质网和肌浆网膜上,是生物体内重要的钙离子转运酶.为进一步探讨肝再生过程中SERCA的表达变化,该研究构建了大鼠2/3肝脏切除模型,用实时荧光定量RT-PCR和测定酶活性的方法研究该酶的两种亚型(SERCA2b和SERCA3)在肝切除后O,1,12,24,48,72,120,168,216 h共9个时间点的表达变化,结果发现肝再生早期两种亚型表达量均下调,但在一定时间内显著应激性上升,分别在12h和48h达到峰值,之后表达量下调至原始水平.同时,酶活性测定结果与基因表达变化相类似,在12~48 h酶活性达到峰值,以上结果表明SERCA参与了肝脏再生过程,可能的途径是调控内质网钙离子,进而影响细胞质的钙震荡和细胞周期.%Sarco ( endo) plasmic reticulum Ca2+-ATPase, SERCA, is thought to play an important role in Ca2+-transporting. It is mainly located in the membranes of sarco ( endo) plasmic reticulum. To characterize its role in liver regeneration, the expression patterns of its two isoforms( SERCA2b,SERCA3) at different time points of 0,1 ,12,24,48,72,120,168,216 h were studied after 2/3 partial hepatectomy(PH) by Real-time quantiatative PCR. And the total enzyme activity was also determined. The results showed that the mRNA level of the two isoforms was down-regulated at the early stage of liver regeneration. However they increased dramtically responding to the PH. SERCA2b peaked at 12 h and the SERCA3 peaked at 48 h. After reaching the peak,the level decreased to the normal. The change of total enzyme activity was consistent with the mRNA level and kept the highest level between the 12~48 h. All these implied that SERCA involved in the liver regeneration. It may play an important role in charging the calcium oscillatory in the cytoplasmic and cell cycle by regulateing the calcium in the ER.

  5. Heavy smoking and liver

    Institute of Scientific and Technical Information of China (English)

    Abdel-Rahman El-Zayadi

    2006-01-01

    Smoking causes a variety of adverse effects on organs that have no direct contact with the smoke itself such as the liver. It induces three major adverse effects on the liver: direct or indirect toxic effects, immunological effects and oncogenic effects. Smoking yields chemical substances with cytotoxic potential which increase necroinflammation and fibrosis. In addition, smoking increases the production of pro-inflammatory cytokines (IL-1, IL-6 and TNF-α) that would be involved in liver cell injury. It contributes to the development of secondary polycythemia and in turn to increased red cell mass and turnover which might be a contributing factor to secondary iron overload disease promoting oxidative stress of hepatocytes. Increased red cell mass and turnover are associated with increased purine catabolism which promotes excessive production of uric acid. Smoking affects both cell-mediated and humoral immune responses by blocking lymphocyte proliferation and inducing apoptosis of lymphocytes.Smoking also increases serum and hepatic iron which induce oxidative stress and lipid peroxidation that lead to activation of stellate cells and development of fibrosis.Smoking yields chemicals with oncogenic potential that increase the risk of hepatocellular carcinoma (HCC)in patients with viral hepatitis and are independent of viral infection as well. Tobacco smoking has been associated with supression of p53 (tumour suppressor gene). In addition, smoking causes suppression of T-cell responses and is associated with decreased surveillance for tumour cells. Moreover, it has been reported that heavy smoking affects the sustained virological response to interferon (IFN) therapy in hepatitis C patients which can be improved by repeated phlebotomy. Smoker's syndrome is a clinico-pathological condition where patients complain of episodes of facial flushing, warmth of the palms and soles of feet, throbbing headache,fullness in the head, dizziness, lethargy, prickling sensation

  6. Pancreatic regeneration: basic research and gene regulation.

    Science.gov (United States)

    Okita, Kenji; Mizuguchi, Toru; Shigenori, Ota; Ishii, Masayuki; Nishidate, Toshihiko; Ueki, Tomomi; Meguro, Makoto; Kimura, Yasutoshi; Tanimizu, Naoki; Ichinohe, Norihisa; Torigoe, Toshihiko; Kojima, Takashi; Mitaka, Toshihiro; Sato, Noriyuki; Sawada, Norimasa; Hirata, Koichi

    2016-06-01

    Pancreatic regeneration (PR) is an interesting phenomenon that could provide clues as to how the control of diabetes mellitus might be achieved. Due to the different regenerative abilities of the pancreas and liver, the molecular mechanism responsible for PR is largely unknown. In this review, we describe five representative murine models of PR and thirteen humoral mitogens that stimulate β-cell proliferation. We also describe pancreatic ontogenesis, including the molecular transcriptional differences between α-cells and β-cells. Furthermore, we review 14 murine models which carry defects in genes related to key transcription factors for pancreatic ontogenesis to gain further insight into pancreatic development.

  7. Fas involvement in Ca(2+)-independent T cell-mediated cytotoxicity.

    Science.gov (United States)

    Rouvier, E; Luciani, M F; Golstein, P

    1993-01-01

    Mechanisms of T cell-mediated cytotoxicity remain poorly defined at the molecular level. To investigate some of these mechanisms, we used as target cells, on the one hand, thymocytes from lpr and gld mouse mutants, and on the other hand, L1210 cells transfected or not with the apoptosis-inducing Fas molecule. These independent mutant or transfectant-based approaches both led to the conclusion that Fas was involved in the Ca(2+)-independent component of cytotoxicity mediated by at least two sources of T cells, namely nonantigen-specific in vitro activated hybridoma cells, and antigen-specific in vivo raised peritoneal exudate lymphocytes. Thus, in these cases, T cell-mediated cytotoxicity involved transduction via Fas of the target cell death signal.

  8. Role of very late antigen-1 in T-cell-mediated immunity to systemic viral infection

    DEFF Research Database (Denmark)

    Ørding Kauffmann, Susanne; Thomsen, Allan Randrup; Christensen, Jan Pravsgaard

    2006-01-01

    The T-cell response to lymphocytic choriomeningitis virus was studied in mice lacking very late antigen-1 (VLA-1). The generation of virus-specific effector T cells was unimpaired in VLA-1(-/-) mice. In the memory phase, VLA-1 deficiency did not influence the number of memory CD8(+) T cells or th......, the current findings indicate that the expression of VLA-1 is not pivotal for T-cell-mediated antiviral immunity to a systemic infection.......-cell-mediated inflammation, no significant influence of VLA-1 was found either in the primary response or in the memory phase. However, alpha-VLA-4 antibody reduced the DTH-like reaction in VLA-1(-/-) mice to a higher degree than in wt mice, suggesting a synergistic effect of blocking both integrins. Taken together...

  9. Impaired cell mediated immunity in haemophilia in the absence of infection with human immunodeficiency virus.

    Science.gov (United States)

    Madhok, R; Gracie, A; Lowe, G D; Burnett, A; Froebel, K; Follett, E; Forbes, C D

    1986-10-18

    The cell mediated immune response was evaluated in vivo in 29 patients with clinically severe haemophilia by means of the dinitrochlorobenzene skin test. All patients had a response below the median normal value, and in 19 the response was on or below the lower limit of the normal range. There was no difference in skin response between patients positive and negative for the human immunodeficiency virus (HIV; formerly known as human T cell lymphotropic virus III or lymphadenopathy associated virus). In the whole group, and in seronegative patients (n = 17), there was an inverse relation between exposure to clotting factor and skin response. In seropositive patients (n = 12) no such association was apparent. This study shows that clotting factor concentrate impairs the cell mediated immune response to a new antigen in the absence of infection with HIV.

  10. Noninvasive Imaging of Cell-Mediated Therapy for Treatment of Cancer

    Science.gov (United States)

    Akins, Elizabeth J.; Dubey, Purnima

    2013-01-01

    Cell-mediated therapy (immunotherapy) for the treatment of cancer is an active area of investigation in animal models and clinical trials. Despite many advances, objective responses to immunotherapy are observed in a small number of cases, for certain tumor types. To better understand differences in outcomes, it is critical to develop assays for tracking effector cell localization and function in situ. The fairly recent use of molecular imaging techniques to track cell populations has presented researchers and clinicians with a powerful diagnostic tool for determining the efficacy of cell-mediated therapy for the treatment of cancer. This review highlights the application of whole-body noninvasive radioisotopic, magnetic, and optical imaging methods for monitoring effector cells in vivo. Issues that affect sensitivity of detection, such as methods of cell marking, efficiency of cell labeling, toxicity, and limits of detection of imaging modalities, are discussed. PMID:18523073

  11. Effect of disodium cromoglycate on mast cell-mediated immediate-type allergic reactions.

    Science.gov (United States)

    Shin, Hye-Young; Kim, Jung-Sook; An, Nyeon-Hyoung; Park, Rae-Kil; Kim, Hyung-Min

    2004-04-23

    We investigated the effect of disodium cromoglycate (DSCG) on mast cell-mediated immediate-type hypersensitivity. DSCG inhibited systemic allergic reaction induced by compound 48/80 dose-dependently. Passive cutaneous anaphylaxis was inhibited by 71.6% by oral administration of DSCG (1 g/kg). When DSCG was pretreated at concentration rang from 0.01-1000 g/kg, the serum histamine levels were reduced in a dose dependent manner. DSCG also significantly inhibited histamine release from rat peritoneal mast cell (RPMC) by compound 48/80. We confirmed that DSCG inhibited compound 48/80-induced degranulation of RPMC by alcian blue/nuclear fast red staining. In addition, DSCG showed a significant inhibitory effect on anti-dinitrophenyl IgE-mediated tumor necrosis factor-alpha production. These results indicate that DSCG inhibits mast cell-mediated immediate-type allergic reaction.

  12. Saos-2 cell-mediated mineralization on collagen gels: Effect of densification and bioglass incorporation.

    Science.gov (United States)

    Liu, Gengbo; Pastakia, Meet; Fenn, Michael B; Kishore, Vipuil

    2016-05-01

    Plastic compression is a collagen densification process that has been widely used for the development of mechanically robust collagen-based materials. Incorporation of bioglass within plastically compressed collagen gels has been shown to mimic the microstructural properties of native bone and enhance in vitro cell-mediated mineralization. The current study seeks to decouple the effects of collagen densification and bioglass incorporation to understand the interplay between collagen packing density and presence of bioglass on cell-mediated mineralization. Saos-2 cell-mediated mineralization was assessed as a measure of the osteoconductivity of four different collagen gels: (1) uncompressed collagen gel (UC), (2) bioglass incorporated uncompressed collagen gel (UC + BG), (3) plastically compressed collagen gel (PC), and (4) bioglass incorporated plastically compressed collagen gel (PC + BG). The results indicated that collagen densification enhanced mineralization as shown by SEM, increased alkaline phosphatase activity and produced significantly higher amounts of mineralized nodules on PC gels compared to UC gels. Further, the amount of nodule formation on PC gels was significantly higher compared to UC + BG gels indicating that increase in matrix stiffness due to collagen densification had a greater effect on cell-mediated mineralization compared to bioglass incorporation into loosely packed UC gels. Incorporation of bioglass into PC gels further enhanced mineralization as evidenced by significantly larger nodule size and higher amount of mineralization on PC + BG gels compared to PC gels. In conclusion, collagen densification via plastic compression improves the osteoconductivity of collagen gels. Further, incorporation of bioglass within PC gels has an additive effect and further enhances the osteoconductivity of collagen gels.

  13. Activation of cell-mediated immunity by Morinda citrifolia fruit extract and its constituents.

    Science.gov (United States)

    Murata, Kazuya; Abe, Yumi; Futamura-Masudaa, Megumi; Uwaya, Akemi; Isami, Fumiyuki; Matsuda, Hideaki

    2014-04-01

    Morinda citrifolia, commonly known as noni, is a traditional natural medicine in French Polynesia and Hawaii. Functional foods derived from M. citrifolia fruit have been marketed to help prevent diseases and promote good health. The objective of this study was to assess the effects of M. citrifolia fruit on cell-mediated immunity. In the picryl chloride-induced contact dermatitis test, M. citrifolia fruit extract (Noni-ext) inhibited the suppression of cell-mediated immunity by immunosuppressive substances isolated from freeze-dried ascites of Ehrlich carcinoma-bearing mice (EC-sup). In addition, Noni-ext inhibited reduction of IL-2 production in EC-sup-treated mice and activated natural killer cells in normal mice. These results suggest that Noni-ext has multiple effects on the recovery of cell-mediated immunity. Furthermore, we investigated the active principles of Noni-ext and identified an iridoid glycoside, deacetylasperulosidic acid. Oral administration of deacetylasperulosidic acid inhibited the reduction of ear swelling, and also cancelled the suppression of IL-2 production along with the activation of natural killer cells in the same manner as that of Noni-ext.

  14. Perfluorodecalin and bone regeneration

    Directory of Open Access Journals (Sweden)

    F Tamimi

    2013-01-01

    Full Text Available Perfluorodecalin (PFD is a chemically and biologically inert biomaterial and, as many perfluorocarbons, is also hydrophobic, radiopaque and has a high solute capacity for gases such as oxygen. In this article we have demonstrated, both in vitro and in vivo, that PFD may significantly enhance bone regeneration. Firstly, the potential benefit of PFD was demonstrated by prolonging the survival of bone marrow cells cultured in anaerobic conditions. These findings translated in vivo, where PFD incorporated into bone-marrow-loaded 3D-printed scaffolds substantially improved their capacity to regenerate bone. Secondly, in addition to biological applications, we have also shown that PFD improves the radiopacity of bone regeneration biomaterials, a key feature required for the visualisation of biomaterials during and after surgical implantation. Finally, we have shown how the extreme hydrophobicity of PFD enables the fabrication of highly cohesive self-setting injectable biomaterials for bone regeneration. In conclusion, perfluorocarbons would appear to be highly beneficial additives to a number of regenerative biomaterials, especially those for bone regeneration.

  15. Regeneração do fígado após hepatectomia parcial em ratos submetidos à hipertensão portal pós-hepática Liver regeneration after partial hepatectomy in rats submitted to post-hepatic portal hypertension

    Directory of Open Access Journals (Sweden)

    Luiz Roberto Farion de Aguiar

    2011-06-01

    : 1. atraso no processo regenerativo diretamente proporcional aos níveis pressóricos no sistema porta; 2. após dez dias, persiste a proliferação de hepatócitos proporcionalmente mais intensa quanto maior a elevação da pressão no sistema porta, porém níveis extremos de pressão portal inibem a proliferação, e, no estímulo para regeneração do fígado, demonstrou-se atraso da angiogênese influenciado pelos valores de pressão portal; 3. hipertensão portal extrema promove elevação da expressão de fator VIII, o que sugere capilarização dos sinusóides; 4. quanto mais elevados os níveis de pressão portal, menor será a quantidade de colágeno depositada, podendo-se inferir que o aumento da pressão portal ocasiona atraso na restauração da matriz extracelular; 5. a análise da função hepática evidenciou que a hepatectomia parcial a 70%, após dez dias, não interferiu com a fisiologia hepática, a qual permaneceu dentro dos limites da normalidade, mas com a hipertensão portal pode haver comprometimento funcional do fígado remanescente durante o processo regenerativo.BACKGROUND: The normal adult liver is quiescent and only a small percentage of its cells is subjected to cell division at any time, but can quickly initiate cell proliferation in response to a stimulus. This process can be triggered by partial hepatectomy. AIM: To evaluate the effect of portal hypertension caused by partial occlusion of hepatic venous drainage on regeneration of remnant liver of rats after partial hepatectomy. METHODS: It was performed two-thirds hepatectomy in 50 adult male Wistar rats. The animals were divided into five groups: a control group and four study groups were subjected to different degrees of plication of inferior vena cava-hepatic above. After 240 hours of the stimulus for regeneration took place relaparotomy with measurement of portal pressure and inferior vena cava, and liver biopsy. Fragments were analyzed by immunohistochemistry for the markers Ki

  16. Evidence against a stem cell origin of new hepatocytes in a common mouse model of chronic liver injury.

    Science.gov (United States)

    Schaub, Johanna R; Malato, Yann; Gormond, Coralie; Willenbring, Holger

    2014-08-21

    Hepatocytes provide most liver functions, but they can also proliferate and regenerate the liver after injury. However, under some liver injury conditions, particularly chronic liver injury where hepatocyte proliferation is impaired, liver stem cells (LSCs) are thought to replenish lost hepatocytes. Conflicting results have been reported about the identity of LSCs and their contribution to liver regeneration. To address this uncertainty, we followed candidate LSC populations by genetic fate tracing in adult mice with chronic liver injury due to a choline-deficient, ethionine-supplemented diet. In contrast to previous studies, we failed to detect hepatocytes derived from biliary epithelial cells or mesenchymal liver cells beyond a negligible frequency. In fact, we failed to detect hepatocytes that were not derived from pre-existing hepatocytes. In conclusion, our findings argue against LSCs, or other nonhepatocyte cell types, providing a backup system for hepatocyte regeneration in this common mouse model of chronic liver injury.

  17. Evidence against a Stem Cell Origin of New Hepatocytes in a Common Mouse Model of Chronic Liver Injury

    Directory of Open Access Journals (Sweden)

    Johanna R. Schaub

    2014-08-01

    Full Text Available Hepatocytes provide most liver functions, but they can also proliferate and regenerate the liver after injury. However, under some liver injury conditions, particularly chronic liver injury where hepatocyte proliferation is impaired, liver stem cells (LSCs are thought to replenish lost hepatocytes. Conflicting results have been reported about the identity of LSCs and their contribution to liver regeneration. To address this uncertainty, we followed candidate LSC populations by genetic fate tracing in adult mice with chronic liver injury due to a choline-deficient, ethionine-supplemented diet. In contrast to previous studies, we failed to detect hepatocytes derived from biliary epithelial cells or mesenchymal liver cells beyond a negligible frequency. In fact, we failed to detect hepatocytes that were not derived from pre-existing hepatocytes. In conclusion, our findings argue against LSCs, or other nonhepatocyte cell types, providing a backup system for hepatocyte regeneration in this common mouse model of chronic liver injury.

  18. Liver Immunology

    Science.gov (United States)

    Bogdanos, Dimitrios P.; Gao, Bin; Gershwin, M. Eric

    2014-01-01

    The liver is the largest organ in the body and is generally regarded by non-immunologists as not having lymphoid function. However, such is far from accurate. This review highlights the importance of the liver as a lymphoid organ. Firstly, we discuss experimental data surrounding the role of liver as a lymphoid organ. The liver facilitates a tolerance rather than immunoreactivity, which protects the host from antigenic overload of dietary components and drugs derived from the gut and is also instrumental to fetal immune tolerance. Loss of liver tolerance leads to autoaggressive phenomena which if are not controlled by regulatory lymphoid populations may lead to the induction of autoimmune liver diseases. Liver-related lymphoid subpopulations also act as critical antigen-presenting cells. The study of the immunological properties of liver and delineation of the microenvironment of the intrahepatic milieu in normal and diseased livers provides a platform to understand the hierarchy of a series of detrimental events which lead to immune-mediated destruction of the liver and the rejection of liver allografts. The majority of emphasis within this review will be on the normal mononuclear cell composition of the liver. However, within this context, we will discus select, but not all, immune mediated liver disease and attempt to place these data in the context of human autoimmunity. PMID:23720323

  19. Bioelectricity and epimorphic regeneration.

    Science.gov (United States)

    Stewart, Scott; Rojas-Muñoz, Agustin; Izpisúa Belmonte, Juan Carlos

    2007-11-01

    All cells have electric potentials across their membranes, but is there really compelling evidence to think that such potentials are used as instructional cues in developmental biology? Numerous reports indicate that, in fact, steady, weak bioelectric fields are observed throughout biology and function during diverse biological processes, including development. Bioelectric fields, generated upon amputation, are also likely to play a key role during vertebrate regeneration by providing the instructive cues needed to direct migrating cells to form a wound epithelium, a structure unique to regenerating animals. However, mechanistic insight is still sorely lacking in the field. What are the genes required for bioelectric-dependent cell migration during regeneration? The power of genetics combined with the use of zebrafish offers the best opportunity for unbiased identification of the molecular players in bioelectricity.

  20. Liver Diseases

    Science.gov (United States)

    Your liver is the largest organ inside your body. It helps your body digest food, store energy, and remove poisons. There are many kinds of liver diseases: Diseases caused by viruses, such as hepatitis ...

  1. Fatty Liver

    Science.gov (United States)

    ... Abbreviations Weights & Measures ENGLISH View Professional English Deutsch Japanese Espaniol Find information on medical topics, symptoms, drugs, ... inside liver cells. Just consuming a high-fat diet does not result in fatty liver. Rarely, fat ...

  2. Liver disease

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000205.htm Liver disease To use the sharing features on this page, please enable JavaScript. The term "liver disease" applies to many conditions that stop the ...

  3. Liver Disease

    Science.gov (United States)

    ... stay still. Liver disease has many causes. Infection Parasites and viruses can infect the liver, causing inflammation ... beyond. National Institute of Diabetes and Digestive and Kidney Diseases. http://digestive.niddk.nih.gov/ddiseases/pubs/ ...

  4. [Regeneration of airway epithelium].

    Science.gov (United States)

    Adam, D; Perotin, J-M; Lebargy, F; Birembaut, P; Deslée, G; Coraux, C

    2014-04-01

    Epithelial regeneration is a complex process. It can lead to the remodeling of the airway epithelium as in asthma, COPD or cystic fibrosis. The development of in vivo and in vitro models has allowed the analysis of remodeling mechanisms and showed the role of components of extracellular matrix, proteases, cytokines and growth factors. Airway epithelial progenitors and stems cells have been studied in these models. However, their identification remains difficult. Identification and characterization of airway epithelial progenitor/stem-cells, and a better knowledge of the regeneration process may allow the development of new therapeutic strategies for airway epithelial reconstitution. Copyright © 2013 SPLF. Published by Elsevier Masson SAS. All rights reserved.

  5. The impact of long-term haemofiltration (continuous veno-venous haemofiltration) on cell-mediated immunity during endotoxaemia

    DEFF Research Database (Denmark)

    Toft, P; Nilsen, B U; Bollen, P;

    2007-01-01

    BACKGROUND: Increased survival with high-volume continuous veno-venous haemofiltration (CVVH) has been demonstrated in critically ill patients. This may be the result of intensified blood purification or an effect on the immune system. We hypothesized that CVVH modifies the cell-mediated immunity....... However, in the long term, CVVH was unable to modify the endotoxin-induced changes in cell-mediated immunity....

  6. Lineage tracing reveals conversion of liver sinusoidal endothelial cells into hepatocytes.

    Science.gov (United States)

    Tan, Zhaoli; Chen, Keyan; Shao, Yong; Gao, Lihua; Wang, Yan; Xu, Jianming; Jin, Yang; Hu, Xianwen; Wang, Youliang

    2016-09-01

    Although liver sinusoidal endothelial cells (LSECs) have long been known to contribute to liver regeneration following injury, the exact role of these cells in liver regeneration remains poorly understood. In this work, we performed lineage tracing of LSECs in mice carrying Tie2-Cre or VE-cadherin-Cre constructs to facilitate fate-mapping of LSECs in liver regeneration. Some YFP-positive LSECs were observed to convert into hepatocytes following a two-thirds partial hepatectomy (PH). Furthermore, human umbilical vein endothelial cells (HUVECs) could be triggered to convert into cells that closely resembled hepatocytes when cultured with serum from mice that underwent an extended PH. These findings suggest that mature non-hepatocyte LSECs play an essential role in mammalian liver regeneration by converting to hepatocytes. The conversion of LSECs to hepatocyte-like (iHep) cells may provide a new approach to tissue engineering.

  7. Infection and Pulp Regeneration

    Directory of Open Access Journals (Sweden)

    Sahng G. Kim

    2016-03-01

    Full Text Available The regeneration of the pulp-dentin complex has been a great challenge to both scientists and clinicians. Previous work has shown that the presence of prior infection may influence the characteristics of tissues formed in the root canal space after regenerative endodontic treatment. The formation of ectopic tissues such as periodontal ligament, bone, and cementum has been observed in the root canal space of immature necrotic teeth with apical periodontitis, while the regeneration of dentin and pulp has been identified in previously non-infected teeth. The current regenerative endodontic therapy utilizes disinfection protocols, which heavily rely on chemical irrigation using conventional disinfectants. From a microbiological point of view, the current protocols may not allow a sufficiently clean root canal microenvironment, which is critical for dentin and pulp regeneration. In this article, the significance of root canal disinfection in regenerating the pulp-dentin complex, the limitations of the current regenerative endodontic disinfection protocols, and advanced disinfection techniques designed to reduce the microorganisms and biofilms in chronic infection are discussed.

  8. THE EFFECT OF MICROBLAL FERMENTS ON LIVER REGENERATION IN THE PARTIALLY HEPATECTOMIZED RATS%微生物酵素对部分肝切除大鼠肝再生的作用

    Institute of Scientific and Technical Information of China (English)

    刘秀红; 李宁; 赵晓飞; 夏仁品; 娄金丽; 戴洁; 周以健; 李勇

    2009-01-01

    目的 观察微生物酵素能否促进大鼠部分肝切除后肝再生.方法 采用大鼠部分肝切除(Partial Hepatectomy,PH)模型[1],通过与对照组和促肝细胞生长素(Hepatocyte Growth-Promoting Factor,pHGF)组比较,在pH后12小时、24小时、48小时、72小时、120小时和168小时,留取相应肝组织,检测反映肝再生的指标肝再生率(Hepatic Regeneration Rate,HRR)、增殖指数(Proliferation Index,PI)和细胞增殖核抗原(Proliferating Cell Nuclear Antigen,PCNA).结果 在pH后12小时和24小时、微生物酵素组同促肝细胞生长素组一样与对照组相比,肝再生率高,差异有统计学意义(P<0.05);pH后12、24、72、120小时,微生物酵素组的PI高于对照组,差异有统计学意义(分别为P<0.05、P<0.01、P<0.05和P<0.05).在pH后72小时和168小时PCNA出现高峰,微生物酵素组与对照组相比,差异有统计学意义(P<0.05).结论 微生物酵素同促肝细胞生长素一样具有早期促进肝再生的作用.

  9. Stimulating endogenous cardiac regeneration

    Directory of Open Access Journals (Sweden)

    Amanda eFinan

    2015-09-01

    Full Text Available The healthy adult heart has a low turnover of cardiac myocytes. The renewal capacity, however, is augmented after cardiac injury. Participants in cardiac regeneration include cardiac myocytes themselves, cardiac progenitor cells, and peripheral stem cells, particularly from the bone marrow compartment. Cardiac progenitor cells and bone marrow stem cells are augmented after cardiac injury, migrate to the myocardium, and support regeneration. Depletion studies of these populations have demonstrated their necessary role in cardiac repair. However, the potential of these cells to completely regenerate the heart is limited. Efforts are now being focused on ways to augment these natural pathways to improve cardiac healing, primarily after ischemic injury but in other cardiac pathologies as well. Cell and gene therapy or pharmacological interventions are proposed mechanisms. Cell therapy has demonstrated modest results and has passed into clinical trials. However, the beneficial effects of cell therapy have primarily been their ability to produce paracrine effects on the cardiac tissue and recruit endogenous stem cell populations as opposed to direct cardiac regeneration. Gene therapy efforts have focused on prolonging or reactivating natural signaling pathways. Positive results have been demonstrated to activate the endogenous stem cell populations and are currently being tested in clinical trials. A potential new avenue may be to refine pharmacological treatments that are currently in place in the clinic. Evidence is mounting that drugs such as statins or beta blockers may alter endogenous stem cell activity. Understanding the effects of these drugs on stem cell repair while keeping in mind their primary function may strike a balance in myocardial healing. To maximize endogenous cardiac regeneration,a combination of these approaches couldameliorate the overall repair process to incorporate the participation ofmultiple cell players.

  10. Fibronectin Extra Domain A Promotes Liver Sinusoid Repair following Hepatectomy

    Science.gov (United States)

    Sackey-Aboagye, Bridget; Olsen, Abby L.; Mukherjee, Sarmistha M.; Ventriglia, Alexander; Yokosaki, Yasuyuki; Greenbaum, Linda E.; Lee, Gi Yun; Naga, Hani

    2016-01-01

    Liver sinusoidal endothelial cells (LSECs) are the main endothelial cells in the liver and are important for maintaining liver homeostasis as well as responding to injury. LSECs express cellular fibronectin containing the alternatively spliced extra domain A (EIIIA-cFN) and increase expression of this isoform after liver injury, although its function is not well understood. Here, we examined the role of EIIIA-cFN in liver regeneration following partial hepatectomy. We carried out two-thirds partial hepatectomies in mice lacking EIIIA-cFN and in their wild type littermates, studied liver endothelial cell adhesion on decellularized, EIIIA-cFN-containing matrices and investigated the role of cellular fibronectins in liver endothelial cell tubulogenesis. We found that liver weight recovery following hepatectomy was significantly delayed and that sinusoidal repair was impaired in EIIIA-cFN null mice, especially females, as was the lipid accumulation t