Histopathological growth pattern, proteolysis and angiogenesis in chemonaive patients resected for multiple colorectal liver metastases

DEFF Research Database (Denmark)

Eefsen, Rikke Løvendahl; Van den Eynden, Gert G; Høyer-Hansen, Gunilla

2012-01-01

The purpose of this study was to characterise growth patterns, proteolysis, and angiogenesis in colorectal liver metastases from chemonaive patients with multiple liver metastases. Twenty-four patients were included in the study, resected for a median of 2.6 metastases. The growth pattern......-type plasminogen activator receptor (P = 0.0008). Angiogenesis was most pronounced in metastases with a pushing growth pattern in comparison to those with desmoplastic (P = 0.0007) and replacement growth pattern (P = 0.021). Although a minor fraction of the patients harboured metastases with different growth...

Impact of associating liver partition and portal vein occlusion for staged hepatectomy on tumor growth in a mouse model of liver metastasis.

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Kikuchi, Yutaro; Hiroshima, Yukihiko; Matsuo, Kenichi; Murakami, Takashi; Kawaguchi, Daisuke; Kasahara, Kohei; Tanaka, Kuniya

2018-01-01

The impact of associating liver partition and portal vein occlusion for staged hepatectomy (ALPPS) on tumor growth activity was investigated. A BALB/c mouse model (male, 8-10 weeks old) of liver metastasis labeled by red fluorescent protein was established. Changes in future liver remnant (FLR) volumes, tumor growth activity, and levels of cytokines and growth factors in liver tissues during the treatment period were compared among the models involving ALPPS, portal vein ligation (PVL), or sham operation. The ratio of the FLR volume to body weight at 24 h after the procedure was greater for ALPPS (4.45 ± 0.12 × 10 -2 ) than for PVL (3.79 ± 0.12 × 10 -2 ; P = 0.003) and sham operation (3.18 ± 0.16 × 10 -2 ; P < 0.001). No differences in tumor progression in the FLR were observed at any time point after the procedures. Within the deportalized liver (DL), although tumor progression was observed during a later period after ALPPS (9 days postoperative) and PVL (12 days postoperative), no acceleration of tumor growth after ALPPS was observed in an early period similar to PVL. ALPPS induces a rapid increase in FLR volume and avoids remnant tumor progression during the early postoperative period. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

The morphological growth patterns of colorectal liver metastases are prognostic for overall survival

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Nielsen, Kåre; Rolff, Hans C; Eefsen, Rikke L

2014-01-01

Colorectal metastases in the liver grow according to three histological patterns: a pushing pattern, a replacement pattern, and a desmoplastic pattern. The objective of the current study was to explore the prognostic significance of these three growth patterns for survival. The study included 217....... Eventually, the growth patterns may contribute to a histology-based prognostic biomarker for patients with colorectal liver metastases.Modern Pathology advance online publication, 23 May 2014; doi:10.1038/modpathol.2014.4....

Mathematical modeling of liver metastases tumour growth and control with radiotherapy

International Nuclear Information System (INIS)

Campbell, Adrienne; Sivakumaran, Thiru; Wong, Eugene; Davidson, Melanie; Lock, Michael

2008-01-01

Generating an optimized radiation treatment plan requires understanding the factors affecting tumour control. Mathematical models of tumour dynamics may help in future studies of factors predicting tumour sensitivity to radiotherapy. In this study, a time-dependent differential model, incorporating biological cancer markers, is presented to describe pre-treatment tumour growth, response to radiation, and recurrence. The model uses Gompertzian-Exponential growth to model pre-treatment tumour growth. The effect of radiotherapy is handled by a realistic cell-kill term that includes a volume-dependent change in tumour sensitivity. Post-treatment, a Gompertzian, accelerated, delayed repopulation is employed. As proof of concept, we examined the fit of the model's prediction using various liver enzyme levels as markers of metastatic liver tumour growth in a liver cancer patient. A tumour clonogen population model was formulated. Each enzyme was coupled to the same tumour population, and served as surrogates of the tumour. This dynamical model was solved numerically and compared to the measured enzyme levels. By minimizing the mean-squared error of the model enzyme predictions, we determined the following tumour model parameters: growth rate prior to treatment was 0.52% per day; the fractional radiation cell kill for the prescribed dose (60 Gy in 15 fractions) was 42% per day, and the tumour repopulation rate was 2.9% per day. These preliminary results provided the basis to test the model in a larger series of patients, to apply biological markers for improving the efficacy of radiotherapy by determining the underlying tumour dynamics.

Harnessing high density lipoproteins to block transforming growth factor beta and to inhibit the growth of liver tumor metastases.

Directory of Open Access Journals (Sweden)

José Medina-Echeverz

Full Text Available Transforming growth factor β (TGF-β is a powerful promoter of cancer progression and a key target for antitumor therapy. As cancer cells exhibit active cholesterol metabolism, high density lipoproteins (HDLs appear as an attractive delivery system for anticancer TGFβ-inhibitory molecules. We constructed a plasmid encoding a potent TGF-β-blocking peptide (P144 linked to apolipoprotein A-I (ApoA-I through a flexible linker (pApoLinkerP144. The ApoLinkerP144 sequence was then incorporated into a hepatotropic adeno-associated vector (AAVApoLinkerP144. The aim was to induce hepatocytes to produce HDLs containing a modified ApoA-I capable of blocking TGF-β. We observed that transduction of the murine liver with pApoLinkerP144 led to the appearance of a fraction of circulating HDL containing the fusion protein. These HDLs were able to attenuate TGF-β signaling in the liver and to enhance IL-12 -mediated IFN-γ production. Treatment of liver metastasis of MC38 colorectal cancer with AAVApoLinkerP144 resulted in a significant reduction of tumor growth and enhanced expression of IFN-γ and GM-CSF in cancerous tissue. ApoLinkerP144 also delayed MC38 liver metastasis in Rag2-/-IL2rγ-/- immunodeficient mice. This effect was associated with downregulation of TGF-β target genes essential for metastatic niche conditioning. Finally, in a subset of ret transgenic mice, a model of aggressive spontaneous metastatic melanoma, AAVApoLinkerP144 delayed tumor growth in association with increased CD8+ T cell numbers in regional lymph nodes. In conclusion, modification of HDLs to transport TGF-β-blocking molecules is a novel and promising approach to inhibit the growth of liver metastases by immunological and non-immunological mechanisms.

FXR blocks the growth of liver cancer cells through inhibiting mTOR-s6K pathway

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Huang, Xiongfei, E-mail: xiongfeihuang@hotmail.com [Department of Pathology and Institute of Oncology, Preclinical School, Fujian Medical University, Fuzhou 350108, Fujian (China); Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350108, Fujian (China); Zeng, Yeting [Department of Pathology and Institute of Oncology, Preclinical School, Fujian Medical University, Fuzhou 350108, Fujian (China); Wang, Xinrui [Department of Biochemistry and Molecular Biology, Fujian Medical University, Fuzhou 350108, Fujian (China); Ma, Xiaoxiao [Department of Diabetes Complications and Metabolism, Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope, CA 91010 (United States); Li, Qianqian; Li, Ningbo; Su, Hongying [Department of Pathology and Institute of Oncology, Preclinical School, Fujian Medical University, Fuzhou 350108, Fujian (China); Huang, Wendong [Department of Diabetes Complications and Metabolism, Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope, CA 91010 (United States)

2016-05-27

The nuclear receptor Farnesoid X Receptor (FXR) is likely a tumor suppressor in liver tissue but its molecular mechanism of suppression is not well understood. In this study, the gene expression profile of human liver cancer cells was investigated by microarray. Bioinformatics analysis of these data revealed that FXR might regulate the mTOR/S6K signaling pathway. This was confirmed by altering the expression level of FXR in liver cancer cells. Overexpression of FXR prevented the growth of cells and induced cell cycle arrest, which was enhanced by the mTOR/S6K inhibitor rapamycin. FXR upregulation also intensified the inhibition of cell growth by rapamycin. Downregulation of FXR produced the opposite effect. Finally, we found that ectopic expression of FXR in SK-Hep-1 xenografts inhibits tumor growth and reduces expression of the phosphorylated protein S6K. Taken together, our data provide the first evidence that FXR suppresses proliferation of human liver cancer cells via the inhibition of the mTOR/S6K signaling pathway. FXR expression can be used as a biomarker of personalized mTOR inhibitor treatment assessment for liver cancer patients. -- Highlights: •FXR inhibits the proliferation of liver cancer cells by prolonging G0/G1 phase. •Microarray results indicate that mTOR-S6k signaling is involved in cellular processes in which FXR plays an important role. •FXR blocks the growth of liver cancer cells via the inhibition of the mTOR/S6K signaling pathway in vitro and in vivo.

FXR blocks the growth of liver cancer cells through inhibiting mTOR-s6K pathway

International Nuclear Information System (INIS)

Huang, Xiongfei; Zeng, Yeting; Wang, Xinrui; Ma, Xiaoxiao; Li, Qianqian; Li, Ningbo; Su, Hongying; Huang, Wendong

2016-01-01

The nuclear receptor Farnesoid X Receptor (FXR) is likely a tumor suppressor in liver tissue but its molecular mechanism of suppression is not well understood. In this study, the gene expression profile of human liver cancer cells was investigated by microarray. Bioinformatics analysis of these data revealed that FXR might regulate the mTOR/S6K signaling pathway. This was confirmed by altering the expression level of FXR in liver cancer cells. Overexpression of FXR prevented the growth of cells and induced cell cycle arrest, which was enhanced by the mTOR/S6K inhibitor rapamycin. FXR upregulation also intensified the inhibition of cell growth by rapamycin. Downregulation of FXR produced the opposite effect. Finally, we found that ectopic expression of FXR in SK-Hep-1 xenografts inhibits tumor growth and reduces expression of the phosphorylated protein S6K. Taken together, our data provide the first evidence that FXR suppresses proliferation of human liver cancer cells via the inhibition of the mTOR/S6K signaling pathway. FXR expression can be used as a biomarker of personalized mTOR inhibitor treatment assessment for liver cancer patients. -- Highlights: •FXR inhibits the proliferation of liver cancer cells by prolonging G0/G1 phase. •Microarray results indicate that mTOR-S6k signaling is involved in cellular processes in which FXR plays an important role. •FXR blocks the growth of liver cancer cells via the inhibition of the mTOR/S6K signaling pathway in vitro and in vivo.

'Obligate' anaerobic Salmonella strain YB1 suppresses liver tumor growth and metastasis in nude mice.

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Li, Chang-Xian; Yu, Bin; Shi, Lei; Geng, Wei; Lin, Qiu-Bin; Ling, Chang-Chun; Yang, Mei; Ng, Kevin T P; Huang, Jian-Dong; Man, Kwan

2017-01-01

The antitumor properties of bacteria have been demonstrated over the past decades. However, the efficacy is limited and unclear. Furthermore, systemic infection remains a serious concern in bacteria treatment. In this study, the effect of YB1, a rationally designed 'obligate' anaerobic Salmonella typhimurium strain, on liver tumor growth and metastasis in a nude mouse orthotopic liver tumor model was investigated. The orthotopic liver tumor model was established in nude mice using the hepatocellular carcinoma cell line MHCC-97L. Two weeks after orthotopic liver tumor implantation, YB1, SL7207 and saline were respectively administered through the tail vein of the mice. Longitudinal monitoring of tumor growth and metastasis was performed using Xenogen IVIS, and direct measurements of tumor volume were taken 3 weeks after treatment. In vitro , MHCC-97L and PLC cells were incubated with YB1 or SL7207 under anaerobic conditions. YB1 was observed to invade tumor cells and induce tumor cell apoptosis and death. The results revealed that all mice in the YB1 group were alive 3 weeks after YB1 injection while all mice in the SL7207 group died within 11 days of the SL7207 injection. The body weight decreased by ~9% on day 1 after YB1 injection and but subsequently recovered. Liver tumor growth and metastases were significantly inhibited following YB1 treatment. By contrast to the control group, a large number of Gr1-positive cells were detected on days 1 to 21 following YB1 treatment. Furthermore, YB1 also effectively invaded tumor cells and induced tumor cell apoptosis and death. In conclusion, YB1 suppressed liver tumor growth and metastasis in a nude mice liver tumor model. The potential mechanism may be through enhancing innate immune response and inducing tumor cell apoptosis and cell death.

Multigenerational epigenetic adaptation of the hepatic wound-healing response.

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Zeybel, Müjdat; Hardy, Timothy; Wong, Yi K; Mathers, John C; Fox, Christopher R; Gackowska, Agata; Oakley, Fiona; Burt, Alastair D; Wilson, Caroline L; Anstee, Quentin M; Barter, Matt J; Masson, Steven; Elsharkawy, Ahmed M; Mann, Derek A; Mann, Jelena

2012-09-01

We investigated whether ancestral liver damage leads to heritable reprogramming of hepatic wound healing in male rats. We found that a history of liver damage corresponds with transmission of an epigenetic suppressive adaptation of the fibrogenic component of wound healing to the male F1 and F2 generations. Underlying this adaptation was less generation of liver myofibroblasts, higher hepatic expression of the antifibrogenic factor peroxisome proliferator-activated receptor γ (PPAR-γ) and lower expression of the profibrogenic factor transforming growth factor β1 (TGF-β1) compared to rats without this adaptation. Remodeling of DNA methylation and histone acetylation underpinned these alterations in gene expression. Sperm from rats with liver fibrosis were enriched for the histone variant H2A.Z and trimethylation of histone H3 at Lys27 (H3K27me3) at PPAR-γ chromatin. These modifications to the sperm chromatin were transmittable by adaptive serum transfer from fibrotic rats to naive rats and similar modifications were induced in mesenchymal stem cells exposed to conditioned media from cultured rat or human myofibroblasts. Thus, it is probable that a myofibroblast-secreted soluble factor stimulates heritable epigenetic signatures in sperm so that the resulting offspring better adapt to future fibrogenic hepatic insults. Adding possible relevance to humans, we found that people with mild liver fibrosis have hypomethylation of the PPARG promoter compared to others with severe fibrosis.

Epidermal growth factor and insulin-like growth factor I upregulate the expression of the epidermal growth factor system in rat liver

DEFF Research Database (Denmark)

Bor, M V; Sørensen, B S; Vinter-Jensen, L

2000-01-01

BACKGROUND/AIM: Both epidermal growth factor and insulin-like growth factor I play a role in connection with the liver. In the present study, the possible interaction of these two growth factor systems was studied by investigating the effect of epidermal growth factor or insulin-like growth factor...... I treatment on the expression of the epidermal growth factor receptor, and its activating ligands, transforming growth factor-alpha and epidermal growth factor. METHODS: Fifty-five male rats received no treatment, human recombinant epidermal growth factor or human recombinant insulin-like growth.......8+/-1.6 fmol/mg protein epidermal growth factor and 144+/-22 fmol/mg protein transforming growth factor-alpha. Both epidermal growth factor and insulin-like growth factor I treatment increased the expression of mRNA for transforming growth factor-alpha and epidermal growth factor receptor, as well...

Cardiovascular adaptation to extrauterine life after intrauterine growth restriction.

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Rodriguez-Guerineau, Luciana; Perez-Cruz, Miriam; Gomez Roig, María D; Cambra, Francisco J; Carretero, Juan; Prada, Fredy; Gómez, Olga; Crispi, Fátima; Bartrons, Joaquim

2018-02-01

Introduction The adaptive changes of the foetal heart in intrauterine growth restriction can persist postnatally. Data regarding its consequences for early circulatory adaptation to extrauterine life are scarce. The aim of this study was to assess cardiac morphometry and function in newborns with late-onset intrauterine growth restriction to test the hypothesis that intrauterine growth restriction causes cardiac shape and functional changes at birth. A comprehensive echocardiographic study was performed in 25 neonates with intrauterine growth restriction and 25 adequate-for-gestational-age neonates. Compared with controls, neonates with intrauterine growth restriction had more globular ventricles, lower longitudinal tricuspid annular motion, and higher left stroke volume without differences in the heart rate. Neonates with intrauterine growth restriction also showed subclinical signs of diastolic dysfunction in the tissue Doppler imaging with lower values of early (e') diastolic annular peak velocities in the septal annulus. Finally, the Tei index in the tricuspid annulus was higher in the intrauterine growth restriction group. Neonates with history of intrauterine growth restriction showed cardiac remodelling and signs of systolic and diastolic dysfunction. Overall, there was a significant tendency to worse cardiac function results in the right heart. The adaptation to extrauterine life occurred with more globular hearts, higher stroke volumes but a similar heart rate compared to adequate-for-gestational-age neonates.

[Insulin-like growth factor-binding protein-1: a new biochemical marker of nonalcoholic fatty liver disease?].

Science.gov (United States)

Graffigna, Mabel Nora; Belli, Susana H; de Larrañaga, Gabriela; Fainboim, Hugo; Estepo, Claudio; Peres, Silvia; García, Natalia; Levalle, Oscar

2009-03-01

to assess the presence of nonalcoholic fatty liver disease in patients with risk factors for this pathology (obesity, dyslipidemia, metabolic syndrome and diabetes type 2) and to determine the role of insulin, HOMA index, insulin-like growth factor-binding protein-1, sex hormone-binding globulin and plasminogen activator inhibitor type 1, as biochemical markers. Ninety-one patients with risk factors for nonalcoholic fatty liver disease were evaluated. Serum transaminases, insulin, sex hormone-binding globulin, insulin-like growth factor-binding protein-1 and plasminogen activator inhibitor type 1 were measured. The diagnosis of fatty liver was performed by ultrasonography and liver biopsies were performed to 31 subjects who had steatosis by ultrasonography and high alanine aminotransferase. Nonalcoholic fatty liver disease was present in 65 out of 91 patients (71,4%). Liver biopsy performed to 31 subjects confirmed nonalcoholic steatohepatitis. Twenty-five patients had different degrees of fibrosis. Those individuals with fatty liver had higher waist circumference, serum levels of triglycerides, insulin and HOMA index, and lower serum insulin-like growth factor-binding protein-1 concentration. The degree ofhepatic steatosis by ultrasonography was positively correlated to waist circumference, triglycerides, insulin and HOMA index (p<0,003; p<0,003; p<0,002 and p<0,001, respectively), and was negatively correlated to HDL-cholesterol and insulin-like growth factor-binding protein-1 (p<0,025 and p<0,018, respectively). We found a high prevalence of NAFLD in patients with risk factors, most of them overweight or obese. Although SHBG and PAI-1 have a closely relationship to insulin resistance, they did not show to be markers of NAFLD. Regardless of low IGFBP-1 levels associated with NAFLD, serum IGFBP-1 measure is less accessible than insulin and triglycerides levels, HOMA index and waist circumference. Moreover, it is not a better marker for NAFLD than the above

Health, growth and psychosocial adaptation of immigrant children.

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Gualdi-Russo, Emanuela; Toselli, Stefania; Masotti, Sabrina; Marzouk, Diaa; Sundquist, Kristina; Sundquist, Jan

2014-08-01

The increasing population diversity in Europe demands clarification of possible ethnic influences on the growth and health of immigrant children and their psychosocial adaptation to the host countries. This article assesses recent data on immigrant children in Europe in comparison to European natives by means of a systematic review of the literature on growth patterns and data on children's health and adaptation. There were wide variations across countries in growth patterns and development of immigrant children and natives, with different trends in Central and Northern Europe with respect to Southern Europe. In general, age at menarche was lower in immigrant girls, while male pubertal progression seemed faster in immigrants than in European natives, even when puberty began after. Owing to the significant differences in anthropometric traits (mainly stature and weight), new reference growth curves for immigrant children were constructed for the largest minority groups in Central Europe. Possible negative effects on growth, health and psychosocial adaptation were pointed out for immigrant children living in low income, disadvantaged communities with a high prevalence of poor lifestyle habits. In conclusion, this review provides a framework for the health and growth of immigrant children in Europe in comparison to native-born children: the differences among European countries in growth and development of migrants and non-migrants are closely related to the clear anthropological differences among the ethnic groups due to genetic influences. Higher morbidity and mortality was frequently associated with the minority status of these children and their low socio-economic status. The observed ethnic differences in health reveal the need for adequate health care in all groups. Therefore, we provide suggestions for the development of health care strategies in Europe. © The Author 2014. Published by Oxford University Press on behalf of the European Public Health Association

Influence of thermally-oxidized vegetable oils and animal fats on growth performance, liver gene expression, and liver and serum cholesterol and triglycerides in young pigs

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To evaluate the effect of feeding thermally-oxidized vegetable oils and animal fats on growth performance, liver gene expression, and liver and serum fatty acid and cholesterol concentration in young pigs, 102 barrows (6.67 ± 0.03 kg BW) were divided into 3 groups and randomly assigned to dietary tr...

Evidence for association of the cloned liver growth hormone receptor with a tyrosine kinase

DEFF Research Database (Denmark)

Wang, X; Uhler, M D; Billestrup, N

1992-01-01

The ability of the cloned liver growth hormone (GH) receptor, when expressed in mammalian cell lines, to copurify with tyrosine kinase activity and be tyrosyl phosphorylated was examined. 125I-human growth hormone-GH receptor complexes isolated from COS-7 cells transiently expressing high levels...... of tyrosine kinase activity with cloned liver GH receptor. The level of phosphorylation of the GH receptor was very low, as compared with the endogenous GH receptor in 3T3-F442A cells, suggesting that tyrosine kinase activity is not intrinsic to the cloned GH receptor but rather resides with a kinase present...... in a variety of cell types. The finding that the level of phosphorylation of GH receptor appears to vary with cell type is consistent with the cloned liver GH receptor being a substrate for an associated tyrosine kinase and with the amount of such a GH receptor-associated tyrosine kinase being cell type-specific....

Recellularization via the bile duct supports functional allogenic and xenogenic cell growth on a decellularized rat liver scaffold.

Science.gov (United States)

Hassanein, Wessam; Uluer, Mehmet C; Langford, John; Woodall, Jhade D; Cimeno, Arielle; Dhru, Urmil; Werdesheim, Avraham; Harrison, Joshua; Rivera-Pratt, Carlos; Klepfer, Stephen; Khalifeh, Ali; Buckingham, Bryan; Brazio, Philip S; Parsell, Dawn; Klassen, Charlie; Drachenberg, Cinthia; Barth, Rolf N; LaMattina, John C

2017-01-02

Recent years have seen a proliferation of methods leading to successful organ decellularization. In this experiment we examine the feasibility of a decellularized liver construct to support growth of functional multilineage cells. Bio-chamber systems were used to perfuse adult rat livers with 0.1% SDS for 24 hours yielding decellularized liver scaffolds. Initially, we recellularized liver scaffolds using a human tumor cell line (HepG2, introduced via the bile duct). Subsequent studies were performed using either human tumor cells co-cultured with human umbilical vein endothelial cells (HUVECs, introduced via the portal vein) or rat neonatal cell slurry (introduced via the bile duct). Bio-chambers were used to circulate oxygenated growth medium via the portal vein at 37C for 5-7 days. Human HepG2 cells grew readily on the scaffold (n = 20). HepG2 cells co-cultured with HUVECs demonstrated viable human endothelial lining with concurrent hepatocyte growth (n = 10). In the series of neonatal cell slurry infusion (n = 10), distinct foci of neonatal hepatocytes were observed to repopulate the parenchyma of the scaffold. The presence of cholangiocytes was verified by CK-7 positivity. Quantitative albumin measurement from the grafts showed increasing albumin levels after seven days of perfusion. Graft albumin production was higher than that observed in traditional cell culture. This data shows that rat liver scaffolds support human cell ingrowth. The scaffold likewise supported the engraftment and survival of neonatal rat liver cell slurry. Recellularization of liver scaffolds thus presents a promising model for functional liver engineering.

Shared liver-like transcriptional characteristics in liver metastases and corresponding primary colorectal tumors.

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Cheng, Jun; Song, Xuekun; Ao, Lu; Chen, Rou; Chi, Meirong; Guo, You; Zhang, Jiahui; Li, Hongdong; Zhao, Wenyuan; Guo, Zheng; Wang, Xianlong

2018-01-01

Background & Aims : Primary tumors of colorectal carcinoma (CRC) with liver metastasis might gain some liver-specific characteristics to adapt the liver micro-environment. This study aims to reveal potential liver-like transcriptional characteristics associated with the liver metastasis in primary colorectal carcinoma. Methods: Among the genes up-regulated in normal liver tissues versus normal colorectal tissues, we identified "liver-specific" genes whose expression levels ranked among the bottom 10% ("unexpressed") of all measured genes in both normal colorectal tissues and primary colorectal tumors without metastasis. These liver-specific genes were investigated for their expressions in both the primary tumors and the corresponding liver metastases of seven primary CRC patients with liver metastasis using microdissected samples. Results: Among the 3958 genes detected to be up-regulated in normal liver tissues versus normal colorectal tissues, we identified 12 liver-specific genes and found two of them, ANGPTL3 and CFHR5 , were unexpressed in microdissected primary colorectal tumors without metastasis but expressed in both microdissected liver metastases and corresponding primary colorectal tumors (Fisher's exact test, P colorectal tumors may express some liver-specific genes which may help the tumor cells adapt the liver micro-environment.

Intrauterine growth restriction and differential patterns of hepatic growth and expression of IGF1, PCK2, and HSDL1 mRNA in the sheep fetus in late gestation.

Science.gov (United States)

Gentili, Sheridan; Morrison, Janna L; McMillen, I Caroline

2009-06-01

Fetal adaptations to periods of substrate deprivation can result in the programming of glucose intolerance, insulin resistance, and metabolic dysfunction in later life. Placental insufficiency can be associated with either sparing or sacrifice of fetal liver growth, and these different responses may have different metabolic consequences. It is unclear what intrahepatic mechanisms determine the differential responses of the fetal liver to substrate restriction. We investigated the effects of placental restriction (PR) on liver growth and the hepatic expression of SLC2A1, IGF1, IGF2, IGF1R, IGF2R, PPARGC1A, PPARA, PRKAA1, PRKAA2, PCK2, and HSDL1 mRNA in fetal sheep at 140-145 days of gestation. A mean gestational arterial partial pressure of oxygen less than 17 mmHg was defined as hypoxic, and a relative liver of weight more than 2 SD below the mean liver weight of controls was defined as reduced liver growth. Fetuses therefore were defined as control-normoxic (C-N; n = 9), PR-normoxic (PR-N; n = 7), PR-hypoxic (PR-H; n = 8), or PR-hypoxic reduced liver growth (PR-H RLG; n = 4). Hepatic SLC2A1 mRNA expression was highest (P fetal substrate restriction may exist that protect the liver from decreased growth and, potentially, from a decreased responsiveness to the actions of insulin in postnatal life.

Synergistic interaction of fatty acids and oxysterols impairs mitochondrial function and limits liver adaptation during nafld progression

Directory of Open Access Journals (Sweden)

Francesco Bellanti

2018-05-01

Full Text Available The complete mechanism accounting for the progression from simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD has not been elucidated. Lipotoxicity refers to cellular injury caused by hepatic free fatty acids (FFAs and cholesterol accumulation. Excess cholesterol autoxidizes to oxysterols during oxidative stress conditions. We hypothesize that interaction of FAs and cholesterol derivatives may primarily impair mitochondrial function and affect biogenesis adaptation during NAFLD progression. We demonstrated that the accumulation of specific non-enzymatic oxysterols in the liver of animals fed high-fat+high-cholesterol diet induces mitochondrial damage and depletion of proteins of the respiratory chain complexes. When tested in vitro, 5α-cholestane-3β,5,6β-triol (triol combined to FFAs was able to reduce respiration in isolated liver mitochondria, induced apoptosis in primary hepatocytes, and down-regulated transcription factors involved in mitochondrial biogenesis. Finally, a lower protein content in the mitochondrial respiratory chain complexes was observed in human non-alcoholic steatohepatitis. In conclusion, hepatic accumulation of FFAs and non-enzymatic oxysterols synergistically facilitates development and progression of NAFLD by impairing mitochondrial function, energy balance and biogenesis adaptation to chronic injury.

Growth pattern of colorectal liver metastasis as a marker of recurrence risk

DEFF Research Database (Denmark)

Eefsen, R L; Vermeulen, P B; Christensen, I J

2015-01-01

from patient and pathology records. Histological GP were evaluated and related to recurrence free and OS. Kaplan-Meier curves, log-rank test and Cox regression analysis were used. The 5-year OS was 41.8% (95% CI 33.8-49.8%). Growth pattern evaluation of the largest liver metastasis was possible in 224...... free survival (RFS) than patients resected for non-desmoplastic liver metastases (p=0.05). When patients were stratified according to neo-adjuvant treatment in the multivariate Cox regression model, hazard ratios for RFS compared to desmoplastic were: pushing (HR=1.37, 95% CI 0.93-2.02, p=0...

Growth and liver histology of Channa punctatus exposed to a common biofertilizer.

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Nath, S; Matozzo, V; Bhandari, D; Faggio, C

2018-01-28

Mustard oil cake (MOC) is widely used as biofertilizer in the field of agriculture and aquaculture. Channa punctatus was exposed to 0.42 g.L -1 sublethal concentration for 4, 7, 14, 21 and 28 days. Due to such exposure, body growth and histological changes in liver were observed. It was revealed that weight, length and breadth of fish were gradually increased with the days of exposure in compare to control fish, whereas, liver showed an increase in sinusoidal space and lipidosis during early days, followed by a recovery from the stress of MOC on the 28th day.

Domain requirements for the Dock adapter protein in growth- cone signaling.

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Rao, Y; Zipursky, S L

1998-03-03

Tyrosine phosphorylation has been implicated in growth-cone guidance through genetic, biochemical, and pharmacological studies. Adapter proteins containing src homology 2 (SH2) domains and src homology 3 (SH3) domains provide a means of linking guidance signaling through phosphotyrosine to downstream effectors regulating growth-cone motility. The Drosophila adapter, Dreadlocks (Dock), the homolog of mammalian Nck containing three N-terminal SH3 domains and a single SH2 domain, is highly specialized for growth-cone guidance. In this paper, we demonstrate that Dock can couple signals in either an SH2-dependent or an SH2-independent fashion in photoreceptor (R cell) growth cones, and that Dock displays different domain requirements in different neurons.

Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress.

Science.gov (United States)

Kim, Seong Hun; Kim, Kook Hwan; Kim, Hyoung-Kyu; Kim, Mi-Jeong; Back, Sung Hoon; Konishi, Morichika; Itoh, Nobuyuki; Lee, Myung-Shik

2015-04-01

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exhibits anti-diabetic and anti-obesity activity. FGF21 expression is increased in patients with and mouse models of obesity or nonalcoholic fatty liver disease (NAFLD). However, the functional role and molecular mechanism of FGF21 induction in obesity or NAFLD are not clear. As endoplasmic reticulum (ER) stress is triggered in obesity and NAFLD, we investigated whether ER stress affects FGF21 expression or whether FGF21 induction acts as a mechanism of the unfolded protein response (UPR) adaptation to ER stress induced by chemical stressors or obesity. Hepatocytes or mouse embryonic fibroblasts deficient in UPR signalling pathways and liver-specific eIF2α mutant mice were employed to investigate the in vitro and in vivo effects of ER stress on FGF21 expression, respectively. The in vivo importance of FGF21 induction by ER stress and obesity was determined using inducible Fgf21-transgenic mice and Fgf21-null mice with or without leptin deficiency. We found that ER stressors induced FGF21 expression, which was dependent on a PKR-like ER kinase-eukaryotic translation factor 2α-activating transcription factor 4 pathway both in vitro and in vivo. Fgf21-null mice exhibited increased expression of ER stress marker genes and augmented hepatic lipid accumulation after tunicamycin treatment. However, these changes were attenuated in inducible Fgf21-transgenic mice. We also observed that Fgf21-null mice with leptin deficiency displayed increased hepatic ER stress response and liver injury, accompanied by deteriorated metabolic variables. Our results suggest that FGF21 plays an important role in the adaptive response to ER stress- or obesity-induced hepatic metabolic stress.

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.

Volumetric Growth of the Liver in the Human Fetus: An Anatomical, Hydrostatic, and Statistical Study

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Michał Szpinda

2015-01-01

Full Text Available Using anatomical, hydrostatic, and statistical methods, liver volumes were assessed in 69 human fetuses of both sexes aged 18–30 weeks. No sex differences were found. The median of liver volume achieved by hydrostatic measurements increased from 6.57 cm3 at 18–21 weeks through 14.36 cm3 at 22–25 weeks to 20.77 cm3 at 26–30 weeks, according to the following regression: y = −26.95 + 1.74 × age ± Z  × (−3.15 + 0.27 × age. The median of liver volume calculated indirectly according to the formula liver volume = 0.55 × liver length × liver transverse diameter × liver sagittal diameter increased from 12.41 cm3 at 18–21 weeks through 28.21 cm3 at 22–25 weeks to 49.69 cm3 at 26–30 weeks. There was a strong relationship (r=0.91, p<0.001 between the liver volumes achieved by hydrostatic (x and indirect (y methods, expressed by y = −0.05 + 2.16x  ± 7.26. The liver volume should be calculated as follows liver volume = 0.26 × liver length × liver transverse diameter × liver sagittal diameter. The age-specific liver volumes are of great relevance in the evaluation of the normal hepatic growth and the early diagnosis of fetal micro- and macrosomias.

Application of spectroscopy (1HMRS) to assess liver metabolite concentrations in rats with intrauterine growth restriction.

Science.gov (United States)

Wang, Tao; Chen, Pingyang; Bian, Dujun; Chen, Juncao

2017-04-01

Proton magnetic resonance spectroscopy ( 1 H-MRS) measurement of liver metabolism in intrauterine growth restriction rats has seldom been reported. This study investigated the application of 1 H-MRS in assessing liver metabolism in newborn pups that experienced intrauterine growth restriction. Intra-uterine growth restriction was established by feeding rats low-protein diets during pregnancy. Newborn pups received conventional magnetic resonance imaging and 1 H-MRS using a 3.0T whole body MR scanner at 3, 8 and 12 weeks post birth. The success rate of 1 H-MRS was 83.33%. Significantly lower body weight, BMI and body length at 3 weeks as well as significantly lower body weight, BMI and waist circumference at 8 and 12 weeks were observed in newborn pups of IUGR rats compared with pups of control rats. Significant differences in ACho/H 2 O, ACr/H 2 O, AGlx/H 2 O and ALipid/H 2 O at 3 and 8 weeks as well as significant differences in ACr/H 2 O, ALipid/H 2 O and AGlx/H 2 O at 12 weeks were observed between pups of control rats and pups of IUGR rats. 1 H-MRS allows noninvasive assessment of liver metabolism in the rat and demonstrated the poor liver development of rats that experienced IUGR.

Domain requirements for the Dock adapter protein in growth- cone signaling

OpenAIRE

Rao, Yong; Zipursky, S. Lawrence

1998-01-01

Tyrosine phosphorylation has been implicated in growth-cone guidance through genetic, biochemical, and pharmacological studies. Adapter proteins containing src homology 2 (SH2) domains and src homology 3 (SH3) domains provide a means of linking guidance signaling through phosphotyrosine to downstream effectors regulating growth-cone motility. The Drosophila adapter, Dreadlocks (Dock), the homolog of mammalian Nck containing three N-terminal SH3 domains and a single SH2 domain, is highly speci...

Metastatic ocular melanoma to the liver exhibits infiltrative and nodular growth patterns

DEFF Research Database (Denmark)

Grossniklaus, Hans E; Zhang, Qing; You, Shuo

2016-01-01

We examined liver specimens from 15 patients with uveal melanoma (UM) who had died of their disseminated disease. We found 2 distinct growth patterns of UM metastasis: infiltrative (n = 12) and nodular (n = 3). In the infiltrative pattern, individual UM cells with a CD133+ cancer stem cell-like p...

Volumetric Growth of the Liver in the Human Fetus: An Anatomical, Hydrostatic, and Statistical Study

Science.gov (United States)

Szpinda, Michał; Paruszewska-Achtel, Monika; Mila-Kierzenkowska, Celestyna; Elminowska-Wenda, Gabriela; Dombek, Małgorzata; Szpinda, Anna; Badura, Mateusz

2015-01-01

Using anatomical, hydrostatic, and statistical methods, liver volumes were assessed in 69 human fetuses of both sexes aged 18–30 weeks. No sex differences were found. The median of liver volume achieved by hydrostatic measurements increased from 6.57 cm3 at 18–21 weeks through 14.36 cm3 at 22–25 weeks to 20.77 cm3 at 26–30 weeks, according to the following regression: y = −26.95 + 1.74 × age ± Z  × (−3.15 + 0.27 × age). The median of liver volume calculated indirectly according to the formula liver volume = 0.55 × liver length × liver transverse diameter × liver sagittal diameter increased from 12.41 cm3 at 18–21 weeks through 28.21 cm3 at 22–25 weeks to 49.69 cm3 at 26–30 weeks. There was a strong relationship (r = 0.91, p hydrostatic (x) and indirect (y) methods, expressed by y = −0.05 + 2.16x  ± 7.26. The liver volume should be calculated as follows liver volume = 0.26 × liver length × liver transverse diameter × liver sagittal diameter. The age-specific liver volumes are of great relevance in the evaluation of the normal hepatic growth and the early diagnosis of fetal micro- and macrosomias. PMID:26413551

Improved liver R2* mapping by pixel-wise curve fitting with adaptive neighborhood regularization.

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Wang, Changqing; Zhang, Xinyuan; Liu, Xiaoyun; He, Taigang; Chen, Wufan; Feng, Qianjin; Feng, Yanqiu

2018-08-01

To improve liver R2* mapping by incorporating adaptive neighborhood regularization into pixel-wise curve fitting. Magnetic resonance imaging R2* mapping remains challenging because of the serial images with low signal-to-noise ratio. In this study, we proposed to exploit the neighboring pixels as regularization terms and adaptively determine the regularization parameters according to the interpixel signal similarity. The proposed algorithm, called the pixel-wise curve fitting with adaptive neighborhood regularization (PCANR), was compared with the conventional nonlinear least squares (NLS) and nonlocal means filter-based NLS algorithms on simulated, phantom, and in vivo data. Visually, the PCANR algorithm generates R2* maps with significantly reduced noise and well-preserved tiny structures. Quantitatively, the PCANR algorithm produces R2* maps with lower root mean square errors at varying R2* values and signal-to-noise-ratio levels compared with the NLS and nonlocal means filter-based NLS algorithms. For the high R2* values under low signal-to-noise-ratio levels, the PCANR algorithm outperforms the NLS and nonlocal means filter-based NLS algorithms in the accuracy and precision, in terms of mean and standard deviation of R2* measurements in selected region of interests, respectively. The PCANR algorithm can reduce the effect of noise on liver R2* mapping, and the improved measurement precision will benefit the assessment of hepatic iron in clinical practice. Magn Reson Med 80:792-801, 2018. © 2018 International Society for Magnetic Resonance in Medicine. © 2018 International Society for Magnetic Resonance in Medicine.

The liver taxis of receptor mediated lactosaminated human growth hormone

International Nuclear Information System (INIS)

Chen Zelian; Shi Lin; Li Tongling; Pang Qijie; He Juying; Guan Changtian

2002-01-01

Radiography imaging is used to assess liver taxis mechanism of anti-dwarfism drug lactosaminated human growth hormone (L-rhGH). Both L-rhGH and rhGH labelled with 131 I are used to study their biodistribution in animals (including rabbits, cocks and rats). The results show that L-rhGH is of specific hepatic targeting property, and the maximum hepatic concentration rate is 76.8%, which is two times of rhGH. Its hepatic binding is receptor mediated

New therapeutic strategies for canine liver disease; Growth factors and liver progenitor cells

NARCIS (Netherlands)

Arends, B.

2008-01-01

The liver has the unique capacity to regulate its mass after loss of functional liver cells due to liver disease, injury, and/or toxicity. Unfortunately, in the course of chronic liver disease this meticulously regulated regeneration process is imbalanced resulting in a decreased regenerative

Effects of disturbed liver growth and oxidative stress of high-fat diet-fed dams on cholesterol metabolism in offspring mice.

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Kim, Juyoung; Kim, Juhae; Kwon, Young Hye

2016-08-01

Changes in nutritional status during gestation and lactation have detrimental effects on offspring metabolism. Several animal studies have shown that maternal high-fat diet (HFD) can predispose the offspring to development of obesity and metabolic diseases, however the mechanisms underlying these transgenerational effects are poorly understood. Therefore, we examined the effect of maternal HFD consumption on metabolic phenotype and hepatic expression of involved genes in dams to determine whether any of these parameters were associated with the metabolic outcomes in the offspring. Female C57BL/6 mice were fed a low-fat diet (LFD: 10% calories from fat) or a high-fat diet (HFD: 45% calories from fat) for three weeks before mating, and during pregnancy and lactation. Dams and their male offspring were studied at weaning. Dams fed an HFD had significantly higher body and adipose tissue weights and higher serum triglyceride and cholesterol levels than dams fed an LFD. Hepatic lipid levels and mRNA levels of genes involved in lipid metabolism, including LXRα, SREBP-2, FXR, LDLR, and ABCG8 were significantly changed by maternal HFD intake. Significantly lower total liver DNA and protein contents were observed in dams fed an HFD, implicating the disturbed liver adaptation in the pregnancy-related metabolic demand. HFD feeding also induced significant oxidative stress in serum and liver of dams. Offspring of dams fed an HFD had significantly higher serum cholesterol levels, which were negatively correlated with liver weights of dams and positively correlated with hepatic lipid peroxide levels in dams. Maternal HFD consumption induced metabolic dysfunction, including altered liver growth and oxidative stress in dams, which may contribute to the disturbed cholesterol homeostasis in the early life of male mice offspring.

Intermittent hypoxia suppression of growth hormone and insulin-like growth factor-I in the neonatal rat liver.

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Cai, Charles; Ahmad, Taimur; Valencia, Gloria B; Aranda, Jacob V; Xu, Jiliu; Beharry, Kay D

2018-03-08

Extremely low gestational age neonates with chronic lung disease requiring oxygen therapy frequently experience fluctuations in arterial oxygen saturation or intermittent hypoxia (IH). These infants are at risk for multi-organ developmental delay, reduced growth, and short stature. The growth hormone (GH)/insulin-like growth factor-I (IGF-1) system, an important hormonal regulator of lipid and carbohydrate metabolism, promotes neonatal growth and development. We tested the hypothesis that increasing episodes of IH delay neonatal growth by influencing the GH/IGF-I axis. Newborn rats were exposed to 2, 4, 6, 8, 10, or 12 hypoxic episodes (12% O 2 ) during hyperoxia (50% O 2 ) from P0-P7, P0-P14 (IH), or allowed to recover from P7-P21 or P14-P21 (IHR) in room air (RA). RA littermates at P7, P14, and P21 served as RA controls; and groups exposed to hyperoxia only (50% O 2 ) served as zero IH controls. Histopathology of the liver; hepatic levels of GH, GHBP, IGF-I, IGFBP-3, and leptin; and immunoreactivities of GH, GHR, IGF-I and IGF-IR were determined. Pathological findings of the liver, including cellular swelling, steatosis, necrosis and focal sinusoid congestion were seen in IH, and were particularly severe in the P7 animals. Hepatic GH levels were significantly suppressed in the IH groups exposed to 6-12 hypoxic episodes per day and were not normalized during IHR. Deficits in the GH levels were associated with reduced body length and increase body weight during IHR suggesting increased adiposity and catchup fat. Catchup fat was also associated with elevations in GHBP, IGF-I, leptin. IH significantly impairs hepatic GH/IGF-1 signaling during the first few weeks of life, which is likely responsible for hepatic GH resistance, increased body fat, and hepatic steatosis. These hormonal perturbations may contribute to long-term organ and body growth impairment, and metabolic dysfunction in preterm infants experiencing frequent IH and/or apneic episodes. Copyright © 2018

Shizukaol D, a Dimeric Sesquiterpene Isolated from Chloranthus serratus, Represses the Growth of Human Liver Cancer Cells by Modulating Wnt Signalling Pathway.

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Lisha Tang

Full Text Available Natural products have become sources of developing new drugs for the treatment of cancer. To seek candidate compounds that inhibit the growth of liver cancer, components of Chloranthus serratus were tested. Here, we report that shizukaol D, a dimeric sesquiterpene from Chloranthus serratus, exerted a growth inhibition effect on liver cancer cells in a dose- and time-dependent manner. We demonstrated that shizukaol D induced cells to undergo apoptosis. More importantly, shizukaol D attenuated Wnt signalling and reduced the expression of endogenous Wnt target genes, which resulted in decreased expression of β-catenin. Collectively, this study demonstrated that shizukaol D inhibited the growth of liver cancer cells by modulating Wnt pathway.

Epidermal Growth Factor Receptor (EGFR) Crosstalks in Liver Cancer

International Nuclear Information System (INIS)

Berasain, Carmen; Latasa, María Ujue; Urtasun, Raquel; Goñi, Saioa; Elizalde, María; Garcia-Irigoyen, Oihane; Azcona, María; Prieto, Jesús; Ávila, Matías A.

2011-01-01

Hepatocarcinogenesis is a complex multistep process in which many different molecular pathways have been implicated. Hepatocellular carcinoma (HCC) is refractory to conventional chemotherapeutic agents, and the new targeted therapies are meeting with limited success. Interreceptor crosstalk and the positive feedback between different signaling systems are emerging as mechanisms of targeted therapy resistance. The identification of such interactions is therefore of particular relevance to improve therapeutic efficacy. Among the different signaling pathways activated in hepatocarcinogenesis the epidermal growth factor receptor (EGFR) system plays a prominent role, being recognized as a “signaling hub” where different extracellular growth and survival signals converge. EGFR can be transactivated in response to multiple heterologous ligands through the physical interaction with multiple receptors, the activity of intracellular kinases or the shedding of EGFR-ligands. In this article we review the crosstalk between the EGFR and other signaling pathways that could be relevant to liver cancer development and treatment

Quantitative Shear-Wave Elastography of the Liver in Preterm Neonates with Intra-Uterine Growth Restriction.

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Marianne Alison

Full Text Available The feasibility and reproducibility of liver stiffness measurements using Supersonic Shear-wave Imaging (SSI in preterm neonate have not been reported. Our aim was to determine if liver stiffness differs between intra-uterine growth restriction (IUGR and appropriate for gestational age (AGA preterm infants with/without cholestasis. We measured liver stiffness (in kPa in 45 AGA and 18 IUGR preterm infants, and assessed reproducibility in 26 preterms using Intraclass Correlation Coefficients (ICC and Bland-Altman tests. Liver stiffness values were compared between AGA and IUGR with and without cholestasis and correlated with birth weight. Measurements showed high reproducibility (ICC = 0.94-0.98 for intra-operator, 0.86 for inter-operator with good agreement (95% limits: -1.24 to 1.24 kPa. During the first postnatal week, liver stiffness was higher in IUGR (7.50 ±1.53 kPa than in AGA infants (5.11 ±0.80 kPa, p<0.001. After day 8, liver stiffness remained unchanged in AGA but increased progressively in IUGR infants (15.57 ±6.49 kPa after day 21. Liver stiffness was higher in IUGR neonates with cholestasis (19.35 ± 9.80 kPa than without cholestasis (7.72 ± 1.27 kPa, p<0.001. In conclusion, quantitative liver SSI in preterms is feasible and reproducible. IUGR preterms who will develop cholestasis present high liver stiffness even at birth, before biological cholestasis occurs.

The CXCR5 chemokine receptor is expressed by carcinoma cells and promotes growth of colon carcinoma in the liver.

Science.gov (United States)

Meijer, Joost; Zeelenberg, Ingrid S; Sipos, Bence; Roos, Ed

2006-10-01

The chemokine receptor CXCR5 is expressed by B cells and certain T cells and controls their migration into and within lymph nodes. Its ligand BCA-1/CXCL13 is present in lymph nodes and spleen and also in the liver. Surprisingly, we detected CXCR5 in several mouse and human carcinoma cell lines. CXCR5 was particularly prominent in pancreatic carcinoma cell lines and was also detected by immunohistochemistry in 7 of 18 human pancreatic carcinoma tissues. Expression in CT26 colon carcinoma was low in vitro, up-regulated in vivo, and rapidly lost when cells were explanted in vitro. CXCL13 strongly promoted proliferation of CXCR5-transfected CT26 cells in vitro. In the liver, after intrasplenic injection, these CXCR5 transfectants initially grew faster than controls, but the growth rate of control tumors accelerated later to become similar to the transfectants, likely due to the up-regulation of CXCR5. Inhibition of CXCR5 function, by trapping CXCR5 in the endoplasmic reticulum using a CXCL13-KDEL "intrakine," had no effect on initial growth of liver foci but later caused a prolonged growth arrest. In contrast, s.c. and lung tumors of CXCR5- and intrakine-transfected cells grew at similar rates as controls. We conclude that expression of CXCR5 on tumor cells promotes the growth of tumor cells in the liver and, at least for CT26 cells, seems to be required for outgrowth to large liver tumors. Given the limited expression on normal cells, CXCR5 may constitute an attractive target for therapy, particularly for pancreatic carcinoma.

Laser-induced thermotherapy (LITT) elevates mRNA expression of connective tissue growth factor (CTGF) associated with reduced tumor growth of liver metastases compared to hepatic resection.

Science.gov (United States)

Isbert, Christoph; Ritz, Jörg-Peter; Roggan, André; Schuppan, Detlef; Ajubi, Navid; Buhr, Heinz Johannes; Hohenberger, Werner; Germer, Christoph-Thomas

2007-01-01

Proliferation and synthesis of hepatocellular tissue after tissue damage are promoted by specific growth factors such as hepatic tissue growth factor (HGF) and connective growth factor (CTGF). Laser-induced thermotherapy (LITT) for the treatment of liver metastases is deemed to be a parenchyma-saving procedure compared to hepatic resection. The aim of this study was to compare the impact of LITT and hepatic resection on intrahepatic residual tumor tissue and expression levels of mRNA HGF/CTGF within liver and tumor tissue. Two independent adenocarcinomas (CC531) were implanted into 75 WAG rats, one in the right (untreated tumor) and one in the left liver lobe (treated tumor). The left lobe tumor was treated either by LITT or partial hepatectomy. The control tumor was submitted to in-situ hybridization of HGF and CTGF 24-96 hours and 14 days after intervention. Volumes of the untreated tumors prior to intervention were 38+/-8 mm(3) in group I (laser), 39 +/- 7 mm(3) in group II (resection), and 42 +/- 12 mm(3) in group III (control) and did not differ significantly (P > 0.05). Fourteen days after the intervention the mean tumor+/-SEM volume of untreated tumor in group I (laser) [223 +/- 36] was smaller than in group II (resection) [1233.28 +/- 181.52; P tumor growth in comparison to hepatic resection. Accelerated tumor growth after hepatic resection is associated with higher mRNA level of HGF and reduced tumor growth after LITT with higher mRNA level of CTGF. The increased CTGF-mediated regulation of ECM may cause reduced residual tumor growth after LITT. (c) 2006 Wiley-Liss, Inc.

Effects of insulin-like growth factor-I on bone metabolism in patients with liver cirrhosis

International Nuclear Information System (INIS)

Li Xiaohong; Gao Wenjin; Wang Mingtao; Hu Haiqiang

2006-01-01

To study the effects of serum insulin-like growth factor-I (IGF-I) on bone metabolism in liver cirrhosis, 44 patients with hepatic cirrhosis were divided into 3 groups according to disease severity (Child Pugh Score) and 38 healthy subjects served as controls. Serum levels of IGF-I and osteocalcin(BGP) were measured in all patients and controls. Results showed that levels of IGF-I, BGP, and BMD were lower significantly in patients with liver cirrhosis than that in controls. When the condition of cirrhosis more deteriorated, these changes became much lower significantly. Serum levels of BGP and BMD were positively correlated with IGF-I. The decreasing level of IGF-I might be an important factor causing osteoporosis in patients with liver cirrhosis. (authors)

The postnatal growth of ICRP target organs in reference humans: Spleen and liver

International Nuclear Information System (INIS)

Walker, J.T.

1989-01-01

Attempts to improve radiation dose estimates to infants and children are hampered because of the lack of mathematical models that describe the age variation in anatomical and physiological parameters. Specifically, for one anatomical parameter, organ size, there are no growth models available to the health physics community. In this paper, an empirical mathematical model is introduced for estimating age-specific masses of two ICRP target organs: the spleen and liver. That model, the Power Logistic Additive (PLA) growth model, is fitted to ICRP 23 organ growth data to determine five growth parameters. This model assumes that organs grow under the influence of two main processes: a primary (power function) and a sexual maturation (logistic function) process, which are additive from birth to adulthood. The results show that the model describes the ICRP growth data quite well. Growth parameters and tables listing the predicted masses and mass velocities as a function of age for each organ are provided for application in the ICRP modeling system

microRNA 21-mediated suppression of Sprouty1 by Pokemon affects liver cancer cell growth and proliferation.

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Jin, Xiu-Li; Sun, Qin-Sheng; Liu, Feng; Yang, Hong-Wei; Liu, Min; Liu, Hong-Xia; Xu, Wei; Jiang, Yu-Yang

2013-07-01

Transcriptional repressor Pokemon is a critical factor in embryogenesis, development, cell proliferation, differentiation, and oncogenesis, thus behaving as an oncogene. Oncomine database suggests a potential correlation between the expressions of Pokemon and Sprouty1. This study investigated the regulatory role of Pokemon in Sprouty1 expression and the effect on liver cancer cell growth and proliferation, revealing a novel miR-21-mediated regulatory circuit. In normal (HL-7702) and cancer (QGY-7703) liver cell lines, Sprouty1 expression is inversely correlated with Pokemon levels. Targeted expression or siRNA-mediated silencing showed that Pokemon is a repressor of Sprouty1 expression at both mRNA and protein levels, but Pokemon cannot affect the promoter activity of Sprouty1. Sprouty1 is a target of miR-21 and interestingly, we found that miR-21 is up-regulated by Pokemon in liver cancer cells. Luciferase reporter assays showed that Pokemon up-regulated miR-21 transcription in a dose-dependent manner, and ChIP assay exhibited a direct binding of Pokemon to the miR-21 promoter at -747 to -399 bp. Site-directed mutagenesis of the GC boxes at -684 to -679 bp and -652 to -647 bp of miR-21 promoter abolished the regulatory activity by Pokemon. Furthermore, we found that the modulation of Pokemon and miR-21 expression affected the growth and proliferation of liver cancer cells QGY-7703. In summary, our findings demonstrate that Pokemon suppresses Sprouty1 expression through a miR-21-mediated mechanism, affecting the growth and proliferation of liver cancer cells. This study recognized miR-21 and Sprouty1 as novel targets of the Pokemon regulatory network. Copyright © 2013 Wiley Periodicals, Inc.

Adapting to Population Growth: The Evolutionary Alternative to Malthus

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Axel Kristinsson

2016-06-01

Full Text Available A long-standing debate on the dynamics of population growth in human history has become polarized between a Malthusian stance and a Boserupian one. The former tends to view population growth as limited by carrying capacity, dependent on environment and technology, whereas the latter sees population growth itself as a major inducement to social, economic and technological developments. In this paper the authors experiment with approaching this debate by using recent developments in evolutionary theory. According to these, evolutionary principles, as expounded by Charles Darwin and subsequent evolutionary scientists, apply not only to biological evolution but also to social or cultural evolution. Here, the role of genes is taken over by culture and, since culture is much more pliable than our DNA, evolution speeds up. As the only organisms on Earth whose evolution relies as heavily on culture as on genes, humans have become extremely adaptable. Their hyper-adaptability suggest that humans, through their cultural evolution, have managed increasingly to adapt to their own growing population, thus succeeding in accommodating ever-growing numbers. This hypothesis fits the Boserupian approach to population very well but less so the Malthusian one, perhaps indicating a gradual shift from a Malthusian regime to a Boserupian one in human history. The hypothesis is discussed and examined through four case studies: The beginning of farming around Göbekli Tepe in southeast Turkey, the productive farming systems of Tiwanaku in South America, the population crisis of late medieval and early modern Iceland, and the ‘collapse’ of Rapa Nui (Easter Island.

Modeling posttraumatic growth among cancer patients: The roles of social support, appraisals, and adaptive coping.

Science.gov (United States)

Cao, Weidan; Qi, Xiaona; Cai, Deborah A; Han, Xuanye

2018-01-01

The purpose of the study was to build a model to explain the relationships between social support, uncontrollability appraisal, adaptive coping, and posttraumatic growth (PTG) among cancer patients in China. The participants who were cancer patients in a cancer hospital in China filled out a survey. The final sample size was 201. Structural equation modeling was used to build a model explaining PTG. Structural equation modeling results indicated that higher levels of social support predicted higher levels of adaptive coping, higher levels of uncontrollability appraisal predicted lower levels of adaptive coping, and higher levels of adaptive coping predicted higher levels of PTG. Moreover, adaptive coping was a mediator between social support and growth, as well as a mediator between uncontrollability and growth. The direct effects of social support and uncontrollability on PTG were insignificant. The model demonstrated the relationships between social support, uncontrollability appraisal, adaptive coping, and PTG. It could be concluded that uncontrollability appraisal was a required but not sufficient condition for PTG. Neither social support nor uncontrollability appraisal had direct influence on PTG. However, social support and uncontrollability might indirectly influence PTG, through adaptive coping. It implies that both internal factors (eg, cognitive appraisal and coping) and external factors (eg, social support) are required in order for growth to happen. Copyright © 2017 John Wiley & Sons, Ltd.

Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models.

Science.gov (United States)

Liu, Shujie; Kawamoto, Taisuke; Morita, Osamu; Yoshinari, Kouichi; Honda, Hiroshi

2017-03-01

Chemical exposure often results in liver hypertrophy in animal tests, characterized by increased liver weight, hepatocellular hypertrophy, and/or cell proliferation. While most of these changes are considered adaptive responses, there is concern that they may be associated with carcinogenesis. In this study, we have employed a toxicogenomic approach using a logistic ridge regression model to identify genes responsible for liver hypertrophy and hypertrophic hepatocarcinogenesis and to develop a predictive model for assessing hypertrophy-inducing compounds. Logistic regression models have previously been used in the quantification of epidemiological risk factors. DNA microarray data from the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System were used to identify hypertrophy-related genes that are expressed differently in hypertrophy induced by carcinogens and non-carcinogens. Data were collected for 134 chemicals (72 non-hypertrophy-inducing chemicals, 27 hypertrophy-inducing non-carcinogenic chemicals, and 15 hypertrophy-inducing carcinogenic compounds). After applying logistic ridge regression analysis, 35 genes for liver hypertrophy (e.g., Acot1 and Abcc3) and 13 genes for hypertrophic hepatocarcinogenesis (e.g., Asns and Gpx2) were selected. The predictive models built using these genes were 94.8% and 82.7% accurate, respectively. Pathway analysis of the genes indicates that, aside from a xenobiotic metabolism-related pathway as an adaptive response for liver hypertrophy, amino acid biosynthesis and oxidative responses appear to be involved in hypertrophic hepatocarcinogenesis. Early detection and toxicogenomic characterization of liver hypertrophy using our models may be useful for predicting carcinogenesis. In addition, the identified genes provide novel insight into discrimination between adverse hypertrophy associated with carcinogenesis and adaptive hypertrophy in risk assessment. Copyright © 2017 Elsevier Inc. All rights reserved.

Placental Growth Factor Contributes to Liver Inflammation, Angiogenesis, Fibrosis in Mice by Promoting Hepatic Macrophage Recruitment and Activation

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Xi Li

2017-07-01

Full Text Available Placental growth factor (PlGF, a member of the vascular endothelial growth factor (VEGF family, mediates wound healing and inflammatory responses, exerting an effect on liver fibrosis and angiogenesis; however, the precise mechanism remains unclear. The aims of this study are to identify the role of PlGF in liver inflammation and fibrosis induced by bile duct ligation (BDL in mice and to reveal the underlying molecular mechanism. PlGF small interfering RNA (siRNA or non-targeting control siRNA was injected by tail vein starting 2 days after BDL. Liver inflammation, fibrosis, angiogenesis, macrophage infiltration, and hepatic stellate cells (HSCs activation were examined. Our results showed that PlGF was highly expressed in fibrotic livers and mainly distributed in activated HSCs and macrophages. Furthermore, PlGF silencing strongly reduced the severity of liver inflammation and fibrosis, and inhibited the activation of HSCs. Remarkably, PlGF silencing also attenuated BDL-induced hepatic angiogenesis, as evidenced by attenuated liver endothelial cell markers CD31 and von Willebrand factor immunostaining and genes or protein expression. Interestingly, these pathological ameliorations by PlGF silencing were due to a marked reduction in the numbers of intrahepatic F4/80+, CD68+, and Ly6C+ cell populations, which were reflected by a lower expression of these macrophage marker molecules in fibrotic livers. In addition, knockdown of PlGF by siRNA inhibited macrophages activation and substantially suppressed the expression of pro-inflammatory cytokines and chemokines in fibrotic livers. Mechanistically, evaluation of cultured RAW 264.7 cells revealed that VEGF receptor 1 (VEGFR1 mainly involved in mediating the role of PlGF in macrophages recruitment and activation, since using VEGFR1 neutralizing antibody blocking PlGF/VEGFR1 signaling axis significantly inhibited macrophages migration and inflammatory responses. Together, these findings indicate

[The liver and the immune system].

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Jakab, Lajos

2015-07-26

The liver is known to be the metabolic centre of the organism and is under the control of the central nervous system. It has a peculiar tissue structure and its anatomic localisation defines it as part of the immune system having an individual role in the defence of the organism. The determinant of its particular tissue build-up is the sinusoid system. In addition to hepatocytes, one cell row "endothelium", stellate cells close to the external surface, Kupffer cells tightly to its inner surface, as well as dendritic cells and other cell types (T and B lymphocytes, natural killer and natural killer T-cells, mast cells, granulocytes) are present. The multitudes and variety of cells make it possible to carry out the tasks according to the assignment of the organism. The liver is a member of the immune system having immune cells largely in an activated state. Its principal tasks are the assurance of the peripheral immune tolerance of the organism with the help of the haemopoetic cells and transforming growth factor-β. The liver takes part in the determination of the manner of the non-specific immune response of the organism. In addition to acute phase reaction of the organism, the liver has a role in the adaptive/specific immune response. These functions include retardation of the T and B lymphocytes and the defence against harmful pathogens. With the collaboration of transforming growth factor-β, immunoglobulins and their subclasses are inhibited just as the response of the T lymphocytes. The only exception is the undisturbed immunoglobulin A production. Particularly important is the intensive participation of the liver in the acute phase reaction of the organism, which is organised and guided by the coordinated functions of the cortico-hypothalamo-hypophysis-adrenal axis. Beside cellular elements, hormones, adhesion molecules, chemokines and cytokines are also involved in the cooperation with the organs. Acute phase reactants play a central role in these processes

The Influence of Estrogens on the Biological and Therapeutic Actions of Growth Hormone in the Liver

Directory of Open Access Journals (Sweden)

Leandro Fernández-Pérez

2012-07-01

Full Text Available GH is main regulator of body growth and composition, somatic development, intermediate metabolism and gender-dependent dimorphism in mammals. The liver is a direct target of estrogens because it expresses estrogen receptors which are connected with development, lipid metabolism and insulin sensitivity, hepatic carcinogenesis, protection from drug-induced toxicity and fertility. In addition, estrogens can modulate GH actions in liver by acting centrally, regulating pituitary GH secretion, and, peripherally, by modulating GHR-JAK2-STAT5 signalling pathway. Therefore, the interactions of estrogens with GH actions in liver are biologically and clinically relevant because disruption of GH signaling may cause alterations of its endocrine, metabolic, and gender differentiated functions and it could be linked to dramatic impact in liver physiology during development as well as in adulthood. Finally, the interplay of estrogens with GH is relevant because physiological roles these hormones have in human, and the widespread exposition of estrogen or estrogen-related compounds in human. This review highlights the importance of these hormones in liver physiology as well as how estrogens modulate GH actions in liver which will help to improve the clinical use of these hormones.

Spider angiomas in patients with liver cirrhosis: Role of vascular endothelial growth factor and basic fibroblast growth factor

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Li, Chung-Pin; Lee, Fa-Yauh; Hwang, Shinn-Jang; Lu, Rei-Hwa; Lee, Wei-Ping; Chao, Yee; Wang, Sung-Sang; Chang, Full-Young; Whang-Peng, Jacqueline; Lee, Shou-Dong

2003-01-01

AIM: To investigate whether vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor (bFGF) are associated with spider angiomas in patients with liver cirrhosis. METHODS: Eighty-six patients with liver cirrhosis were enrolled and the number and size of the spider angiomas were recorded. Fifty-three healthy subjects were selected as controls. Plasma levels of VEGF and bFGF were measured in both the cirrhotics and the controls. RESULTS: Plasma VEGF and bFGF were increased in cirrhotics compared with controls (122 ± 13 vs. 71 ± 11 pg/mL, P = 0.003 for VEGF; 5.1 ± 0.5 vs. 3.4 ± 0.5 pg/mL, P = 0.022 for bFGF). In cirrhotics, plasma VEGF and bFGF were also higher in patients with spider angiomas compared with patients without spider angiomas (185 ± 28 vs. 90 ± 10 pg/mL, P = 0.003 for VEGF; 6.8 ± 1.0 vs. 4.1 ± 0.5 pg/mL, P = 0.017 for bFGF). Multivariate logistic regression showed that young age and increased plasma levels of VEGF and bFGF were the most significant predictors for the presence of spider angiomas in cirrhotic patients (odds ratio [OR] = 6.64, 95% confidence interval [CI] = 2.02-21.79, P = 0.002; OR = 4.35, 95%CI = 1.35-14.01, P = 0.014; OR = 5.66, 95%CI = 1.72-18.63, P = 0.004, respectively). CONCLUSION: Plasma VEGF and bFGF are elevated in patients with liver cirrhosis. Age as well as plasma levels of VEGF and bFGF are significant predictors for spider angiomas in cirrhotic patients. PMID:14669345

TRANSFORMING GROWTH FACTOR 1 IN CHILDREN OF EARLY AGE WITH LIVER TRANSPLANTATION

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R. M. Kurabekova

2014-01-01

Full Text Available Transforming growth factor β1 (TGF-β1 plays a key role in the development of the immune response, as well as in the process of liver regeneration. Measuring the level of TGF-β1 may have important clinical implications in liver transplantation, because cytokine concentration in the tissue and in blood plasma varies with different liver diseases. Aim. To analyze the dynamics of TGF-β1 levels in children-recipients with liver transplant from related donors, including from incompatible blood groups.Materials and methods. The study involved 127 children aged 3 to 72 months (median – 8, average age – 12 ± 14 months, including 57 boys and 70 girls, with liver cirrhosis, developed as the result of congenital and hereditary diseases of the hepatobiliary system. All patients underwent transplantation of the left lateral liver sector from living related donors: 98 patients were transplantedfragment of a liver from identical or AB0-compatible donors and 29 – from incompatible donors. The concentration of TGF-β1 was determined by enzyme immunoassay method in blood plasma samples.Results. Average level of TGF-β1 in blood plasma of children with liver cirrhosis, developed as the result of congenital and hereditary diseases of the hepatobiliary system was 5,2 ± 5,5 ng/ml. A month after liver transplantation from a related donor level of TGF-β1 in blood plasma of recipients increased to 8,1 ± 9,6 ng/ml. One year after transplantation, the average level of TGF-β1 in the recipients of liver fragment was 7,7 ± 8,4 ng/ml, and signifi cantly (p = 0,00 differed from the level prior to transplantation. No association between TGF-β1 level in a month and a year after transplantation and the compatibility of the recipient with AB0 donor was found. A correlation (r = –0,23, p < 0,05 between level of TGF-β1 prior to transplantation and the development of graft dysfunction was observed: in recipients with graft dysfunction (16 cases

Immunohistochemical examination of effects of kefir, koumiss and commercial probiotic capsules on platelet derived growth factor-c and platelet derived growth factor receptor-alpha expression in mouse liver and kidney.

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Bakir, B; Sari, E K; Aydin, B D; Yildiz, S E

2015-04-01

We investigated using immunohistochemistry the effects of kefir, koumiss and commercial probiotic capsules on the expression of platelet derived growth factor-c (PDGF-C) and platelet derived growth factor receptor-alpha (PDGFR-α) in mouse liver and kidney. Mice were assigned to four groups: group 1 was given commercial probiotic capsules, group 2 was given kefir, group 3 was given koumiss and group 4 was untreated. After oral administration for 15 days, body weights were recorded and liver and kidney tissue samples were obtained. Hematoxylin and eosin staining was used to examine histology. PDGF-C and PDGFR-α in liver and kidney were localized using the streptavidin-biotin peroxidase complex method (ABC). We found that the weights of the mice in the kefir, koumiss and commercial probiotic capsules groups increased compared to the control group. No differences in liver and kidney histology were observed in any of the experimental groups. Kefir, koumiss and the commercial probiotic preparation increased PDGF-C and PDGFR-α expression.

The significant relationships between hormonal growth pattern parameters in children with chronic liver disease

International Nuclear Information System (INIS)

Ayad, S.K.

2009-01-01

Present study was undertaken to investigate the disturbance in GH. IGF-I and IGFBP-3 axis by evaluating their levels in serum of children with chronic liver disease. twenty-two under normal growth children suffering from cholestasis and chronic viral hepatitis B or C (3-7 years) with mean value (5.05± 1.18 years) compared with twenty healthy children with mean age value (5.07+ 1.37 years) served as control. the malnourished children were classified into 2 groups (l) included 8 cholestatic children and ll: included 14 children with chronic viral hepatitis (HBV or HCV).the biochemical analysis for lover disease as serum alanine aminotransferase (ALT),aspartate aminotransferase (ASTt), alkaline phosphatase (ALP), γ-glutamyl transferase ( γ-GT), total bilirubin, total protein (P), total albumin (A), and prothrombin concentration were performed by colorimetric technique. serum growth hormone (GH), insulin -like growth factor-l (IGF-l) and insulin -like growth factor binding protein- 3 (IGFBP-3) were estimated by radioisotope technique as marker for growth. the biochemical results showed highly significant increases (P< 0.01) in ALT, AST, ALP, γ-GT and total bilirubin respectively in both malnourished groups with chronic liver disease when matched to that of control . total protein , total albumin and prothrombin concentration recorded highly significant decreases (P<0.001) particularly in GR.ll when compared with healthy children . total protein showed non-significant difference in gr.l when compared to control. GH level showed highly significant increases (P<0.01), while IGF-l and IGFBP-3 reported highly significant reduction (P<0.001) in both manourished groups when compared to the normal growth children . the elevation of GH level and reduction of both IGF-l and IGFBP-3 levels were more prominent in children with chronic viral hepatitis than cholestatic children

The effect of copper deficiency on fetal growth and liver anti-oxidant capacity in the Cohen diabetic rat model

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Ergaz, Zivanit, E-mail: zivanit@hadassah.org.il [Hebrew University Hadassah Medical School, Jerusalem (Israel); Shoshani-Dror, Dana [Hebrew University Hadassah Medical School, Jerusalem (Israel); Guillemin, Claire [Department of Pharmacology and Therapeutics, McGill University, Montreal (Canada); Neeman-azulay, Meytal; Fudim, Liza [Hebrew University Hadassah Medical School, Jerusalem (Israel); Weksler-Zangen, Sarah [Diabetes Research Unit, Hebrew University Hadassah Medical School and Hospital, Jerusalem (Israel); Stodgell, Christopher J.; Miller, Richard K. [Department of Obstetrics and Gynecology, University of Rochester, Rochester, MN (United States); Ornoy, Asher [Hebrew University Hadassah Medical School, Jerusalem (Israel)

2012-12-01

High sucrose low copper diet induces fetal growth restriction in the three strains of the Cohen diabetic rats: an inbred copper deficient resistant (CDr), an inbred copper deficient sensitive (CDs that become diabetic on high sucrose low copper diet -HSD) and an outbred Wistar derived Sabra rats. Although those growth restricted fetuses also exhibit increased oxidative stress, antioxidants do not restore normal growth. In the present study, we evaluated the role of copper deficiency in the HSD induced fetal growth restriction by adding to the drinking water of the rats 1 ppm or 2 ppm of copper throughout their pregnancy. Fetal and placental growth in correlation with fetal liver copper content and anti-oxidant capacity was evaluated on day 21 of pregnancy. HSD compared to regular chow induced fetal growth restriction, which was most significant in the Cohen diabetic sensitive animals. The addition of 1 ppm and 2 ppm copper to the drinking water normalized fetal growth in a dose dependent manner and reduced the degree of hyperglycemia in the diabetes sensitive rats. The CDs fetuses responded to the HSD with lower catalase like activity, and less reduced superoxide dismutase levels compared to the Sabra strain, and had high malondialdehyde levels even when fed regular chow. Immunostaining was higher for nitrotyrosine among the CDr and higher for hypoxia factor 1 α among the CDs. We conclude that in our model of dietary-induced fetal growth restriction, copper deficiency plays a major etiologic role in the decrease of fetal growth and anti-oxidant capacity. -- Highlights: ► High sucrose low copper diet restricted fetal growth in the Cohen diabetic rat model ► Maternal copper blood levels directly correlated with fetal liver copper content ► Copper supplementation decreased embryonic resorption in the inbred strains ► Copper supplementation reduced hyperglycemia in the sucrose sensitive inbred strain ► Copper supplementation alleviated growth restriction and

The effect of copper deficiency on fetal growth and liver anti-oxidant capacity in the Cohen diabetic rat model

International Nuclear Information System (INIS)

Ergaz, Zivanit; Shoshani-Dror, Dana; Guillemin, Claire; Neeman-azulay, Meytal; Fudim, Liza; Weksler-Zangen, Sarah; Stodgell, Christopher J.; Miller, Richard K.; Ornoy, Asher

2012-01-01

High sucrose low copper diet induces fetal growth restriction in the three strains of the Cohen diabetic rats: an inbred copper deficient resistant (CDr), an inbred copper deficient sensitive (CDs that become diabetic on high sucrose low copper diet -HSD) and an outbred Wistar derived Sabra rats. Although those growth restricted fetuses also exhibit increased oxidative stress, antioxidants do not restore normal growth. In the present study, we evaluated the role of copper deficiency in the HSD induced fetal growth restriction by adding to the drinking water of the rats 1 ppm or 2 ppm of copper throughout their pregnancy. Fetal and placental growth in correlation with fetal liver copper content and anti-oxidant capacity was evaluated on day 21 of pregnancy. HSD compared to regular chow induced fetal growth restriction, which was most significant in the Cohen diabetic sensitive animals. The addition of 1 ppm and 2 ppm copper to the drinking water normalized fetal growth in a dose dependent manner and reduced the degree of hyperglycemia in the diabetes sensitive rats. The CDs fetuses responded to the HSD with lower catalase like activity, and less reduced superoxide dismutase levels compared to the Sabra strain, and had high malondialdehyde levels even when fed regular chow. Immunostaining was higher for nitrotyrosine among the CDr and higher for hypoxia factor 1 α among the CDs. We conclude that in our model of dietary-induced fetal growth restriction, copper deficiency plays a major etiologic role in the decrease of fetal growth and anti-oxidant capacity. -- Highlights: ► High sucrose low copper diet restricted fetal growth in the Cohen diabetic rat model ► Maternal copper blood levels directly correlated with fetal liver copper content ► Copper supplementation decreased embryonic resorption in the inbred strains ► Copper supplementation reduced hyperglycemia in the sucrose sensitive inbred strain ► Copper supplementation alleviated growth restriction and

Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models

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Liu, Shujie; Kawamoto, Taisuke; Morita, Osamu [R& D, Safety Science Research, Kao Corporation, Tochigi (Japan); Yoshinari, Kouichi [Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka (Japan); Honda, Hiroshi, E-mail: honda.hiroshi@kao.co.jp [R& D, Safety Science Research, Kao Corporation, Tochigi (Japan)

2017-03-01

Chemical exposure often results in liver hypertrophy in animal tests, characterized by increased liver weight, hepatocellular hypertrophy, and/or cell proliferation. While most of these changes are considered adaptive responses, there is concern that they may be associated with carcinogenesis. In this study, we have employed a toxicogenomic approach using a logistic ridge regression model to identify genes responsible for liver hypertrophy and hypertrophic hepatocarcinogenesis and to develop a predictive model for assessing hypertrophy-inducing compounds. Logistic regression models have previously been used in the quantification of epidemiological risk factors. DNA microarray data from the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System were used to identify hypertrophy-related genes that are expressed differently in hypertrophy induced by carcinogens and non-carcinogens. Data were collected for 134 chemicals (72 non-hypertrophy-inducing chemicals, 27 hypertrophy-inducing non-carcinogenic chemicals, and 15 hypertrophy-inducing carcinogenic compounds). After applying logistic ridge regression analysis, 35 genes for liver hypertrophy (e.g., Acot1 and Abcc3) and 13 genes for hypertrophic hepatocarcinogenesis (e.g., Asns and Gpx2) were selected. The predictive models built using these genes were 94.8% and 82.7% accurate, respectively. Pathway analysis of the genes indicates that, aside from a xenobiotic metabolism-related pathway as an adaptive response for liver hypertrophy, amino acid biosynthesis and oxidative responses appear to be involved in hypertrophic hepatocarcinogenesis. Early detection and toxicogenomic characterization of liver hypertrophy using our models may be useful for predicting carcinogenesis. In addition, the identified genes provide novel insight into discrimination between adverse hypertrophy associated with carcinogenesis and adaptive hypertrophy in risk assessment. - Highlights: • Hypertrophy (H) and hypertrophic

Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models

International Nuclear Information System (INIS)

Liu, Shujie; Kawamoto, Taisuke; Morita, Osamu; Yoshinari, Kouichi; Honda, Hiroshi

2017-01-01

Chemical exposure often results in liver hypertrophy in animal tests, characterized by increased liver weight, hepatocellular hypertrophy, and/or cell proliferation. While most of these changes are considered adaptive responses, there is concern that they may be associated with carcinogenesis. In this study, we have employed a toxicogenomic approach using a logistic ridge regression model to identify genes responsible for liver hypertrophy and hypertrophic hepatocarcinogenesis and to develop a predictive model for assessing hypertrophy-inducing compounds. Logistic regression models have previously been used in the quantification of epidemiological risk factors. DNA microarray data from the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System were used to identify hypertrophy-related genes that are expressed differently in hypertrophy induced by carcinogens and non-carcinogens. Data were collected for 134 chemicals (72 non-hypertrophy-inducing chemicals, 27 hypertrophy-inducing non-carcinogenic chemicals, and 15 hypertrophy-inducing carcinogenic compounds). After applying logistic ridge regression analysis, 35 genes for liver hypertrophy (e.g., Acot1 and Abcc3) and 13 genes for hypertrophic hepatocarcinogenesis (e.g., Asns and Gpx2) were selected. The predictive models built using these genes were 94.8% and 82.7% accurate, respectively. Pathway analysis of the genes indicates that, aside from a xenobiotic metabolism-related pathway as an adaptive response for liver hypertrophy, amino acid biosynthesis and oxidative responses appear to be involved in hypertrophic hepatocarcinogenesis. Early detection and toxicogenomic characterization of liver hypertrophy using our models may be useful for predicting carcinogenesis. In addition, the identified genes provide novel insight into discrimination between adverse hypertrophy associated with carcinogenesis and adaptive hypertrophy in risk assessment. - Highlights: • Hypertrophy (H) and hypertrophic

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.

Growth hormone increases and maturation decreases glutamine synthetase turnover rate in rat liver

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Lin, C.K.

1985-01-01

An investigation was made of the effect of hypophysectomy and growth hormone (GH) replacement regimen (1 mg/100 g twice daily for 30 days); and maturation (from 25 up to 90 days) on the liver and brain glutamine synthetase (GS) mass and turnover rates in rats. The first order decay rate of enzyme 14 C radioactivity was determined between 1 and 4 days to obtain the half-life (T/sub 1/2/) of GS. The hepatic GS mass was determined by immunoassay. GS turnover (GS/sub s/) was calculated from T/sub 1/2/ and the GS mass (i.e., K = 0.693/T/sub 1/2/; GS/sub s/ = K x GS mass). It was concluded that: (1) GS specific activity is not decreased by hypophysectomy or increased by GH. These results suggested that observed endocrine induced changes in GS are due to changes in GS mass. (2) The liver GS turnover rate is significantly reduced by hypophysectomy and increased by GH replacement. It was proposed that GH specifically enhances synthesis of GS in the liver. (3) Maturation (25, 40, 60, and 90 days) decreases GS turnover rate in both liver and brain of normal rats. This similar effect of maturation suggests that the observed age induced decline in GS turnover rate is not related to GH in all tissues

Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration.

Science.gov (United States)

Alvarez-Sola, Gloria; Uriarte, Iker; Latasa, M Ujue; Fernandez-Barrena, Maite G; Urtasun, Raquel; Elizalde, Maria; Barcena-Varela, Marina; Jiménez, Maddalen; Chang, Haisul C; Barbero, Roberto; Catalán, Victoria; Rodríguez, Amaia; Frühbeck, Gema; Gallego-Escuredo, José M; Gavaldà-Navarro, Aleix; Villarroya, Francesc; Rodriguez-Ortigosa, Carlos M; Corrales, Fernando J; Prieto, Jesus; Berraondo, Pedro; Berasain, Carmen; Avila, Matias A

2017-10-01

Fibroblast growth factor 15/19 (FGF15/19), an enterokine that regulates synthesis of hepatic bile acids (BA), has been proposed to influence fat metabolism. Without FGF15/19, mouse liver regeneration after partial hepatectomy (PH) is severely impaired. We studied the role of FGF15/19 in response to a high fat diet (HFD) and its regulation by saturated fatty acids. We developed a fusion molecule encompassing FGF19 and apolipoprotein A-I, termed Fibapo, and evaluated its pharmacological properties in fatty liver regeneration. Fgf15 -/- mice were fed a HFD. Liver fat and the expression of fat metabolism and endoplasmic reticulum (ER) stress-related genes were measured. Influence of palmitic acid (PA) on FGF15/19 expression was determined in mice and in human liver cell lines. In vivo half-life and biological activity of Fibapo and FGF19 were compared. Hepatoprotective and proregenerative activities of Fibapo were evaluated in obese db/db mice undergoing PH. Hepatosteatosis and ER stress were exacerbated in HFD-fed Fgf15 -/- mice. Hepatic expression of Pparγ2 was elevated in Fgf15 -/- mice, being reversed by FGF19 treatment. PA induced FGF15/19 expression in mouse ileum and human liver cells, and FGF19 protected from PA-mediated ER stress and cytotoxicity. Fibapo reduced liver BA and lipid accumulation, inhibited ER stress and showed enhanced half-life. Fibapo provided increased db/db mice survival and improved regeneration upon PH. FGF15/19 is essential for hepatic metabolic adaptation to dietary fat being a physiological regulator of Pparγ2 expression . Perioperative administration of Fibapo improves fatty liver regeneration. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Evolution of hepatic steatosis to fibrosis and adenoma formation in liver specific growth hormone receptor knockout (GHRLD mice

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Yong eFan

2014-12-01

Full Text Available Background: Non-alcoholic fatty liver disease (NAFLD is one of the most common forms of chronic liver diseases closely associated with obesity and insulin resistance; deficient growth hormone (GH action in liver has been implicated as a mechanism. Here, we investigated the evolution of NAFLD in aged mice with liver-specific GHR deletion. Methods: We examined glucose tolerance, insulin responsiveness and lipid profiles in aged male mice (44-50 weeks with GHRLD. We performed proteomics analysis, pathway-based Superarray assay, as well as quantitative RT-PCR to gain molecular insight into the mechanism(s of GHR-deficiency mediated NAFLD. In addition, we examined the pathological changes of livers of aged GHRLD male mice. Results: The biochemical profile was consistent with that of the metabolic syndrome: abnormal glucose tolerance, impaired insulin secretion, and hyperlipidemia. RT-qPCR analysis of key markers of inflammation revealed a 3-5 fold increase in TNFα and CCL3, confirming the presence of inflammation. Expression of fibrotic markers (e.g., Col1A2 and Col3A1 was significantly increased, together with a 2-3 fold increase in TGFβ transcripts. Proteomics analyses showed a marked decrease of Mup1 and Selenbp2. In addition, pathway-analysis showed that the expression of cell cycle and growth relevant genes (i.e., Ccnd1, Socs2, Socs3 and Egfr were markedly affected in GHRLD liver. Microscopic analyses (H&E of GHRLD livers revealed the presence of hepatic adenomas of different stages of malignancy. Conclusion: Abrogation of GH-signaling in male liver leads to metabolic syndrome, hepatic steatosis, increased inflammation and fibrosis, and development of hepatic tumor. Since obesity, a common precursor of NAFLD, is a state of deficient GH secretion and action, the GHRLD model could be used to unravel the contribution of compromised hepatic GH-signaling in these pathological processes, and help to identify potential targets for intervention.

Polyploidization of liver cells.

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Celton-Morizur, Séverine; Desdouets, Chantal

2010-01-01

Eukaryotic organisms usually contain a diploid complement of chromosomes. However, there are a number of exceptions. Organisms containing an increase in DNA content by whole number multiples of the entire set of chromosomes are defined as polyploid. Cells that contain more than two sets of chromosomes were first observed in plants about a century ago and it is now recognized that polyploidy cells form in many eukaryotes under a wide variety of circumstance. Although it is less common in mammals, some tissues, including the liver, show a high percentage of polyploid cells. Thus, during postnatal growth, the liver parenchyma undergoes dramatic changes characterized by gradual polyploidization during which hepatocytes of several ploidy classes emerge as a result of modified cell-division cycles. This process generates the successive appearance of tetraploid and octoploid cell classes with one or two nuclei (mononucleated or binucleated). Liver cells polyploidy is generally considered to indicate terminal differentiation and senescence and to lead both to the progressive loss of cell pluripotency and a markedly decreased replication capacity. In adults, liver polyploidization is differentially regulated upon loss of liver mass and liver damage. Interestingly, partial hepatectomy induces marked cell proliferation followed by an increase in liver ploidy. In contrast, during hepatocarcinoma (HCC), growth shifts to a nonpolyploidizing pattern and expansion of the diploid hepatocytes population is observed in neoplastic nodules. Here we review the current state of understanding about how polyploidization is regulated during normal and pathological liver growth and detail by which mechanisms hepatocytes become polyploid.

Immune mediated liver failure.

Science.gov (United States)

Wang, Xiaojing; Ning, Qin

2014-01-01

Liver failure is a clinical syndrome of various etiologies, manifesting as jaundice, encephalopathy, coagulopathy and circulatory dysfunction, which result in subsequent multiorgan failure. Clinically, liver failure is classified into four categories: acute, subacute, acute-on-chronic and chronic liver failure. Massive hepatocyte death is considered to be the core event in the development of liver failure, which occurs when the extent of hepatocyte death is beyond the liver regenerative capacity. Direct damage and immune-mediated liver injury are two major factors involved in this process. Increasing evidence has suggested the essential role of immune-mediated liver injury in the pathogenesis of liver failure. Here, we review the evolved concepts concerning the mechanisms of immune-mediated liver injury in liver failure from human and animal studies. Both innate and adaptive immunity, especially the interaction of various immune cells and molecules as well as death receptor signaling system are discussed. In addition, we highlight the concept of "immune coagulation", which has been shown to be related to the disease progression and liver injury exacerbation in HBV related acute-on-chronic liver failure.

Adaptive diversification of growth allometry in the plant Arabidopsis thaliana.

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Vasseur, François; Exposito-Alonso, Moises; Ayala-Garay, Oscar J; Wang, George; Enquist, Brian J; Vile, Denis; Violle, Cyrille; Weigel, Detlef

2018-03-27

Seed plants vary tremendously in size and morphology; however, variation and covariation in plant traits may be governed, at least in part, by universal biophysical laws and biological constants. Metabolic scaling theory (MST) posits that whole-organismal metabolism and growth rate are under stabilizing selection that minimizes the scaling of hydrodynamic resistance and maximizes the scaling of resource uptake. This constrains variation in physiological traits and in the rate of biomass accumulation, so that they can be expressed as mathematical functions of plant size with near-constant allometric scaling exponents across species. However, the observed variation in scaling exponents calls into question the evolutionary drivers and the universality of allometric equations. We have measured growth scaling and fitness traits of 451 Arabidopsis thaliana accessions with sequenced genomes. Variation among accessions around the scaling exponent predicted by MST was correlated with relative growth rate, seed production, and stress resistance. Genomic analyses indicate that growth allometry is affected by many genes associated with local climate and abiotic stress response. The gene with the strongest effect, PUB4 , has molecular signatures of balancing selection, suggesting that intraspecific variation in growth scaling is maintained by opposing selection on the trade-off between seed production and abiotic stress resistance. Our findings suggest that variation in allometry contributes to local adaptation to contrasting environments. Our results help reconcile past debates on the origin of allometric scaling in biology and begin to link adaptive variation in allometric scaling to specific genes. Copyright © 2018 the Author(s). Published by PNAS.

In Vivo Zonal Variation and Liver Cell-Type Specific NF-κB Localization after Chronic Adaptation to Ethanol and following Partial Hepatectomy.

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Harshavardhan Nilakantan

Full Text Available NF-κB is a major inflammatory response mediator in the liver, playing a key role in the pathogenesis of alcoholic liver injury. We investigated zonal as well as liver cell type-specific distribution of NF-κB activation across the liver acinus following adaptation to chronic ethanol intake and 70% partial hepatectomy (PHx. We employed immunofluorescence staining, digital image analysis and statistical distributional analysis to quantify subcellular localization of NF-κB in hepatocytes and hepatic stellate cells (HSCs. We detected significant spatial heterogeneity of NF-κB expression and cellular localization between cytoplasm and nucleus across liver tissue. Our main aims involved investigating the zonal bias in NF-κB localization and determining to what extent chronic ethanol intake affects this zonal bias with in hepatocytes at baseline and post-PHx. Hepatocytes in the periportal area showed higher NF-κB expression than in the pericentral region in the carbohydrate-fed controls, but not in the ethanol group. However, the distribution of NF-κB nuclear localization in hepatocytes was shifted towards higher levels in pericentral region than in periportal area, across all treatment conditions. Chronic ethanol intake shifted the NF-κB distribution towards higher nuclear fraction in hepatocytes as compared to the pair-fed control group. Ethanol also stimulated higher NF-κB expression in a subpopulation of HSCs. In the control group, PHx elicited a shift towards higher NF-κB nuclear fraction in hepatocytes. However, this distribution remained unchanged in the ethanol group post-PHx. HSCs showed a lower NF-κB expression following PHx in both ethanol and control groups. We conclude that adaptation to chronic ethanol intake attenuates the liver zonal variation in NF-κB expression and limits the PHx-induced NF-κB activation in hepatocytes, but does not alter the NF-κB expression changes in HSCs in response to PHx. Our findings provide new

Radiation absorbed-dose estimates for the liver, spleen, and metaphyseal growth complexes in children undergoing gallium-67 citrate scanning

International Nuclear Information System (INIS)

Thomas, S.R.; Gelfand, M.J.; Burns, G.S.; Purdom, R.C.; Kereiakes, J.G.; Maxon, H.R.

1983-01-01

Quantitative conjugate-view external counting techniques were applied to estimate the radiation dose to the liver, spleen, and metaphyseal growth complexes (distal femur and proximal tibia) for ten pediatric patients undergoing gallium-67 scanning procedures. The effective half-life of Ga 67 in these organs was approximately 78 hours. The dose per unit of administered activity for the liver and spleen was between 0.3 and 4.0 rad/mCi (0.08 to 1.08 Gy/GBq) and 0.5 and 7.0 rad/mCi (0.13 to 1.89 Gy/GBq), respectively. For the metaphyseal growth plates, the range was 2.3 to 14.3 rad/mCi (0.62 to 3.86 Gy/GBq)

Prenatal ethanol exposure programs an increased susceptibility of non-alcoholic fatty liver disease in female adult offspring rats

International Nuclear Information System (INIS)

Shen, Lang; Liu, Zhongfen; Gong, Jun; Zhang, Li; Wang, Linlong; Magdalou, Jacques; Chen, Liaobin; Wang, Hui

2014-01-01

Prenatal ethanol exposure (PEE) induces dyslipidemia and hyperglycemia in fetus and adult offspring. However, whether PEE increases the susceptibility to non-alcoholic fatty liver disease (NAFLD) in offspring and its underlying mechanism remain unknown. This study aimed to demonstrate an increased susceptibility to high-fat diet (HFD)-induced NAFLD and its intrauterine programming mechanisms in female rat offspring with PEE. Rat model of intrauterine growth retardation (IUGR) was established by PEE, the female fetus and adult offspring that fed normal diet (ND) or HFD were sacrificed. The results showed that, in PEE + ND group, serum corticosterone (CORT) slightly decreased and insulin-like growth factor-1 (IGF-1) and glucose increased with partial catch-up growth; In PEE + HFD group, serum CORT decreased, while serum IGF-1, glucose and triglyceride (TG) increased, with notable catch-up growth, higher metabolic status and NAFLD formation. Enhanced liver expression of the IGF-1 pathway, gluconeogenesis, and lipid synthesis as well as reduced expression of lipid output were accompanied in PEE + HFD group. In PEE fetus, serum CORT increased while IGF-1 decreased, with low body weight, hyperglycemia, and hepatocyte ultrastructural changes. Hepatic IGF-1 expression as well as lipid output was down-regulated, while lipid synthesis significantly increased. Based on these findings, we propose a “two-programming” hypothesis for an increased susceptibility to HFD-induced NAFLD in female offspring of PEE. That is, the intrauterine programming of liver glucose and lipid metabolic function is “the first programming”, and postnatal adaptive catch-up growth triggered by intrauterine programming of GC-IGF1 axis acts as “the second programming”. - Highlights: • Prenatal ethanol exposure increase the susceptibility of NAFLD in female offspring. • Prenatal ethanol exposure reprograms fetal liver’s glucose and lipid metabolism . • Prenatal ethanol exposure cause

Prenatal ethanol exposure programs an increased susceptibility of non-alcoholic fatty liver disease in female adult offspring rats

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Shen, Lang; Liu, Zhongfen; Gong, Jun; Zhang, Li [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Wang, Linlong [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Magdalou, Jacques [UMR 7561 CNRS-Nancy Université, Faculté de Médicine, Vandoeuvre-lès-Nancy (France); Chen, Liaobin [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Wang, Hui [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China)

2014-01-15

Prenatal ethanol exposure (PEE) induces dyslipidemia and hyperglycemia in fetus and adult offspring. However, whether PEE increases the susceptibility to non-alcoholic fatty liver disease (NAFLD) in offspring and its underlying mechanism remain unknown. This study aimed to demonstrate an increased susceptibility to high-fat diet (HFD)-induced NAFLD and its intrauterine programming mechanisms in female rat offspring with PEE. Rat model of intrauterine growth retardation (IUGR) was established by PEE, the female fetus and adult offspring that fed normal diet (ND) or HFD were sacrificed. The results showed that, in PEE + ND group, serum corticosterone (CORT) slightly decreased and insulin-like growth factor-1 (IGF-1) and glucose increased with partial catch-up growth; In PEE + HFD group, serum CORT decreased, while serum IGF-1, glucose and triglyceride (TG) increased, with notable catch-up growth, higher metabolic status and NAFLD formation. Enhanced liver expression of the IGF-1 pathway, gluconeogenesis, and lipid synthesis as well as reduced expression of lipid output were accompanied in PEE + HFD group. In PEE fetus, serum CORT increased while IGF-1 decreased, with low body weight, hyperglycemia, and hepatocyte ultrastructural changes. Hepatic IGF-1 expression as well as lipid output was down-regulated, while lipid synthesis significantly increased. Based on these findings, we propose a “two-programming” hypothesis for an increased susceptibility to HFD-induced NAFLD in female offspring of PEE. That is, the intrauterine programming of liver glucose and lipid metabolic function is “the first programming”, and postnatal adaptive catch-up growth triggered by intrauterine programming of GC-IGF1 axis acts as “the second programming”. - Highlights: • Prenatal ethanol exposure increase the susceptibility of NAFLD in female offspring. • Prenatal ethanol exposure reprograms fetal liver’s glucose and lipid metabolism . • Prenatal ethanol exposure cause

Swimming training induces liver adaptations to oxidative stress and insulin sensitivity in rats submitted to high-fat diet.

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Zacarias, Aline Cruz; Barbosa, Maria Andrea; Guerra-Sá, Renata; De Castro, Uberdan Guilherme Mendes; Bezerra, Frank Silva; de Lima, Wanderson Geraldo; Cardoso, Leonardo M; Santos, Robson Augusto Souza Dos; Campagnole-Santos, Maria José; Alzamora, Andréia Carvalho

2017-11-01

Oxidative stress, physical inactivity and high-fat (FAT) diets are associated with hepatic disorders such as metabolic syndrome (MS). The therapeutic effects of physical training (PT) were evaluated in rats with MS induced by FAT diet for 13 weeks, on oxidative stress and insulin signaling in the liver, during the last 6 weeks. FAT-sedentary (SED) rats increased body mass, retroperitoneal fat, mean arterial pressure (MAP) and heart rate (HR), and total cholesterol, serum alanine aminotransferase, glucose and insulin. Livers of FAT-SED rats increased superoxide dismutase activity, thiobarbituric acid-reactive substances, protein carbonyl and oxidized glutathione (GSSG); and decreased catalase activity, reduced glutathione/GSSG ratio, and the mRNA expression of insulin receptor substrate 1 (IRS-1) and serine/threonine kinase 2. FAT-PT rats improved in fitness and reduced their body mass, retroperitoneal fat, and glucose, insulin, total cholesterol, MAP and HR; and their livers increased superoxide dismutase and catalase activities, the reduced glutathione/GSSG ratio and the expression of peroxisome proliferator-activated receptor gamma and insulin receptor compared to FAT-SED rats. These findings indicated adaptive responses to PT by restoring the oxidative balance and insulin signaling in the liver and certain biometric and biochemical parameters as well as MAP in MS rats.

The Intrauterine Growth Restriction Phenotype: Fetal Adaptations and Potential Implications for Later Life Insulin Resistance and Diabetes

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Thorn, Stephanie R.; Rozance, Paul J.; Brown, Laura D.; Hay, William W.

2011-01-01

The intrauterine growth restricted (IUGR) fetus develops unique metabolic adaptations in response to exposure to reduced nutrient supply. These adaptations provide survival value for the fetus by enhancing the capacity of the fetus to take up and use nutrients, thereby reducing the need for nutrient supply. Each organ and tissue in the fetus adapts differently, with the brain showing the greatest capacity for maintaining nutrient supply and growth. Such adaptations, if persistent, also have the potential in later life to promote nutrient uptake and storage, which directly lead to complications of obesity, insulin resistance, reduced insulin production, and type 2 diabetes. PMID:21710398

Genetic basis of growth adaptation of Escherichia coli after deletion of pgi, a major metabolic gene.

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Pep Charusanti

2010-11-01

Full Text Available Bacterial survival requires adaptation to different environmental perturbations such as exposure to antibiotics, changes in temperature or oxygen levels, DNA damage, and alternative nutrient sources. During adaptation, bacteria often develop beneficial mutations that confer increased fitness in the new environment. Adaptation to the loss of a major non-essential gene product that cripples growth, however, has not been studied at the whole-genome level. We investigated the ability of Escherichia coli K-12 MG1655 to overcome the loss of phosphoglucose isomerase (pgi by adaptively evolving ten replicates of E. coli lacking pgi for 50 days in glucose M9 minimal medium and by characterizing endpoint clones through whole-genome re-sequencing and phenotype profiling. We found that 1 the growth rates for all ten endpoint clones increased approximately 3-fold over the 50-day period; 2 two to five mutations arose during adaptation, most frequently in the NADH/NADPH transhydrogenases udhA and pntAB and in the stress-associated sigma factor rpoS; and 3 despite similar growth rates, at least three distinct endpoint phenotypes developed as defined by different rates of acetate and formate secretion. These results demonstrate that E. coli can adapt to the loss of a major metabolic gene product with only a handful of mutations and that adaptation can result in multiple, alternative phenotypes.

Genetic Adaptation to Growth Under Laboratory Conditions in Escherichia coli and Salmonella enterica

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Anna Knöppel

2018-04-01

Full Text Available Experimental evolution under controlled laboratory conditions is becoming increasingly important to address various evolutionary questions, including, for example, the dynamics and mechanisms of genetic adaptation to different growth and stress conditions. In such experiments, mutations typically appear that increase the fitness under the conditions tested (medium adaptation, but that are not necessarily of interest for the specific research question. Here, we have identified mutations that appeared during serial passage of E. coli and S. enterica in four different and commonly used laboratory media and measured the relative competitive fitness and maximum growth rate of 111 genetically re-constituted strains, carrying different single and multiple mutations. Little overlap was found between the mutations that were selected in the two species and the different media, implying that adaptation occurs via different genetic pathways. Furthermore, we show that commonly occurring adaptive mutations can generate undesired genetic variation in a population and reduce the accuracy of competition experiments. However, by introducing media adaptation mutations with large effects into the parental strain that was used for the evolution experiment, the variation (standard deviation was decreased 10-fold, and it was possible to measure fitness differences between two competitors as small as |s| < 0.001.

Dietary moderately oxidized oil induces expression of fibroblast growth factor 21 in the liver of pigs

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Varady Juliane

2012-03-01

Full Text Available Abstract Background Fibroblast growth factor 21 (FGF21, whose expression is induced by peroxisome proliferator-activated receptor α (PPARα, has been recently identified as a novel metabolic regulator which plays a crucial role in glucose homeostasis, lipid metabolism, insulin sensitivity and obesity. Previous studies have shown that administration of oxidized fats leads to an activation of PPARα in the liver. Therefore, the present study investigated the hypothesis that feeding of oxidized fats causes an induction of FGF21 in the liver. Methods Twenty four crossbred pigs were allocated to two groups of 12 pigs each and fed nutritionally adequate diets with either fresh rapeseed oil or oxidized rapeseed oil prepared by heating at a temperature of 175°C for 72 h. Results In pigs fed the oxidized fat mRNA abundance and protein concentrations of FGF21 in liver were significantly increased (P P P Conclusion The present study shows for the first time that administration of an oxidized fat induces the expression of FGF21 in the liver, probably mediated by activation of PPARα. Induction of FGF21 could be involved in several effects observed in animals administered an oxidized fat.

Immunoneutralization of endogenous glucagon-like peptide-2 reduces adaptive intestinal growth in diabetic rats

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Hartmann, Bolette; Thulesen, Jesper; Hare, Kristine Juul

2002-01-01

in the proximal part of the small intestine (10.84+/-0.44 mm(2)). Antibody treatment had no effect on body weight, blood glucose concentrations and food intake. Thus, blocking of endogenous GLP-2 in a model of adaptive intestinal growth reduces the growth response, providing strong evidence for a physiological......Supraphysiological doses of glucagon-like peptide-2 (GLP-2) have been shown to induce intestinal growth by increasing villus height and crypt depth and by decreasing apoptosis, but a physiological effect of GLP-2 has not yet been demonstrated. Earlier, we found elevated levels of endogenous GLP-2...... in untreated streptozotocin diabetic rats associated with marked intestinal growth. In the present study, we investigated the role of endogenous GLP-2 for this adaptive response. We included four groups of six rats: (1) diabetic rats treated with saline, (2) diabetic rats treated with non-specific antibodies...

A model for arterial adaptation combining microstructural collagen remodeling and 3D tissue growth

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Machyshyn, I.; Bovendeerd, P.H.M.; Ven, van de A.A.F.; Rongen, P.M.J.; Vosse, van de F.N.

2010-01-01

Long-term adaptation of soft tissues is realized through growth and remodeling (G&R). Mathematical models are powerful tools in testing hypotheses on G&R and supporting the design and interpretation of experiments. Most theoretical G&R studies concentrate on description of either growth or

Placental adaptations to the maternal-fetal environment: implications for fetal growth and developmental programming.

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Sandovici, Ionel; Hoelle, Katharina; Angiolini, Emily; Constância, Miguel

2012-07-01

The placenta is a transient organ found in eutherian mammals that evolved primarily to provide nutrients for the developing fetus. The placenta exchanges a wide array of nutrients, endocrine signals, cytokines and growth factors with the mother and the fetus, thereby regulating intrauterine development. Recent studies show that the placenta is not just a passive organ mediating maternal-fetal exchange. It can adapt its capacity to supply nutrients in response to intrinsic and extrinsic variations in the maternal-fetal environment. These dynamic adaptations are thought to occur to maximize fetal growth and viability at birth in the prevailing conditions in utero. However, some of these adaptations may also affect the development of individual fetal tissues, with patho-physiological consequences long after birth. Here, this review summarizes current knowledge on the causes, possible mechanisms and consequences of placental adaptive responses, with a focus on the regulation of transporter-mediated processes for nutrients. This review also highlights the emerging roles that imprinted genes and epigenetic mechanisms of gene regulation may play in placental adaptations to the maternal-fetal environment. Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Adaptive Liver Stereotactic Body Radiation Therapy: Automated Daily Plan Reoptimization Prevents Dose Delivery Degradation Caused by Anatomy Deformations

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Leinders, Suzanne M. [Erasmus Medical Center-Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Delft University of Technology, Delft (Netherlands); Breedveld, Sebastiaan; Méndez Romero, Alejandra [Erasmus Medical Center-Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Schaart, Dennis [Delft University of Technology, Delft (Netherlands); Seppenwoolde, Yvette, E-mail: y.seppenwoolde@erasmusmc.nl [Erasmus Medical Center-Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Heijmen, Ben J.M. [Erasmus Medical Center-Daniel den Hoed Cancer Center, Rotterdam (Netherlands)

2013-12-01

Purpose: To investigate how dose distributions for liver stereotactic body radiation therapy (SBRT) can be improved by using automated, daily plan reoptimization to account for anatomy deformations, compared with setup corrections only. Methods and Materials: For 12 tumors, 3 strategies for dose delivery were simulated. In the first strategy, computed tomography scans made before each treatment fraction were used only for patient repositioning before dose delivery for correction of detected tumor setup errors. In adaptive second and third strategies, in addition to the isocenter shift, intensity modulated radiation therapy beam profiles were reoptimized or both intensity profiles and beam orientations were reoptimized, respectively. All optimizations were performed with a recently published algorithm for automated, multicriteria optimization of both beam profiles and beam angles. Results: In 6 of 12 cases, violations of organs at risk (ie, heart, stomach, kidney) constraints of 1 to 6 Gy in single fractions occurred in cases of tumor repositioning only. By using the adaptive strategies, these could be avoided (<1 Gy). For 1 case, this needed adaptation by slightly underdosing the planning target volume. For 2 cases with restricted tumor dose in the planning phase to avoid organ-at-risk constraint violations, fraction doses could be increased by 1 and 2 Gy because of more favorable anatomy. Daily reoptimization of both beam profiles and beam angles (third strategy) performed slightly better than reoptimization of profiles only, but the latter required only a few minutes of computation time, whereas full reoptimization took several hours. Conclusions: This simulation study demonstrated that replanning based on daily acquired computed tomography scans can improve liver stereotactic body radiation therapy dose delivery.

Fasting-induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health.

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Fuhrmeister, Jessica; Zota, Annika; Sijmonsma, Tjeerd P; Seibert, Oksana; Cıngır, Şahika; Schmidt, Kathrin; Vallon, Nicola; de Guia, Roldan M; Niopek, Katharina; Berriel Diaz, Mauricio; Maida, Adriano; Blüher, Matthias; Okun, Jürgen G; Herzig, Stephan; Rose, Adam J

2016-06-01

Recent studies have demonstrated that repeated short-term nutrient withdrawal (i.e. fasting) has pleiotropic actions to promote organismal health and longevity. Despite this, the molecular physiological mechanisms by which fasting is protective against metabolic disease are largely unknown. Here, we show that, metabolic control, particularly systemic and liver lipid metabolism, is aberrantly regulated in the fasted state in mouse models of metabolic dysfunction. Liver transcript assays between lean/healthy and obese/diabetic mice in fasted and fed states uncovered "growth arrest and DNA damage-inducible" GADD45β as a dysregulated gene transcript during fasting in several models of metabolic dysfunction including ageing, obesity/pre-diabetes and type 2 diabetes, in both mice and humans. Using whole-body knockout mice as well as liver/hepatocyte-specific gain- and loss-of-function strategies, we revealed a role for liver GADD45β in the coordination of liver fatty acid uptake, through cytoplasmic retention of FABP1, ultimately impacting obesity-driven hyperglycaemia. In summary, fasting stress-induced GADD45β represents a liver-specific molecular event promoting adaptive metabolic function. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Changes in foetal liver T2* measurements by MRI in response to maternal oxygen breathing: application to diagnosing foetal growth restriction

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Morris, David M; Semple, Scott IK; Gilbert, Fiona J; Redpath, Thomas W; Ross, John AS; McVicar, Alexandra; Haggarty, Paul; Abramovich, David R; Smith, Norman

2010-01-01

The motivation of the project was to investigate the use of oxygen-challenge magnetic resonance imaging (OC-MRI) as a method of diagnosing foetal growth restriction. Foetal growth restriction is associated with restricted foetal oxygen supply and is also associated with increased risks of perinatal mortality and morbidity, and a number of serious and chronic health problems. Measurements of T2* relaxation time, an MRI parameter which increases with blood oxygenation, were made in the right lobe of the foetal liver in 80 singleton pregnancies, before and after the mother breathed oxygen. The groups consisted of 41 foetuses with normal growth and 39 with apparent growth restriction. The mean ± SD gestational age at scanning was 35 ± 3 weeks. Changes in foetal liver T2* on maternal oxygen breathing showed no significant difference between the groups therefore the OC-MRI protocol used in this study has no value in the diagnosis of foetal growth restriction. A secondary finding was that a significant positive correlation of T2* change with gestational age was observed. Future studies on the use of oxygen-challenge MRI to investigate foetal growth restriction may therefore need to control for gestational age at the time of MR scanning in order to observe any underlying foetal growth-related effects

The acid-labile subunit of the ternary insulin-like growth factor complex in cirrhosis: relation to liver dysfunction

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Møller, S; Juul, A; Becker, U

2000-01-01

BACKGROUND/AIMS: In the circulation, insulin-like growth factor-I (IGF-I) is bound in a trimeric complex of 150 kDa with IGF binding protein-3 (IGFBP-3) and the acid-labile subunit (ALS). Whereas circulating IGF-I and IGFBP-3 are reported to be low in patients with chronic liver failure, the leve...... with significant relations to liver dysfunction and other components of the IGF complex. A small hepatic extraction was found in controls, which suggests extrahepatic production of ALS. Future studies should focus on organ-specific removal of ALS.......BACKGROUND/AIMS: In the circulation, insulin-like growth factor-I (IGF-I) is bound in a trimeric complex of 150 kDa with IGF binding protein-3 (IGFBP-3) and the acid-labile subunit (ALS). Whereas circulating IGF-I and IGFBP-3 are reported to be low in patients with chronic liver failure, the level...... of ALS has not been described in relation to hepatic dysfunction. The aim of the present study was therefore to measure circulating and hepatic venous concentrations of ALS in relation to hepatic function and the IGF axis. METHODS: Twenty-five patients with cirrhosis (Child class A/B/C:5/10/10) and 30...

Brachytherapy Using Elastin-Like Polypeptides with (131)I Inhibit Tumor Growth in Rabbits with VX2 Liver Tumor.

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Liu, Xinpei; Shen, Yiming; Zhang, Xuqian; Lin, Rui; Jia, Qiang; Chang, Yixiang; Liu, Wenge; Liu, Wentian

2016-10-01

Brachytherapy is a targeted type of radiotherapy utilized in the treatment of cancers. Elastin-like polypeptides are a unique class of genetically engineered peptide polymers that have several attractive properties for brachytherapy. To explore the feasibility and application of brachytherapy for VX2 liver tumor using elastin-like polypeptides with (131)I so as to provide reliable experimental evidence for a new promising treatment of liver cancer. Elastin-like polypeptide as carrier was labeled with (131)I using the iodogen method. Ten eligible rabbits with VX2 liver tumor were randomly divided into the treatment group (n = 5) and control group (n = 5). The treatment group received brachytherapy using elastin-like polypeptide with (131)I, and in the control group, elastin-like polypeptide was injected into the VX2 liver tumor as a control. Periodic biochemical and imaging surveillances were required to assess treatment efficacy. The stability of elastin-like polypeptide with (131)I in vitro was maintained at over 96.8 % for 96 h. Biochemistry and imaging indicated brachytherapy using elastin-like polypeptide with (131)I for liver tumor can improve liver function and inhibit tumor growth (P Elastin-like polypeptide can be an ideal carrier of (131)I and have high labeling efficiency, radiochemical purity and stability. Brachytherapy using elastin-like polypeptide with (131)I for liver tumor is a useful therapy that possesses high antitumor efficacy advantages.

Taurine Biosynthesis in a Fish Liver Cell Line (ZFL) Adapted to a Serum-Free Medium.

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Liu, Chieh-Lun; Watson, Aaron M; Place, Allen R; Jagus, Rosemary

2017-05-25

Although taurine has been shown to play multiple important physiological roles in teleosts, little is known about the molecular mechanisms underlying dietary requirements. Cell lines can provide useful tools for deciphering biosynthetic pathways and their regulation. However, culture media and sera contain variable taurine levels. To provide a useful cell line for the investigation of taurine homeostasis, an adult zebrafish liver cell line (ZFL) has been adapted to a taurine-free medium by gradual accommodation to a commercially available synthetic medium, UltraMEM™-ITES. Here we show that ZFL cells are able to synthesize taurine and be maintained in medium without taurine. This has allowed for the investigation of the effects of taurine supplementation on cell growth, cellular amino acid pools, as well as the expression of the taurine biosynthetic pathway and taurine transporter genes in a defined fish cell type. After taurine supplementation, cellular taurine levels increase but hypotaurine levels stay constant, suggesting little suppression of taurine biosynthesis. Cellular methionine levels do not change after taurine addition, consistent with maintenance of taurine biosynthesis. The addition of taurine to cells grown in taurine-free medium has little effect on transcript levels of the biosynthetic pathway genes for cysteine dioxygenase (CDO), cysteine sulfinate decarboxylase (CSAD), or cysteamine dioxygenase (ADO). In contrast, supplementation with taurine causes a 30% reduction in transcript levels of the taurine transporter, TauT. This experimental approach can be tailored for the development of cell lines from aquaculture species for the elucidation of their taurine biosynthetic capacity.

Mitochondria-associated endoplasmic reticulum membranes allow adaptation of mitochondrial metabolism to glucose availability in the liver.

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Theurey, Pierre; Tubbs, Emily; Vial, Guillaume; Jacquemetton, Julien; Bendridi, Nadia; Chauvin, Marie-Agnès; Alam, Muhammad Rizwan; Le Romancer, Muriel; Vidal, Hubert; Rieusset, Jennifer

2016-04-01

Mitochondria-associated endoplasmic reticulum membranes (MAM) play a key role in mitochondrial dynamics and function and in hepatic insulin action. Whereas mitochondria are important regulators of energy metabolism, the nutritional regulation of MAM in the liver and its role in the adaptation of mitochondria physiology to nutrient availability are unknown. In this study, we found that the fasted to postprandial transition reduced the number of endoplasmic reticulum-mitochondria contact points in mouse liver. Screening of potential hormonal/metabolic signals revealed glucose as the main nutritional regulator of hepatic MAM integrity both in vitro and in vivo Glucose reduced organelle interactions through the pentose phosphate-protein phosphatase 2A (PP-PP2A) pathway, induced mitochondria fission, and impaired respiration. Blocking MAM reduction counteracted glucose-induced mitochondrial alterations. Furthermore, disruption of MAM integrity mimicked effects of glucose on mitochondria dynamics and function. This glucose-sensing system is deficient in the liver of insulin-resistant ob/ob and cyclophilin D-KO mice, both characterized by chronic disruption of MAM integrity, mitochondrial fission, and altered mitochondrial respiration. These data indicate that MAM contribute to the hepatic glucose-sensing system, allowing regulation of mitochondria dynamics and function during nutritional transition. Chronic disruption of MAM may participate in hepatic mitochondrial dysfunction associated with insulin resistance. © The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

Expression and Function of Myostatin in Obesity, Diabetes, and Exercise Adaptation

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Allen, David L.; Hittel, Dustin S.; McPherron, Alexandra C.

2011-01-01

Myostatin is a member of the transforming growth factor-beta/bone morphogenetic protein (TGF-β/BMP) super-family of secreted factors that functions as a potent inhibitor of skeletal muscle growth. Moreover, considerable evidence has accumulated that myostatin also regulates metabolism and that its inhibition can significantly attenuate the progression of obesity and diabetes. While at least part of these effects on metabolism can be attributable to myostatin’s influence over skeletal muscle growth and therefore on the total volume of metabolically active lean body mass, there is mounting evidence that myostatin affects the growth and metabolic state of other tissues, including the adipose and the liver. In addition, recent work has explored the role of myostatin in substrate mobilization, uptake and/or utilization of muscle independent of its effects on body composition. Finally, the effects of both endurance and resistance exercise on myostatin expression, as well as the potential role of myostatin in the beneficial metabolic adaptations occurring in response to exercise, have also begun to be delineated in greater detail. The purpose of this review is to summarize the work to date on the expression and function of myostatin in obesity, diabetes, and exercise adaptation. PMID:21364474

Cyclophilin A enhances cell proliferation and tumor growth of liver fluke-associated cholangiocarcinoma

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Sawanyawisuth Kanlayanee

2011-08-01

Full Text Available Abstract Background Cyclophilin A (CypA expression is associated with malignant phenotypes in many cancers. However, the role and mechanisms of CypA in liver fluke-associated cholangiocarcinoma (CCA are not presently known. In this study, we investigated the expression of CypA in CCA tumor tissues and CCA cell lines as well as regulation mechanisms of CypA in tumor growth using CCA cell lines. Methods CypA expression was determined by real time RT-PCR, Western blot or immunohistochemistry. CypA silence or overexpression in CCA cells was achieved using gene delivery techniques. Cell proliferation was assessed using MTS assay or Ki-67 staining. The effect of silencing CypA on CCA tumor growth was determined in nude mice. The effect of CypA knockdown on ERK1/2 activation was assessed by Western blot. Results CypA was upregulated in 68% of CCA tumor tissues. Silencing CypA significantly suppressed cell proliferation in several CCA cell lines. Likewise, inhibition of CypA peptidyl-prolyl cis-trans isomerase (PPIase activity using cyclosporin A (CsA decreased cell proliferation. In contrast, overexpression of CypA resulted in 30% to 35% increases in proliferation of CCA cell lines. Interestingly, neither silence nor overexpression of CypA affected cell proliferation of a non-tumor human cholangiocyte cell line, MMNK1. Suppression of CypA expression attenuated ERK1/2 activity in CCA M139 cells by using both transient and stable knockdown methods. In the in vivo study, there was a 43% reduction in weight of tumors derived from CypA-silenced CCA cell lines compared with control vector CCA tumors in mice; these tumors with stable CypA silencing showed a reduced cell proliferation. Conclusions CypA is upregulated in majority of CCA patients' tissues and confers a significant growth advantage in CCA cells. Suppression of CypA expression decreases proliferation of CCA cell lines in vitro and reduces tumor growth in the nude mouse model. Inhibition of Cyp

Climate Change Adaptation. Challenges and Opportunities for a Smart Urban Growth

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Adriana Galderisi

2014-04-01

Full Text Available Climate change is one of the main environmental issues challenging cities in the 21th century. At present, more than half of the world population lives in cities and the latter are responsible for 60% to 80% of global energy consumption and greenhouse gas (GHG emissions, which are the main causes of the change in climate conditions. In the meantime, they are seriously threatened by the heterogeneous climate-related phenomena, very often exacerbated by the features of the cities themselves. In the last decade, international and European efforts have been mainly focused on mitigation rather than on adaptation strategies. Europe is one of the world leaders in global mitigation policies, while the issue of adaptation has gained growing importance in the last years. As underlined by the EU Strategy on adaptation to climate change, even though climate change mitigation still remains a priority for the global community, large room has to be devoted to adaptation measures, in order to effectively face the unavoidable impacts and related economic, environmental and social costs of climate change (EC, 2013. Thus, measures for adaptation to climate change are receiving an increasing financial support and a growing number of European countries are implementing national and urban adaptation strategies to deal with the actual and potential climate change impacts. According to the above considerations, this paper explores strengths and weaknesses of current adaptation strategies in European cities. First the main suggestions of the European Community to improve urban adaptation to climate change are examined; then, some recent Adaptation Plans are analyzed, in order to highlight challenges and opportunities arising from the adaptation processes at urban level and to explore the potential of Adaptation Plans to promote a smart growth in the European cities.

Table of Policy Options for Smart Growth Fixes for Climate Adaptation and Resilience

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Sortable table of policy options discussed in the publication Smart Growth Fixes for Climate Adaptation and Resilience, which can help local governments prepare for climate change while gaining other environmental, economic, health, and social benefits

Prolactin receptors in liver, kidney, and gill of the tilapia (Oreochromis mossambicus): Characterization and effect of salinity on specific binding of iodinated ovine prolactin

International Nuclear Information System (INIS)

Dauder, S.; Young, G.; Hass, L.; Bern, H.A.

1990-01-01

Specific binding of 125 I-ovine prolactin (oPRL) to microsomal fractions from gill, kidney, and liver of adult tilapia was determined. Specific binding varied among tissues, the highest values being displayed by kidney membranes. In the liver, the binding of oPRL was not strongly displaced by tilapia prolactins (tPRL177 and tPRL188), although tPRL177 was six times more potent than tPRL188. On the other hand, in kidney and gill membranes, the two tPRLs were equipotent. Tilapia PRLs showed low potency in competing for oPRL-binding sites when pregnant rat liver membranes were utilized. Tilapia growth hormone (tGH) and human growth hormone (hGH) displaced 125 I-oPRL from liver as well as did tPRL177 but were not recognized well by renal or branchial receptors. Two 125 I-oPRL-binding sites were detected in every tissue tested. These binding sites are subject to physiological regulation since adaptation to seawater resulted in a significant decrease in specific binding

DYNAMICS OF INSULIN-LIKE GROWTH FACTOR-1 (IGF-1 IN CHILDREN AFTER AB0-INCOMPATIBLE LIVER TRANSPLANTATION

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O.P. Shevchenko

2014-01-01

Full Text Available It is shown that liver transplantation (LT from donor with incompatible blood type (AB0i may be effective and safe, but the impact of such operation upon the various systems of the body has not been investigated yet. Insulinlike growth factor-1 (IGF-1 is synthesized in the liver and mediates the action of growth hormone. The level of IGF-1 is a marker of the processes of cell proliferation and tissue regeneration. Aim. To evaluate levels of IGF-1 in children-recipients with liver transplant from AB0i (incompatible and AB0c (compatible donors.Materials and methods. 140 children aged 3 to 36 (19,5 ± 16,5 months with congenital diseases of the hepatobiliar system, 58 of them boys, were surveyed. All patients underwent transplantation of left lateral liver sector from living related donors: 111 children were transplanted with fragment of the liver from AB0c donors, 29 – from AB0i donors; in 10 children with AB0i liver before and/or after LT operation anti-group antibodies (anti-A/B were revealed. The concentration of IGF-1 was determined by ELISA using specifi c kits (Immunodiagnostic System, USA in samples of blood plasma, which were received up to a month and a year after a liver transplant.Results. Average level of IGF-1 21,0 ± 29,5 μg/l in patients before LT was signifi cantly lower than in healthy children (52,2 ± 26,3 μg/l, p < 0,001 and did not vary in children, having received later a piece of liver from a compatible (AB0c donor and from donor AB0i (23,5 ± 30,9 and 21,2 ± 23,2 μg/l respectively, p = 0,70. In patients with anti-A/B prior to surgery average level of IGF-1 was not different from that of the patients without antibodies (32,6 ± 27,6 and 22,3 ± 29,6 μg/l respectively, p = 0,4. One month after LT level of IGF-1 has increased both in the general group, and in patients with AB0c and AV0i liver (92,1 ± 77,8 and 131,2 ± 106,7 μg/l respectively, p = 0,09. The level of IGF-1 was not varied in the group with antibodies

Effects of cortisol and lipopolysaccharide on expression of select growth-, stress- and immune-related genes in rainbow trout liver

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Many studies have shown that stress-induced cortisol levels negatively influence growth and immunity in finfish. Despite this knowledge, few studies have assessed the direct effects of cortisol on liver immune function in finfish. Using real-time PCR, the expression of three cortisol-responsive ge...

Inhibition of vascular endothelial growth factor signaling facilitates liver repair from acute ethanol-induced injury in zebrafish

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Changwen Zhang

2016-11-01

Full Text Available Alcoholic liver disease (ALD results from alcohol overconsumption and is among the leading causes of liver-related morbidity and mortality worldwide. Elevated expression of vascular endothelial growth factor (VEGF and its receptors has been observed in ALD, but how it contributes to ALD pathophysiology is unclear. Here, we investigated the impact of VEGF signaling inhibition on an established zebrafish model of acute alcoholic liver injury. Kdrl activity was blocked by chemical inhibitor treatment or by genetic mutation. Exposing 4-day-old zebrafish larvae to 2% ethanol for 24 h induced hepatic steatosis, angiogenesis and fibrogenesis. The liver started self-repair once ethanol was removed. Although inhibiting Kdrl did not block the initial activation of hepatic stellate cells during ethanol treatment, it suppressed their proliferation, extracellular matrix protein deposition and fibrogenic gene expression after ethanol exposure, thus enhancing the liver repair. It also ameliorated hepatic steatosis and attenuated hepatic angiogenesis that accelerated after the ethanol treatment. qPCR showed that hepatic stellate cells are the first liver cell type to increase the expression of VEGF ligand and receptor genes in response to ethanol exposure. Both hepatic stellate cells and endothelial cells, but not hepatic parenchymal cells, expressed kdrl upon ethanol exposure and were likely the direct targets of Kdrl inhibition. Ethanol-induced steatosis and fibrogenesis still occurred in cloche mutants that have hepatic stellate cells but lack hepatic endothelial cells, and Kdrl inhibition suppressed both phenotypes in the mutants. These results suggest that VEGF signaling mediates interactions between activated hepatic stellate cells and hepatocytes that lead to steatosis. Our study demonstrates the involvement of VEGF signaling in regulating sustained liver injuries after acute alcohol exposure. It also provides a proof of principle of using the

CP-31398 inhibits the growth of p53-mutated liver cancer cells in vitro and in vivo.

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He, Xing-Xing; Zhang, Yu-Nan; Yan, Jun-Wei; Yan, Jing-Jun; Wu, Qian; Song, Yu-Hu

2016-01-01

The tumor suppressor p53 is one of the most frequently mutated genes in hepatocellular carcinoma (HCC). Previous studies demonstrated that CP-31398 restored the native conformation of mutant p53 and trans-activated p53 downstream genes in tumor cells. However, the research on the application of CP-31398 to liver cancer has not been reported. Here, we investigated the effects of CP-31398 on the phenotype of HCC cells carrying p53 mutation. The effects of CP-31398 on the characteristic of p53-mutated HCC cells were evaluated through analyzing cell cycle, cell apoptosis, cell proliferation, and the expression of p53 downstream genes. In tumor xenografts developed by PLC/PRF/5 cells, the inhibition of tumor growth by CP-31398 was analyzed through gross morphology, growth curve, and the expression of p53-related genes. Firstly, we demonstrated that CP-31398 inhibited the growth of p53-mutated liver cancer cells in a dose-dependent and p53-dependent manner. Then, further study showed that CP-31398 re-activated wild-type p53 function in p53-mutated HCC cells, which resulted in inhibitive response of cell proliferation and an induction of cell-cycle arrest and apoptosis. Finally, in vivo data confirmed that CP-31398 blocked the growth of xenografts tumors through transactivation of p53-responsive downstream molecules. Our results demonstrated that CP-31398 induced desired phenotypic change of p53-mutated HCC cells in vitro and in vivo, which revealed that CP-31398 would be developed as a therapeutic candidate for HCC carrying p53 mutation.

Morphology and morphometry of fetal liver at 16-26 weeks of gestation by magnetic resonance imaging: Comparison with embryonic liver at Carnegie stage 23.

Science.gov (United States)

Hamabe, Yui; Hirose, Ayumi; Yamada, Shigehito; Uwabe, Chigako; Okada, Tomohisa; Togashi, Kaori; Kose, Katsumi; Takakuwa, Tetsuya

2013-06-01

Normal liver growth was described morphologically and morphometrically using magnetic resonance imaging (MRI) data of human fetuses, and compared with embryonic liver to establish a normal reference chart for clinical use. MRI images from 21 fetuses at 16-26 weeks of gestation and eight embryos at Carnegie stage (CS)23 were investigated in the present study. Using the image data, the morphology of the liver as well as its adjacent organs was extracted and reconstructed three-dimensionally. Morphometry of fetal liver growth was performed using simple regression analysis. The fundamental morphology was similar in all cases of the fetal livers examined. The liver tended to grow along the transversal axis. The four lobes were clearly recognizable in the fetal liver but not in the embryonic liver. The length of the liver along the three axes, liver volume and four lobes correlated with the bodyweight (BW). The morphogenesis of the fetal liver on the dorsal and caudal sides was affected by the growth of the abdominal organs, such as the stomach, duodenum and spleen, and retroperitoneal organs, such as the right adrenal gland and right kidney. The main blood vessels such as inferior vena cava, portal vein and umbilical vein made a groove on the surface of the liver. Morphology of the fetal liver was different from that of the embryonic liver at CS23. The present data will be useful for evaluating the development of the fetal liver and the adjacent organs that affect its morphology. © 2012 The Japan Society of Hepatology.

Global Liver Proteome Analysis Using iTRAQ Reveals AMPK-mTOR-Autophagy Signaling Is Altered by Intrauterine Growth Restriction in Newborn Piglets.

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Long, Baisheng; Yin, Cong; Fan, Qiwen; Yan, Guokai; Wang, Zhichang; Li, Xiuzhi; Chen, Changqing; Yang, Xingya; Liu, Lu; Zheng, Zilong; Shi, Min; Yan, Xianghua

2016-04-01

Intrauterine growth restriction (IUGR) impairs fetal growth and development, perturbs nutrient metabolism, and increases the risk of developing diseases in postnatal life. However, the underlying mechanisms by which IUGR affects fetal liver development and metabolism remain incompletely understood. Here, we applied a high-throughput proteomics approach and biochemical analysis to investigate the impact of IUGR on the liver of newborn piglets. As a result, we identified 78 differentially expressed proteins in the three biological replicates, including 31 significantly up-regulated proteins and 47 significantly down-regulated proteins. Among them, a majority of differentially expressed proteins were related to nutrient metabolism and mitochondrial function. Additionally, many significantly down-regulated proteins participated in the mTOR signaling pathway and the phagosome maturation signaling pathway. Further analysis suggested that glucose concentration and hepatic glycogen storage were both reduced in IUGR newborn piglets, which may contribute to AMPK activation and mTORC1 inhibition. However, AMPK activation and mTORC1 inhibition failed to induce autophagy in the liver of IUGR neonatal pigs. A possible reason is that PP2Ac, a potential candidate in autophagy regulation, is significantly down-regulated in the liver of IUGR newborn piglets. These findings may provide implications for preventing and treating IUGR in human beings and domestic animals.

Insulin-like growth factor 1, liver enzymes, and insulin resistance in patients with PCOS and hirsutism

OpenAIRE

ÇAKIR, Evrim; TOPALOĞLU, Oya; BOZKURT, Nujen ÇOLAK; BAYRAKTAR, Başak KARBEK

2015-01-01

Hyperinsulinemia and insulin resistance are commonly seen in patients with hirsutism and polycystic ovary syndrome (PCOS), and are associated with cardiovascular disease risk. However, it is not yet known whether insulin-like growth factor I (IGF-I) and alanine transaminase (ALT) produced by the liver play roles in hyperinsulinemia and subclinical atherosclerotic process in patients with PCOS and idiopathic hirsutism (IH). Materials and methods: This was a prospective case-controlled study....

Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice

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Takemura, Takayo; Yoshida, Yuichi [Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Osaka (Japan); Kiso, Shinichi, E-mail: kiso@gh.med.osaka-u.ac.jp [Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Osaka (Japan); Kizu, Takashi; Furuta, Kunimaro; Ezaki, Hisao; Hamano, Mina; Egawa, Mayumi; Chatani, Norihiro; Kamada, Yoshihiro [Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Osaka (Japan); Imai, Yasuharu [Department of Gastroenterology, Ikeda Municipal Hospital, Ikeda, Osaka (Japan); Higashiyama, Shigeki [Department of Biochemistry and Molecular Genetics, Ehime University, Graduate School of Medicine and Department of Cell Growth and Tumor Regulation, Proteo-Medicine Research Center (ProMRes), Ehime University, Shitsukawa, Toon, Ehime (Japan); Iwamoto, Ryo; Mekada, Eisuke [Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka (Japan); Takehara, Tetsuo [Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Osaka (Japan)

2013-07-26

Highlights: •HB-EGF expression was increased during the development of liver fibrosis. •Conditional HB-EGF knockout mouse showed enhanced experimental liver fibrosis. •HB-EGF antagonized TGF-β-induced activation of hepatic stellate cells. •We report a possible protective role of HB-EGF in cholestatic liver fibrosis. -- Abstract: Our aims were to evaluate the involvement of heparin-binding EGF-like growth factor (HB-EGF) in liver fibrogenesis of humans and mice and to elucidate the effect of HB-EGF deficiency on cholestatic liver fibrosis using conditional HB-EGF knockout (KO) mice. We first demonstrated that gene expression of HB-EGF had a positive significant correlation with that of collagen in human fibrotic livers, and was increased in bile duct ligation (BDL)-induced fibrotic livers in mouse. We then generated conditional HB-EGF knockout (KO) mice using the interferon inducible Mx-1 promoter driven Cre recombinase transgene and wild type (WT) and KO mice were subjected to BDL. After BDL, KO mice exhibited enhanced liver fibrosis with increased expression of collagen, compared with WT mice. Finally, we used mouse hepatic stellate cells (HSCs) to examine the role of HB-EGF in the activation of these cells and showed that HB-EGF antagonized TGF-β-induced gene expression of collagen in mouse primary HSCs. Interestingly, HB-EGF did not prevent the TGF-β-induced nuclear accumulation of Smad3, but did lead to stabilization of the Smad transcriptional co-repressor TG-interacting factor. In conclusion, our data suggest a possible protective role of HB-EGF in cholestatic liver fibrosis.

Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice

International Nuclear Information System (INIS)

Takemura, Takayo; Yoshida, Yuichi; Kiso, Shinichi; Kizu, Takashi; Furuta, Kunimaro; Ezaki, Hisao; Hamano, Mina; Egawa, Mayumi; Chatani, Norihiro; Kamada, Yoshihiro; Imai, Yasuharu; Higashiyama, Shigeki; Iwamoto, Ryo; Mekada, Eisuke; Takehara, Tetsuo

2013-01-01

Highlights: •HB-EGF expression was increased during the development of liver fibrosis. •Conditional HB-EGF knockout mouse showed enhanced experimental liver fibrosis. •HB-EGF antagonized TGF-β-induced activation of hepatic stellate cells. •We report a possible protective role of HB-EGF in cholestatic liver fibrosis. -- Abstract: Our aims were to evaluate the involvement of heparin-binding EGF-like growth factor (HB-EGF) in liver fibrogenesis of humans and mice and to elucidate the effect of HB-EGF deficiency on cholestatic liver fibrosis using conditional HB-EGF knockout (KO) mice. We first demonstrated that gene expression of HB-EGF had a positive significant correlation with that of collagen in human fibrotic livers, and was increased in bile duct ligation (BDL)-induced fibrotic livers in mouse. We then generated conditional HB-EGF knockout (KO) mice using the interferon inducible Mx-1 promoter driven Cre recombinase transgene and wild type (WT) and KO mice were subjected to BDL. After BDL, KO mice exhibited enhanced liver fibrosis with increased expression of collagen, compared with WT mice. Finally, we used mouse hepatic stellate cells (HSCs) to examine the role of HB-EGF in the activation of these cells and showed that HB-EGF antagonized TGF-β-induced gene expression of collagen in mouse primary HSCs. Interestingly, HB-EGF did not prevent the TGF-β-induced nuclear accumulation of Smad3, but did lead to stabilization of the Smad transcriptional co-repressor TG-interacting factor. In conclusion, our data suggest a possible protective role of HB-EGF in cholestatic liver fibrosis

The feasibility of a group stress management Liver SMART intervention for patients with end-stage liver disease: A pilot study.

Science.gov (United States)

Jutagir, Devika R; Saracino, Rebecca M; Cunningham, Amy; Foran-Tuller, Kelly A; Driscoll, Mary A; Sledge, William H; Emre, Sukru H; Fehon, Dwain C

2018-06-04

Structured, empirically supported psychological interventions are lacking for patients who require organ transplantation. This stage IA psychotherapy development project developed and tested the feasibility, acceptability, tolerability, and preliminary efficacy of an 8-week group cognitive behavioral stress management intervention adapted for patients with end-stage liver disease awaiting liver transplantation. Twenty-nine English-speaking United Network for Organ Sharing-registered patients with end-stage liver disease from a single transplantation center enrolled in 8-week, group cognitive-behavioral liver stress management and relaxation training intervention adapted for patients with end-stage liver disease. Patients completed pre- and postintervention surveys that included the Beck Depression Inventory II and the Beck Anxiety Inventory. Feasibility, acceptability, tolerability, and preliminary efficacy were assessed.ResultAttendance rate was 69.40%. The intervention was rated as "good" to "excellent" by 100% of participants who completed the postintervention survey in teaching them new skills to relax and to cope with stress, and by 94.12% of participants in helping them feel supported while waiting for a liver transplant. No adverse events were recorded over the course of treatment. Attrition was 13.79%. Anxious and depressive symptoms were not statistically different after the intervention.Significance of resultsThe liver stress management and relaxation training intervention is feasible, acceptable, and tolerable to end-stage liver disease patients within a transplant clinic setting. Anxious and depressive symptoms remained stable postintervention. Randomized controlled trials are needed to study the intervention's effectiveness in this population.

Adaptação cultural do Chronic Liver Disease Questionnaire (CLDQ para população brasileira Cross-cultural adaptation of the Chronic Liver Disease Questionnaire (CLDQ to the Brazilian population

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Samantha Mucci

2010-01-01

Full Text Available Nesse estudo realizaram-se a tradução para o português e a adaptação cultural do instrumento Chronic Liver Disease Questionnaire (CLDQ para uso no Brasil. O instrumento foi traduzido da versão original (inglês para a língua portuguesa pelos autores e, posteriormente, revisado e avaliado quanto ao grau de dificuldade das traduções e equivalência por tradutores bilíngües. O instrumento foi, então, aplicado em 20 pacientes com hepatopatia crônica selecionados aleatoriamente. Não houve dificuldade na compreensão do instrumento, todas as questões foram consideradas aplicáveis pelos pacientes, e a equivalência cultural do CLDQ foi demonstrada sem que mudanças na tradução original precisassem ser feitas. A tradução e a adaptação cultural do CLDQ para o português, no Brasil, foram realizadas, tendo sido cumprida esta importante etapa para sua validação e utilização em nosso meio.The aims of this study were the English-to-Portuguese translation and cross-cultural adaptation of the Chronic Liver Disease Questionnaire (CLDQ for use in Brazil. The instrument was translated from the original language, English, to Portuguese by the authors, and was subsequently reviewed and evaluated as to the degree of difficulty of the translation and equivalence, by bilingual translators. The questionnaire was then applied to 20 randomly selected patients with chronic liver disease. Patients had no difficulty understanding the questionnaire and considered all the questions applicable. The cultural equivalence of the CLDQ was demonstrated, without requiring changes in the original translation. The translation into Portuguese and cross-cultural adaptation of the CLDQ successfully completed this important stage for its validation and use in Brazil.

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.

Contradictory Immune Response in Post Liver Transplantation Hepatitis B and C

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Akinobu Takaki

2014-01-01

Full Text Available Hepatitis B and C often progress to decompensated liver cirrhosis requiring orthotopic liver transplantation (OLT. After OLT, hepatitis B recurrence is clinically controlled with a combination of hepatitis B immunoglobulin (HBIG and nucleos(tide analogues. Another approach is to induce self-producing anti-hepatitis B virus (HBV antibodies using a HBV envelope antigen vaccine. Patients who had not been HBV carriers such as acutely infected liver failure or who received liver from HBV self-limited donor are good candidate. For chronic HBV carrier patients, a successful response can only be achieved in selected patients such as those treated with experimentally reduced immunosuppression protocols or received an anti-HBV adaptive memory carrying donor liver. Hepatitis C virus (HCV reinfects transplanted livers at a rate of >90%. HCV reinfected patients show different severities of hepatitis, from mild and slowly progressing to severe and rapidly progressing, possibly resulting from different adaptive immune responses. More than half the patients require interferon treatment, although the success rate is low and carries risks for leukocytopenia and rejection. Managing the immune response has an important role in controlling recurrent hepatitis C. This study aimed to review the adaptive immune response in post-OLT hepatitis B and C.

Changes in activities of adaptive liver enzymes in rats after non-lethal x-irradiation

International Nuclear Information System (INIS)

Toropila, M.; Ahlersova, E.; Ahlers, I.; Benova, K.

1998-01-01

The effect of a single dose of whole-body X-irradiation of 2.39 Gy (250 R) on the activities of selected adaptive rat liver enzymes and blood serum corticosterone concentrations was followed for a period of 28 days. Rats of Wistar strain SPF breeding (VELAZ Prague) were used. Both irradiated and control animals were fed in pairs with the same amount of feed as was consumed by irradiated animals in the pilot experiment. The feed intake of irradiated animals decreased significantly until the fourth day. During the rest of the experimental period no significant differences were recorded in feed intake between the experimental and control groups. The activity of tyrosine aminotransferase (TAT) in the liver of irradiated animals increased, with the exception of the initial period. Similar changes were recorded in the activity of tryptophane-2-3 dioxygenase (TO). A significant increase on the third day and a significant decrease from the seventh day after irradiation was recorded in the activity of aspartate aminotransferase (AST). Similar changes were observed with alanine aminotransferase (ALT). It is necessary to stress that the activity of this enzyme decreased also on the first day after irradiation. Until the third day there was a marked increase of serum corticosterone in the irradiated animals. The results point not only towards significant changes to the parameters observed, caused by a non-lethal irradiation dose, but also towards the importance of the nutritional regime, so-called paired feeding

The gut-liver axis

NARCIS (Netherlands)

Visschers, Ruben G. J.; Luyer, Misha D.; Schaap, Frank G.; Olde Damink, Steven W. M.; Soeters, Peter B.

2013-01-01

The liver adaptively responds to extra-intestinal and intestinal inflammation. In recent years, the role of the autonomic nervous system, intestinal failure and gut microbiota has been investigated in the development of hepatic, intestinal and extra-intestinal disease. The autonomic nervous system

Effects of varying dietary carbohydrate levels on growth performance, body composition and liver histology of Malaysian mahseer fingerlings (Tor tambroides).

Science.gov (United States)

Ishak, Sairatul Dahlianis; Kamarudin, Mohd Salleh; Ramezani-Fard, Ehsan; Saad, Che Roos; Yusof, Yus Aniza

2016-07-01

We investigated the effects of four iso-nitrogenous (40% crude protein) and iso-caloric (17.6 kJ g(-1)) diets with different dietary carbohydrate levels (15%, 20%, 25% and 30%) on the growth performance, feed utilization efficiency, body composition and liver histology of Malaysian mahseer (Tor tambroides) fingerlings in a 10-week feeding trial. Fish (initial weight of 0.8?0.1 g; initial total length 4.2?0.1 cm) were fed twice daily at 4% body mass. Dietary carbohydrate level had significant effects (P<0.05) on weight gain, SGR (specific growth rate), FCR (feed conversion rate), PER (protein efficiency rate), survival percentage and all nutrient retention values (PRV, LRV, CRV, ERV). Protein, carbohydrate and gross energy composition of the fish body were also significantly differed (P<0.05) among treatments. Liver histology showed mild hepatic steatosis and hypertrophy for fishes receiving a higher dietary carbohydrate inclusion. In general, treatments with 20% and 25% dietary carbohydrate levels produced better growth results compared to the rest of the treatments. Using a second-order polynomial regression analysis model, the optimal dietary carbohydrate level of 23.4% was estimated for mahseer fingerlings. ?

Role of Serum Insulin-Like Growth Factor I and Ghrelin in Chronic Liver Diseases

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EI-Nashar, N A [Health Radiation Research Dept., National Centre for Radiation Research alld Technology (NCRRT), P.G: 29 Nasr City, Cairo (Egypt)

2008-07-01

Chronic liver disease (CLD) is characterized by numerous metabolic alterations resulting in the clinical picture of malnutrition or even cachexia and contributing to complications such as hepatic encephalopathy and ascetics. In view of these alternations, this study was conducted to investigate the role of serum insulin-like growth factor-I (IGF-I) and ghrelin in CLD with or without cirrhosis and evaluate their relationships with liver functions and clinical complications. Serum IGF-I levels were very highly significantly lowered (P< 0.0001) in hepatitis C virus (HCV) patients and in hepatocellular carcinoma (HCC) patients than in the control group. However, serum ghrelin levels were significantly elevated in HCV and in HCC patients when compared with controls (P< 0.05). IGF-I significantly decreased with every stage of cirrhosis according to Child-Pugh classification. In contrast, serum ghrelin levels were significantly elevated in Child C liver cirrhosis compared to non cirrhotic patients (Child A and Child B cirrhosis). IGF-I levels inversely correlated with prothrombin time (PT.), total bilirubin and positively correlated with serum albumin. While serum ghrelin correlated with clinical complications of CLD. No correlations were found between IGF-I and ghrelin in all studied groups, however, both inversely correlated with a-feto protein (AFP) in HCC patients. We conclude that IGF-I.and ghrelin can predict the diagnosis and prognosis of patients with severe CLD as they have potential relationships with hepatic failure and HCC.

Role of Serum Insulin-Like Growth Factor I and Ghrelin in Chronic Liver Diseases

International Nuclear Information System (INIS)

EI-Nashar, N.A.

2008-01-01

Chronic liver disease (CLD) is characterized by numerous metabolic alterations resulting in the clinical picture of malnutrition or even cachexia and contributing to complications such as hepatic encephalopathy and ascetics. In view of these alternations, this study was conducted to investigate the role of serum insulin-like growth factor-I (IGF-I) and ghrelin in CLD with or without cirrhosis and evaluate their relationships with liver functions and clinical complications. Serum IGF-I levels were very highly significantly lowered (P< 0.0001) in hepatitis C virus (HCV) patients and in hepatocellular carcinoma (HCC) patients than in the control group. However, serum ghrelin levels were significantly elevated in HCV and in HCC patients when compared with controls (P< 0.05). IGF-I significantly decreased with every stage of cirrhosis according to Child-Pugh classification. In contrast, serum ghrelin levels were significantly elevated in Child C liver cirrhosis compared to non cirrhotic patients (Child A and Child B cirrhosis). IGF-I levels inversely correlated with prothrombin time (PT.), total bilirubin and positively correlated with serum albumin. While serum ghrelin correlated with clinical complications of CLD. No correlations were found between IGF-I and ghrelin in all studied groups, however, both inversely correlated with a-feto protein (AFP) in HCC patients. We conclude that IGF-I.and ghrelin can predict the diagnosis and prognosis of patients with severe CLD as they have potential relationships with hepatic failure and HCC

Thrombospondin-1 is a novel negative regulator of liver regeneration after partial hepatectomy through transforming growth factor-beta1 activation in mice.

Science.gov (United States)

Hayashi, Hiromitsu; Sakai, Keiko; Baba, Hideo; Sakai, Takao

2012-05-01

The matricellular protein, thrombospondin-1 (TSP-1), is prominently expressed during tissue repair. TSP-1 binds to matrix components, proteases, cytokines, and growth factors and activates intracellular signals through its multiple domains. TSP-1 converts latent transforming growth factor-beta1 (TGF-β1) complexes into their biologically active form. TGF-β plays significant roles in cell-cycle regulation, modulation of differentiation, and induction of apoptosis. Although TGF-β1 is a major inhibitor of proliferation in cultured hepatocytes, the functional requirement of TGF-β1 during liver regeneration remains to be defined in vivo. We generated a TSP-1-deficient mouse model of a partial hepatectomy (PH) and explored TSP-1 induction, progression of liver regeneration, and TGF-β-mediated signaling during the repair process after hepatectomy. We show here that TSP-1-mediated TGF-β1 activation plays an important role in suppressing hepatocyte proliferation. TSP-1 expression was induced in endothelial cells (ECs) as an immediate early gene in response to PH. TSP-1 deficiency resulted in significantly reduced TGF-β/Smad signaling and accelerated hepatocyte proliferation through down-regulation of p21 protein expression. TSP-1 induced in ECs by reactive oxygen species (ROS) modulated TGF-β/Smad signaling and proliferation in hepatocytes in vitro, suggesting that the immediately and transiently produced ROS in the regenerating liver were the responsible factor for TSP-1 induction. We have identified TSP-1 as an inhibitory element in regulating liver regeneration by TGF-β1 activation. Our work defines TSP-1 as a novel immediate early gene that could be a potential therapeutic target to accelerate liver regeneration. Copyright © 2011 American Association for the Study of Liver Diseases.

Fraction from human and rat liver which is inhibitory for proliferation of liver cells.

Science.gov (United States)

Chen, T S; Ottenweller, J; Luke, A; Santos, S; Keeting, P; Cuy, R; Lea, M A

1989-01-01

A comparative study was undertaken with human and rat liver of a fraction reported to have growth inhibitory activity when prepared from rat liver. Fractions which were soluble in 70% ethanol and insoluble in 87% ethanol were prepared from liver cytosols. Electrophoretic analysis under denaturing conditions indicated that there were several quantitative or qualitative differences in the fractions from the two species. Fractions from both human and rat liver were found to be inhibitory for the incorporation of 3H-thymidine into DNA of foetal chick hepatocytes. Under conditions in which the rat fraction inhibited precursor incorporation into DNA of rat liver epithelial cells there was not a significant inhibitory effect with the fraction from human liver. DNA synthesis in a rat hepatoma cell line was not significantly inhibited by preparations from either species. The data suggested that corresponding fractions from both rat and human liver could have inhibitory effects on precursor incorporation into DNA but the magnitude of the effects and target cell specificity may differ.

Projections in donor organs available for liver transplantation in the United States: 2014-2025.

Science.gov (United States)

Parikh, Neehar D; Hutton, David; Marrero, Wesley; Sanghani, Kunal; Xu, Yongcai; Lavieri, Mariel

2015-06-01

With the aging US population, demographic shifts, and obesity epidemic, there is potential for further exacerbation of the current liver donor shortage. We aimed to project the availability of liver grafts in the United States. We performed a secondary analysis of the Organ Procurement and Transplantation Network database of all adult donors from 2000 to 2012 and calculated the total number of donors available and transplanted donor livers stratified by age, race, and body mass index (BMI) group per year. We used National Health and Nutrition Examination Survey and Centers for Disease Control and Prevention historical data to stratify the general population by age, sex, race, and BMI. We then used US population age and race projections provided by the US Census Bureau and the Weldon Cooper Center for Public Service and made national and regional projections of available donors and donor liver utilization from 2014 to 2025. We performed sensitivity analyses and varied the rate of the rise in obesity, proportion of Hispanics, population growth, liver utilization rate, and donation after cardiac death (DCD) utilization. The projected adult population growth in the United States from 2014 to 2025 will be 7.1%. However, we project that there will be a 6.1% increase in the number of used liver grafts. There is marked regional heterogeneity in liver donor growth. Projections were significantly affected by changes in BMI, DCD utilization, and liver utilization rates but not by changes in the Hispanic proportion of the US population or changes in the overall population growth. Overall population growth will outpace the growth of available donor organs and thus potentially exacerbate the existing liver graft shortage. The projected growth in organs is highly heterogeneous across different United Network for Organ Sharing regions. Focused strategies to increase the liver donor pool are warranted. © 2015 American Association for the Study of Liver Diseases.

Growth Performance and Stress Responses of Larval Mississippi Paddlefish Polyodon spathula to Hypoxia under Different Diet Treatments

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Ya Zhu

2014-01-01

Full Text Available A growth trial was conducted to detect the effects of different diets on the growth performance and hypoxia adaptation capacity of Mississippi Paddlefish (Polyodon spathula larvae. The larvae were fed with live food, formulated diets, and 1/2 live food with 1/2 formulated diets. After a 15-d growth trial, final body weight and total body length were measured, and five larvae from each dietary group were subjected to 1 h of hypoxia treatment. Serum total antioxidant capacity (T-AOC, serum superoxide dismutase (SOD, and liver malondialdehyde (MDA were measured. Final body weight and weight gain of the fish fed live food were significantly higher than the values for the other two groups. Total body length of the fish fed live food and 1/2 live food with 1/2 formulated diets exhibited no significant difference. After hypoxia treatment, serum T-AOC and SOD activities of the fish fed formulated diets were significantly lower than those of the other two groups. Liver MDA content of the fish fed with live food was significantly higher than that of the other two groups. In conclusion, larval paddlefish fed with an appropriate proportion of live food and formulated diets exhibit improved adaptive capacity to hypoxia.

Skeletal Muscle Derived IL-6 in Liver and Adipose Tissue Metabolism

DEFF Research Database (Denmark)

Knudsen, Jakob Grunnet

Summary Physical activity can lead to metabolic disease and treatment of several metabolic diseases include exercise training. Skeletal muscle has, due to its central role in glucose and fat metabolism at rest and during exercise been studied in detail with regard to exercise training. The role...... of both liver and adipose tissue regulation in whole body metabolism has come in to focus and it has been shown that both tissues are subject to exercise training-induced adaptations. However, the contribution of endocrine factors to the regulation of exercise training-induced adaptations in liver...... and adipose tissue metabolism is unknown. It has been suggested that myokines, such as IL-6, released from skeletal muscle affects liver and adipose tissue and are involved in the regulation of exercise training adaptations. Thus, the aim of this thesis was to investigate the role of skeletal muscle derived...

Irreversibility of a bad start: early exposure to osmotic stress limits growth and adaptive developmental plasticity.

Science.gov (United States)

Wu, Chi-Shiun; Gomez-Mestre, Ivan; Kam, Yeong-Choy

2012-05-01

Harsh environments experienced early in development have immediate effects and potentially long-lasting consequences throughout ontogeny. We examined how salinity fluctuations affected survival, growth and development of Fejervarya limnocharis tadpoles. Specifically, we tested whether initial salinity effects on growth and rates of development were reversible and whether they affected the tadpoles' ability to adaptively accelerate development in response to deteriorating conditions later in development. Tadpoles were initially assigned to either low or high salinity, and then some were switched between salinity levels upon reaching either Gosner stage 30 (early switch) or 38 (late switch). All tadpoles initially experiencing low salinity survived whereas those initially experiencing high salinity had poor survival, even if switched to low salinity. Growth and developmental rates of tadpoles initially assigned to high salinity did not increase after osmotic stress release. Initial low salinity conditions allowed tadpoles to attain a fast pace of development even if exposed to high salinity afterwards. Tadpoles experiencing high salinity only late in development metamorphosed faster and at a smaller size, indicating an adaptive acceleration of development to avoid osmotic stress. Nonetheless, early exposure to high salinity precluded adaptive acceleration of development, always causing delayed metamorphosis relative to those in initially low salinity. Our results thus show that stressful environments experienced early in development can critically impact life history traits, having long-lasting or irreversible effects, and restricting their ability to produce adaptive plastic responses.

Distinct CCR2(+) Gr1(+) cells control growth of the Yersinia pestis ΔyopM mutant in liver and spleen during systemic plague.

Science.gov (United States)

Ye, Zhan; Uittenbogaard, Annette M; Cohen, Donald A; Kaplan, Alan M; Ambati, Jayakrishna; Straley, Susan C

2011-02-01

We are using a systemic plague model to identify the cells and pathways that are undermined by the virulence protein YopM of the plague bacterium Yersinia pestis. In this study, we pursued previous findings that Gr1(+) cells are required to selectively limit growth of ΔyopM Y. pestis and that CD11b(+) cells other than polymorphonuclear leukocytes (PMNs) are selectively lost in spleens infected with parent Y. pestis. When PMNs were ablated from mice, ΔyopM Y. pestis grew as well as the parent strain in liver but not in spleen, showing that these cells are critical for controlling growth of the mutant in liver but not spleen. In mice lacking expression of the chemokine receptor CCR2, wild-type growth was restored to ΔyopM Y. pestis in both organs. In spleen, the Gr1(+) cells differentially recruited by parent and ΔyopM Y. pestis infections were CCR2(+) Gr1(+) CD11b(+) CD11c(Lo-Int) MAC3(+) iNOS(+) (inducible nitric oxide synthase-positive) inflammatory dendritic cells (iDCs), and their recruitment to spleen from blood was blocked when YopM was present in the infecting strain. Consistent with influx of iDCs being affected by YopM in spleen, the growth defect of the ΔyopM mutant was relieved by the parent Y. pestis strain in a coinfection assay in which the parent strain could affect the fate of the mutant in trans. In a mouse model of bubonic plague, CCR2 also was shown to be required for ΔyopM Y. pestis to show wild-type growth in skin. The data imply that YopM's pathogenic effect indirectly undermines signaling through CCR2. We propose a model for how YopM exerts its different effects in liver and spleen.

Prognostic value of insulinlike growth factor I and its binding protein in patients with alcohol-induced liver disease. EMALD group

DEFF Research Database (Denmark)

Møller, Søren; Becker, Povl Ulrik; Juul, A

1996-01-01

Insulinlike growth factor I (IGF-I) is a single-polypeptide chain with important anabolic and endocrine activities. The liver is the major source of IGF-I and its binding protein, IGFBP-3. Circulating concentrations of IGF-I and IGFBP-3 are decreased in patients with chronic liver disease...... and correlate with the severity. The aim of this study was to assess the additional prognostic value of IGF-I and IGFBP-3 in patients entered in a large multicenter study (EMALD). Three hundred thirty-seven patients with alcohol-induced liver disease were studied in a randomized placebo-controlled trial...... of malotilate with a mean follow-up period of 569 days (range, 7-1,544). A multivariate Cox regression analysis of pertinent clinical and biochemical variables showed a significant independent prognostic value of years of alcohol intake, coagulation factors 2, 7, and 10, alkaline phosphatases, serum creatinine...

Hepatic regeneration after sublethal partial liver irradiation in cirrhotic rats

International Nuclear Information System (INIS)

Gu Ke; Lai Songtao; Ma Ningyi; Zhao Jiandong; Ren Zhigang; Wang Jian; Liu Jin; Jiang Guoliang

2011-01-01

Our previous animal study had demonstrated that partial liver irradiation (IR) could stimulate regeneration in the protected liver, which supported the measurements adopted in radiotherapy planning for hepatocellular carcinoma. The purpose of this present study is to investigate whether cirrhotic liver repopulation could be triggered by partial liver IR. The cirrhosis was induced by thioacetamide (TAA) in rats. After cirrhosis establishment, TAA was withdrawn. In Experiment 1, only right-half liver was irradiated with single doses of 5 Gy, 10 Gy and 15 Gy, respectively. In Experiment 2, right-half liver was irradiated to 15 Gy, and the left-half to 2.5 Gy, 5 Gy and 7.5 Gy, respectively. The regeneration endpoints, including liver index (LI); mitotic index (MI); liver proliferation index (LPI); proliferating cell nuclear antigen-labeling index (PCNA-LI); serum hepatic growth factor (HGF), vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-α and interleukin (IL)-6, were evaluated on 0 day, 30-day, 60-day, 90-day, 120-day and 150-day after IR. Serum and in situ TGF-β1 were also measured. In both experimental groups, the IR injuries were sublethal, inducing no more than 9% animal deaths. Upon TAA withdrawal, hepatic regeneration decelerated in the controls. In Experiment 1 except for LI, all other regeneration parameters were significantly higher than those in controls for both right-half and left-half livers. In Experiment 2 all regeneration parameters were also higher compared with those in controls for both half livers. Serum HGF and VEGF were increased compared with that of controls. Both unirradiated and low dose-irradiated cirrhotic liver were able to regenerate triggered by sublethal partial liver IR and higher doses and IR to both halves liver triggered a more enhanced regeneration. (author)

Inclusion bodies of aggregated hemosiderins in liver macrophages.

Science.gov (United States)

Hayashi, Hisao; Tatsumi, Yasuaki; Wakusawa, Shinya; Shigemasa, Ryota; Koide, Ryoji; Tsuchida, Ken-Ichi; Morotomi, Natsuko; Yamashita, Tetsuji; Kumagai, Kotaro; Ono, Yukiya; Hayashi, Kazuhiko; Ishigami, Masatoshi; Goto, Hidemi; Kato, Ayako; Kato, Koichi

2017-12-01

Hemosiderin formation is a structural indication of iron overload. We investigated further adaptations of the liver to excess iron. Five patients with livers showing iron-rich inclusions larger than 2 µm were selected from our database. The clinical features of patients and structures of the inclusions were compared with those of 2 controls with mild iron overload. All patients had severe iron overload with more than 5000 ng/mL of serum ferritin. Etiologies were variable, from hemochromatosis to iatrogenic iron overload. Their histological stages were either portal fibrosis or cirrhosis. Inclusion bodies were ultra-structurally visualized as aggregated hemosiderins in the periportal macrophages. X-ray analysis always identified, in addition to a large amount of iron complexes including oxygen and phosphorus, a small amount of copper and sulfur in the mosaic matrixes of inclusions. There were no inclusions in the control livers. Inclusion bodies, when the liver is loaded with excess iron, may appear in the macrophages as isolated organella of aggregated hemosiderins. Trace amounts of copper-sulfur complexes were always identified in the mosaic matrices of the inclusions, suggesting cuproprotein induction against excess iron. In conclusion, inclusion formation in macrophages may be an adaptation of the liver loaded with excess iron.

Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver

Directory of Open Access Journals (Sweden)

Arne Hinrichs

2018-05-01

Full Text Available Objective: Laron syndrome (LS is a rare, autosomal recessive disorder in humans caused by loss-of-function mutations of the growth hormone receptor (GHR gene. To establish a large animal model for LS, pigs with GHR knockout (KO mutations were generated and characterized. Methods: CRISPR/Cas9 technology was applied to mutate exon 3 of the GHR gene in porcine zygotes. Two heterozygous founder sows with a 1-bp or 7-bp insertion in GHR exon 3 were obtained, and their heterozygous F1 offspring were intercrossed to produce GHR-KO, heterozygous GHR mutant, and wild-type pigs. Since the latter two groups were not significantly different in any parameter investigated, they were pooled as the GHR expressing control group. The characterization program included body and organ growth, body composition, endocrine and clinical-chemical parameters, as well as signaling studies in liver tissue. Results: GHR-KO pigs lacked GHR and had markedly reduced serum insulin-like growth factor 1 (IGF1 levels and reduced IGF-binding protein 3 (IGFBP3 activity but increased IGFBP2 levels. Serum GH concentrations were significantly elevated compared with control pigs. GHR-KO pigs had a normal birth weight. Growth retardation became significant at the age of five weeks. At the age of six months, the body weight of GHR-KO pigs was reduced by 60% compared with controls. Most organ weights of GHR-KO pigs were reduced proportionally to body weight. However, the weights of liver, kidneys, and heart were disproportionately reduced, while the relative brain weight was almost doubled. GHR-KO pigs had a markedly increased percentage of total body fat relative to body weight and displayed transient juvenile hypoglycemia along with decreased serum triglyceride and cholesterol levels. Analysis of insulin receptor related signaling in the liver of adult fasted pigs revealed increased phosphorylation of IRS1 and PI3K. In agreement with the loss of GHR, phosphorylation of STAT5 was

Prolactin receptor, growth hormone receptor, and putative somatolactin receptor in Mozambique tilapia: tissue specific expression and differential regulation by salinity and fasting.

Science.gov (United States)

Pierce, A L; Fox, B K; Davis, L K; Visitacion, N; Kitahashi, T; Hirano, T; Grau, E G

2007-01-01

In fish, pituitary growth hormone family peptide hormones (growth hormone, GH; prolactin, PRL; somatolactin, SL) regulate essential physiological functions including osmoregulation, growth, and metabolism. Teleost GH family hormones have both differential and overlapping effects, which are mediated by plasma membrane receptors. A PRL receptor (PRLR) and two putative GH receptors (GHR1 and GHR2) have been identified in several teleost species. Recent phylogenetic analyses and binding studies suggest that GHR1 is a receptor for SL. However, no studies have compared the tissue distribution and physiological regulation of all three receptors. We sequenced GHR2 from the liver of the Mozambique tilapia (Oreochromis mossambicus), developed quantitative real-time PCR assays for the three receptors, and assessed their tissue distribution and regulation by salinity and fasting. PRLR was highly expressed in the gill, kidney, and intestine, consistent with the osmoregulatory functions of PRL. PRLR expression was very low in the liver. GHR2 was most highly expressed in the muscle, followed by heart, testis, and liver, consistent with this being a GH receptor with functions in growth and metabolism. GHR1 was most highly expressed in fat, liver, and muscle, suggesting a metabolic function. GHR1 expression was also high in skin, consistent with a function of SL in chromatophore regulation. These findings support the hypothesis that GHR1 is a receptor for SL. In a comparison of freshwater (FW)- and seawater (SW)-adapted tilapia, plasma PRL was strongly elevated in FW, whereas plasma GH was slightly elevated in SW. PRLR expression was reduced in the gill in SW, consistent with PRL's function in freshwater adaptation. GHR2 was elevated in the kidney in FW, and correlated negatively with plasma GH, whereas GHR1 was elevated in the gill in SW. Plasma IGF-I, but not GH, was reduced by 4 weeks of fasting. Transcript levels of GHR1 and GHR2 were elevated by fasting in the muscle. However

Nutrition for children with cholestatic liver disease

NARCIS (Netherlands)

Los, E. Leonie; Lukovac, Sabina; Werner, Anniek; Dijkstra, Tietie; Verkade, Henkjan J.; Rings, Edmond H. H. M.; Cooke, RJ; Vandenplas, Y; Wahn, U

2007-01-01

Cholestatic liver disease (CLD) in children negatively affects nutritional status, growth and development, which all lead to an increased risk of morbidity and mortality. This is illustrated by the fact that the clinical outcome of children with CLD awaiting a liver transplantation is in part

Metabolic adaptations in models of fatty liver disease : Of mice and math

NARCIS (Netherlands)

Hijmans, Brenda

2017-01-01

The increasing incidence of overweight is accompanied by a plethora of medical symptoms together called the metabolic syndrome. Non-alcoholic fatty liver disease, characterized by persistent storage of lipids in the liver, is regarded as the hepatic component of the metabolic syndrome. An imbalance

Rearing Mozambique tilapia in tidally-changing salinities: Effects on growth and the growth hormone/insulin-like growth factor I axis.

Science.gov (United States)

Moorman, Benjamin P; Yamaguchi, Yoko; Lerner, Darren T; Grau, E Gordon; Seale, Andre P

2016-08-01

The growth hormone (GH)/insulin-like growth factor (IGF) axis plays a central role in the regulation of growth in teleosts and has been shown to be affected by acclimation salinity. This study was aimed at characterizing the effects of rearing tilapia, Oreochromis mossambicus, in a tidally-changing salinity on the GH/IGF axis and growth. Tilapia were raised in fresh water (FW), seawater (SW), or in a tidally-changing environment, in which salinity is switched between FW (TF) and SW (TS) every 6h, for 4months. Growth was measured over all time points recorded and fish reared in a tidally-changing environment grew significantly faster than other groups. The levels of circulating growth hormone (GH), insulin-like growth factor I (IGF-I), pituitary GH mRNA, gene expression of IGF-I, IGF-II, and growth hormone receptor 2 (GHR) in the muscle and liver were also determined. Plasma IGF-I was higher in FW and TS than in SW and TF tilapia. Pituitary GH mRNA was higher in TF and TS than in FW and SW tilapia. Gene expression of IGF-I in the liver and of GHR in both the muscle and liver changed between TF and TS fish. Fish growth was positively correlated with GH mRNA expression in the pituitary, and GHR mRNA expression in muscle and liver tissues. Our study indicates that rearing fish under tidally-changing salinities elicits a distinct pattern of endocrine regulation from that observed in fish reared in steady-state conditions, and may provide a new approach to increase tilapia growth rate and study the regulation of growth in euryhaline fish. Copyright © 2016 Elsevier Inc. All rights reserved.

Epidermal growth factor receptor restoration rescues the fatty liver regeneration in mice.

Science.gov (United States)

Zimmers, Teresa A; Jin, Xiaoling; Zhang, Zongxiu; Jiang, Yanlin; Koniaris, Leonidas G

2017-10-01

Hepatic steatosis is a common histological finding in obese patients. Even mild steatosis is associated with delayed hepatic regeneration and poor outcomes following liver resection or transplantation. We sought to identify and target molecular pathways that mediate this dysfunction. Lean mice and mice made obese through feeding of a high-fat, hypercaloric diet underwent 70 or 80% hepatectomy. After 70% resection, obese mice demonstrated 100% survival but experienced increased liver injury, reduced energy stores, reduced mitoses, increased necroapoptosis, and delayed recovery of liver mass. Increasing liver resection to 80% was associated with mortality of 40% in lean and 80% in obese mice ( P steatosis might promote liver regeneration and survival following hepatic resection or transplantation. Copyright © 2017 the American Physiological Society.

Distribution of intrahepatic T, NK and CD3(+)CD56(+)NKT cells alters after liver transplantation: Shift from innate to adaptive immunity?

Science.gov (United States)

Werner, Jens M; Lang, Corinna; Scherer, Marcus N; Farkas, Stefan A; Geissler, Edward K; Schlitt, Hans J; Hornung, Matthias

2011-07-01

The liver is an immunological organ containing a large number of T, NK and NKT cells, but little is known about intrahepatic immunity after LTx. Here, we investigated whether the distribution of T, NK and CD3(+)CD56(+)NKT cells is altered in transplanted livers under different circumstances. Core biopsies of transplanted livers were stained with antibodies against CD3 and CD56. Several cell populations including T (CD3(+)CD56(-)), NK (CD3(-)CD56(+)) and NKT cells (CD3(+)CD56(+)) were studied by fluorescence microscopy. Cell numbers were analyzed in relation to the time interval after LTx, immunosuppressive therapy and stage of acute graft rejection (measured with the rejection activity index: RAI) compared to tumor free liver tissue from patients after liver resection due to metastatic disease as control. Recruitment of CD3(+)CD56(+)NKT cells revealed a significant decrease during high RAI scores in comparison to low and middle RAI scores (RAI 7-9: 0.03±0.01/HPF vs. RAI 4-6: 0.1±0.005/HPF). CD3(+)CD56(+)NKT cells were also lower during immunosuppressive therapy with tacrolimus (0.03±0.01/HPF) than with cyclosporine (0.1±0.003/HPF), cyclosporine/MMF (0.1±0.003/HPF) or sirolimus (0.1±0.01/HPF) treatment. Intrahepatic T cell numbers increased significantly 50days after LTx compared to control liver tissue (4.5±0.2/HPF vs. 1.9±0.1/HPF). In contrast, NK cells (0.3±0.004/HPF) were significantly fewer in all biopsies after LTx compared to the control (0.7±0.04/HPF). These data indicate significant alterations in the hepatic recruitment of T, NK and CD3(+)CD56(+)NKT cells after LTx. The increase in T cells and the decrease in NK and CD3(+)CD56(+)NKT cells suggest a shift from innate to adaptive hepatic immunity in the liver graft. Copyright © 2011 Elsevier B.V. All rights reserved.

Synchronous resection of colorectal liver metastasis- a case report ...

African Journals Online (AJOL)

We present a case report of a young patient of. Carcinoma sigmoid colon with multiple liver metastases who was managed with synchronous resection of colorectal liver metastasis. The patient had an ulceroproliferative growth in the sigmoid colon 18 cm from the anal verge with multiple bilobar liver metastases. The CEA

Serial analysis of gene expression (SAGE) in rat liver regeneration

International Nuclear Information System (INIS)

Cimica, Velasco; Batusic, Danko; Haralanova-Ilieva, Borislava; Chen, Yonglong; Hollemann, Thomas; Pieler, Tomas; Ramadori, Giuliano

2007-01-01

We have applied serial analysis of gene expression for studying the molecular mechanism of the rat liver regeneration in the model of 70% partial hepatectomy. We generated three SAGE libraries from a normal control liver (NL library: 52,343 tags), from a sham control operated liver (Sham library: 51,028 tags), and from a regenerating liver (PH library: 53,061 tags). By SAGE bioinformatics analysis we identified 40 induced genes and 20 repressed genes during the liver regeneration. We verified temporal expression of such genes by real time PCR during the regeneration process and we characterized 13 induced genes and 3 repressed genes. We found connective tissue growth factor transcript and protein induced very early at 4 h after PH operation before hepatocytes proliferation is triggered. Our study suggests CTGF as a growth factor signaling mediator that could be involved directly in the mechanism of liver regeneration induction

Human fetal liver stromal cells that overexpress bFGF support growth and maintenance of human embryonic stem cells.

Directory of Open Access Journals (Sweden)

Jiafei Xi

Full Text Available In guiding hES cell technology toward the clinic, one key issue to be addressed is to culture and maintain hES cells much more safely and economically in large scale. In order to avoid using mouse embryonic fibroblasts (MEFs we isolated human fetal liver stromal cells (hFLSCs from 14 weeks human fetal liver as new human feeder cells. hFLSCs feeders could maintain hES cells for 15 passages (about 100 days. Basic fibroblast growth factor (bFGF is known to play an important role in promoting self-renewal of human embryonic stem (hES cells. So, we established transgenic hFLSCs that stably express bFGF by lentiviral vectors. These transgenic human feeder cells--bFGF-hFLSCs maintained the properties of H9 hES cells without supplementing with any exogenous growth factors. H9 hES cells culturing under these conditions maintained all hES cell features after prolonged culture, including the developmental potential to differentiate into representative tissues of all three embryonic germ layers, unlimited and undifferentiated proliferative ability, and maintenance of normal karyotype. Our results demonstrated that bFGF-hFLSCs feeder cells were central to establishing the signaling network among bFGF, insulin-like growth factor 2 (IGF-2, and transforming growth factor β (TGF-β, thereby providing the framework in which hES cells were instructed to self-renew or to differentiate. We also found that the conditioned medium of bFGF-hFLSCs could maintain the H9 hES cells under feeder-free conditions without supplementing with bFGF. Taken together, bFGF-hFLSCs had great potential as feeders for maintaining pluripotent hES cell lines more safely and economically.

Liver cell-targeted delivery of therapeutic molecules.

Science.gov (United States)

Kang, Jeong-Hun; Toita, Riki; Murata, Masaharu

2016-01-01

The liver is the largest internal organ in mammals and is involved in metabolism, detoxification, synthesis of proteins and lipids, secretion of cytokines and growth factors and immune/inflammatory responses. Hepatitis, alcoholic or non-alcoholic liver disease, hepatocellular carcinoma, hepatic veno-occlusive disease, and liver fibrosis and cirrhosis are the most common liver diseases. Safe and efficient delivery of therapeutic molecules (drugs, genes or proteins) into the liver is very important to increase the clinical efficacy of these molecules and to reduce their side effects in other organs. Several liver cell-targeted delivery systems have been developed and tested in vivo or ex vivo/in vitro. In this review, we discuss the literature concerning liver cell-targeted delivery systems, with a particular emphasis on the results of in vivo studies.

Adaptive growth factor delivery from a polyelectrolyte coating promotes synergistic bone tissue repair and reconstruction

Science.gov (United States)

Shah, Nisarg J.; Hyder, Md. Nasim; Quadir, Mohiuddin A.; Dorval Courchesne, Noémie-Manuelle; Seeherman, Howard J.; Nevins, Myron; Spector, Myron; Hammond, Paula T.

2014-01-01

Traumatic wounds and congenital defects that require large-scale bone tissue repair have few successful clinical therapies, particularly for craniomaxillofacial defects. Although bioactive materials have demonstrated alternative approaches to tissue repair, an optimized materials system for reproducible, safe, and targeted repair remains elusive. We hypothesized that controlled, rapid bone formation in large, critical-size defects could be induced by simultaneously delivering multiple biological growth factors to the site of the wound. Here, we report an approach for bone repair using a polyelectrolye multilayer coating carrying as little as 200 ng of bone morphogenetic protein-2 and platelet-derived growth factor-BB that were eluted over readily adapted time scales to induce rapid bone repair. Based on electrostatic interactions between the polymer multilayers and growth factors alone, we sustained mitogenic and osteogenic signals with these growth factors in an easily tunable and controlled manner to direct endogenous cell function. To prove the role of this adaptive release system, we applied the polyelectrolyte coating on a well-studied biodegradable poly(lactic-co-glycolic acid) support membrane. The released growth factors directed cellular processes to induce bone repair in a critical-size rat calvaria model. The released growth factors promoted local bone formation that bridged a critical-size defect in the calvaria as early as 2 wk after implantation. Mature, mechanically competent bone regenerated the native calvaria form. Such an approach could be clinically useful and has significant benefits as a synthetic, off-the-shelf, cell-free option for bone tissue repair and restoration. PMID:25136093

Hepatocytes polyploidization and cell cycle control in liver physiopathology.

Science.gov (United States)

Gentric, Géraldine; Desdouets, Chantal; Celton-Morizur, Séverine

2012-01-01

Most cells in mammalian tissues usually contain a diploid complement of chromosomes. However, numerous studies have demonstrated a major role of "diploid-polyploid conversion" during physiopathological processes in several tissues. In the liver parenchyma, progressive polyploidization of hepatocytes takes place during postnatal growth. Indeed, at the suckling-weaning transition, cytokinesis failure events induce the genesis of binucleated tetraploid liver cells. Insulin signalling, through regulation of the PI3K/Akt signalling pathway, is essential in the establishment of liver tetraploidization by controlling cytoskeletal organisation and consequently mitosis progression. Liver cell polyploidy is generally considered to indicate terminal differentiation and senescence, and both lead to a progressive loss of cell pluripotency associated to a markedly decreased replication capacity. Although adult liver is a quiescent organ, it retains a capacity to proliferate and to modulate its ploidy in response to various stimuli or aggression (partial hepatectomy, metabolic overload (i.e., high copper and iron hepatic levels), oxidative stress, toxic insult, and chronic hepatitis etc.). Here we review the mechanisms and functional consequences of hepatocytes polyploidization during normal and pathological liver growth.

Hepatocytes Polyploidization and Cell Cycle Control in Liver Physiopathology

Directory of Open Access Journals (Sweden)

Géraldine Gentric

2012-01-01

Full Text Available Most cells in mammalian tissues usually contain a diploid complement of chromosomes. However, numerous studies have demonstrated a major role of “diploid-polyploid conversion” during physiopathological processes in several tissues. In the liver parenchyma, progressive polyploidization of hepatocytes takes place during postnatal growth. Indeed, at the suckling-weaning transition, cytokinesis failure events induce the genesis of binucleated tetraploid liver cells. Insulin signalling, through regulation of the PI3K/Akt signalling pathway, is essential in the establishment of liver tetraploidization by controlling cytoskeletal organisation and consequently mitosis progression. Liver cell polyploidy is generally considered to indicate terminal differentiation and senescence, and both lead to a progressive loss of cell pluripotency associated to a markedly decreased replication capacity. Although adult liver is a quiescent organ, it retains a capacity to proliferate and to modulate its ploidy in response to various stimuli or aggression (partial hepatectomy, metabolic overload (i.e., high copper and iron hepatic levels, oxidative stress, toxic insult, and chronic hepatitis etc.. Here we review the mechanisms and functional consequences of hepatocytes polyploidization during normal and pathological liver growth.

Imaged-guided liver stereotactic body radiotherapy using VMAT and real-time adaptive tumor gating. Concerns about technique and preliminary clinical results.

Science.gov (United States)

Llacer-Moscardo, Carmen; Riou, Olivier; Azria, David; Bedos, Ludovic; Ailleres, Norbert; Quenet, Francois; Rouanet, Philippe; Ychou, Marc; Fenoglietto, Pascal

2017-01-01

Motion management is a major challenge in abdominal SBRT. We present our study of SBRT for liver tumors using intrafraction motion review (IMR) allowing simultaneous KV information and MV delivery to synchronize the beam during gated RapidArc treatment. Between May 2012 and March 2015, 41 patients were treated by liver SBRT using gated RapidArc technique in a Varian Novalis Truebeam STx linear accelerator. PTV was created by expanding 5 mm from the ITV. Dose prescription ranged from 40 to 50 Gy in 5-10 fractions. The prescribed dose and fractionation were chosen depending on hepatic function and dosimetric results. Thirty-four patients with a minimal follow-up of six months were analyzed for local control and toxicity. Accuracy for tumor repositioning was evaluated for the first ten patients. With a median follow-up of 13 months, the treatment was well tolerated and no patient presented RILD, perforation or gastrointestinal bleeding. Acute toxicity was found in 3 patients with G1 abdominal pain, 2 with G1 nausea, 10 with G1 asthenia and 1 with G2 asthenia. 6 patients presented asymptomatic transitory perturbation of liver enzymes. In-field local control was 90.3% with 7 complete responses, 14 partial responses and 7 stabilisations. 3 patients evolved "in field". 12 patients had an intrahepatic progression "out of field". Mean intrafraction deviation of fiducials in the craneo-caudal direction was 0.91 mm (0-6 mm). The clinical tolerance and oncological outcomes were favorable when using image-guided liver SBRT with real-time adaptive tumor gating.

The c-Met Inhibitor MSC2156119J Effectively Inhibits Tumor Growth in Liver Cancer Models

Energy Technology Data Exchange (ETDEWEB)

Bladt, Friedhelm, E-mail: Friedhelm.Bladt@merckgroup.com; Friese-Hamim, Manja; Ihling, Christian; Wilm, Claudia; Blaukat, Andree [EMD Serono, and Merck Serono Research and Development, Merck KGaA, Darmstadt 64293 (Germany)

2014-08-19

The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase with hepatocyte growth factor (HGF) as its only high-affinity ligand. Aberrant activation of c-Met is associated with many human malignancies, including hepatocellular carcinoma (HCC). We investigated the in vivo antitumor and antimetastatic efficacy of the c-Met inhibitor MSC2156119J (EMD 1214063) in patient-derived tumor explants. BALB/c nude mice were inoculated with MHCC97H cells or with tumor fragments of 10 patient-derived primary liver cancer explants selected according to c-Met/HGF expression levels. MSC2156119J (10, 30, and 100 mg/kg) and sorafenib (50 mg/kg) were administered orally as single-agent treatment or in combination, with vehicle as control. Tumor response, metastases formation, and alpha fetoprotein (AFP) levels were measured. MSC2156119J inhibited tumor growth and induced complete regression in mice bearing subcutaneous and orthotopic MHCC97H tumors. AFP levels were undetectable after 5 weeks of MSC2156119J treatment, and the number of metastatic lung foci was reduced. Primary liver explant models with strong c-Met/HGF activation showed increased responsiveness to MSC2156119J, with MSC2156119J showing similar or superior activity to sorafenib. Tumors characterized by low c-Met expression were less sensitive to MSC2156119J. MSC2156119J was better tolerated than sorafenib, and combination therapy did not improve efficacy. These findings indicate that selective c-Met/HGF inhibition with MSC2156119J is associated with marked regression of c-Met high-expressing tumors, supporting its clinical development as an antitumor treatment for HCC patients with active c-Met signaling.

Two insulin-like growth factor I messenger RNAs are expressed in human liver

International Nuclear Information System (INIS)

Rotwein, P.

1986-01-01

Through use of a synthetic radiolabelled oligonucleotide probe, human insulin-like growth factor I (IGF-I) cDNA clones were isolated from a liver library. Two types of cDNAs were defined by restriction enzyme analysis and DNA sequencing. Both encode IGF-I precursors of either 195 or 153 amino acids. The two predicted protein precursors are identical from their amino terminus to a lysine residue 16 codons beyond the IGF-I sequence, and then they diverge. Both cDNAs predict additional unique carboxyl-terminal extension peptides. Since there is only one IGF-I gene in the human genome, the finding of two different cDNAs suggests that alternative RNA processing plays a role in IGF-I gene expression. The functions of the different extension peptides remain to be elucidates

gamma-Glutamyl transpeptidase overexpression increases metastatic growth of B16 melanoma cells in the mouse liver.

Science.gov (United States)

Obrador, Elena; Carretero, Julian; Ortega, Angel; Medina, Ignacio; Rodilla, Vicente; Pellicer, José A; Estrela, José M

2002-01-01

B16 melanoma (B16M) cells with high glutathione (GSH) content show rapid proliferation in vitro and high metastatic activity in the liver in vivo. gamma-Glutamyl transpeptidase (GGT)-mediated extracellular GSH cleavage and intracellular GSH synthesis were studied in vitro in B16M cells with high (F10) and low (F1) metastatic potential. GGT activity was modified by transfection with the human GGT gene (B16MF1/Tet-GGT cells) or by acivicin-induced inhibition. B16MF1/Tet-GGT and B16MF10 cells exhibited higher GSH content (35 +/- 6 and 40 +/- 5 nmol/10(6) cells, respectively) and GGT activity (89 +/- 9 and 37 +/- 7 mU/10(6) cells, respectively) as compared (P <.05) with B16MF1 cells (10 +/- 3 nmol GSH and 4 mU GGT/10(6) cells). Metastasis (number of foci/100 mm(3) of liver) increased in B16MF1 cells pretreated with GSH ester ( approximately 3-fold, P <.01), and decreased in B16MF1/Tet-GGT and B16MF10 cells pretreated with the GSH synthesis inhibitor L-buthionine (S,R)-sulphoximine ( approximately 5-fold and 2-fold, respectively, P <.01). Liver, kidney, brain, lung, and erythrocyte GSH content in B16MF1/Tet-GGT- or B16MF10-bearing mice decreased as compared with B16MF1- and non-tumor-bearing mice. Organic anion transporting polypeptide 1-independent sinusoidal GSH efflux from hepatocytes increased in B16MF1/Tet-GGT- or B16MF10-bearing mice ( approximately 2-fold, P <.01) as compared with non-tumor-bearing mice. Our results indicate that tumor GGT activity and an intertissue flow of GSH can regulate GSH content of melanoma cells and their metastatic growth in the liver.

Effect of modeled microgravity on radiation-induced adaptive response of root growth in Arabidopsis thaliana

International Nuclear Information System (INIS)

Deng, Chenguang; Wang, Ting; Wu, Jingjing; Xu, Wei; Li, Huasheng; Liu, Min

2017-01-01

Highlights: • The radio-adaptive response (RAR) of A. thaliana root growth is modulated in microgravity. • The DNA damage repairs in RAR are regulated by microgravity. • The phytohormone auxin plays a regulatory role in the modulation of microgravity on RAR of root growth. - Abstract: Space particles have an inevitable impact on organisms during space missions; radio-adaptive response (RAR) is a critical radiation effect due to both low-dose background and sudden high-dose radiation exposure during solar storms. Although it is relevant to consider RAR within the context of microgravity, another major space environmental factor, there is no existing evidence as to its effects on RAR. In the present study, we established an experimental method for detecting the effects of gamma-irradiation on the primary root growth of Arabidopsis thaliana, in which RAR of root growth was significantly induced by several dose combinations. Microgravity was simulated using a two-dimensional rotation clinostat. It was shown that RAR of root growth was significantly inhibited under the modeled microgravity condition, and was absent in pgm-1 plants that had impaired gravity sensing in root tips. These results suggest that RAR could be modulated in microgravity. Time course analysis showed that microgravity affected either the development of radio-resistance induced by priming irradiation, or the responses of plants to challenging irradiation. After treatment with the modeled microgravity, attenuation in priming irradiation-induced expressions of DNA repair genes (AtKu70 and AtRAD54), and reduced DNA repair efficiency in response to challenging irradiation were observed. In plant roots, the polar transportation of the phytohormone auxin is regulated by gravity, and treatment with an exogenous auxin (indole-3-acetic acid) prevented the induction of RAR of root growth, suggesting that auxin might play a regulatory role in the interaction between microgravity and RAR of root growth.

Effect of modeled microgravity on radiation-induced adaptive response of root growth in Arabidopsis thaliana

Energy Technology Data Exchange (ETDEWEB)

Deng, Chenguang [Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences (China); Key Laboratory of Environmental Toxicology and Pollution Control Technology of Anhui Province (China); Institute of Technical Biology and Agriculture Engineering, Chinese Academy of Sciences, 350 Shushanhu Road, Hefei 230031 (China); University of Science and Technology of China, Hefei 230026 (China); Wang, Ting [Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences (China); Key Laboratory of Environmental Toxicology and Pollution Control Technology of Anhui Province (China); Institute of Technical Biology and Agriculture Engineering, Chinese Academy of Sciences, 350 Shushanhu Road, Hefei 230031 (China); Wu, Jingjing [Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences (China); Key Laboratory of Environmental Toxicology and Pollution Control Technology of Anhui Province (China); Institute of Technical Biology and Agriculture Engineering, Chinese Academy of Sciences, 350 Shushanhu Road, Hefei 230031 (China); University of Science and Technology of China, Hefei 230026 (China); Xu, Wei [Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences (China); Key Laboratory of Environmental Toxicology and Pollution Control Technology of Anhui Province (China); Institute of Technical Biology and Agriculture Engineering, Chinese Academy of Sciences, 350 Shushanhu Road, Hefei 230031 (China); Li, Huasheng; Liu, Min [China Space Molecular Biological Lab, China Academy of Space Technology, Beijing 100086 (China); and others

2017-02-15

Highlights: • The radio-adaptive response (RAR) of A. thaliana root growth is modulated in microgravity. • The DNA damage repairs in RAR are regulated by microgravity. • The phytohormone auxin plays a regulatory role in the modulation of microgravity on RAR of root growth. - Abstract: Space particles have an inevitable impact on organisms during space missions; radio-adaptive response (RAR) is a critical radiation effect due to both low-dose background and sudden high-dose radiation exposure during solar storms. Although it is relevant to consider RAR within the context of microgravity, another major space environmental factor, there is no existing evidence as to its effects on RAR. In the present study, we established an experimental method for detecting the effects of gamma-irradiation on the primary root growth of Arabidopsis thaliana, in which RAR of root growth was significantly induced by several dose combinations. Microgravity was simulated using a two-dimensional rotation clinostat. It was shown that RAR of root growth was significantly inhibited under the modeled microgravity condition, and was absent in pgm-1 plants that had impaired gravity sensing in root tips. These results suggest that RAR could be modulated in microgravity. Time course analysis showed that microgravity affected either the development of radio-resistance induced by priming irradiation, or the responses of plants to challenging irradiation. After treatment with the modeled microgravity, attenuation in priming irradiation-induced expressions of DNA repair genes (AtKu70 and AtRAD54), and reduced DNA repair efficiency in response to challenging irradiation were observed. In plant roots, the polar transportation of the phytohormone auxin is regulated by gravity, and treatment with an exogenous auxin (indole-3-acetic acid) prevented the induction of RAR of root growth, suggesting that auxin might play a regulatory role in the interaction between microgravity and RAR of root growth.

Different transcriptional responses from slow and fast growth rate strains of Listeria monocytogenes adapted to low temperature

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Ninoska eCordero

2016-03-01

Full Text Available Listeria monocytogenes has become one of the principal foodborne pathogens worldwide. The capacity of this bacterium to grow at low temperatures has opened an interesting field of study in terms of the identification and classification of new strains of L. monocytogenes with different growth capacities at low temperatures. We determined the growth rate at 8 ºC of 110 strains of L. monocytogenes isolated from different food matrices. We identified a group of slow and fast strains according to their growth rate at 8 °C and performed a global transcriptomic assay in strains previously adapted to low temperature. We then identified shared and specific transcriptional mechanisms, metabolic and cellular processes of both groups; bacterial motility was the principal process capable of differentiating the adaptation capacity of L. monocytogenes strains with different ranges of tolerance to low temperatures. Strains belonging to the fast group were less motile, which may allow these strains to achieve a greater rate of proliferation at low temperature.

Molecular Characterization and Expression Analysis of Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-1 Genes in Qinghai-Tibet Plateau and Lowland

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Ya-bing Chen

2015-01-01

Full Text Available Insulin-like growth factor-1 (IGF-1 and insulin-like growth factor binding protein-1 (IGFBP-1 play a pivotal role in regulating cellular hypoxic response. In this study, we cloned and characterized the genes encoding IGF-1 and IGFBP-1 to improve the current knowledge on their roles in highland Bos grunniens (Yak. We also compared their expression levels in the liver and kidney tissues between yaks and lowland cattle. We obtained full-length 465 bp IGF-1 and 792 bp IGFBP-1, encoding 154 amino acids (AA IGF-1, and 263 AA IGFBP-1 protein, respectively using reverse transcriptase-polyerase chain reaction (RT-PCR technology. Analysis of their corresponding amino acid sequences showed a high identity between B. grunniens and lowland mammals. Moreover, the two genes were proved to be widely distributed in the examined tissues through expression pattern analysis. Real-time PCR results revealed that IGF-1 expression was higher in the liver and kidney tissues in B. grunniens than in Bos taurus (p<0.05. The IGFBP-1 gene was expressed at a higher level in the liver (p<0.05 of B. taurus than B. grunniens, but it has a similar expression level in the kidneys of the two species. These results indicated that upregulated IGF-1 and downregulated IGFBP-1 are associated with hypoxia adaptive response in B. grunniens.

Postoperative Insulin-Like Growth Factor 1 Levels Reflect the Graft's Function and Predict Survival after Liver Transplantation.

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Daniele Nicolini

Full Text Available The reduction of insulin-like growth factor 1 (IGF-1 plasma levels is associated with the degree of liver dysfunction and mortality in cirrhotic patients. However, little research is available on the recovery of the IGF-1 level and its prognostic role after liver transplantation (LT.From April 2010 to May 2011, 31 patients were prospectively enrolled (25/6 M/F; mean age±SEM: 55.2±1.4 years, and IGF-1 serum levels were assessed preoperatively and at 15, 30, 90, 180 and 365 days after transplantation. The influence of the donor and recipient characteristics (age, use of extended criteria donor grafts, D-MELD and incidence of early allograft dysfunction on hormonal concentration was analyzed. The prognostic role of IGF-1 level on patient survival and its correlation with routine liver function tests were also investigated.All patients showed low preoperative IGF-1 levels (mean±SEM: 29.5±2.1, and on postoperative day 15, a significant increase in the IGF-1 plasma level was observed (102.7±11.7 ng/ml; p65 years or extended criteria donor grafts. An inverse correlation between IGF-1 and bilirubin serum levels at day 15 (r = -0.3924, p = 0.0320 and 30 (r = -0.3894, p = 0.0368 was found. After multivariate analysis, early (within 15 days IGF-1 normalization [Exp(b = 3.913; p = 0.0484] was the only prognostic factor associated with an increased 3-year survival rate.IGF-1 postoperative levels are correlated with the graft's quality and reflect liver function. Early IGF-1 recovery is associated with a higher 3-year survival rate after LT.

Fibroblast growth factor receptor 4 polymorphism is associated with liver cirrhosis in hepatocarcinoma.

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Ming-Jen Sheu

Full Text Available Fibroblast growth factor receptor 4 (FGFR4 polymorphisms are positively correlated with tumor progression in numerous malignant tumors. However, the association between FGFR4 genetic variants and the risk of hepatocellular carcinoma (HCC has not yet been determined. In this study, we investigated the potential associations of FGFR4 single nucleotide polymorphisms (SNPs with HCC susceptibility and its clinicopathological characteristics.Four SNPs in FGFR4 (rs1966265, rs351855, rs2011077, and rs7708357 were analyzed among 884 participants, including 595 controls and 289 patients with HCC. The samples were further analyzed to clarify the associations between these gene polymorphisms and the risk of HCC, and the impact of these SNPs on the susceptibility and clinicopathological characteristics of HCC. After adjusting for other covariants, HCC patients who carrying at least one A genotype (GA and AA at rs351855 were observed to have a higher risk of liver cirrhosis compared with those carrying the wild-type genotype (GG (OR: 2.113, 95% CI: 1.188-3.831. Moreover, the patients with at least one A genotype were particularly showed a high level of alpha-fetoprotein (AFP.Our findings suggest that genetic polymorphism in FGFR4 rs351855 may be associated with the risk of HCC coupled with liver cirrhosis and may markedly increase the AFP level in Taiwanese patients with HCC. In addition, this is the first study that evaluated the risk factors associated with FGFR4 polymorphism variants in Taiwanese patients with HCC.

Plasticity in reproduction and growth among 52 range-wide populations of a Mediterranean conifer: adaptive responses to environmental stress.

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Santos-Del-Blanco, L; Bonser, S P; Valladares, F; Chambel, M R; Climent, J

2013-09-01

A plastic response towards enhanced reproduction is expected in stressful environments, but it is assumed to trade off against vegetative growth and efficiency in the use of available resources deployed in reproduction [reproductive efficiency (RE)]. Evidence supporting this expectation is scarce for plants, particularly for long-lived species. Forest trees such as Mediterranean pines provide ideal models to study the adaptive value of allocation to reproduction vs. vegetative growth given their among-population differentiation for adaptive traits and their remarkable capacity to cope with dry and low-fertility environments. We studied 52 range-wide Pinus halepensis populations planted into two environmentally contrasting sites during their initial reproductive stage. We investigated the effect of site, population and their interaction on vegetative growth, threshold size for female reproduction, reproductive-vegetative size relationships and RE. We quantified correlations among traits and environmental variables to identify allocation trade-offs and ecotypic trends. Genetic variation for plasticity was high for vegetative growth, whereas it was nonsignificant for reproduction. Size-corrected reproduction was enhanced in the more stressful site supporting the expectation for adverse conditions to elicit plastic responses in reproductive allometry. However, RE was unrelated with early reproductive investment. Our results followed theoretical predictions and support that phenotypic plasticity for reproduction is adaptive under stressful environments. Considering expectations of increased drought in the Mediterranean, we hypothesize that phenotypic plasticity together with natural selection on reproductive traits will play a relevant role in the future adaptation of forest tree species. © 2013 The Authors. Journal of Evolutionary Biology © 2013 European Society For Evolutionary Biology.

Exploring the molecular mechanisms underlying the potentiation of exogenous growth hormone on alcohol-induced fatty liver diseases in mice

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Tian Ya-ping

2010-11-01

Full Text Available Abstract Background Growth hormone (GH is an essential regulator of intrahepatic lipid metabolism by activating multiple complex hepatic signaling cascades. Here, we examined whether chronic exogenous GH administration (via gene therapy could ameliorate liver steatosis in animal models of alcoholic fatty liver disease (AFLD and explored the underlying molecular mechanisms. Methods Male C57BL/6J mice were fed either an alcohol or a control liquid diet with or without GH therapy for 6 weeks. Biochemical parameters, liver histology, oxidative stress markers, and serum high molecular weight (HMW adiponectin were measured. Quantitative real-time PCR and western blotting were also conducted to determine the underlying molecular mechanism. Results Serum HMW adiponectin levels were significantly higher in the GH1-treated control group than in the control group (3.98 ± 0.71 μg/mL vs. 3.07 ± 0.55 μg/mL; P P P P P Conclusions GH therapy had positive effects on AFLD and may offer a promising approach to prevent or treat AFLD. These beneficial effects of GH on AFLD were achieved through the activation of the hepatic adiponectin-SIRT1-AMPK and PPARα-AMPK signaling systems.

Memory NK cells: why do they reside in the liver?

OpenAIRE

Jiang, Xiaojun; Chen, Yonglin; Peng, Hui; Tian, Zhigang

2013-01-01

Immune memory is the hallmark of adaptive immunity. However, recent studies have shown that natural killer (NK) cells, key components of the innate immune system, also mediate memory responses in mice and humans. Strikingly, memory NK cells were liver-resident in some models, raising the question as to whether the liver is a special organ for the acquisition of NK cell memory. Here, we review the characteristics of NK cell memory by summarizing recent progress and discuss how the liver may ge...

Redox state, reactive oxygen species and adaptive growth in colonial hydroids.

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Blackstone, N W

2001-06-01

Colonial metazoans often encrust surfaces over which the food supply varies in time or space. In such an environment, adaptive colony development entails adjusting the timing and spacing of feeding structures and gastrovascular connections to correspond to this variable food supply. To investigate the possibility of such adaptive growth, within-colony differential feeding experiments were carried out using the hydroid Podocoryna carnea. Indeed, such colonies strongly exhibited adaptive growth, developing dense arrays of polyps (feeding structures) and gastrovascular connections in areas that were fed relative to areas that were starved, and this effect became more consistent over time. To investigate mechanisms of signaling between the food supply and colony development, measurements were taken of metabolic parameters that have been implicated in signal transduction in other systems, particularly redox state and levels of reactive oxygen species. Utilizing fluorescence microscopy of P. carnea cells in vivo, simultaneous measurements of redox state [using NAD(P)H] and hydrogen peroxide (using 2',7'-dichlorofluorescin diacetate) were taken. Both measures focused on polyp epitheliomuscular cells, since these exhibit the greatest metabolic activity. Colonies 3-5h after feeding were relatively oxidized, with low levels of peroxide, while colonies 24h after feeding were relatively reduced, with high levels of peroxide. The functional role of polyps in feeding and generating gastrovascular flow probably produced this dichotomy. Polyps 3-5h after feeding contract maximally, and this metabolic demand probably shifts the redox state in the direction of oxidation and diminishes levels of reactive oxygen species. In contrast, 24h after feeding, polyps are quiescent, and this lack of metabolic demand probably shifts the redox state in the direction of reduction and increases levels of reactive oxygen species. Within-colony differential feeding experiments were carried out on

Characterization of the growth and degradation of glycogen in the liver

International Nuclear Information System (INIS)

Youn, J.; Bergman, R.

1986-01-01

The patterns of the growth and degradation of hepatic glycogen were studied using a computer model. The database was that of Devos and Hers on the distribution of label in glycogen from [1- 14 C] galactose injected at different times after the start of refeeding 40 h fasted mice. The data was simulated to examine the following hypotheses (H): Glycogen Synthesis H.S1: all glycogen molecules grow simultaneously. H.S2: at each moment of synthesis only a fixed number of molecules grow. H.S3: the number of growing molecules increases linearly with respect to time. H.S4: increase in the number of growing molecules is accelerated as glycogen is synthesized. Glycogen Degradation H.D1: glycogen molecules to be attacked by degrading enzymes are randomly chosen. H.D2: glycogen molecules are degraded sequentially in the reverse order of synthesis. H.D3: glycogen molecules have different probabilities of degradation depending upon the time of synthesis. The growth and degradation according to hypotheses S4 and D3, respectively, could best account for the data. The modelling study predicts that, at the beginning of refeeding, only a small number of molecules grow. But, as glycogen is synthesized, the rate of seeding of new glycogen molecules increases with time, causing a nonlinear proliferation of the number of growing molecules. During degradation glycogen molecules synthesized later have a greater chance to be degraded first, a characteristic which may be explained by the rosette structure of liver glycogen

Preoperative Right Portal Vein Embolization in Patients with metastatic liver disease. Metastatic liver volumes after RPVE

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Barbaro, B.; Stasi, C.D.I.; Marano, P.; Nuzzo, G.; Vellone, M.; Giuliante, F.

2003-01-01

Purpose:To quantify liver metastases and future remnant liver (FRL) volumes in patients who underwent right portal vein embolization (RPVE) and to evaluate the effects of this procedure on metastase growth. Material and Methods:Nine patients with liver metastases from primary colon (n = 5), rectal lesions (n = 1) and carcinoid tumors (n = 3) underwent spiral CT to evaluate the ratio of the non-tumorous parenchymal volume of the resected liver to that of the whole liver volume (R2). Hand tracing was used to isolate the entire liver, the resected liver and metastase volumes. All patients with R2 > 60% underwent RPVE. Results:FRL exhibited a 101-336 cm3 (average 241 cm3) increase in volume 1 month after RPVE. One patient refused surgery for 2 months and before surgery the increase in volume of the FRL was similar to that of other patients (180.64 cm3). Percent metastases volume from colorectal carcinoma in embolized liver parenchyma increased from 62.4% to 138.4% at 1 month and to 562% at 2 months after RPVE. Metastase volume from carcinoid tumors was unchanged. Conclusion:One month after RPVE, hypertrophy of the FRL is evident. In the embolized liver, there was a progressive increase in metastase volume from colorectal carcinoma while metastase volume from carcinoid tumor was unchanged in embolized and non-embolized liver

Idiosyncratic Drug-Induced Liver Injury: Is Drug-Cytokine Interaction the Linchpin?

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Roth, Robert A; Maiuri, Ashley R; Ganey, Patricia E

2017-02-01

Idiosyncratic drug-induced liver injury continues to be a human health problem in part because drugs that cause these reactions are not identified in current preclinical testing and because progress in prevention is hampered by incomplete knowledge of mechanisms that underlie these adverse responses. Several hypotheses involving adaptive immune responses, inflammatory stress, inability to adapt to stress, and multiple, concurrent factors have been proposed. Yet much remains unknown about how drugs interact with the liver to effect death of hepatocytes. Evidence supporting hypotheses implicating adaptive or innate immune responses in afflicted patients has begun to emerge and is bolstered by results obtained in experimental animal models and in vitro systems. A commonality in adaptive and innate immunity is the production of cytokines, including interferon-γ (IFNγ). IFNγ initiates cell signaling pathways that culminate in cell death or inhibition of proliferative repair. Tumor necrosis factor-α, another cytokine prominent in immune responses, can also promote cell death. Furthermore, tumor necrosis factor-α interacts with IFNγ, leading to enhanced cellular responses to each cytokine. In this short review, we propose that the interaction of drugs with these cytokines contributes to idiosyncratic drug-induced liver injury, and mechanisms by which this could occur are discussed. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Normal liver tissue sparing by intensity-modulated proton stereotactic body radiotherapy for solitary liver tumours

International Nuclear Information System (INIS)

Petersen, Joergen B. B.; Hansen, Anders T.; Lassen, Yasmin; Grau, Cai; Hoeyer, Morten; Muren, Ludvig P.

2011-01-01

Background. Stereotactic body radiotherapy (SBRT) is often the preferred treatment for the advanced liver tumours which owing to tumour distribution, size and multi-focality are out of range of surgical resection or radiofrequency ablation. However, only a minority of patients with liver tumours may be candidates for conventional SBRT because of the limited radiation tolerance of normal liver, intestine and other normal tissues. Due to the favourable depth-dose characteristics of protons, intensity-modulated proton therapy (IMPT) may be a superior alternative to photon-based SBRT. The purpose of this treatment planning study was therefore to investigate the potential sparing of normal liver by IMPT compared to photon-based intensity-modulated radiotherapy (IMRT) for solitary liver tumours. Material and methods. Ten patients with solitary liver metastasis treated at our institution with multi-field SBRT were retrospectively re-planned with IMRT and proton pencil beam scanning techniques. For the proton plans, two to three coplanar fields were used in contrast to five to six coplanar and non-coplanar photon fields. The same planning objectives were used for both techniques. A risk adapted dose prescription to the PTV surface of 12.5-16.75 Gy x 3 was used. Results. The spared liver volume for IMPT was higher compared to IMRT in all 10 patients. At the highest prescription dose level, the median liver volume receiving less than 15 Gy was 1411 cm 3 for IMPT and 955 cm 3 for IMRT (p D 15 Gy > 700 cm 3 constraint. For the D mean = 15 Gy constraint, nine of 10 cases could be treated at the highest dose level using IMPT whereas with IMRT, only two cases met this constraint at the highest dose level and six at the lowest dose level. Conclusion. A considerable sparing of normal liver tissue can be obtained using proton-based SBRT for solitary liver tumours

Adaptation, growth and survival of tilapia (Oreochromis niloticus) in Bafgh brackish water

OpenAIRE

Sarsangi, A.H.; Mohammadi, M.; Mashaii, N.; Rajabipou, F.; Bitaraf, A.; Askari, H.M.; Moazedi, J.; Nezamabadi, H.; Hosseinzadeh Sahafi, H.

2012-01-01

An experiment was conducted to evaluate the possibility of adaptation, growth and survival of Nile tilapia (Oreochromis niloticus) with 0.3g initial weight and red tilapia (Oreochromis sp.) with 0.7g initial weight in underground brackish water. Fry of Nile tilapia and red tilapia imported from Indonesia and after passing larviculture (25g) were examined separately in fiber glass tank by two replicate. Fish were fed at a restricted feeding program according to standard table during the light ...

Combined Stimulation with the Tumor Necrosis Factor α and the Epidermal Growth Factor Promotes the Proliferation of Hepatocytes in Rat Liver Cultured Slices

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Francis Finot

2012-01-01

Full Text Available The culture liver slices are mainly used to investigate drug metabolism and xenobiotic-mediated liver injuries while apoptosis and proliferation remain unexplored in this culture model. Here, we show a transient increase in LDH release and caspase activities indicating an ischemic injury during the slicing procedure. Then, caspase activities decrease and remain low in cultured slices demonstrating a low level of apoptosis. The slicing procedure is also associated with the G0/G1 transition of hepatocytes demonstrated by the activation of stress and proliferation signalling pathways including the ERK1/2 and JNK1/2/3 MAPKinases and the transient upregulation of c-fos. The cells further progress up to mid-G1 phase as indicated by the sequential induction of c-myc and p53 mRNA levels after the slicing procedure and at 24 h of culture, respectively. The stimulation by epidermal growth factor induces the ERK1/2 phosphorylation but fails to activate expression of late G1 and S phase markers such as cyclin D1 and Cdk1 indicating that hepatocytes are arrested in mid-G1 phase of the cell cycle. However, we found that combined stimulation by the proinflammatory cytokine tumor necrosis factor α and the epidermal growth factor promotes the commitment to DNA replication as observed in vivo during the liver regeneration.

Placental Adaptations in Growth Restriction

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Zhang, Song; Regnault, Timothy R.H.; Barker, Paige L.; Botting, Kimberley J.; McMillen, Isabella C.; McMillan, Christine M.; Roberts, Claire T.; Morrison, Janna L.

2015-01-01

The placenta is the primary interface between the fetus and mother and plays an important role in maintaining fetal development and growth by facilitating the transfer of substrates and participating in modulating the maternal immune response to prevent immunological rejection of the conceptus. The major substrates required for fetal growth include oxygen, glucose, amino acids and fatty acids, and their transport processes depend on morphological characteristics of the placenta, such as placental size, morphology, blood flow and vascularity. Other factors including insulin-like growth factors, apoptosis, autophagy and glucocorticoid exposure also affect placental growth and substrate transport capacity. Intrauterine growth restriction (IUGR) is often a consequence of insufficiency, and is associated with a high incidence of perinatal morbidity and mortality, as well as increased risk of cardiovascular and metabolic diseases in later life. Several different experimental methods have been used to induce placental insufficiency and IUGR in animal models and a range of factors that regulate placental growth and substrate transport capacity have been demonstrated. While no model system completely recapitulates human IUGR, these animal models allow us to carefully dissect cellular and molecular mechanisms to improve our understanding and facilitate development of therapeutic interventions. PMID:25580812

Role of the peroxisome proliferator-activated receptor α (PPARα) in responses to trichloroethylene and metabolites, trichloroacetate and dichloroacetate in mouse liver

International Nuclear Information System (INIS)

Laughter, Ashley R.; Dunn, Corrie S.; Swanson, Cynthia L.; Howroyd, Paul; Cattley, Russell C.; Christopher Corton, J.

2004-01-01

Trichloroethylene (TCE) is an industrial solvent and a widespread environmental contaminant. Induction of liver cancer in mice by TCE is thought to be mediated by two carcinogenic metabolites, dichloroacetate (DCA) and trichloroacetate (TCA). TCE is considered to be a relatively weak peroxisome proliferator (PP), a group of rodent hepatocarcinogens that cause adaptive responses in liver through the PP-activated receptor alpha (PPARα). The objectives of this study were to determine whether effects of TCE, TCA and DCA in the liver associated with carcinogenesis are mediated by PPARα. Male wild-type and PPARα-null mice were given TCE by gavage for 3 days or 3 weeks; TCA or DCA were given in the drinking water for 1 week. Increases in relative liver and kidney weights by TCE were dependent on PPARα whereas liver weight increases by DCA were PPARα-independent. Dose-dependent increases in hepatocyte proliferation observed in wild-type mice after TCE exposure as determined by BrdU-labeling of hepatocytes were PPARα-dependent. Transcript profiling using macroarrays containing ∼1200 genes showed that 93% (40 out of 43) of all expression changes observed in wild-type mice upon TCE exposure were dependent on PPARα and included known targets of PP (Cyp4a12, epidermal growth factor receptor) and additional genes involved in cell growth. Increases in enzymes that catalyze β- and ω-oxidation of fatty acids were dependent on PPARα after exposure to TCE, TCA or DCA. TCE altered a unique set of genes in the livers of PPARα-null mice compared to wild-type mice including those that respond to different forms of stress. These data support the hypothesis that PPARα plays a dominant role in mediating the effects associated with hepatocarcinogenesis upon TCE exposure

Constraints and trade-offs in climate-dependent adaptation: energy budgets and growth in a latitudinal cline

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Hans O. Pörtner

2005-12-01

Full Text Available Characteristics of temperature-dependent metabolic adaptation as well as their implications for associated changes in energy budgets are analysed based on comparisons of fish and invertebrates from various latitudinal clines in northern and southern hemispheres and on integrated ecological and physiological approaches. To identify putative “bottlenecks” of adaptation and for a general cause and effect understanding, the temperature sensitivity of growth as a key energy budget component is investigated, considering underlying processes at population, whole animal and cellular levels. Available data support the hypothesis that natural selection favours individuals for energy efficiency and maximised growth, but is subject to constraints of limited energy availability and temperature. According to emerging relationships between energy turnover, temperature variability and thermal tolerance, the notion that selection should favour a certain metabolic rate according to mean temperature is too simplistic. Within the energy budget, savings in maintenance costs set free energy for growth, visible as growth increments at a low standard metabolic rate. Such energy savings are maximised at the permanently low temperature of the Antarctic. However, some variability persists as pelagic lifestyles in the Antarctic are fuelled by higher metabolic rates at the expense of reduced growth. Temperature variability in the cold, as in the Subarctic, causes a rise in maintenance costs at the expense of growth, but in favour of exercise and thus foraging capacity. Such transitions in energy cost between sub-polar and polar areas are not visible in the southern hemisphere, where there is less temperature variability. However, these patterns—as well as many of the underlying mechanisms—still remain incompletely investigated, especially with respect to the suggested hierarchy in energy allocation to energy budget components.

Transient mTOR inhibition facilitates continuous growth of liver tumors by modulating the maintenance of CD133+ cell populations.

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Zhaojuan Yang

Full Text Available The mammalian target of the rapamycin (mTOR pathway, which drives cell proliferation, is frequently hyperactivated in a variety of malignancies. Therefore, the inhibition of the mTOR pathway has been considered as an appropriate approach for cancer therapy. In this study, we examined the roles of mTOR in the maintenance and differentiation of cancer stem-like cells (CSCs, the conversion of conventional cancer cells to CSCs and continuous tumor growth in vivo. In H-Ras-transformed mouse liver tumor cells, we found that pharmacological inhibition of mTOR with rapamycin greatly increased not only the CD133+ populations both in vitro and in vivo but also the expression of stem cell-like genes. Enhancing mTOR activity by over-expressing Rheb significantly decreased CD133 expression, whereas knockdown of the mTOR yielded an opposite effect. In addition, mTOR inhibition severely blocked the differentiation of CD133+ to CD133- liver tumor cells. Strikingly, single-cell culture experiments revealed that CD133- liver tumor cells were capable of converting to CD133+ cells and the inhibition of mTOR signaling substantially promoted this conversion. In serial implantation of tumor xenografts in nude BALB/c mice, the residual tumor cells that were exposed to rapamycin in vivo displayed higher CD133 expression and had increased secondary tumorigenicity compared with the control group. Moreover, rapamycin treatment also enhanced the level of stem cell-associated genes and CD133 expression in certain human liver tumor cell lines, such as Huh7, PLC/PRC/7 and Hep3B. The mTOR pathway is significantly involved in the generation and the differentiation of tumorigenic liver CSCs. These results may be valuable for the design of more rational strategies to control clinical malignant HCC using mTOR inhibitors.

Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver.

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Hinrichs, Arne; Kessler, Barbara; Kurome, Mayuko; Blutke, Andreas; Kemter, Elisabeth; Bernau, Maren; Scholz, Armin M; Rathkolb, Birgit; Renner, Simone; Bultmann, Sebastian; Leonhardt, Heinrich; de Angelis, Martin Hrabĕ; Nagashima, Hiroshi; Hoeflich, Andreas; Blum, Werner F; Bidlingmaier, Martin; Wanke, Rüdiger; Dahlhoff, Maik; Wolf, Eckhard

2018-05-01

Laron syndrome (LS) is a rare, autosomal recessive disorder in humans caused by loss-of-function mutations of the growth hormone receptor (GHR) gene. To establish a large animal model for LS, pigs with GHR knockout (KO) mutations were generated and characterized. CRISPR/Cas9 technology was applied to mutate exon 3 of the GHR gene in porcine zygotes. Two heterozygous founder sows with a 1-bp or 7-bp insertion in GHR exon 3 were obtained, and their heterozygous F1 offspring were intercrossed to produce GHR-KO, heterozygous GHR mutant, and wild-type pigs. Since the latter two groups were not significantly different in any parameter investigated, they were pooled as the GHR expressing control group. The characterization program included body and organ growth, body composition, endocrine and clinical-chemical parameters, as well as signaling studies in liver tissue. GHR-KO pigs lacked GHR and had markedly reduced serum insulin-like growth factor 1 (IGF1) levels and reduced IGF-binding protein 3 (IGFBP3) activity but increased IGFBP2 levels. Serum GH concentrations were significantly elevated compared with control pigs. GHR-KO pigs had a normal birth weight. Growth retardation became significant at the age of five weeks. At the age of six months, the body weight of GHR-KO pigs was reduced by 60% compared with controls. Most organ weights of GHR-KO pigs were reduced proportionally to body weight. However, the weights of liver, kidneys, and heart were disproportionately reduced, while the relative brain weight was almost doubled. GHR-KO pigs had a markedly increased percentage of total body fat relative to body weight and displayed transient juvenile hypoglycemia along with decreased serum triglyceride and cholesterol levels. Analysis of insulin receptor related signaling in the liver of adult fasted pigs revealed increased phosphorylation of IRS1 and PI3K. In agreement with the loss of GHR, phosphorylation of STAT5 was significantly reduced. In contrast, phosphorylation

Polyploidization in liver tissue.

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Gentric, Géraldine; Desdouets, Chantal

2014-02-01

Polyploidy (alias whole genome amplification) refers to organisms containing more than two basic sets of chromosomes. Polyploidy was first observed in plants more than a century ago, and it is known that such processes occur in many eukaryotes under a variety of circumstances. In mammals, the development of polyploid cells can contribute to tissue differentiation and, therefore, possibly a gain of function; alternately, it can be associated with development of disease, such as cancer. Polyploidy can occur because of cell fusion or abnormal cell division (endoreplication, mitotic slippage, or cytokinesis failure). Polyploidy is a common characteristic of the mammalian liver. Polyploidization occurs mainly during liver development, but also in adults with increasing age or because of cellular stress (eg, surgical resection, toxic exposure, or viral infections). This review will explore the mechanisms that lead to the development of polyploid cells, our current state of understanding of how polyploidization is regulated during liver growth, and its consequence on liver function. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Role of the autonomic nervous system in rat liver regeneration.

Science.gov (United States)

Xu, Cunshuan; Zhang, Xinsheng; Wang, Gaiping; Chang, Cuifang; Zhang, Lianxing; Cheng, Qiuyan; Lu, Ailing

2011-05-01

To study the regulatory role of autonomic nervous system in rat regenerating liver, surgical operations of rat partial hepatectomy (PH) and its operation control (OC), sympathectomy combining partial hepatectomy (SPH), vagotomy combining partial hepatectomy (VPH), and total liver denervation combining partial hepatectomy (TDPH) were performed, then expression profiles of regenerating livers at 2 h after operation were detected using Rat Genome 230 2.0 array. It was shown that the expressions of 97 genes in OC, 230 genes in PH, 253 genes in SPH, 187 genes in VPH, and 177 genes in TDPH were significantly changed in biology. The relevance analysis showed that in SPH, genes involved in stimulus response, immunity response, amino acids and K(+) transport, amino acid catabolism, cell adhesion, cell proliferation mediated by JAK-STAT, Ca(+), and platelet-derived growth factor receptor, cell growth and differentiation through JAK-STAT were up-regulated, while the genes involved in chromatin assembly and disassembly, and cell apoptosis mediated by MAPK were down-regulated. In VPH, the genes associated with chromosome modification-related transcription factor, oxygen transport, and cell apoptosis mediated by MAPK pathway were up-regulated, but the genes associated with amino acid catabolism, histone acetylation-related transcription factor, and cell differentiation mediated by Wnt pathway were down-regulated. In TDPH, the genes related to immunity response, growth and development of regenerating liver, cell growth by MAPK pathway were up-regulated. Our data suggested that splanchnic and vagal nerves could regulate the expressions of liver regeneration-related genes.

Effects of palm kernel cake (PKC on growth performance, blood components and liver histopathology of sex reversed red tilapia (Oreochromis niloticus

Directory of Open Access Journals (Sweden)

Sukasem, N.

2007-09-01

Full Text Available Effects of Palm Kernel Cake (PKC on growth performance, blood components and liver histopathology of sex- reversed red tilapia Oreochromis niloticus were studied using seven isocaloric diets (3400 kCal/ kg containing different levels of protein and PKC. Diet 1, 2 and 3 contained 20% protein with the supplementation of 15, 30 and 45% PKC, respectively. Diets 4, 5 and 6 contained 24% protein in combinationwith the same PKC supplemention levels mentioned above, and diet 7 was commercial feed containing 20% protein as a control diet. Experimental diets were fed to experimental fish of 48.65 g initial average body weight cultured in floating cages (3 cages/diet for 10 weeks. Fish fed diets containing higher protein (24%; diets 4, 5 and 6 had significantly better growth performance (p<0.05 than those fed lower protein (20%; diets 1, 2 and 3. Considering the effect of PKC, fish fed diet 5 (Prot. 24%, PKC 30% gave the greatest growth performance (p<0.05 and all the PKC-fed groups had significantly higher growth than fish fed control diet. There was evidence that supplementation of PKC in fish feed ranging from 15 to 45% had no effect to the survival rate, blood components, or hepatocytic cells of tilapia. However, liver tissue showed higher numbers of lipid droplets in fish fed diet contained 45% PKC (diets 3 and 6. For the production cost, all test diets with PKC supplementation had significantly higher price (p<0.05 than commercial feed. However, when considering the feeding cost per unit of fish production, fish reared with PKC supplemented diets had significantly lower cost (p<0.05 than fish fed commercial feed.

Radiation adaptive response for the growth of cultured glial cells

International Nuclear Information System (INIS)

Suzuki, S.; Miura, Y.; Kano, M.; Toda, T.; Urano, S.

2003-01-01

Full text: To examine the molecular mechanism of radiation adaptive response (RAR) for the growth of cultured glial cells and to investigate the influence of aging on the response, glial cells were cultured from young and aged rats (1 month and 24 months old). RAR for the growth of glial cells conditioned with a low dose of X-rays and subsequently exposed to a high dose of X-rays was examined for cell number and BrdU incorporation. Involvement of the subcellular signaling pathway factors in RAR was investigated using their inhibitors, activators and mutated glial cells. RAR was observed in cells cultured from young rats, but was not in cells from aged rats. The inhibitors of protein kinase C (PKC) and DNA-dependent protein kinase (DNA-PK) or phosphatidylinositol 3-kinase (PI3K) suppressed RAR. The activators of PKC instead of low dose irradiation also caused RAR. Moreover, glial cells cultured from severe combined immunodeficiency (scid) mice (CB-17 scid) and ataxia-telangiectasia (AT) cells from AT patients showed no RAR. These results indicated that PKC, ATM, DNAPK and/or PI3K were involved in RAR for growth and BrdU incorporation of cultured glial cells and RAR decreased with aging. Proteomics data of glial cells exposed to severe stress of H 2 O 2 or X-rays also will be presented in the conference since little or no difference has not been observed with slight stress yet

Estimating functional liver reserve following hepatic irradiation: Adaptive normal tissue response models

International Nuclear Information System (INIS)

Stenmark, Matthew H.; Cao, Yue; Wang, Hesheng; Jackson, Andrew; Ben-Josef, Edgar; Ten Haken, Randall K.; Lawrence, Theodore S.; Feng, Mary

2014-01-01

Purpose: To estimate the limit of functional liver reserve for safe application of hepatic irradiation using changes in indocyanine green, an established assay of liver function. Materials and methods: From 2005 to 2011, 60 patients undergoing hepatic irradiation were enrolled in a prospective study assessing the plasma retention fraction of indocyanine green at 15-min (ICG-R15) prior to, during (at 60% of planned dose), and after radiotherapy (RT). The limit of functional liver reserve was estimated from the damage fraction of functional liver (DFL) post-RT [1 − (ICG-R15 pre-RT /ICG-R15 post-RT )] where no toxicity was observed using a beta distribution function. Results: Of 48 evaluable patients, 3 (6%) developed RILD, all within 2.5 months of completing RT. The mean ICG-R15 for non-RILD patients pre-RT, during-RT and 1-month post-RT was 20.3%(SE 2.6), 22.0%(3.0), and 27.5%(2.8), and for RILD patients was 6.3%(4.3), 10.8%(2.7), and 47.6%(8.8). RILD was observed at post-RT damage fractions of ⩾78%. Both DFL assessed by during-RT ICG and MLD predicted for DFL post-RT (p < 0.0001). Limiting the post-RT DFL to 50%, predicted a 99% probability of a true complication rate <15%. Conclusion: The DFL as assessed by changes in ICG during treatment serves as an early indicator of a patient’s tolerance to hepatic irradiation

Post-traumatic growth enhances social identification in liver transplant patients: A longitudinal study.

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Scrignaro, Marta; Sani, Fabio; Wakefield, Juliet Ruth Helen; Bianchi, Elisabetta; Magrin, Maria Elena; Gangeri, Laura

2016-09-01

The main aim of this paper is to investigate the prediction that greater subjective identification with relevant groups and social categories (i.e. 'family' and 'transplantees') can be an outcome of post-traumatic growth (PTG). To date there are no studies that have explored these relationships. A longitudinal study was conducted with a group of 100 liver transplant patients from the outpatient populations of the participating centre. Data were collected by means of a self-report questionnaire, which was completed at two different time points (T1 and T2) that were 24months apart. PTG was assessed using the Post-Traumatic Growth Inventory, while both transplantee and family identification were assessed using group identification scales. A path model was tested, using a structural equation model (SEM) approach, to examine the reciprocal effects among family identification, transplantee identification, and PTG over time. As predicted, we found that greater PTG T1 predicted both greater family identification T2 and marginally greater transplantee identification T2. However, the two identification variables did not predict PTG over time. The results show that family identification and transplantee identification may be outcomes of the PTG process, confirming the importance of adopting a thriving multidimensional model of adjustment to medical illness, whereby people facing adverse life events, such as transplantation, may flourish rather than deteriorate psychologically. Copyright © 2016 Elsevier Inc. All rights reserved.

Analysing the mechanical performance and growth adaptation of Norway spruce using a non-linear finite-element model and experimental data.

Science.gov (United States)

Lundström, T; Jonas, T; Volkwein, A

2008-01-01

Thirteen Norway spruce [Picea abies (L.) Karst.] trees of different size, age, and social status, and grown under varying conditions, were investigated to see how they react to complex natural static loading under summer and winter conditions, and how they have adapted their growth to such combinations of load and tree state. For this purpose a non-linear finite-element model and an extensive experimental data set were used, as well as a new formulation describing the degree to which the exploitation of the bending stress capacity is uniform. The three main findings were: material and geometric non-linearities play important roles when analysing tree deflections and critical loads; the strengths of the stem and the anchorage mutually adapt to the local wind acting on the tree crown in the forest canopy; and the radial stem growth follows a mechanically high-performance path because it adapts to prevailing as well as acute seasonal combinations of the tree state (e.g. frozen or unfrozen stem and anchorage) and load (e.g. wind and vertical and lateral snow pressure). Young trees appeared to adapt to such combinations in a more differentiated way than older trees. In conclusion, the mechanical performance of the Norway spruce studied was mostly very high, indicating that their overall growth had been clearly influenced by the external site- and tree-specific mechanical stress.

Memory NK cells: why do they reside in the liver?

Science.gov (United States)

Jiang, Xiaojun; Chen, Yonglin; Peng, Hui; Tian, Zhigang

2013-05-01

Immune memory is the hallmark of adaptive immunity. However, recent studies have shown that natural killer (NK) cells, key components of the innate immune system, also mediate memory responses in mice and humans. Strikingly, memory NK cells were liver-resident in some models, raising the question as to whether the liver is a special organ for the acquisition of NK cell memory. Here, we review the characteristics of NK cell memory by summarizing recent progress and discuss how the liver may generate both the initiation and the recall phase of memory. We propose that the liver may have unique precursors for memory NK cells, which are developmentally distinct from NK cells derived from bone marrow.

Identifying Students at Risk: An Examination of Computer-Adaptive Measures and Latent Class Growth Analysis

Science.gov (United States)

Keller-Margulis, Milena; McQuillin, Samuel D.; Castañeda, Juan Javier; Ochs, Sarah; Jones, John H.

2018-01-01

Multitiered systems of support depend on screening technology to identify students at risk. The purpose of this study was to examine the use of a computer-adaptive test and latent class growth analysis (LCGA) to identify students at risk in reading with focus on the use of this methodology to characterize student performance in screening.…

Urinary growth hormone (U-GH) excretion and serum insulin-like growth factor 1 (IGF-1) in patients with alcoholic cirrhosis

DEFF Research Database (Denmark)

Møller, S; Grønbaek, M; Main, K

1993-01-01

was significantly higher in patients than in the healthy controls (p liver function assessed by modified Child-Turcotte score (p encephalopathy (p ...Basal serum growth hormone (GH) levels are elevated and insulin-like growth factor 1 (IGF-1) concentrations in serum are suppressed in patients with chronic liver disease. The aim of this study was to measure the urinary GH (U-GH) excretion and IGF-1 concentrations in patients with cirrhosis...... and correlated with liver function (p

T cells infiltrate the liver and kill hepatocytes in HLA-B(∗)57:01-associated floxacillin-induced liver injury.

Science.gov (United States)

Wuillemin, Natascha; Terracciano, Luigi; Beltraminelli, Helmut; Schlapbach, Christoph; Fontana, Stefano; Krähenbühl, Stephan; Pichler, Werner J; Yerly, Daniel

2014-06-01

Drug-induced liver injury is a major safety issue. It can cause severe disease and is a common cause of the withdrawal of drugs from the pharmaceutical market. Recent studies have identified the HLA-B(∗)57:01 allele as a risk factor for floxacillin (FLUX)-induced liver injury and have suggested a role for cytotoxic CD8(+) T cells in the pathomechanism of liver injury caused by FLUX. This study aimed to confirm the importance of FLUX-reacting cytotoxic lymphocytes in the pathomechanism of liver injury and to dissect the involved mechanisms of cytotoxicity. IHC staining of a liver biopsy from a patient with FLUX-induced liver injury revealed periportal inflammation and the infiltration of cytotoxic CD3(+) CD8(+) lymphocytes into the liver. The infiltration of cytotoxic lymphocytes into the liver of a patient with FLUX-induced liver injury demonstrates the importance of FLUX-reacting T cells in the underlying pathomechanism. Cytotoxicity of FLUX-reacting T cells from 10 HLA-B(∗)57:01(+) healthy donors toward autologous target cells and HLA-B(∗)57:01-transduced hepatocytes was analyzed in vitro. Cytotoxicity of FLUX-reacting T cells was concentration dependent and required concentrations in the range of peak serum levels after FLUX administration. Killing of target cells was mediated by different cytotoxic mechanisms. Our findings emphasize the role of the adaptive immune system and especially of activated drug-reacting T cells in human leukocyte antigen-associated, drug-induced liver injury. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Effects of naphthenic acid exposure on development and liver metabolic processes in anuran tadpoles

International Nuclear Information System (INIS)

Melvin, Steven D.; Lanctôt, Chantal M.; Craig, Paul M.; Moon, Thomas W.; Peru, Kerry M.; Headley, John V.; Trudeau, Vance L.

2013-01-01

Naphthenic acids (NA) are used in a variety of commercial and industrial applications, and are primary toxic components of oil sands wastewater. We investigated developmental and metabolic responses of tadpoles exposed to sub-lethal concentrations of a commercial NA blend throughout development. We exposed Lithobates pipiens tadpoles to 1 and 2 mg/L NA for 75 days and monitored growth and development, condition factor, gonad and liver sizes, and levels of liver glucose, glycogen, lipids and cholesterol following exposure. NA decreased growth and development, significantly reduced glycogen stores and increased triglycerides, indicating disruption to processes associated with energy metabolism and hepatic glycolysis. Effects on liver function may explain reduced growth and delayed development observed in this and previous studies. Our data highlight the need for greater understanding of the mechanisms leading to hepatotoxicity in NA-exposed organisms, and indicate that strict guidelines may be needed for the release of NA into aquatic environments. -- Highlights: ► We exposed Lithobates pipiens tadpoles to 1–2 mg/L NA in the laboratory. ► We monitored survival, growth and development for 75 days. ► We measured liver glycogen, glucose, triglycerides, and cholesterol levels. ► NA significantly reduced growth and development compared to controls. ► NA significantly reduced glycogen levels and increased triglycerides. -- Leopard frog (Lithobates pipiens) tadpoles chronically exposed to sub-lethal NA concentrations (1–2 mg/L) suffered decreased growth and development and disruption to liver metabolic processes

Chemoprotective effect of insulin-like growth factor I against acetaminophen-induced cell death in Chang liver cells via ERK1/2 activation

International Nuclear Information System (INIS)

Hwang, Hye-Jung; Kwon, Mi-Jin; Nam, Taek-Jeong

2007-01-01

The insulin-like growth factor (IGF) system and type-I IGF receptor (IGF-IR) signaling are involved in protecting against chemotherapeutic drug-induced cell death in human hepatoma cells. Acetaminophen (AAP) hepatotoxicity is the leading cause of liver failure, and the prevention of AAP-induced cell death has been the focus of many studies. We determined whether IGF-I could protect against AAP-induced cell death in Chang liver cells and investigated the protective mechanism. Based on the results of MTS assays, LDH release assays, Hoechst 33342 cell staining, and DNA fragmentation experiments, AAP induced cell death in a dose-dependent manner. According to Western blot analysis, treatment with AAP increased the level of poly(ADP-ribose) polymerase (PARP) fragments in cells compared with that in control cells; however, caspase-3, a critical signaling molecule in apoptosis, was not activated after AAP overdose. Moreover, combined treatment with AAP and IGF-I inhibited PARP cleavage, which was consistent with the ability of IGF-I to restore the level of glutathione (GSH) and cell viability in GSH and MTS assays, respectively. We investigated whether the protective effect of IGF-I against AAP cytotoxicity is related to the extracellular signal-related kinase ERK1/2, which is generally activated by mitogenic and proliferative stimuli such as growth factors. Compared with AAP treatment alone, IGF-I and AAP co-treatment increased ERK1/2 phosphorylation but inhibited PARP cleavage. Thus ERK1/2 activation is instrumental in the protective effect of IGF-I against AAP-induced cell death in Chang liver cells

Long-term pathological and immunohistochemical features in the liver after intraoperative whole-liver irradiation in rats

International Nuclear Information System (INIS)

Imaeda, Masumi; Yoshida, Yukari; Ohkubo, Yu; Musha, Atsushi; Komachi, Mayumi; Nakano, Takashi; Ishikawa, Hitoshi; Takahashi, Takeo; Nakazato, Yoichi

2014-01-01

Radiation therapy (RT) has become particularly important recently for treatment of liver tumors, but there are few experimental investigations pertaining to radiation-induced liver injuries over long-term follow-up periods. Thus, the present study examined pathological liver features over a 10-month period using an intraoperative whole-liver irradiation model. Liver function tests were performed in blood samples, whereas cell death, cell proliferation, and fibrotic changes were evaluated pathologically in liver tissues, which were collected from irradiated rats 24 h, 1, 2, 4 and 40 weeks following administration of single irradiation doses of 0 (control), 15 or 30 Gy. The impaired liver function, increased hepatocyte number, and decreased apoptotic cell proportion observed in the 15 Gy group, but not the 30 Gy group, returned to control group levels after 40 weeks; however, the Ki-67 indexes in the 15 Gy group were still higher than those in the control group after 40 weeks. Azan staining showed a fibrotic pattern in the irradiated liver in the 30 Gy group only, but the expression levels of alpha smooth muscle actin (α-SMA) and transforming growth factor-beta 1 (TGF-β1) in both the 15 and 30 Gy groups were significantly higher than those in the control group (P < 0.05). There were differences in the pathological features of the irradiated livers between the 15 Gy and 30 Gy groups, but TGF-β1 and α-SMA expression patterns supported the gradual progression of radiation-induced liver fibrosis in both groups. These findings will be useful in the future development of protective drugs for radiation-induced liver injury. (author)

Extracellular Vesicles from Human Liver Stem Cells Reduce Injury in an Ex Vivo Normothermic Hypoxic Rat Liver Perfusion Model.

Science.gov (United States)

Rigo, Federica; De Stefano, Nicola; Navarro-Tableros, Victor; David, Ezio; Rizza, Giorgia; Catalano, Giorgia; Gilbo, Nicholas; Maione, Francesca; Gonella, Federica; Roggio, Dorotea; Martini, Silvia; Patrono, Damiano; Salizzoni, Mauro; Camussi, Giovanni; Romagnoli, Renato

2018-05-01

The gold standard for organ preservation before transplantation is static cold storage, which is unable to fully protect suboptimal livers from ischemia/reperfusion injury. An emerging alternative is normothermic machine perfusion (NMP), which permits organ reconditioning. Here, we aimed to explore the feasibility of a pharmacological intervention on isolated rat livers by using a combination of NMP and human liver stem cells-derived extracellular vesicles (HLSC-EV). We established an ex vivo murine model of NMP capable to maintain liver function despite an ongoing hypoxic injury induced by hemodilution. Livers were perfused for 4 hours without (control group, n = 10) or with HLSC-EV (treated group, n = 9). Bile production was quantified; perfusate samples were collected hourly to measure metabolic (pH, pO2, pCO2) and cytolysis parameters (AST, alanine aminotransferase, lactate dehydrogenase). At the end of perfusion, we assessed HLSC-EV engraftment by immunofluorescence, tissue injury by histology, apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, tissue hypoxia-inducible factor 1-α, and transforming growth factor-beta 1 RNA expression by quantitative reverse transcription-polymerase chain reaction. During hypoxic NMP, livers were able to maintain homeostasis and produce bile. In the treated group, AST (P = 0.018) and lactate dehydrogenase (P = 0.032) levels were significantly lower than those of the control group at 3 hours of perfusion, and AST levels persisted lower at 4 hours (P = 0.003). By the end of NMP, HLSC-EV had been uptaken by hepatocytes, and EV treatment significantly reduced histological damage (P = 0.030), apoptosis (P = 0.049), and RNA overexpression of hypoxia-inducible factor 1-α (P < 0.0001) and transforming growth factor-beta 1 (P = 0.014). HLSC-EV treatment, even in a short-duration model, was feasible and effectively reduced liver injury during hypoxic NMP.

Liver proteomics in progressive alcoholic steatosis

Energy Technology Data Exchange (ETDEWEB)

Fernando, Harshica [Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555 (United States); Wiktorowicz, John E.; Soman, Kizhake V. [Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77555 (United States); Kaphalia, Bhupendra S.; Khan, M. Firoze [Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555 (United States); Shakeel Ansari, G.A., E-mail: sansari@utmb.edu [Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555 (United States)

2013-02-01

Fatty liver is an early stage of alcoholic and nonalcoholic liver disease (ALD and NALD) that progresses to steatohepatitis and other irreversible conditions. In this study, we identified proteins that were differentially expressed in the livers of rats fed 5% ethanol in a Lieber–DeCarli diet daily for 1 and 3 months by discovery proteomics (two-dimensional gel electrophoresis and mass spectrometry) and non-parametric modeling (Multivariate Adaptive Regression Splines). Hepatic fatty infiltration was significantly higher in ethanol-fed animals as compared to controls, and more pronounced at 3 months of ethanol feeding. Discovery proteomics identified changes in the expression of proteins involved in alcohol, lipid, and amino acid metabolism after ethanol feeding. At 1 and 3 months, 12 and 15 different proteins were differentially expressed. Of the identified proteins, down regulation of alcohol dehydrogenase (− 1.6) at 1 month and up regulation of aldehyde dehydrogenase (2.1) at 3 months could be a protective/adaptive mechanism against ethanol toxicity. In addition, betaine-homocysteine S-methyltransferase 2 a protein responsible for methionine metabolism and previously implicated in fatty liver development was significantly up regulated (1.4) at ethanol-induced fatty liver stage (1 month) while peroxiredoxin-1 was down regulated (− 1.5) at late fatty liver stage (3 months). Nonparametric analysis of the protein spots yielded fewer proteins and narrowed the list of possible markers and identified D-dopachrome tautomerase (− 1.7, at 3 months) as a possible marker for ethanol-induced early steatohepatitis. The observed differential regulation of proteins have potential to serve as biomarker signature for the detection of steatosis and its progression to steatohepatitis once validated in plasma/serum. -- Graphical abstract: The figure shows the Hierarchial cluster analysis of differentially expressed protein spots obtained after ethanol feeding for 1 (1–3

Translation, adaptation and validation of two versions of the Chronic Liver Disease Questionnaire in Malaysian patients for speakers of both English and Malay languages: a cross-sectional study.

Science.gov (United States)

Khairullah, Shasha; Mahadeva, Sanjiv

2017-05-25

We aimed to adapt, translate and validate the Chronic Liver Disease Questionnaire (CLDQ) in Malaysian patients with chronic liver diseases of various aetiologies. Tertiary level teaching institution in Malaysia. The validation process involved 211 adult patients (English language n=101, Malay language n=110) with chronic liver disease. Characteristics of the study subjects were as follows: mean (SD) age was 56 (12.8) years, 58.3% were male and 41.7% female. The inclusion criteria were patients 18 years or older with chronic hepatitis and/or liver cirrhosis of any aetiology. The exclusion criteria were as follows: presence of hepatic encephalopathy, ongoing treatment with interferon and presence of other chronic conditions that have an impact on health-related quality of life (HRQOL). A cross-sectional study was conducted. Cultural adaptation of the English version of the CLDQ was performed, and a Malay version was developed following standard forward-backward translation by independent native speakers. Psychometric properties of both versions were determined by assessing their internal consistency, test-retest reliability and discriminant and convergent validity. Cronbach's alpha for internal consistency across the various domains of the CLDQ was 0.95 for the English version and 0.92 for the Malay version. Test-retest analysis showed excellent reliability with an intraclass correlation coefficient of 0.89 for the English version and 0.93 for the Malay version. The average scores of both the English and Malay versions of the CLDQ demonstrated adequate discriminant validity by differentiating between non-cirrhosis (English 6.3, Malay 6.1), compensated cirrhosis (English 5.6, Malay 6.0) and decompensated cirrhosis (English 5.1, Malay 4.9) (p<0.001). Convergent validity showed that correlation was fair between the English (ρ=0.59) and Malay (p=0.47) CLDQ versions with the EQ-5D, a generic HRQOL instrument. The English and Malay versions of the CLDQ are reliable and

Fisetin inhibits liver cancer growth in a mouse model: Relation to dopamine receptor.

Science.gov (United States)

Liu, Xiang-Feng; Long, Hai-Jiao; Miao, Xiong-Ying; Liu, Guo-Li; Yao, Hong-Liang

2017-07-01

Fisetin (3,3',4',7-tetrahydroxyflavone), a natural abundant flavonoid, is produced in different vegetables and fruits. Fisetin has been reported to relate to various positive biological effects, including anti-proliferative, anticancer, anti-oxidative and neuroprotective effects. Dopamine receptors (DRs) belonging to G protein‑coupled receptor family, are known as the target of ~50% of all modern medicinal drugs. DRs consist of various proteins, functioning as transduction of intracellular signals for extracellular stimuli. We found that fisetin performed as DR2 agonist to suppress liver cancer cells proliferation, migration and invasion. Caspase-3 signaling was activated to induce apoptosis for fisetin administration. Furthermore, TGF‑β1 was also inhibited in fisetin-treated liver cancer cells, reducing epithelial-mesenchymal transition (EMT). Additionally, fisetin downregulated VEGFR1, p-ERK1/2, p38 and pJNK, ameliorating liver cancer progression. In vivo, the orthotopically implanted tumors from mice were inhibited by fisetin adminisatration accompanied by prolonged survival rate and higher levels of dopamine. Together, the results indicated a novel therapeutic strategy to suppress liver cancer progression associated with DR2 regulation, indicating that dopamine might be of importance in liver cancer progression.

Adaptation to statins restricts human tumour growth in Nude mice

International Nuclear Information System (INIS)

Follet, Julie; Rémy, Lionel; Hesry, Vincent; Simon, Brigitte; Gillet, Danièle; Auvray, Pierrick; Corcos, Laurent; Le Jossic-Corcos, Catherine

2011-01-01

Statins have long been used as anti-hypercholesterolemia drugs, but numerous lines of evidence suggest that they may also bear anti-tumour potential. We have recently demonstrated that it was possible to isolate cancer cells adapted to growth in the continuous presence of lovastatin. These cells grew more slowly than the statin-sensitive cells of origin. In the present study, we compared the ability of both statin-sensitive and statin-resistant cells to give rise to tumours in Nude mice. HGT-1 human gastric cancer cells and L50 statin-resistant derivatives were injected subcutaneously into Nude mice and tumour growth was recorded. At the end of the experiment, tumours were recovered and marker proteins were analyzed by western blotting, RT-PCR and immunohistochemistry. L50 tumours grew more slowly, showed a strong decrease in cyclin B1, over-expressed collagen IV, and had reduced laminin 332, VEGF and CD34 levels, which, collectively, may have restricted cell division, cell adhesion and neoangiogenesis. Taken together, these results showed that statin-resistant cells developed into smaller tumours than statin-sensitive cells. This may be reflective of the cancer restricting activity of statins in humans, as suggested from several retrospective studies with subjects undergoing statin therapy for several years

Quality measurement and improvement in liver transplantation.

Science.gov (United States)

Mathur, Amit K; Talwalkar, Jayant

2018-06-01

There is growing interest in the quality of health care delivery in liver transplantation. Multiple stakeholders, including patients, transplant providers and their hospitals, payers, and regulatory bodies have an interest in measuring and monitoring quality in the liver transplant process, and understanding differences in quality across centres. This article aims to provide an overview of quality measurement and regulatory issues in liver transplantation performed within the United States. We review how broader definitions of health care quality should be applied to liver transplant care models. We outline the status quo including the current regulatory agencies, public reporting mechanisms, and requirements around quality assurance and performance improvement (QAPI) activities. Additionally, we further discuss unintended consequences and opportunities for growth in quality measurement. Quality measurement and the integration of quality improvement strategies into liver transplant programmes hold significant promise, but multiple challenges to successful implementation must be addressed to optimise value. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Effect of physical training on liver expression of activin A and follistatin in a nonalcoholic fatty liver disease model in rats

International Nuclear Information System (INIS)

Silva, R.N.; Bueno, P.G.; Avó, L.R.S.; Nonaka, K.O.; Selistre-Araújo, H.S.; Leal, A.M.O.

2014-01-01

Nonalcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in the liver and is associated with obesity and insulin resistance. Activin A is a member of the transforming growth factor beta (TGF)-β superfamily and inhibits hepatocyte growth. Follistatin antagonizes the biological actions of activin. Exercise is an important therapeutic strategy to reduce the metabolic effects of obesity. We evaluated the pattern of activin A and follistatin liver expression in obese rats subjected to swimming exercise. Control rats (C) and high-fat (HF) diet-fed rats were randomly assigned to a swimming training group (C-Swim and HF-Swim) or a sedentary group (C-Sed and HF-Sed). Activin βA subunit mRNA expression was significantly higher in HF-Swim than in HF-Sed rats. Follistatin mRNA expression was significantly lower in C-Swim and HF-Swim than in either C-Sed or HF-Sed animals. There was no evidence of steatosis or inflammation in C rats. In contrast, in HF animals the severity of steatosis ranged from grade 1 to grade 3. The extent of liver parenchyma damage was less in HF-Swim animals, with the severity of steatosis ranging from grade 0 to grade 1. These data showed that exercise may reduce the deleterious effects of a high-fat diet on the liver, suggesting that the local expression of activin-follistatin may be involved

Effect of physical training on liver expression of activin A and follistatin in a nonalcoholic fatty liver disease model in rats

Energy Technology Data Exchange (ETDEWEB)

Silva, R.N. [Departamento de Fisioterapia, Universidade Federal de São Carlos, São Carlos, SP (Brazil); Bueno, P.G. [Departamento de Ciências Fisiológicas, Universidade Federal de São Carlos, São Carlos, SP (Brazil); Avó, L.R.S. [Departamento de Medicina, Universidade Federal de São Carlos, São Carlos, SP (Brazil); Nonaka, K.O.; Selistre-Araújo, H.S. [Departamento de Ciências Fisiológicas, Universidade Federal de São Carlos, São Carlos, SP (Brazil); Leal, A.M.O. [Departamento de Medicina, Universidade Federal de São Carlos, São Carlos, SP (Brazil)

2014-07-25

Nonalcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in the liver and is associated with obesity and insulin resistance. Activin A is a member of the transforming growth factor beta (TGF)-β superfamily and inhibits hepatocyte growth. Follistatin antagonizes the biological actions of activin. Exercise is an important therapeutic strategy to reduce the metabolic effects of obesity. We evaluated the pattern of activin A and follistatin liver expression in obese rats subjected to swimming exercise. Control rats (C) and high-fat (HF) diet-fed rats were randomly assigned to a swimming training group (C-Swim and HF-Swim) or a sedentary group (C-Sed and HF-Sed). Activin βA subunit mRNA expression was significantly higher in HF-Swim than in HF-Sed rats. Follistatin mRNA expression was significantly lower in C-Swim and HF-Swim than in either C-Sed or HF-Sed animals. There was no evidence of steatosis or inflammation in C rats. In contrast, in HF animals the severity of steatosis ranged from grade 1 to grade 3. The extent of liver parenchyma damage was less in HF-Swim animals, with the severity of steatosis ranging from grade 0 to grade 1. These data showed that exercise may reduce the deleterious effects of a high-fat diet on the liver, suggesting that the local expression of activin-follistatin may be involved.

Role of stellate cells in alcoholic liver fibrosis

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Krzysztof Plewka

2009-07-01

Full Text Available Many different diseases and toxins can cause liver damage, which is diffi cult to treat and often leads to the development of liver fi brosis or even cirrhosis. The key event in this process is the activation of hepatic stellate cells (HSCs. During such activation, HSCs undergo a dramatic transformation in morphology and behavior, changing from a neuronal-like to a fi broblast-like morphology. After activation, HSCs increase their proliferation rate and extracellular matrix (ECM production. Overproduction of ECM, which contains mainly collagen type I, is a direct cause of liver disruption. HSCs also produce substances which inhibit protease activities, such as TIMPs, which enhance ECM deposition in the liver. On the molecular level, HSCs are activated by cytokines, growth factors, and oxidative stress, which are abundant in affl icted liver. These factors induce intracellular signals transmitted by many kinases, the most important of which are JNK, ERK1/2, p38, TAK-1, PKC, FAK, and P3IK. Signals transmitted via these pathways change the activities of transcription factors such as Smad, AP-1, and NF-κβ. This in turn causes changes In gene transcription and ultimately alters the whole cell’s behavior and morphology. The cell begins the production collagen type I, TIMP-1, and aSMA. Activated HSCs can sustain their own activation by producing growth factors such as PDGF and TGF-β. Despite the vast knowledge about the mechanisms causing liver fi brosis and cirrhosis, there is still no effective cure. Further studies are therefore needed to solve this problem.

Liver hyperplasia and regression after lead nitrate administration

International Nuclear Information System (INIS)

Columbano, A.; Ledda-Columbano, G.M.; Coni, P.P.; Vargiu, M.; Faa, G.; Pani, P.

1984-01-01

The effect of a single intravenous injection of lead nitrate on liver, was investigated in male Wistar rats. Lead nitrate at 5 and 10 mumoles/100 g of body weight stimulated a 19-fold increase in the incorporation of 3 H-thymidine into liver DNA and resulted in temporal changes in DNA synthesis, as determined by assays of specific activity. Thirty-six hours after lead nitrate administration, the incorporation of 3 H-thymidine reached its maximum and returned to normal levels within 3 days. A significant increase in the number of cells entering mitosis at 36 hours indicated the capacity of lead to stimulate liver cell proliferation. Enlargement of the liver after lead treatment was also observed in both female Wistar rats as well in male Fischer rats. This stimulatory effect of lead on liver growth was reversible; during the involution of the liver, cell death morphologically similar to the one described as apoptosis was observed in histological sections of liver from animals sacrificed 4-7 days after lead treatment

Ontogeny and nutritional programming of mitochondrial proteins in the ovine kidney, liver and lung.

Science.gov (United States)

Yakubu, D P; Mostyn, A; Hyatt, M A; Kurlak, L O; Budge, H; Stephenson, T; Symonds, M E

2007-12-01

This study investigated the developmental and nutritional programming of two important mitochondrial proteins, namely voltage-dependent anion channel (VDAC) and cytochrome c, in the sheep kidney, liver and lung. The effect of maternal nutrient restriction between early and mid-gestation (i.e. 28- to 80-day gestation, the period of maximal placental growth) on the abundance of these proteins was also examined in fetal and juvenile offspring. Fetuses were sampled at 80 and 140 days of gestation (term approximately 147 days), and postnatal animals at 1 and 30 days and 6 months of age. The abundance of VDAC peaked at 140 days of gestation in the lung, compared with 1 day after birth in the kidney and liver, whereas cytochrome c abundance was greatest at 140 days of gestation in the liver, 1 day after birth in the kidney and 6 months of age in lungs. This differential ontogeny in mitochondrial protein abundance between tissues was accompanied with very different tissue-specific responses to changes in maternal food intake. In the liver, maternal nutrient restriction only increased mitochondrial protein abundance at 80 days of gestation, compared with no effect in the kidney. In contrast, in the lung mitochondrial protein, abundance was raised near to term, whereas VDAC abundance was decreased by 6 months of age. These findings demonstrate the tissue-specific nature of mitochondrial protein development that reflects differences in functional adaptation after birth. The divergence in mitochondrial response between tissues to maternal nutrient restriction early in pregnancy further reflects these differential ontogenies.

Cloning and expression analysis of myostatin, fibroblast growth factor 6, insulin-like growth factor I and II in liver and muscle of sea bass (Dicentrarchus labrax, L. during long-term fasting and refeeding

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M. Saroglia

2010-04-01

Full Text Available The exceptionally fast growth that fish experience after periods of fasting has been called “compensatory growth”. This phenomenon has been studied in intensive aquaculture as a means of enhancing growth rates, but the mechanisms by which food intake activates an increase in somatic growth, and especially in muscle growth, are complex and not yet fully understood. In the present paper, we describe the molecular cloning and sequencing of sea bass (Dicentrarchus labrax myostatin (MSTN and fibroblast growth factor 6 (FGF6, which have been shown to be major genetic determinants of skeletal muscle growth, together with insulin-like growth factor I (IGFI and IGF-II, which are potent mitogens known to play important roles in growth and development. We then report the pattern of expression of the four aforementioned genes, in liver and myotomal muscle in response to prolonged fasting and refeeding. Nutritional status significantly influenced the expression of IGF-I, IGF-II and MSTN, whereas the muscular FGF6 expression levels were not affected by the feeding status of the animals. Taken together these data indicate that IGF-I, IGF-II and MSTN are involved in the sea bass muscle compensatory growth induced by refeeding, whereas FGF6 probably has not a role in this phenomenon.

Role of PGC-1{alpha} in exercise and fasting induced adaptations in mouse liver

DEFF Research Database (Denmark)

Haase, Tobias Nørresø; Jørgensen, Stine Ringholm; Leick, Lotte

2011-01-01

The transcriptional coactivator peroxisome proliferator activated receptor (PPAR)-¿ coactivator (PGC)-1a plays a role in regulation of several metabolic pathways. By use of whole body PGC-1a knockout (KO) mice we investigated the role of PGC-1a in fasting, acute exercise and exercise training ind...... role in regulation of Cyt c and COXI expression in the liver in response to a single exercise bout and prolonged exercise training, which implies that exercise training induced improvements in oxidative capacity of the liver is regulated by PGC-1a.......The transcriptional coactivator peroxisome proliferator activated receptor (PPAR)-¿ coactivator (PGC)-1a plays a role in regulation of several metabolic pathways. By use of whole body PGC-1a knockout (KO) mice we investigated the role of PGC-1a in fasting, acute exercise and exercise training...... induced regulation of key proteins in gluconeogenesis and metabolism in the liver. In both wild type (WT) and PGC-1a KO mice liver, the mRNA content of the gluconeogenic proteins glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) was upregulated during fasting. Pyruvate...

Evaluation of immunological escape mechanisms in a mouse model of colorectal liver metastases

International Nuclear Information System (INIS)

Grimm, Martin; Thalheimer, Andreas; Gasser, Martin; Bueter, Marco; Strehl, Johanna; Wang, Johann; Nichiporuk, Ekaterina; Meyer, Detlef; Germer, Christoph T; Waaga-Gasser, Ana M

2010-01-01

The local and systemic activation and regulation of the immune system by malignant cells during carcinogenesis is highly complex with involvement of the innate and acquired immune system. Despite the fact that malignant cells do have antigenic properties their immunogenic effects are minor suggesting tumor induced mechanisms to circumvent cancer immunosurveillance. The aim of this study is the analysis of tumor immune escape mechanisms in a colorectal liver metastases mouse model at different points in time during tumor growth. CT26.WT murine colon carcinoma cells were injected intraportally in Balb/c mice after median laparotomy using a standardized injection technique. Metastatic tumor growth in the liver was examined by standard histological procedures at defined points in time during metastatic growth. Liver tissue with metastases was additionally analyzed for cytokines, T cell markers and Fas/Fas-L expression using immunohistochemistry, immunofluorescence and RT-PCR. Comparisons were performed by analysis of variance or paired and unpaired t test when appropriate. Intraportal injection of colon carcinoma cells resulted in a gradual and time dependent metastatic growth. T cells of regulatory phenotype (CD4+CD25+Foxp3+) which might play a role in protumoral immune response were found to infiltrate peritumoral tissue increasingly during carcinogenesis. Expression of cytokines IL-10, TGF-β and TNF-α were increased during tumor growth whereas IFN-γ showed a decrease of the expression from day 10 on following an initial increase. Moreover, liver metastases of murine colon carcinoma show an up-regulation of FAS-L on tumor cell surface with a decreased expression of FAS from day 10 on. CD8+ T cells express FAS and show an increased rate of apoptosis at perimetastatic location. This study describes cellular and macromolecular changes contributing to immunological escape mechanisms during metastatic growth in a colorectal liver metastases mouse model simulating the

Molecular signatures associated with HCV-induced hepatocellular carcinoma and liver metastasis.

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Valeria De Giorgi

Full Text Available Hepatocellular carcinomas (HCCs are a heterogeneous group of tumors that differ in risk factors and genetic alterations. In Italy, particularly Southern Italy, chronic hepatitis C virus (HCV infection represents the main cause of HCC. Using high-density oligoarrays, we identified consistent differences in gene-expression between HCC and normal liver tissue. Expression patterns in HCC were also readily distinguishable from those associated with liver metastases. To characterize molecular events relevant to hepatocarcinogenesis and identify biomarkers for early HCC detection, gene expression profiling of 71 liver biopsies from HCV-related primary HCC and corresponding HCV-positive non-HCC hepatic tissue, as well as gastrointestinal liver metastases paired with the apparently normal peri-tumoral liver tissue, were compared to 6 liver biopsies from healthy individuals. Characteristic gene signatures were identified when normal tissue was compared with HCV-related primary HCC, corresponding HCV-positive non-HCC as well as gastrointestinal liver metastases. Pathway analysis classified the cellular and biological functions of the genes differentially expressed as related to regulation of gene expression and post-translational modification in HCV-related primary HCC; cellular Growth and Proliferation, and Cell-To-Cell Signaling and Interaction in HCV-related non HCC samples; Cellular Growth and Proliferation and Cell Cycle in metastasis. Also characteristic gene signatures were identified of HCV-HCC progression for early HCC diagnosis.A diagnostic molecular signature complementing conventional pathologic assessment was identified.

Hepatocyte growth factor gene-modified adipose-derived mesenchymal stem cells ameliorate radiation induced liver damage in a rat model.

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Jiamin Zhang

Full Text Available Liver damage caused by radiotherapy is associated with a high mortality rate, but no established treatment exists. Adipose-derived mesenchymal stem cells (ADSCs are capable of migration to injured tissue sites, where they aid in the repair of the damage. Hepatocyte growth factor (HGF is critical for damage repair due to its anti-apoptotic, anti-fibrotic and cell regeneration-promoting effects. This study was performed to investigate the therapeutic effects of HGF-overexpressing ADSCs on radiation-induced liver damage (RILD. ADSCs were infected with a lentivirus encoding HGF and HGF-shRNA. Sprague-Dawley (SD rats received 60Gy of irradiation to induce liver injury and were immediately given either saline, ADSCs, ADSCs + HGF or ADSCs + shHGF. Two days after irradiation, a significant reduction in apoptosis was observed in the HGF-overexpressing ADSC group compared with the RILD group, as assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL staining. Scanning electron microscopy showed chromatin condensation after irradiation, which was ameliorated in the group that received ADSCs and was reversed in the group that received HGF-overexpressing ADSCs. HGF-overexpressing ADSCs ameliorated radiation- induced liver fibrosis through down regulation of α-SMA and fibronectin. Hepatocyte regeneration was significantly improved in rats treated with ADSCs compared with rats from the RILD group, as assessed by Ki-67 immunohistochemistry. Rats that received HGF-overexpressing ADSCs showed an even greater level of hepatocyte regeneration. HGF-overexpressing ADSCs completely blocked the radiation-induced increase in the enzymes ALT and AST. The effect of mitigating RILD was compromised in the ADSC + shHGF group compared with the ADSC group. Altogether, these results suggest that HGF-overexpressing ADSCs can significantly improve RILD in a rat model, which may serve as a valuable therapeutic alternative.

Liver BCATm transgenic mouse model reveals the important role of the liver in maintaining BCAA homeostasis.

Science.gov (United States)

Ananieva, Elitsa A; Van Horn, Cynthia G; Jones, Meghan R; Hutson, Susan M

2017-02-01

Unlike other amino acids, the branched-chain amino acids (BCAAs) largely bypass first-pass liver degradation due to a lack of hepatocyte expression of the mitochondrial branched-chain aminotransferase (BCATm). This sets up interorgan shuttling of BCAAs and liver-skeletal muscle cooperation in BCAA catabolism. To explore whether complete liver catabolism of BCAAs may impact BCAA shuttling in peripheral tissues, the BCATm gene was stably introduced into mouse liver. Two transgenic mouse lines with low and high hepatocyte expression of the BCATm transgene (LivTg-LE and LivTg-HE) were created and used to measure liver and plasma amino acid concentrations and determine whether the first two BCAA enzymatic steps in liver, skeletal muscle, heart and kidney were impacted. Expression of the hepatic BCATm transgene lowered the concentrations of hepatic BCAAs while enhancing the concentrations of some nonessential amino acids. Extrahepatic BCAA metabolic enzymes and plasma amino acids were largely unaffected, and no growth rate or body composition differences were observed in the transgenic animals as compared to wild-type mice. Feeding the transgenic animals a high-fat diet did not reverse the effect of the BCATm transgene on the hepatic BCAA catabolism, nor did the high-fat diet cause elevation in plasma BCAAs. However, the high-fat-diet-fed BCATm transgenic animals experienced attenuation in the mammalian target of rapamycin (mTOR) pathway in the liver and had impaired blood glucose tolerance. These results suggest that complete liver BCAA metabolism influences the regulation of glucose utilization during diet-induced obesity. Copyright © 2016 Elsevier Inc. All rights reserved.

Insulin-like growth factor-II (IGF II) receptor from rat brain is of lower apparent molecular weight than the IGF II receptor from rat liver

International Nuclear Information System (INIS)

McElduff, A.; Poronnik, P.; Baxter, R.C.

1987-01-01

The binding subunits of the insulin and insulin-like growth factor-I (IGF I) receptors from rat brain are of lower molecular weight than the corresponding receptor in rat liver, possibly due to variations in sialic acid content. We have compared the IGF II receptor from rat brain and rat liver. The brain receptor is of smaller apparent mol wt (about 10 K) on sodium dodecyl sulfate polyacrylamide gel electrophoresis. This size difference is independent of ligand binding as it persists in iodinated and specifically immunoprecipitated receptors. From studies of wheat germ agglutinin binding and the effect of neuraminidase on receptor mobility, we conclude that this difference is not simply due to variations in sialic acid content. Treatment with endoglycosidase F results in reduction in the molecular size of both liver and brain receptors and after this treatment the aglycoreceptors are of similar size. We conclude that in rat brain tissue the IGF II receptor like the binding subunits of the insulin and IGF I receptors is of lower molecular size than the corresponding receptors in rat liver. This difference is due to differences in N-linked glycosylation

The regulation of cytoskeletal and liver-specific gene expression during liver regeneration and primary hepatocyte culture

International Nuclear Information System (INIS)

Robinson, G.S.

1989-01-01

The focus of this dissertation is to determine what role(s) the extracellular matrix and expression of certain cytoskeletal genes play in the regulation of hepatocyte growth and the maintenance of a differential state. The expression of several cytoskeletal and liver-specific genes was examined during liver regeneration and in hepatocyte cultures maintained in a hormonally-defined, serum-free medium and plated on two different matrices: rat tail collagen and the EHS matrix. During liver regeneration and in hepatocytes cultured on rat tail collagen, there was a dramatic increase in tubulin mRNA levels coincident with but not linked to DNA synthesis. The message levels for other cytoskeletal genes similarly increased, while a decrease was observed in the mRNA levels of the liver-specific genes, serum albumin and alpha 1 inhibitor III. Hepatocytes cultured on the EHS matrix resulted in the maintenance of low levels of cytoskeletal gene expression and high levels of liver-specific gene expression, similar to that observed in the normal liver. Results from subcellar fractionation and two-dimensional gel electrophoresis of 35 S-labelled proteins paralleled the results seen at the mRNA level. Preliminary work suggests that microtubule organization may play a role in the expression of the liver-specific genes which encode secreted proteins. These studies, which compare hepatocytes cultured on collagen or the EHS matrix gel, reveal that both cell-cell and cell-matrix interactions play a major role in the maintenance of the differential phenotype in hepatocytes

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 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.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.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 in ALF, emphasizing the close relationship between

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.

Modifying the Dietary Carbohydrate-to-Protein Ratio Alters the Postprandial Macronutrient Oxidation Pattern in Liver of AMPK-Deficient Mice.

Science.gov (United States)

Chalvon-Demersay, Tristan; Even, Patrick C; Chaumontet, Catherine; Piedcoq, Julien; Viollet, Benoit; Gaudichon, Claire; Tomé, Daniel; Foretz, Marc; Azzout-Marniche, Dalila

2017-09-01

Background: Hepatic AMP-activated kinase (AMPK) activity is sensitive to the dietary carbohydrate-to-protein ratio. However, the role of AMPK in metabolic adaptations to variations in dietary macronutrients remains poorly understood. Objective: The objective of this study was to determine the role of hepatic AMPK in the adaptation of energy metabolism in response to modulation of the dietary carbohydrate-to-protein ratio. Methods: Male 7-wk-old wild-type (WT) and liver AMPK-deficient (knockout) mice were fed either a normal-protein and normal-carbohydrate diet (NP-NC; 14% protein, 76% carbohydrate on an energy basis), a low-protein and high-carbohydrate diet (LP-HC; 5% protein, 85% carbohydrate), or a high-protein and low-carbohydrate diet (HP-LC; 55% protein, 35% carbohydrate) for 3 wk. During this period, after an overnight fast, metabolic parameters were measured and indirect calorimetry was performed in mice during the first hours after refeeding a 1-g calibrated meal of their own diet in order to investigate lipid and carbohydrate metabolism. Results: Knockout mice fed an LP-HC or HP-LC meal exhibited 24% and 8% lower amplitudes in meal-induced carbohydrate and lipid oxidation changes. By contrast, knockout mice fed an NP-NC meal displayed normal carbohydrate and lipid oxidation profiles. These mice exhibited a transient increase in hepatic triglycerides and a decrease in hepatic glycogen. These changes were associated with a 650% higher secretion of fibroblast growth factor 21 (FGF21) 2 h after refeeding. Conclusions: The consequences of hepatic AMPK deletion depend on the dietary carbohydrate-to-protein ratio. In mice fed the NP-NC diet, deletion of AMPK in the liver led to an adaptation of liver metabolism resulting in increased secretion of FGF21. These changes possibly compensated for the absence of hepatic AMPK, as these mice exhibited normal postprandial changes in carbohydrate and lipid oxidation. By contrast, in mice fed the LP-HC and HP-LC diets, the

Effect of physical training on liver expression of activin A and follistatin in a nonalcoholic fatty liver disease model in rats

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R.N. Silva

2014-09-01

Full Text Available Nonalcoholic fatty liver disease (NAFLD is characterized by fat accumulation in the liver and is associated with obesity and insulin resistance. Activin A is a member of the transforming growth factor beta (TGF-β superfamily and inhibits hepatocyte growth. Follistatin antagonizes the biological actions of activin. Exercise is an important therapeutic strategy to reduce the metabolic effects of obesity. We evaluated the pattern of activin A and follistatin liver expression in obese rats subjected to swimming exercise. Control rats (C and high-fat (HF diet-fed rats were randomly assigned to a swimming training group (C-Swim and HF-Swim or a sedentary group (C-Sed and HF-Sed. Activin βA subunit mRNA expression was significantly higher in HF-Swim than in HF-Sed rats. Follistatin mRNA expression was significantly lower in C-Swim and HF-Swim than in either C-Sed or HF-Sed animals. There was no evidence of steatosis or inflammation in C rats. In contrast, in HF animals the severity of steatosis ranged from grade 1 to grade 3. The extent of liver parenchyma damage was less in HF-Swim animals, with the severity of steatosis ranging from grade 0 to grade 1. These data showed that exercise may reduce the deleterious effects of a high-fat diet on the liver, suggesting that the local expression of activin-follistatin may be involved.

Rice LTG1 is involved in adaptive growth and fitness under low ambient temperature.

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Lu, Guangwen; Wu, Fu-Qing; Wu, Weixun; Wang, Hong-Jun; Zheng, Xiao-Ming; Zhang, Yunhui; Chen, Xiuling; Zhou, Kunneng; Jin, Mingna; Cheng, Zhijun; Li, Xueyong; Jiang, Ling; Wang, Haiyang; Wan, Jianmin

2014-05-01

Low temperature (LT) is one of the most prevalent factors limiting the productivity and geographical distribution of rice (Oryza sativa L.). Although significant progress has been made in elucidating the effect of LT on seed germination and reproductive development in rice, the genetic component affecting vegetative growth under LT remains poorly understood. Here, we report that rice cultivars harboring the dominant LTG1 (Low Temperature Growth 1) allele are more tolerant to LT (15-25°C, a temperature range prevalent in high-altitude, temperate zones and high-latitude areas), than those with the ltg1 allele. Using a map-based cloning strategy, we show that LTG1 encodes a casein kinase I. A functional nucleotide polymorphism was identified in the coding region of LTG1, causing a single amino acid substitution (I357K) that is associated with the growth rate, heading date and yield of rice plants grown at LT. We present evidence that LTG1 affects rice growth at LT via an auxin-dependent process(es). Furthermore, phylogenetic analysis of this locus suggests that the ltg1 haplotype arose before the domestication of rice in tropical climates. Together, our data demonstrate that LTG1 plays an important role in the adaptive growth and fitness of rice cultivars under conditions of low ambient temperature. © 2014 The Authors. The Plant Journal © 2014 John Wiley & Sons Ltd.

Role of IRAK-M in alcohol induced liver injury.

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Yipeng Wang

Full Text Available Increasing evidence suggests that innate immunity plays an important role in alcohol-induced liver injury and most studies have focused on positive regulation of innate immunity. The main objective of this study was to investigate the negative regulator of innate immunity, IL-1/Toll-like receptor (TLR signaling pathways and interleukin receptor-associated kinase-M (IRAK-M in alcoholic liver injury. We established an alcohol-induced liver injury model using wild type and IRAK-M deficient B6 mice and investigated the possible mechanisms. We found that in the absence of IRAK-M, liver damage by alcohol was worse with higher alanine transaminase (ALT, more immune cell infiltration and increased numbers of IFNγ producing cells. We also found enhanced phagocytic activity in CD68(+ cells. Moreover, our results revealed altered gut bacteria after alcohol consumption and this was more striking in the absence of IRAK-M. Our study provides evidence that IRAK-M plays an important role in alcohol-induced liver injury and IRAK-M negatively regulates the innate and possibly the adaptive immune response in the liver reacting to acute insult by alcohol. In the absence of IRAK-M, the hosts developed worse liver injury, enhanced gut permeability and altered gut microbiota.

Effects of Feeding Milk Replacer Ad Libitum or in Restricted Amounts for the First Five Weeks of Life on the Growth, Metabolic Adaptation, and Immune Status of Newborn Calves

Science.gov (United States)

Schäff, Christine T.; Gruse, Jeannine; Maciej, Josefine; Mielenz, Manfred; Wirthgen, Elisa; Hoeflich, Andreas; Schmicke, Marion; Pfuhl, Ralf; Jawor, Paulina; Stefaniak, Tadeusz

2016-01-01

The pre-weaning period is critical for calf health and growth, and intensive milk feeding programs may assist postnatal development by improving body growth and organ maturation. The aim of the present work was to study the effects of ad libitum milk replacer (MR) feeding on the growth, metabolic adaptation, health, and immune status of newborn calves. Twenty-eight newborn Holstein and Holstein x Charolais crossbred calves were fed ad libitum (ADLIB) or in restricted amounts (6 liters per day; RES) during the first five weeks of life. The MR intake in the ADLIB treatment was gradually reduced at weeks 6 and 7, and all calves then received 6 liters of MR per day until day 60. Blood samples were collected to measure the plasma concentrations of metabolites, insulin, insulin-like growth factor (IGF)-I and IGF binding proteins (IGFBP), immunoglobulins, and acute phase proteins. The expression of mRNA associated with both the somatotropic axis and gluconeogenic enzymes was measured in the liver on day 60. Intensive feeding improved MR intake and growth in ADLIB without influencing concentrate intake. Carcass weight, perirenal fat, and muscle mass were greater in ADLIB. Plasma concentrations of glucose, triglycerides, insulin, and IGF-I were greater, whereas plasma concentrations of β-hydroxybutyrate, total protein, albumin, urea, IGFBP-2 and -4, and fibrinogen were lower at distinct time points in ADLIB. The hepatic mRNA expression of cytosolic phosphoenolpyruvate carboxykinase was greater in ADLIB. Most metabolic and endocrine differences occurred during the MR feeding period, but a slightly greater concentrate intake was associated with increased plasma IGF-I and insulin at the end of the study. The immune and health status of the calves were not affected by MR feeding. However, increased plasma fibrinogen in the RES group suggested differences in the acute phase response. PMID:28036351

The limits of adaptation of functional protein synthesis to sever undernutrition

International Nuclear Information System (INIS)

Jahoor, F.; Bhattiprolu, S.; Reeds, P.; Forrester, T.; Boyne, M.

1994-01-01

Our goal is to determine how the stress of infections alters the adaptation to reduced food intake in children. We think that an important element is the need for hepatic synthesis of rapidly turning over acute-phase proteins, a critical factor in overall maintenance of host defenses. When the child's prior intake has been adequate, even though growth may temporarily cease, the presence of adequate amino acid stores in tissues allows the hepatic response to stress to be maintained at the same time as an adequate rate of synthesis of nutrient transport proteins. However, when the immune system is activated in a children whose nutrition is already suboptimal the ability of the liver to synthesize nutrient transport proteins is compromised thereby further impeding nutrient utilization. We will use stable isotope tracer methodology to determine the effects of severe protein energy malnutrition, with and without infection, on the rates of synthesis of nutrient transport proteins and acute-phase proteins in undernourished children at three time points during treatment; in the early resuscitative period, after appetite has returned, and at the end of the catch-up growth phase when normal growth has resumed. (author). 12 refs, 1 fig., 1 tab

The limits of adaptation of functional protein synthesis to sever undernutrition

Energy Technology Data Exchange (ETDEWEB)

Jahoor, F; Bhattiprolu, S; Reeds, P [Baylor Coll. of Medicine, Houston, TX (United States). Children` s Nutrition Research Centre; Forrester, T; Boyne, M [West Indies Univ., Mona (Jamaica). Tropical Metabolism Research Unit

1994-12-31

Our goal is to determine how the stress of infections alters the adaptation to reduced food intake in children. We think that an important element is the need for hepatic synthesis of rapidly turning over acute-phase proteins, a critical factor in overall maintenance of host defenses. When the child`s prior intake has been adequate, even though growth may temporarily cease, the presence of adequate amino acid stores in tissues allows the hepatic response to stress to be maintained at the same time as an adequate rate of synthesis of nutrient transport proteins. However, when the immune system is activated in a children whose nutrition is already suboptimal the ability of the liver to synthesize nutrient transport proteins is compromised thereby further impeding nutrient utilization. We will use stable isotope tracer methodology to determine the effects of severe protein energy malnutrition, with and without infection, on the rates of synthesis of nutrient transport proteins and acute-phase proteins in undernourished children at three time points during treatment; in the early resuscitative period, after appetite has returned, and at the end of the catch-up growth phase when normal growth has resumed. (author). 12 refs, 1 fig., 1 tab.

Bioartificial liver and liver transplantation: new modalities for the treatment of liver failure

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DING Yitao

2017-09-01

Full Text Available The main features of liver failure are extensive necrosis of hepatocytes, rapid disease progression, and poor prognosis, and at present, there are no effective drugs and methods for the treatment of liver failure. This article summarizes four treatment methods for liver failure, i.e., medical treatment, cell transplantation, liver transplantation, and artificial liver support therapy, and elaborates on the existing treatment methods. The current medical treatment regimen should be optimized; cell transplantation has not been used in clinical practice; liver transplantation is the most effective method, but it is limited by donor liver shortage and high costs; artificial liver can effectively remove toxic substances in human body. Therefore, this article puts forward artificial liver as a transition for liver transplantation; artificial liver can buy time for liver regeneration or liver transplantation and prolong patients′ survival time and thus has a promising future. The new treatment modality of bioartificial liver combined with liver transplantation may bring good news to patients with liver failure.

Transcriptome adaptation of group B Streptococcus to growth in human amniotic fluid.

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Izabela Sitkiewicz

Full Text Available BACKGROUND: Streptococcus agalactiae (group B Streptococcus is a bacterial pathogen that causes severe intrauterine infections leading to fetal morbidity and mortality. The pathogenesis of GBS infection in this environment is poorly understood, in part because we lack a detailed understanding of the adaptation of this pathogen to growth in amniotic fluid. To address this knowledge deficit, we characterized the transcriptome of GBS grown in human amniotic fluid (AF and compared it with the transcriptome in rich laboratory medium. METHODS: GBS was grown in Todd Hewitt-yeast extract medium and human AF. Bacteria were collected at mid-logarithmic, late-logarithmic and stationary growth phase. We performed global expression microarray analysis using a custom-made Affymetrix GeneChip. The normalized hybridization values derived from three biological replicates at each growth point were obtained. AF/THY transcript ratios representing greater than a 2-fold change and P-value exceeding 0.05 were considered to be statistically significant. PRINCIPAL FINDINGS: We have discovered that GBS significantly remodels its transcriptome in response to exposure to human amniotic fluid. GBS grew rapidly in human AF and did not exhibit a global stress response. The majority of changes in GBS transcripts in AF compared to THY medium were related to genes mediating metabolism of amino acids, carbohydrates, and nucleotides. The majority of the observed changes in transcripts affects genes involved in basic bacterial metabolism and is connected to AF composition and nutritional requirements of the bacterium. Importantly, the response to growth in human AF included significant changes in transcripts of multiple virulence genes such as adhesins, capsule, and hemolysin and IL-8 proteinase what might have consequences for the outcome of host-pathogen interactions. CONCLUSIONS/SIGNIFICANCE: Our work provides extensive new information about how the transcriptome of GBS responds

Nuclear receptor CAR (NR1I3) is essential for DDC-induced liver injury and oval cell proliferation in mouse liver.

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Yamazaki, Yuichi; Moore, Rick; Negishi, Masahiko

2011-11-01

The liver is endowed with the ability to regenerate hepatocytes in response to injury. When this regeneration ability is impaired during liver injury, oval cells, which are considered to be postnatal hepatic progenitors, proliferate and differentiate into hepatocytes. Here we have demonstrated that 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) activates the nuclear receptor constitutive active/androstane receptor (CAR), resulting in proliferation of oval cells in mouse liver. Activation of CAR by DDC was shown by hepatic nuclear CAR accumulation and cytochrome P450 (CYP)2B10 mRNA induction after feeding a 0.1% DDC-containing diet to Car(+/+) mice. After being fed the DDC diet, Car(+/+), but not Car(-/-) mice, developed severe liver injury and an A6 antibody-stained ductular reaction in an area around the portal tract. Oval cell proliferation was confirmed by laser capture microdissection and real-time PCR; mRNAs for the two oval cell markers epithelial cell adhesion molecule and TROP2 were specifically induced in the periportal region of DDC diet-fed Car(+/+), but not Car(-/-) mice. Although rates of both hepatocyte growth and death were initially enhanced only in DDC diet-fed Car(+/+) mice, growth was attenuated when oval cells proliferated, whereas death continued unabated. DDC-induced liver injury, which differs from other CAR activators such as phenobarbital, occurred in the periportal region where cells developed hypertrophy, accumulated porphyrin crystals and inflammation developed, all in association with the proliferation of oval cells. Thus, CAR provides an excellent experimental model for further investigations into its roles in liver regeneration, as well as the development of diseases such as hepatocellular carcinoma.

Adaptation of BAp crystal orientation to stress distribution in rat mandible during bone growth

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Nakano, T; Fujitani, W; Ishimoto, T [Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, 2-1, Yamada-oka, Suita, Osaka 565-0871 (Japan); Umakoshi, Y [National Institute for Materials Science, 1-2-1, Sengen, Tsukuba, Ibaragi, 305-0471 (Japan)], E-mail: nakano@mat.eng.osaka-u.ac.jp

2009-05-01

Biological apatite (BAp) c-axis orientation strongly depends on stress distribution in vivo and tends to align along the principal stress direction in bones. Dentulous mandible is subjected to a complicated stress condition in vivo during chewing but few studies have been carried out on the BAp c-axis orientation; so the adaptation of BAp crystal orientation to stress distribution was examined in rat dentulous mandible during bone growth and mastication. Female SD rats 4 to 14 weeks old were prepared, and the bone mineral density (BMD) and BAp crystal orientation were analyzed in a cross-section of mandible across the first molar focusing on two positions: separated from and just under the tooth root on the same cross-section perpendicular to the mesiodistal axis. The degree of BAp orientation was analyzed by a microbeam X-ray diffractometer using Cu-K{alpha} radiation equipped with a detector of curved one-dimensional PSPC and two-dimensional PSPC in the reflection and transmission optics, respectively. BMD quickly increased during bone growth up to 14 weeks, although it was independent of the position from the tooth root. In contrast, BAp crystal orientation strongly depended on the age and the position from the tooth root, even in the same cross-section and direction, especially along the mesiodistal and the biting axes. With increased biting stress during bone growth, the degree of BAp orientation increased along the mesiodistal axis in a position separated from the tooth root more than that near the tooth root. In contrast, BAp preferential alignment clearly appeared along the biting axis near the tooth root. We conclude that BAp orientation rather than BMD sensitively adapts to local stress distribution, especially from the chewing stress in vivo in the mandible.

TWEAK induces liver progenitor cell proliferation

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Jakubowski, Aniela; Ambrose, Christine; Parr, Michael; Lincecum, John M.; Wang, Monica Z.; Zheng, Timothy S.; Browning, Beth; Michaelson, Jennifer S.; Baestcher, Manfred; Wang, Bruce; Bissell, D. Montgomery; Burkly, Linda C.

2005-01-01

Progenitor (“oval”) cell expansion accompanies many forms of liver injury, including alcohol toxicity and submassive parenchymal necrosis as well as experimental injury models featuring blocked hepatocyte replication. Oval cells can potentially become either hepatocytes or biliary epithelial cells and may be critical to liver regeneration, particularly when hepatocyte replication is impaired. The regulation of oval cell proliferation is incompletely understood. Herein we present evidence that a TNF family member called TWEAK (TNF-like weak inducer of apoptosis) stimulates oval cell proliferation in mouse liver through its receptor Fn14. TWEAK has no effect on mature hepatocytes and thus appears to be selective for oval cells. Transgenic mice overexpressing TWEAK in hepatocytes exhibit periportal oval cell hyperplasia. A similar phenotype was obtained in adult wild-type mice, but not Fn14-null mice, by administering TWEAK-expressing adenovirus. Oval cell expansion induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was significantly reduced in Fn14-null mice as well as in adult wild-type mice with a blocking anti-TWEAK mAb. Importantly, TWEAK stimulated the proliferation of an oval cell culture model. Finally, we show increased Fn14 expression in chronic hepatitis C and other human liver diseases relative to its expression in normal liver, which suggests a role for the TWEAK/Fn14 pathway in human liver injury. We conclude that TWEAK has a selective mitogenic effect for liver oval cells that distinguishes it from other previously described growth factors. PMID:16110324

Proteomic profiling of liver from Elaphe taeniura, a common snake in eastern and southeastern Asia

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Liang Chen

2013-01-01

Full Text Available Snake liver has been implicated in the adaptation of snakes to a variety of habitats. However, to date, there has been no systematic analysis of snake liver proteins. In this study, we undertook a proteomic analysis of liver from the colubrid snake Elaphe taeniura using a combination of two-dimensional electrophoresis (2-DE and matrix-assisted laser desorption/ionization time of flightmass spectrometry (MALDI-TOF MS. We also constructed a local protein sequence database based on transcriptome sequencing to facilitate protein identification. Of the 268 protein spots revealed by 2-DE 109 gave positive MS signals, 84 of which were identified by searching the NCBInr, Swiss-Prot and local databases. The other 25 protein spots could not be identified, possibly because their transcripts were not be stable enough to be detected by transcriptome sequencing. GO analysis showed that most proteins may be involved in binding, catalysis, cellular processes and metabolic processes. Forty-two of the liver proteins identified were found in other reptiles and in amphibians. The findings of this study provide a good reference map of snake liver proteins that will be useful in molecular investigations of snake physiology and adaptation.

Monocytes with angiogenic potential are selectively induced by liver resection and accumulate near the site of liver regeneration.

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Schauer, Dominic; Starlinger, Patrick; Zajc, Philipp; Alidzanovic, Lejla; Maier, Thomas; Buchberger, Elisabeth; Pop, Lorand; Gruenberger, Birgit; Gruenberger, Thomas; Brostjan, Christine

2014-10-30

Monocytes reportedly contribute to liver regeneration. Three subsets have been identified to date: classical, intermediate, non-classical monocytes. The intermediate population and a subtype expressing TIE2 (TEMs) were suggested to promote angiogenesis. In a clinical setting, we investigated which monocyte subsets are regulated after liver resection and correlate with postoperative liver function. In 38 patients monocyte subsets were evaluated in blood and subhepatic wound fluid by flow cytometry before and 1-3 days after resection of colorectal liver metastases. The monocyte-regulating cytokines macrophage colony stimulating factor (M-CSF), transforming growth factor beta 1 (TGFβ1), and angiopoietin 2 (ANG-2) were measured in patient plasma by ELISA. C-reactive protein (CRP) and liver function parameters were retrieved from routine hospital analyses. On post-operative day (POD) 1 blood monocytes shifted to significantly elevated levels of intermediate monocytes. In wound fluid, a delayed surge in intermediate monocytes was detected by POD 3. Furthermore, TEMs were highly enriched in wound fluid as compared to circulation. CRP and M-CSF levels were substantially increased in patient blood after surgery and correlated significantly with the frequency of intermediate monocytes. In addition, liver function parameters showed a significant association with intermediate monocyte levels on POD 3. The reportedly pro-angiogenic subsets of monocytes are selectively increased upon liver resection and accumulate next to the site of liver regeneration. As previously proposed by in vitro experiments, the release of CRP and M-CSF may trigger the induction of intermediate monocytes. The correlation with liver parameters points to a functional involvement of these monocyte populations in liver regeneration which warrants further investigation.

Plant adaptation to temperature and photoperiod

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O. JUNTTILA

2008-12-01

Full Text Available Plants respond to environmental conditions both by adaptation and by acclimation. The ability of the plants to grow, reproduce and survive under changing climatic conditions depends on the efficiency of adaptation and acclimation. The adaptation of developmental processes in plants to temperature and photoperiod is briefly reviewed. In annual plants this adaptation is related to growth capacity and to the timing of reproduction. In perennial plants growing under northern conditions, adaptation of the annual growth cycle to the local climatic cycle is of primary importance. Examples of the role of photothermal conditions in regulation of these phenological processes are given and discussed. The genetic and physiological bases for climatic adaptation in plants are briefly examined.;

Precursors for liver gluconeogenesis in periparturient dairy cows

DEFF Research Database (Denmark)

Larsen, Mogens; Kristensen, Niels Bastian

2013-01-01

-organ transfer of nitrogen from catabolised AA. AAs seem to be prioritised for anabolic purposes, indicating the relevance of investigating effects of supplying additional protein to post partum dairy cows. Combining data from quantitative and qualitative experimental techniques on L-lactate metabolism point...... to the conclusion that the quantitatively most important adaptation of metabolism to support the increased glucose demand in the immediate post partum period is endogenous recycling of glucogenic carbon through lactate. This is mediated by a dual site of adaptation of metabolism in the liver and in the peripheral...

Treatment and follow-up of children with common chronic liver diseases in children

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LYU Xintong

2017-10-01

Full Text Available Chronic liver diseases in children greatly affect their growth and development and quality of life in future. There are many causes of chronic liver diseases in children, and such causes, diet, and treatment guidance are closely associated with prognosis. This article discusses the guidance and follow-up of common chronic liver diseases in children, such as infantile cholestatic liver disease, chronic hepatitis B, hepatolenticular degeneration, and nonalcoholic fatter liver disease, in order to deepen the understanding of these diseases among patients, raise the awareness of follow-up in medical staff, and improve the cure rate of liver diseases with different causes and children’s quality of life.

The Dynamics of Glutathione Species and Ophthalmate Concentrations in Plasma from the VX2 Rabbit Model of Secondary Liver Tumors

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R. Abbas

2011-01-01

Full Text Available Purpose. Available tumor markers have low sensitivity/specificity for the diagnosis of liver tumors. The present study was designed to evaluate the oxidoreductive status of the liver as surrogates of tumor subsistence and growth. Methods. Glutathione species (GSH:GSSG, ophthalmate (OA concentrations, and their turnover were measured in plasma of rabbits (n=6 in their healthy state and in the state of tumor growth after implantation of the VX2 carcinoma in their liver. Tumors were allowed to grow for a period of 14 days when rabbits were sacrificed. Livers were removed and cysteine concentration was measured in liver tissue. Results. Tumor growth was found in 100% of the rabbits. Concentration and labeling of GSH/GSSG were similar in experimental animals before and after tumor implantation and to sham animals. In contrast, OA concentration increased significantly in experimental animals after tumor implantation when compared to same animals prior to tumor implantation and to sham animals (P<.05. The concentration of cysteine, a precursor of GSH, was found to be significantly lower in the liver tissue adjacent to the tumor (P<.05. Conclusion. Disturbances in the oxidoreductive state of livers appear to be a surrogate of early tumor growth.

Mushroom poisoning in children: liver MDCT findings in three cases

International Nuclear Information System (INIS)

Cakir, Banu; Kirbas, Ismail; Cevik, Belma; Teksam, Mehmet; Coskun, Mehmet

2007-01-01

Wild mushroom poisoning occurs quite frequently in Turkey, usually during late summer and autumn when climatic conditions favour fungal growth. We report the MDCT findings of the liver in three children after mushroom poisoning. In all three patients, precontrast MDCT findings showed diffuse reduction of hepatic attenuation compared with the spleen. Contrast-enhanced MDCT images showed homogeneous contrast enhancement of the liver. All three patients recovered after medical treatment. A follow-up precontrast MDCT examination was performed in one patient in whom the density of the liver parenchyma had returned to normal. (orig.)

Optimizing Perfusion-Decellularization Methods of Porcine Livers for Clinical-Scale Whole-Organ Bioengineering

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Qiong Wu

2015-01-01

Full Text Available Aim. To refine the decellularization protocol of whole porcine liver, which holds great promise for liver tissue engineering. Methods. Three decellularization methods for porcine livers (1% sodium dodecyl sulfate (SDS, 1% Triton X-100 + 1% sodium dodecyl sulfate, and 1% sodium deoxycholate + 1% sodium dodecyl sulfate were studied. The obtained liver scaffolds were processed for histology, residual cellular content analysis, and extracellular matrix (ECM components evaluation to investigate decellularization efficiency and ECM preservation. Rat primary hepatocytes were seeded into three kinds of scaffold to detect the biocompatibility. Results. The whole liver decellularization was successfully achieved following all three kinds of treatment. SDS combined with Triton had a high efficacy of cellular removal and caused minimal disruption of essential ECM components; it was also the most biocompatible procedure for primary hepatocytes. Conclusion. We have refined a novel, standardized, time-efficient, and reproducible protocol for the decellularization of whole liver which can be further adapted to liver tissue engineering.

Branched-Chain Amino Acids Ameliorate Fibrosis and Suppress Tumor Growth in a Rat Model of Hepatocellular Carcinoma with Liver Cirrhosis

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Cha, Jung Hoon; Bae, Si Hyun; Kim, Hye Lim; Park, Na Ri; Choi, Eun Suk; Jung, Eun Sun; Choi, Jong Young; Yoon, Seung Kew

2013-01-01

Purpose Recent studies have revealed that branched-chain amino acids (BCAA) reduce the development of hepatocellular carcinoma (HCC) in patients with obesity and hepatitis C virus infection by improving insulin resistance (IR). The aim of this study was to examine the anti-cancer and anti-fibrotic effects of BCAA on the development of diethylnitrosamine (DEN)-induced HCC and liver cirrhosis in a rat model. Methods Male SD rats received weekly intraperitoneal injections of DEN (50 mg/kg of body weight) for 16 weeks to induce HCC. They were fed a diet containing 3% casein, 3% or 6% BCAA for 13 weeks beginning 6 weeks after DEN administration. DEN was used to induce HCC through stepwise development from cirrhosis to HCC. The effect of BCAA was evaluated in tumor tissues by histopathologic analyses, reverse transcription-polymerase chain reaction, and Western blotting. Results The mean area and number of dysplastic nodules (DNs) and tumors in the casein group tended to be larger than those in the BCAA group 16 weeks after DEN administration. The mean fibrotic area in the BCAA group was smaller than that in the casein group. The BCAA group showed decreased mRNA levels for markers of fibrosis, angiogenesis, and apoptosis inhibition. Compared with the casein group, the BCAA group had lower levels of α-smooth muscle actin, vascular endothelial growth factor, p-β-catenin, p-p38 mitogen-activated protein kinase, proliferating cell nuclear antigen, and caspase-3 protein expression, as well as a higher level of cleaved caspase-3 protein expression. Conclusions BCAA supplementation of the diet ameliorated liver fibrosis and HCC development in a DEN-induced rat model of HCC with liver cirrhosis, but not in the IR model. These results provide a rationale for anti-fibrosis and chemoprevention using BCAA treatment for HCC with liver cirrhosis, as well as decreasing the ammonia level. PMID:24223741

Branched-chain amino acids ameliorate fibrosis and suppress tumor growth in a rat model of hepatocellular carcinoma with liver cirrhosis.

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Jung Hoon Cha

Full Text Available PURPOSE: Recent studies have revealed that branched-chain amino acids (BCAA reduce the development of hepatocellular carcinoma (HCC in patients with obesity and hepatitis C virus infection by improving insulin resistance (IR. The aim of this study was to examine the anti-cancer and anti-fibrotic effects of BCAA on the development of diethylnitrosamine (DEN-induced HCC and liver cirrhosis in a rat model. METHODS: Male SD rats received weekly intraperitoneal injections of DEN (50 mg/kg of body weight for 16 weeks to induce HCC. They were fed a diet containing 3% casein, 3% or 6% BCAA for 13 weeks beginning 6 weeks after DEN administration. DEN was used to induce HCC through stepwise development from cirrhosis to HCC. The effect of BCAA was evaluated in tumor tissues by histopathologic analyses, reverse transcription-polymerase chain reaction, and Western blotting. RESULTS: The mean area and number of dysplastic nodules (DNs and tumors in the casein group tended to be larger than those in the BCAA group 16 weeks after DEN administration. The mean fibrotic area in the BCAA group was smaller than that in the casein group. The BCAA group showed decreased mRNA levels for markers of fibrosis, angiogenesis, and apoptosis inhibition. Compared with the casein group, the BCAA group had lower levels of α-smooth muscle actin, vascular endothelial growth factor, p-β-catenin, p-p38 mitogen-activated protein kinase, proliferating cell nuclear antigen, and caspase-3 protein expression, as well as a higher level of cleaved caspase-3 protein expression. CONCLUSIONS: BCAA supplementation of the diet ameliorated liver fibrosis and HCC development in a DEN-induced rat model of HCC with liver cirrhosis, but not in the IR model. These results provide a rationale for anti-fibrosis and chemoprevention using BCAA treatment for HCC with liver cirrhosis, as well as decreasing the ammonia level.

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...

Analysis of the kinetics of sup(99m)Tc-HIDA using an adaptive model

International Nuclear Information System (INIS)

Misochko, I.V.; Gordeev, V.F.; Kharlap, V.I.; Toropchina, I.A.

1985-01-01

The paper is concerned with the results of assaying hepatocyte function on the basis of an adaptive pharmacokinetic model worked out by the authors. Hepatoscintigraphy with sup(99m)Tc-HIDA was used in 3 phases: the vascular phase of radiopharmaceutical transport (the 1st min of investigation, scintigrams with a 2 s interval), the parenchymatous phase (with a 20 s interval in subsequent 10 min), the biliary phase (with a 3 min interval). The hepatocytic phase of sUp(99m)Tc-HIDA transport was evaluated on the basis of the adaptive 5-compartmental model calculating the value of transpopt constants. In terms of differential diagnosis, the intercompartmental constants Ksub(1,2) (blood-liver) and Ksub(2,1) (liver-blood) turned out to be the most informative. The assaying of hepatocyte transport function using the proposed adaptive model helps to define the degree of liver involvement in a pathological process, to choose the therapeutic tactics and method, to evaluate its efficacy and to predict possible complications

Neonatal cardiovascular system adaptation in babies with intrauterine growth retardation

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I. N. Petrova

2016-01-01

Full Text Available Objective: to reveal the adaptive features of the cardiovascular system in newborn infants with intrauterine growth retardation (IUGR on the basis of a clinical instrumental study.Subjects and methods. A study group included 100 newborn infants with IUGR; a control group consisted of 40 babies with normal anthropometric measurements at birth. Medical history and clinical data and electrocardiographic and echocardiographic findings were analyzed.Results. All the examinees with IUGR had manifestations of cardiovascular system dysadaptation. There was a high rate of electrocardiographic changes, such as cardiac arrhythmias; low voltage; systolic overload of the right heart and left ventricle; signs of ventricular hypertrophy; and transient myocardial ischemia. The specific features of cardiac hemodynamics were decreased sizes of the left ventricle, lower parameters of its systolic function, and longer functioning of fetal communications.Conclusion. IUGR is associated with the development of cardiovascular system dysadaptation syndrome, which is due to prior perinatal hypoxia. The findings necessitate a follow-up of children by involving a cardiologist.

High resolution crop growth simulation for identification of potential adaptation strategies under climate change

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Kim, K. S.; Yoo, B. H.

2016-12-01

Impact assessment of climate change on crop production would facilitate planning of adaptation strategies. Because socio-environmental conditions would differ by local areas, it would be advantageous to assess potential adaptation measures at a specific area. The objectives of this study was to develop a crop growth simulation system at a very high spatial resolution, e.g., 30 m, and to assess different adaptation options including shift of planting date and use of different cultivars. The Decision Support System for Agrotechnology Transfer (DSSAT) model was used to predict yields of soybean and maize in Korea. Gridded data for climate and soil were used to prepare input data for the DSSAT model. Weather input data were prepared at the resolution of 30 m using bilinear interpolation from gridded climate scenario data. Those climate data were obtained from Korean Meteorology Administration. Spatial resolution of temperature and precipitation was 1 km whereas that of solar radiation was 12.5 km. Soil series data at the 30 m resolution were obtained from the soil database operated by Rural Development Administration, Korea. The SOL file, which is a soil input file for the DSSAT model was prepared using physical and chemical properties of a given soil series, which were available from the soil database. Crop yields were predicted by potential adaptation options based on planting date and cultivar. For example, 10 planting dates and three cultivars were used to identify ideal management options for climate change adaptation. In prediction of maize yield, combination of 20 planting dates and two cultivars was used as management options. Predicted crop yields differed by site even within a relatively small region. For example, the maximum of average yields for 2001-2010 seasons differed by sites In a county of which areas is 520 km2 (Fig. 1). There was also spatial variation in the ideal management option in the region (Fig. 2). These results suggested that local

Ethanol and liver: Recent insights into the mechanisms of ethanol-induced fatty liver

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Liu, Jinyao

2014-01-01

Alcoholic fatty liver disease (AFLD), a potentially pathologic condition, can progress to steatohepatitis, fibrosis, and cirrhosis, leading to an increased probability of hepatic failure and death. Alcohol induces fatty liver by increasing the ratio of reduced form of nicotinamide adenine dinucleotide to oxidized form of nicotinamide adenine dinucleotide in hepatocytes; increasing hepatic sterol regulatory element-binding protein (SREBP)-1, plasminogen activator inhibitor (PAI)-1, and early growth response-1 activity; and decreasing hepatic peroxisome proliferator-activated receptor-α activity. Alcohol activates the innate immune system and induces an imbalance of the immune response, which is followed by activated Kupffer cell-derived tumor necrosis factor (TNF)-α overproduction, which is in turn responsible for the changes in the hepatic SREBP-1 and PAI-1 activity. Alcohol abuse promotes the migration of bone marrow-derived cells (BMDCs) to the liver and then reprograms TNF-α expression from BMDCs. Chronic alcohol intake triggers the sympathetic hyperactivity-activated hepatic stellate cell (HSC) feedback loop that in turn activates the HSCs, resulting in HSC-derived TNF-α overproduction. Carvedilol may block this feedback loop by suppressing sympathetic activity, which attenuates the progression of AFLD. Clinical studies evaluating combination therapy of carvedilol with a TNF-α inhibitor to treat patients with AFLD are warranted to prevent the development of alcoholic liver disease. PMID:25356030

Oxidative damage in liver after perinatal intoxication with lead and/or cadmium.

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Massó, Elvira Luján; Corredor, Laura; Antonio, Maria Teresa

2007-01-01

Lead acetate (300 mg Pb/L) and/or cadmium acetate (10mg Cd/L) in blood and liver were administrated as drinking water to pregnant Wistar rats from day 1 of pregnancy to parturition (day 0) or until weaning (day 21), to investigate the toxic effects in blood and in the liver. Both metals produced mycrocitic anaemia in the pups as well as oxidative damage in the liver, as suggested by the significant increase in TBARS production and the high catalase activity. Moreover, intense alkaline and acid phosphatase activity, used as biomarkers of liver adaptation to damaging factors, was observed. In addition, the toxikinetics are different for Pb and Cd: while Cd is a hepatotoxic from day 0, Pb is not until day 21. Finally, simultaneous perinatal administration of both metals seems to protect, at least, in the liver TBARS production against the toxicity produced by Cd or Pb separately.

Short-term effect of recombinant human growth hormone in patients with alcoholic cirrhosis

DEFF Research Database (Denmark)

Møller, S; Becker, U; Grønbaek, M

1994-01-01

As growth hormone possesses anabolic properties that are active on protein metabolism, and thus of potential benefit to patients with chronic liver disease, we determined the metabolic effects of recombinant human growth hormone on insulin-like growth factor-I (IGF-I) its specific binding proteins......, and liver function. Twenty consecutive patients with cirrhosis were randomized to recombinant human growth hormone (Norditropin, 4 I.U. twice daily) subcutaneously for 6 weeks (n = 10) or conventional medical treatment (n = 10). The serum concentrations of insulin-like growth factor-I in the recombinant...... patients as well as in controls, whereas no change in insulin-like growth factor binding protein-1 concentrations was found. No significant changes were seen in the area under the curve for biochemical liver function tests. We conclude that administration of recombinant human growth hormone induces...

Portal Vein Embolization with Contralateral Application of Stem Cells Facilitates Increase of Future Liver Remnant Volume in Patients with Liver Metastases

International Nuclear Information System (INIS)

Ludvík, Jaroslav; Duras, Petr; Třeška, Vladislav; Matoušková, Táňa; Brůha, Jan; Fichtl, Jakub; Lysák, Daniel; Ferda, Jiří; Baxa, Jan

2017-01-01

ObjectivesThis study aimed to evaluate the progress of future liver remnant volume (FLRV) in patients with liver metastases after portal vein embolization (PVE) with the application of hematopoietic stem cells (HSCs) and compare it with a patients control group after PVE only.MethodsTwenty patients (group 1) underwent PVE with contralateral HSC application. Subsequently, CT volumetry with the determination of FLRV was performed at weekly intervals, in total three weeks. A sample of twenty patients (group 2) who underwent PVE without HSC application was used as a control group.ResultsThe mean of FLRV increased by 173.2 mL during three weeks after the PVE/HSC procedure, whereas by 98.9 mL after PVE only (p = 0.015). Furthermore, the mean daily growth of FLRV by 7.6 mL in group 1 was significantly higher in comparison with 4.1 mL in group 2 (p = 0.007).ConclusionsPVE with the application of HSC significantly facilitates growth of FLRV in comparison with PVE only. This method could be one of the new suitable approaches to increase the resectability of liver tumours.

Portal Vein Embolization with Contralateral Application of Stem Cells Facilitates Increase of Future Liver Remnant Volume in Patients with Liver Metastases

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Ludvík, Jaroslav, E-mail: ludvikj@fnplzen.cz; Duras, Petr [Charles University, Department of Imaging Methods, University Hospital and Faculty of Medicine in Pilsen (Czech Republic); Třeška, Vladislav [Charles University, Department of Surgery, University Hospital and Faculty of Medicine in Pilsen (Czech Republic); Matoušková, Táňa [Charles University, Department of Imaging Methods, University Hospital and Faculty of Medicine in Pilsen (Czech Republic); Brůha, Jan; Fichtl, Jakub [Charles University, Department of Surgery, University Hospital and Faculty of Medicine in Pilsen (Czech Republic); Lysák, Daniel [Charles University, Department of Haemato-Oncology, University Hospital and Faculty of Medicine in Pilsen (Czech Republic); Ferda, Jiří; Baxa, Jan [Charles University, Department of Imaging Methods, University Hospital and Faculty of Medicine in Pilsen (Czech Republic)

2017-05-15

ObjectivesThis study aimed to evaluate the progress of future liver remnant volume (FLRV) in patients with liver metastases after portal vein embolization (PVE) with the application of hematopoietic stem cells (HSCs) and compare it with a patients control group after PVE only.MethodsTwenty patients (group 1) underwent PVE with contralateral HSC application. Subsequently, CT volumetry with the determination of FLRV was performed at weekly intervals, in total three weeks. A sample of twenty patients (group 2) who underwent PVE without HSC application was used as a control group.ResultsThe mean of FLRV increased by 173.2 mL during three weeks after the PVE/HSC procedure, whereas by 98.9 mL after PVE only (p = 0.015). Furthermore, the mean daily growth of FLRV by 7.6 mL in group 1 was significantly higher in comparison with 4.1 mL in group 2 (p = 0.007).ConclusionsPVE with the application of HSC significantly facilitates growth of FLRV in comparison with PVE only. This method could be one of the new suitable approaches to increase the resectability of liver tumours.

A small population of liver endothelial cells undergoes endothelial-to-mesenchymal transition in response to chronic liver injury.

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Ribera, Jordi; Pauta, Montse; Melgar-Lesmes, Pedro; Córdoba, Bernat; Bosch, Anna; Calvo, Maria; Rodrigo-Torres, Daniel; Sancho-Bru, Pau; Mira, Aurea; Jiménez, Wladimiro; Morales-Ruiz, Manuel

2017-11-01

Rising evidence points to endothelial-to-mesenchymal transition (EndMT) as a significant source of the mesenchymal cell population in fibrotic diseases. In this context, we hypothesized that liver endothelial cells undergo EndMT during fibrosis progression. Cirrhosis in mice was induced by CCl 4 A transgenic mouse expressing a red fluorescent protein reporter under the control of Tie2 promoter (Tie2-tdTomato) was used to trace the acquisition of EndMT. Sinusoidal vascular connectivity was evaluated by intravital microscopy and high-resolution three-dimensional confocal microscopy. A modest but significant fraction of liver endothelial cells from both cirrhotic patients and CCl 4 -treated Tie2-tdTomato mice acquired an EndMT phenotype characterized by the coexpression of CD31 and α-smooth muscle actin, compared with noncirrhotic livers. Bone morphogenetic protein-7 (BMP-7) inhibited the acquisition of EndMT induced by transforming growth factor-β1 (TGF-β1) treatment in cultured primary mouse liver endothelial cells from control mice. EndMT was also reduced significantly in vivo in cirrhotic Tie2-tdTomato mice treated intraperitoneally with BMP-7 compared with untreated mice (1.9 ± 0.2 vs. 3.8 ± 0.3%, respectively; P livers correlated with a significant decrease in liver fibrosis ( P livers in both animal models and patients. BMP-7 treatment decreases the occurrence of the EndMT phenotype and has a positive impact on the severity of disease by reducing fibrosis and sinusoidal vascular disorganization. NEW & NOTEWORTHY A subpopulation of liver endothelial cells from cirrhotic patients and mice with liver fibrosis undergoes endothelial-to-mesenchymal transition. Liver endothelial cells from healthy mice could transition into a mesenchymal phenotype in culture in response to TGF-β1 treatment. Fibrotic livers treated chronically with BMP-7 showed lower EndMT acquisition, reduced fibrosis, and improved vascular organization. Copyright © 2017 the American

The impact of surgical resection of the primary tumor on the development of synchronous colorectal liver metastasis: a systematic review.

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Pinson, H; Cosyns, S; Ceelen, Wim P

2018-05-22

In recent years different therapeutic strategies for synchronously liver metastasized colorectal cancer were described. Apart from the classical staged surgical approach, simultaneous and liver-first strategies are now commonly used. One theoretical drawback of the classical approach is, however, the stimulatory effect on liver metastases growth that may result from resection of the primary tumour. This systematic review, therefore, aims to investigate the current insights on the stimulatory effects of colorectal surgery on the growth of synchronous colorectal liver metastases in humans. The systematic review was conducted according to the PRISMA statement. A literature search was performed using PubMed and Embase. Articles investigating the effects of colorectal surgery on synchronous colorectal liver metastases were included. Primary endpoints were metastatic tumor volume, metabolic and proliferative activity and tumour vascularization. Four articles meeting the selection criteria were found involving 200 patients. These studies investigate the effects of resection of the primary tumour on synchronous liver metastases using histological and radiological techniques. These papers support a possible stimulatory effect of resection of the primary tumor. Some limited evidence supports the hypothesis that colorectal surgery might stimulate the growth and development of synchronous colorectal liver metastases.

Liver transplant for cholestatic liver diseases.

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Carrion, Andres F; Bhamidimarri, Kalyan Ram

2013-05-01

Cholestatic liver diseases include a group of diverse disorders with different epidemiology, pathophysiology, clinical course, and prognosis. Despite significant advances in the clinical care of patients with cholestatic liver diseases, liver transplant (LT) remains the only definitive therapy for end-stage liver disease, regardless of the underlying cause. As per the United Network for Organ Sharing database, the rate of cadaveric LT for cholestatic liver disease was 18% in 1991, 10% in 2000, and 7.8% in 2008. This review summarizes the available evidence on various common and rare cholestatic liver diseases, disease-specific issues, and pertinent aspects of LT. Copyright © 2013 Elsevier Inc. All rights reserved.

Augmenter of liver regeneration (ALR) protects human hepatocytes against apoptosis

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Ilowski, Maren [Liver Regeneration Group, Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Kleespies, Axel [Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Toni, Enrico N. de [Department of Medicine II, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Donabauer, Barbara [Liver Regeneration Group, Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Jauch, Karl-Walter [Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Hengstler, Jan G. [Leibniz Research Centre for Working Environment and Human Factors, Technical University, Dortmund (Germany); Thasler, Wolfgang E., E-mail: wolfgang.thasler@med.uni-muenchen.de [Liver Regeneration Group, Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany)

2011-01-07

Research highlights: {yields} ALR decreases cytochrome c release from mitochondria. {yields} ALR protects hepatocytes against apoptosis induction by ethanol, TRAIL, anti-Apo, TGF-{beta} and actinomycin D. {yields} ALR exerts a liver-specific anti-apoptotic effect. {yields} A possible medical usage of ALR regarding protection of liver cells during apoptosis inducing therapies. -- Abstract: Augmenter of liver regeneration (ALR) is known to support liver regeneration and to stimulate proliferation of hepatocytes. However, it is not known if ALR exerts anti-apoptotic effects in human hepatocytes and whether this protective effect is cell type specific. This is relevant, because compounds that protect the liver against apoptosis without undesired effects, such as protection of metastatic tumour cells, would be appreciated in several clinical settings. Primary human hepatocytes (phH) and organotypic cancer cell lines were exposed to different concentrations of apoptosis inducers (ethanol, TRAIL, anti-Apo, TGF-{beta}, actinomycin D) and cultured with or without recombinant human ALR (rhALR). Apoptosis was evaluated by the release of cytochrome c from mitochondria and by FACS with propidium iodide (PI) staining. ALR significantly decreased apoptosis induced by ethanol, TRAIL, anti-Apo, TGF-{beta} and actinomycin D. Further, the anti-apoptotic effect of ALR was observed in primary human hepatocytes and in HepG2 cells but not in bronchial (BC1), colonic (SW480), gastric (GC1) and pancreatic (L3.6PL) cell lines. Therefore, the hepatotrophic growth factor ALR acts in a liver specific manner with regards to both its mitogenic and its anti-apoptotic effect. Unlike the growth factors HGF and EGF, rhALR acts in a liver specific manner. Therefore, ALR is a promising candidate for further evaluation as a possible hepatoprotective factor in clinical settings.

Augmenter of liver regeneration (ALR) protects human hepatocytes against apoptosis

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Ilowski, Maren; Kleespies, Axel; Toni, Enrico N. de; Donabauer, Barbara; Jauch, Karl-Walter; Hengstler, Jan G.; Thasler, Wolfgang E.

2011-01-01

Research highlights: → ALR decreases cytochrome c release from mitochondria. → ALR protects hepatocytes against apoptosis induction by ethanol, TRAIL, anti-Apo, TGF-β and actinomycin D. → ALR exerts a liver-specific anti-apoptotic effect. → A possible medical usage of ALR regarding protection of liver cells during apoptosis inducing therapies. -- Abstract: Augmenter of liver regeneration (ALR) is known to support liver regeneration and to stimulate proliferation of hepatocytes. However, it is not known if ALR exerts anti-apoptotic effects in human hepatocytes and whether this protective effect is cell type specific. This is relevant, because compounds that protect the liver against apoptosis without undesired effects, such as protection of metastatic tumour cells, would be appreciated in several clinical settings. Primary human hepatocytes (phH) and organotypic cancer cell lines were exposed to different concentrations of apoptosis inducers (ethanol, TRAIL, anti-Apo, TGF-β, actinomycin D) and cultured with or without recombinant human ALR (rhALR). Apoptosis was evaluated by the release of cytochrome c from mitochondria and by FACS with propidium iodide (PI) staining. ALR significantly decreased apoptosis induced by ethanol, TRAIL, anti-Apo, TGF-β and actinomycin D. Further, the anti-apoptotic effect of ALR was observed in primary human hepatocytes and in HepG2 cells but not in bronchial (BC1), colonic (SW480), gastric (GC1) and pancreatic (L3.6PL) cell lines. Therefore, the hepatotrophic growth factor ALR acts in a liver specific manner with regards to both its mitogenic and its anti-apoptotic effect. Unlike the growth factors HGF and EGF, rhALR acts in a liver specific manner. Therefore, ALR is a promising candidate for further evaluation as a possible hepatoprotective factor in clinical settings.

Liver transplant

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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 ...

Hemolysis, Elevated Liver Enzymes, and Low Platelets, Severe Fetal Growth Restriction, Postpartum Subarachnoid Hemorrhage, and Craniotomy: A Rare Case Report and Systematic Review

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Shadi Rezai

2017-01-01

Full Text Available Introduction. Hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome is a relatively uncommon but traumatic condition occurring in the later stage of pregnancy as a complication of severe preeclampsia or eclampsia. Prompt brain computed tomography (CT or magnetic resonance imaging (MRI and a multidisciplinary management approach are required to improve perinatal outcome. Case. A 37-year-old, Gravida 6, Para 1-0-4-1, Hispanic female with a history of chronic hypertension presented at 26 weeks and 6 days of gestational age. She was noted to have hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome accompanied by fetal growth restriction (FGR, during ultrasound evaluation, warranting premature delivery. The infant was delivered in stable condition suffering no permanent neurological deficit. Conclusion. HELLP syndrome is an uncommon and traumatic obstetric event which can lead to neurological deficits if not managed in a responsive and rapid manner. The central aggravating factor seems to be hypertension induced preeclamptic or eclamptic episode and complications thereof. The syndrome itself is manifested by hemolytic anemia, increased liver enzymes, and decreasing platelet counts with a majority of neurological defects resulting from hemorrhagic stroke or subarachnoid hemorrhage (SAH. To minimize adverse perinatal outcomes, obstetric management of this medical complication must include rapid clinical assessment, diagnostic examination, and neurosurgery consultation.

Effective treatment of steatosis and steatohepatitis by fibroblast growth factor 1 in mouse models of nonalcoholic fatty liver disease.

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Liu, Weilin; Struik, Dicky; Nies, Vera J M; Jurdzinski, Angelika; Harkema, Liesbeth; de Bruin, Alain; Verkade, Henkjan J; Downes, Michael; Evans, Ronald M; van Zutphen, Tim; Jonker, Johan W

2016-02-23

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder and is strongly associated with obesity and type 2 diabetes. Currently, there is no approved pharmacological treatment for this disease, but improvement of insulin resistance using peroxisome proliferator-activated receptor-γ (PPARγ) agonists, such as thiazolidinediones (TZDs), has been shown to reduce steatosis and steatohepatitis effectively and to improve liver function in patients with obesity-related NAFLD. However, this approach is limited by adverse effects of TZDs. Recently, we have identified fibroblast growth factor 1 (FGF1) as a target of nuclear receptor PPARγ in visceral adipose tissue and as a critical factor in adipose remodeling. Because FGF1 is situated downstream of PPARγ, it is likely that therapeutic targeting of the FGF1 pathway will eliminate some of the serious adverse effects associated with TZDs. Here we show that pharmacological administration of recombinant FGF1 (rFGF1) effectively improves hepatic inflammation and damage in leptin-deficient ob/ob mice and in choline-deficient mice, two etiologically different models of NAFLD. Hepatic steatosis was effectively reduced only in ob/ob mice, suggesting that rFGF1 stimulates hepatic lipid catabolism. Potentially adverse effects such as fibrosis or proliferation were not observed in these models. Because the anti-inflammatory effects were observed in both the presence and absence of the antisteatotic effects, our findings further suggest that the anti-inflammatory property of rFGF1 is independent of its effect on lipid catabolism. Our current findings indicate that, in addition to its potent glucose-lowering and insulin-sensitizing effects, rFGF1 could be therapeutically effective in the treatment of NAFLD.

Liver-derived systemic factors drive β-cell hyperplasia in insulin resistant states

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El Ouaamari, Abdelfattah; Kawamori, Dan; Dirice, Ercument; Liew, Chong Wee; Shadrach, Jennifer L.; Hu, Jiang; Katsuta, Hitoshi; Hollister-Lock, Jennifer; Qian, Weijun; Wagers, Amy J.; Kulkarni, Rohit N.

2013-02-21

Integrative organ cross-talk regulates key aspects of energy homeostasis and its dysregulation may underlie metabolic disorders such as obesity and diabetes. To test the hypothesis that cross-talk between the liver and pancreatic islets modulates β-cell growth in response to insulin resistance, we used the Liver-specific Insulin Receptor Knockout (LIRKO) mouse, a unique model that exhibits dramatic islet hyperplasia. Using complementary in vivo parabiosis and transplantation assays, and in vitro islet culture approaches, we demonstrate that humoral, non-neural, non-cell autonomous factor(s) induce β-cell proliferation in LIRKO mice. Furthermore, we report that a hepatocyte-derived factor(s) stimulates mouse and human β-cell proliferation in ex vivo assays, independent of ambient glucose and insulin levels. These data implicate the liver as a critical source of β-cell growth factors in insulin resistant states.

The Impact of Liver Graft Injury on Cancer Recurrence Posttransplantation.

Science.gov (United States)

Li, Chang-Xian; Man, Kwan; Lo, Chung-Mau

2017-11-01

Liver transplantation is the most effective treatment for selected patients with hepatocellular carcinoma. However, cancer recurrence, posttransplantation, remains to be the critical issue that affects the long-term outcome of hepatocellular carcinoma recipients. In addition to tumor biology itself, increasing evidence demonstrates that acute-phase liver graft injury is a result of hepatic ischemia reperfusion injury (which is an inevitable consequence during liver transplantation) and may promote cancer recurrence at late phase posttransplantation. The liver grafts from living donors, donors after cardiac death, and steatotic donors have been considered as promising sources of organs for liver transplantation and are associated with high incidence of liver graft injury. The acute-phase liver graft injury will trigger a series of inflammatory cascades, which may not only activate the cell signaling pathways regulating the tumor cell invasion and migration but also mobilize the circulating progenitor and immune cells to facilitate tumor recurrence and metastasis. The injured liver graft may also provide the favorable microenvironment for tumor cell growth, migration, and invasion through the disturbance of microcirculatory barrier function, induction of hypoxia and angiogenesis. This review aims to summarize the latest findings about the role and mechanisms of liver graft injury resulted from hepatic ischemia reperfusion injury on tumor recurrence posttransplantation, both in clinical and animal cohorts.

Inhibition of liver fibrosis by solubilized coenzyme Q10: Role of Nrf2 activation in inhibiting transforming growth factor-β1 expression

International Nuclear Information System (INIS)

Choi, Hoo-Kyun; Pokharel, Yuba Raj; Lim, Sung Chul; Han, Hyo-Kyung; Ryu, Chang Seon; Kim, Sang Kyum; Kwak, Mi Kyong; Kang, Keon Wook

2009-01-01

Coenzyme Q10 (CoQ10), an endogenous antioxidant, is important in oxidative phosphorylation in mitochondria. It has anti-diabetic and anti-cardiovascular disease effects, but its ability to protect against liver fibrosis has not been studied. Here, we assessed the ability of solubilized CoQ10 to improve dimethylnitrosamine (DMN)-induced liver fibrogenesis in mice. DMN treatments for 3 weeks produced a marked liver fibrosis as assessed by histopathological examination and tissue 4-hydroxyproline content. Solubilized CoQ10 (10 and 30 mg/kg) significantly inhibited both the increases in fibrosis score and 4-hydroxyproline content induced by DMN. Reverse transcription-polymerase chain reaction and Western blot analyses revealed that solubilized CoQ10 inhibited increases in the transforming growth factor-β1 (TGF-β1) mRNA and α-smooth muscle actin (α-SMA) protein by DMN. Interestingly, hepatic glutamate-cysteine ligase (GCL) and glutathione S-transferase A2 (GSTA2) were up-regulated in mice treated with CoQ10. Solubilized CoQ10 also up-regulated antioxidant enzymes such as catalytic subunits of GCL and GSTA2 via activating NF-E2 related factor2 (Nrf2)/antioxidant response element (ARE) in H4IIE hepatoma cells. Moreover, CoQ10's inhibition of α-SMA and TGF-β1 expressions disappeared in Nrf2-null MEF cells. In contrast, Nrf2 overexpression significantly decreased the basal expression levels of α-SMA and TGF-β1 in Nrf2-null MEF cells. These results demonstrated that solubilized CoQ10 inhibited DMN-induced liver fibrosis through suppression of TGF-β1 expression via Nrf2/ARE activation.

Modulation of gene expression in heart and liver of hibernating black bears (Ursus americanus

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Yan Jun

2011-03-01

Full Text Available Abstract Background Hibernation is an adaptive strategy to survive in highly seasonal or unpredictable environments. The molecular and genetic basis of hibernation physiology in mammals has only recently been studied using large scale genomic approaches. We analyzed gene expression in the American black bear, Ursus americanus, using a custom 12,800 cDNA probe microarray to detect differences in expression that occur in heart and liver during winter hibernation in comparison to summer active animals. Results We identified 245 genes in heart and 319 genes in liver that were differentially expressed between winter and summer. The expression of 24 genes was significantly elevated during hibernation in both heart and liver. These genes are mostly involved in lipid catabolism and protein biosynthesis and include RNA binding protein motif 3 (Rbm3, which enhances protein synthesis at mildly hypothermic temperatures. Elevated expression of protein biosynthesis genes suggests induction of translation that may be related to adaptive mechanisms reducing cardiac and muscle atrophies over extended periods of low metabolism and immobility during hibernation in bears. Coordinated reduction of transcription of genes involved in amino acid catabolism suggests redirection of amino acids from catabolic pathways to protein biosynthesis. We identify common for black bears and small mammalian hibernators transcriptional changes in the liver that include induction of genes responsible for fatty acid β oxidation and carbohydrate synthesis and depression of genes involved in lipid biosynthesis, carbohydrate catabolism, cellular respiration and detoxification pathways. Conclusions Our findings show that modulation of gene expression during winter hibernation represents molecular mechanism of adaptation to extreme environments.

Modulation of gene expression in heart and liver of hibernating black bears (Ursus americanus).

Science.gov (United States)

Fedorov, Vadim B; Goropashnaya, Anna V; Tøien, Øivind; Stewart, Nathan C; Chang, Celia; Wang, Haifang; Yan, Jun; Showe, Louise C; Showe, Michael K; Barnes, Brian M

2011-03-31

Hibernation is an adaptive strategy to survive in highly seasonal or unpredictable environments. The molecular and genetic basis of hibernation physiology in mammals has only recently been studied using large scale genomic approaches. We analyzed gene expression in the American black bear, Ursus americanus, using a custom 12,800 cDNA probe microarray to detect differences in expression that occur in heart and liver during winter hibernation in comparison to summer active animals. We identified 245 genes in heart and 319 genes in liver that were differentially expressed between winter and summer. The expression of 24 genes was significantly elevated during hibernation in both heart and liver. These genes are mostly involved in lipid catabolism and protein biosynthesis and include RNA binding protein motif 3 (Rbm3), which enhances protein synthesis at mildly hypothermic temperatures. Elevated expression of protein biosynthesis genes suggests induction of translation that may be related to adaptive mechanisms reducing cardiac and muscle atrophies over extended periods of low metabolism and immobility during hibernation in bears. Coordinated reduction of transcription of genes involved in amino acid catabolism suggests redirection of amino acids from catabolic pathways to protein biosynthesis. We identify common for black bears and small mammalian hibernators transcriptional changes in the liver that include induction of genes responsible for fatty acid β oxidation and carbohydrate synthesis and depression of genes involved in lipid biosynthesis, carbohydrate catabolism, cellular respiration and detoxification pathways. Our findings show that modulation of gene expression during winter hibernation represents molecular mechanism of adaptation to extreme environments.

Antepartal insulin-like growth factor 1 and insulin-like growth factor binding protein 2 concentrations are indicative of ketosis in dairy cows.

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Piechotta, M; Mysegades, W; Ligges, U; Lilienthal, J; Hoeflich, A; Miyamoto, A; Bollwein, H

2015-05-01

A study involving a small number of cows found that the concentrations of insulin-like growth hormone 1 (IGF1) may be a useful predictor of metabolic disease. Further, IGF1 may provide also a pathophysiological link to metabolic diseases such as ketosis. The objective of the current study was to test whether the low antepartal total IGF1 or IGF1 binding protein (IGFBP) concentrations might predict ketosis under field conditions. Clinical examinations and blood sampling were performed antepartum (262-270 d after artificial insemination) on 377 pluriparous pregnant Holstein Friesian cows. The presence of postpartum diseases were recorded (ketosis, fatty liver, displacement of the abomasum, hypocalcemia, mastitis, retention of fetal membranes, and clinical metritis or endometritis), and the concentrations of IGF1, IGFBP2, IGFBP3, and nonesterified fatty acids were measured. Cows with postpartum clinical ketosis had lower IGF1 concentrations antepartum than healthy cows. The sensitivity of antepartal IGF1 as a marker for postpartum ketosis was 0.87, and the specificity was 0.43; a positive predictive value of 0.91 and a negative predictive value of 0.35 were calculated. The cows with ketosis and retained fetal membranes had lower IGFBP2 concentrations compared with the healthy cows. It can be speculated that lower IGF1 production in the liver during late pregnancy may increase growth hormone secretions and lipolysis, thereby increasing the risk of ketosis. Lower IGFBP2 concentrations may reflect the suppression of IGFBP2 levels through higher growth hormone secretion. In conclusion, compared with nonesterified fatty acids as a predictive parameter, IGF1 and IGFBP2 may represent earlier biomarkers of inadequate metabolic adaptation to the high energy demand required postpartum. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Adaptive statistical iterative reconstruction versus filtered back projection in the same patient: 64 channel liver CT image quality and patient radiation dose

International Nuclear Information System (INIS)

Mitsumori, Lee M.; Shuman, William P.; Busey, Janet M.; Kolokythas, Orpheus; Koprowicz, Kent M.

2012-01-01

To compare routine dose liver CT reconstructed with filtered back projection (FBP) versus low dose images reconstructed with FBP and adaptive statistical iterative reconstruction (ASIR). In this retrospective study, patients had a routine dose protocol reconstructed with FBP, and again within 17 months (median 6.1 months), had a low dose protocol reconstructed twice, with FBP and ASIR. These reconstructions were compared for noise, image quality, and radiation dose. Nineteen patients were included. (12 male, mean age 58). Noise was significantly lower in low dose images reconstructed with ASIR compared to routine dose images reconstructed with FBP (liver: p <.05, aorta: p < 0.001). Low dose FBP images were scored significantly lower for subjective image quality than low dose ASIR (2.1 ± 0.5, 3.2 ± 0.8, p < 0.001). There was no difference in subjective image quality scores between routine dose FBP images and low dose ASIR images (3.6 ± 0.5, 3.2 ± 0.8, NS).Radiation dose was 41% less for the low dose protocol (4.4 ± 2.4 mSv versus 7.5 ± 5.5 mSv, p < 0.05). Our initial results suggest low dose CT images reconstructed with ASIR may have lower measured noise, similar image quality, yet significantly less radiation dose compared with higher dose images reconstructed with FBP. (orig.)

Adaptive statistical iterative reconstruction versus filtered back projection in the same patient: 64 channel liver CT image quality and patient radiation dose

Energy Technology Data Exchange (ETDEWEB)

Mitsumori, Lee M.; Shuman, William P.; Busey, Janet M.; Kolokythas, Orpheus; Koprowicz, Kent M. [University of Washington School of Medicine, Department of Radiology, Seattle, WA (United States)

2012-01-15

To compare routine dose liver CT reconstructed with filtered back projection (FBP) versus low dose images reconstructed with FBP and adaptive statistical iterative reconstruction (ASIR). In this retrospective study, patients had a routine dose protocol reconstructed with FBP, and again within 17 months (median 6.1 months), had a low dose protocol reconstructed twice, with FBP and ASIR. These reconstructions were compared for noise, image quality, and radiation dose. Nineteen patients were included. (12 male, mean age 58). Noise was significantly lower in low dose images reconstructed with ASIR compared to routine dose images reconstructed with FBP (liver: p <.05, aorta: p < 0.001). Low dose FBP images were scored significantly lower for subjective image quality than low dose ASIR (2.1 {+-} 0.5, 3.2 {+-} 0.8, p < 0.001). There was no difference in subjective image quality scores between routine dose FBP images and low dose ASIR images (3.6 {+-} 0.5, 3.2 {+-} 0.8, NS).Radiation dose was 41% less for the low dose protocol (4.4 {+-} 2.4 mSv versus 7.5 {+-} 5.5 mSv, p < 0.05). Our initial results suggest low dose CT images reconstructed with ASIR may have lower measured noise, similar image quality, yet significantly less radiation dose compared with higher dose images reconstructed with FBP. (orig.)

Chloroquine inhibits hepatocellular carcinoma cell growth in vitro and in vivo

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HU, TAO; LI, PEI; LUO, ZHONGGUANG; CHEN, XIAOYU; ZHANG, JINGYANG; WANG, CHUNYAO; CHEN, PING; DONG, ZIMING

2016-01-01

Recently, chloroquine (CQ) has been widely used to improve the efficacy of different chemotherapy drugs to treat tumors. However, the effects of single treatment of CQ on liver cancer have not been investigated. In the present study, we examined the effects of CQ on the growth and viability of liver cancer cells in vitro and in vivo, and revealed that CQ treatment triggered G0/G1 cell cycle arrest, induced DNA damage and apoptosis in a dose- and time-dependent manner in liver cancer cells. Moreover, administration of CQ to tumor-bearing mice suppressed the tumor growth in an orthotopic xenograft model of liver cancer. These findings extend our understanding and suggest that CQ could be repositioned as a treatment option for liver cancer as a single treatment or in combination. PMID:26530158

Angiogenesis-Related Biomarkers in Patients with Alcoholic Liver Disease: Their Association with Liver Disease Complications and Outcome

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Beata Kasztelan-Szczerbinska

2014-01-01

Full Text Available Angiogenesis is believed to be implicated in the pathogenesis of alcoholic liver disease (ALD. We aimed to explore the usefulness and accuracy of plasma angiogenic biomarkers for noninvasive evaluation of the severity of liver failure and ALD outcome. One hundred and forty-seven patients with ALD were prospectively enrolled and assessed based on their (1 gender, (2 age, (3 severity of liver dysfunction according to the Child-Turcotte-Pugh and MELD scores, and (4 the presence of ALD complications. Plasma levels of vascular endothelial growth factor (VEGF-A and angiopoietins 1 and 2 (Ang1 and Ang2 were investigated using ELISAs. Multivariable logistic regression was applied in order to select independent predictors of advanced liver dysfunction and the disease complications. Significantly higher concentrations of Ang2 and VEGF-A in ALD patients as compared to controls were found. There was no difference in Ang1 levels in both groups. A positive correlation of Ang2 levels with INR (Rho 0.66; P<0.0001 and its inverse correlation with plasma albumin levels (Rho –0.62; P<0.0001 were found. High Ang2 concentrations turned out to be an independent predictor of severe liver dysfunction, as well as hepatic encephalopathy and renal impairment. Ang2 possessed the highest diagnostic and prognostic potential among three studied angiogenesis-related molecules.

[Liver transplantation for the treatment of hyperammonemia due to urea cycle disorder: report of four cases].

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Zhu, Zhijun; Sun, Liying; Wei, Lin; Qu, Wei; Zeng, Zhigui; Liu, Ying; Zhang, Liang; He, Enhui; Wang, Dong

2015-02-01

To analyze clinical efficacy and prognosis of liver transplantation in children with hyperammonemia caused by urea cycle disorders. A retrospective analysis was performed on the occurrence of disease, operation and the follow-up post liver transplantation in 4 patients with urea cycle disorders who underwent liver transplantation during June 2001 to May 2014. Four girls were diagnosed with ornithine carbamoyl transferase deficiency by genetic test. They had the clinical onset at the age of 1.5 to 3.0 years. Liver transplantation had been performed at their age of 53.9 months, 40.6 months, 40.3 months and 22.8 months, respectively. The grafts of case 1 and case 2 were from left lateral lobe of liver of cadaveric donor, the graft of case 3 was from left lateral lobe of liver of a living donor, the graft of case 4 was a whole liver of a dead child. The liver function of 4 patients gradually returned to normal, blood ammonia levels were normal and restored the normal diet, 4 children were discharged on postoperative 25-30 days. Regular follow-up was done, the liver function, biochemical features and growth status have been followed up for 162.2 months, 124.2 months, 12.0 months and 4.8 months after liver transplantation, respectively. Now, all the four cases are healthy and growth is normal. Liver transplantation is an important way to the patients with severe hyperammonemia caused by urea cycle disorders. In this study, the patients with ornithine carbamoyl transferase defect got satisfactory long-term outcome after liver transplantation.

Ursodeoxycholic acid in advanced polycystic liver disease: A phase 2 multicenter randomized controlled trial.

Science.gov (United States)

D'Agnolo, Hedwig M A; Kievit, Wietske; Takkenberg, R Bart; Riaño, Ioana; Bujanda, Luis; Neijenhuis, Myrte K; Brunenberg, Ellen J L; Beuers, Ulrich; Banales, Jesus M; Drenth, Joost P H

2016-09-01

Ursodeoxycholic acid (UDCA) inhibits proliferation of polycystic human cholangiocytes in vitro and hepatic cystogenesis in a rat model of polycystic liver disease (PLD) in vivo. Our aim was to test whether UDCA may beneficially affect liver volume in patients with advanced PLD. We conducted an international, multicenter, randomized controlled trial in symptomatic PLD patients from three tertiary referral centers. Patients with PLD and total liver volume (TLV) ⩾2500ml were randomly assigned to UDCA treatment (15-20mg/kg/day) for 24weeks, or to no treatment. Primary endpoint was proportional change in TLV. Secondary endpoints were change in symptoms and health-related quality of life. We performed a post-hoc analysis of the effect of UDCA on liver cyst volume (LCV). We included 34 patients and were able to assess primary endpoint in 32 patients, 16 with autosomal dominant polycystic kidney disease (ADPKD) and 16 with autosomal dominant polycystic liver disease (ADPLD). Proportional TLV increased by 4.6±7.7% (mean TLV increased from 6697ml to 6954ml) after 24weeks of UDCA treatment compared to 3.1±3.8% (mean TLV increased from 5512ml to 5724ml) in the control group (p=0.493). LCV was not different after 24weeks between controls and UDCA treated patients (p=0.848). However, UDCA inhibited LCV growth in ADPKD patients compared to ADPKD controls (p=0.049). UDCA administration for 24weeks did not reduce TLV in advanced PLD, but UDCA reduced LCV growth in ADPKD patients. Future studies might explore whether ADPKD and ADPLD patients respond differently to UDCA treatment. Current therapies for polycystic liver disease are invasive and have high recurrence risks. Our trial showed that the drug, ursodeoxycholic acid, was not able to reduce liver volume in patients with polycystic liver disease. However, a subgroup analysis in patients that have kidney cysts as well showed that liver cyst volume growth was reduced in patients who received ursodeoxycholic acid in comparison

ADAPTATION TO UNFAVORABLE CONDITIONS OF GROWTH: PATHOGENICITY OF ACHOLEPLASMA LAIDLAWII PG8

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Maxim V. Trushin

2006-11-01

Full Text Available ABSTRACT:As a result of cultivation of A. laidlawii PG8 cells on the deficient medium during 480 days, the mycoplasma culture adapted in vitro to unfavorable growth conditions was obtained. The culture consisted of cells with sizes less than 0.2 µm and features of A. laidlawii PG8 ultramicroforms, nanocells. A. laidlawii PG8 culture adapted in vitro to unfavorable growth conditions shows more evident phytopathogenicity than the unadapted one. Infecting plants V. minor L. by A. laidlawii PG8 culture adapted in vitro to UGC resulted in the appearance of chloroses in 75%, necrosis – 50%, leaves marcescence – 50% and abnormalities of bine development in 30% of plants through 12 days, while infecting plants by A. laidlawii PG8 culture unadapted to UGC led to respective signs in 40%, 25%, 25% and 0% of samples, respectively, through 30 days. The ability of A. laidlawii PG8 to form UMF resistant to stress factors in UGC with high phytopathogenic potential seems to demand a new approach to investigate the precise mechanisms of interacting the mycoplasma with host organisms.RESUMENComo resultado del cultivo de células de A. laidlawii PG8 en medio deficiente durante 480 días, fue obtenido un cultivo de mycoplasma adaptado in vitro a las condiciones desfavorables del crecimiento. El cultivo consistió en células con tamaño menor de 0.2 µm y características PG8 ultramicroformas de A. laidlawii nanocélulas. El cultivo de A. laidlawii PG8 adaptado in vitro a condiciones desfavorables del crecimiento muestra más evidente fitopatogenicidad que el inadaptado. Plantas infectadas V. minor L. por el cultivo del A. laidlawii PG8 adaptado in vitro a UGC dio como resultado la aparición de clorosis en el 75%, necrosis en el 50%, marcescencia de las hojas en el 50% y anormalidades del desarrollo del bine en el 30% de plantas a los 12 días, mientras que las plantas infectadas por el cultivo del A. laidlawii PG8 inadaptado a UGC, condujo a dichos signos en

Front tracking based modeling of the solid grain growth on the adaptive control volume grid

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Seredyński, Mirosław; Łapka, Piotr

2017-07-01

The paper presents the micro-scale model of unconstrained solidification of the grain immersed in under-cooled liquid, based on the front tracking approach. For this length scale, the interface tracked through the domain is meant as the solid-liquid boundary. To prevent generation of huge meshes the energy transport equation is discretized on the adaptive control volume (c.v.) mesh. The coupling of dynamically changing mesh and moving front position is addressed. Preliminary results of simulation of a test case, the growth of single grain, are presented and discussed.

Association genetics of growth and adaptive traits in loblolly pine (Pinus taeda L.) using whole-exome-discovered polymorphisms

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Mengmeng Lu; Konstantin V. Krutovsky; C. Dana Nelson; Jason B. West; Nathalie A. Reilly; Carol A. Loopstra

2017-01-01

In the USA, forest genetics research began over 100 years ago and loblolly pine breeding programs were established in the 1950s. However, the genetics underlying complex traits of loblolly pine remains to be discovered. To address this, adaptive and growth traits were measured and analyzed in a clonally tested loblolly pine (Pinus taeda L.) population. Over 2.8 million...

Changes in the renin angiotensin system during the development of colorectal cancer liver metastases

International Nuclear Information System (INIS)

Neo, Jaclyn H; Ager, Eleanor I; Angus, Peter W; Zhu, Jin; Herath, Chandana B; Christophi, Christopher

2010-01-01

Blockade of the renin angiotensin system (RAS) via angiotensin I converting enzyme (ACE) inhibition reduces growth of colorectal cancer (CRC) liver metastases in a mouse model. In this work we defined the expression of the various components of the RAS in both tumor and liver during the progression of this disease. Immunohistochemistry and quantitative RT-PCR was used to examine RAS expression in a mouse CRC liver metastases model. CRC metastases and liver tissue was assessed separately at key stages of CRC liver metastases development in untreated (control) mice and in mice treated with the ACE inhibitor captopril (750 mg/kg/day). Non-tumor induced (sham) mice indicated the effect of tumors on normal liver RAS. The statistical significance of multiple comparisons was determined using one-way analysis of variance followed by Bonferroni adjustment with SAS/STAT software. Reduced volume of CRC liver metastases with captopril treatment was evident. Local RAS of CRC metastases differed from the surrounding liver, with lower angiotensin II type 1 receptor (AT1R) expression but increased ANG-(1-7) receptor (MasR) compared to the liver. The AT1R localised to cancer and stromal infiltrating cells, while other RAS receptors were detected in cancer cells only. Tumor induction led to an initial increase in AT1R and ACE expression while captopril treatment significantly increased ACE expression in the final stages of tumor growth. Conversely, captopril treatment decreased expression of AT1R and angiotensinogen. These results demonstrate significant changes in RAS expression in the tumor-bearing captopril treated liver and in CRC metastases. The data suggests the existence of a tumor-specific RAS that can be independently targeted by RAS blockade

Bone morphogenetic protein 9 as a key regulator of liver progenitor cells in DDC-induced cholestatic liver injury.

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Addante, Annalisa; Roncero, Cesáreo; Almalé, Laura; Lazcanoiturburu, Nerea; García-Álvaro, María; Fernández, Margarita; Sanz, Julián; Hammad, Seddik; Nwosu, Zeribe C; Lee, Se-Jin; Fabregat, Isabel; Dooley, Steven; Ten Dijke, Peter; Herrera, Blanca; Sánchez, Aránzazu

2018-05-11

Bone morphogenetic protein 9 (BMP9) interferes with liver regeneration upon acute injury, while promoting fibrosis upon carbon tetrachloride-induced chronic injury. We have now addressed the role of BMP9 in 3,5 diethoxicarbonyl-1,4 dihydrocollidine (DDC)-induced cholestatic liver injury, a model of liver regeneration mediated by hepatic progenitor cell (known as oval cell), exemplified as ductular reaction and oval cell expansion. WT and BMP9KO mice were submitted to DDC diet. Livers were examined for liver injury, fibrosis, inflammation and oval cell expansion by serum biochemistry, histology, RT-qPCR and western blot. BMP9 signalling and effects in oval cells were studied in vitro using western blot and transcriptional assays, plus functional assays of DNA synthesis, cell viability and apoptosis. Crosslinking assays and short hairpin RNA approaches were used to identify the receptors mediating BMP9 effects. Deletion of BMP9 reduces liver damage and fibrosis, but enhances inflammation upon DDC feeding. Molecularly, absence of BMP9 results in overactivation of PI3K/AKT, ERK-MAPKs and c-Met signalling pathways, which together with an enhanced ductular reaction and oval cell expansion evidence an improved regenerative response and decreased damage in response to DDC feeding. Importantly, BMP9 directly targets oval cells, it activates SMAD1,5,8, decreases cell growth and promotes apoptosis, effects that are mediated by Activin Receptor-Like Kinase 2 (ALK2) type I receptor. We identify BMP9 as a negative regulator of oval cell expansion in cholestatic injury, its deletion enhancing liver regeneration. Likewise, our work further supports BMP9 as an attractive therapeutic target for chronic liver diseases. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Liver scanning in diffuse liver disease

International Nuclear Information System (INIS)

Aiginger, P.; Atefie, K.; Scherak, O.; Wolf, A.; Hoefer, R.; Seyfried, H.

1975-01-01

The results of liver scans performed with sup(99m)Tc-sulphur colloid in 169 patients suffering from diffuse liver diseases and in 48 normal controls were evaluated. The patients with reactive hepatitis, acute hepatitis, chronic persistent hepatitis, fatty liver and fibrosis of the liver show only minimal deviations from the scintigraphic pattern. On the contrary, highly increased colloid uptake in the spleen is found in cases of chronic aggressive hepatitis, whilst the intrahepatic distribution of the colloid is approximately normal. In cases of liver cirrhosis, increased colloid uptake is found in the left lobe of the liver as well as in the spleen and in the bone marrow. Either normal findings or cirrhosis-like changes of the colloid distribution are observed in patients with alcoholic hepatitis. (orig.) [de

Recovering from a bad start: rapid adaptation and tradeoffs to growth below a threshold density

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Marx Christopher J

2012-07-01

Full Text Available Abstract Background Bacterial growth in well-mixed culture is often assumed to be an autonomous process only depending upon the external conditions under control of the investigator. However, increasingly there is awareness that interactions between cells in culture can lead to surprising phenomena such as density-dependence in the initiation of growth. Results Here I report the unexpected discovery of a density threshold for growth of a strain of Methylobacterium extorquens AM1 used to inoculate eight replicate populations that were evolved in methanol. Six of these populations failed to grow to the expected full density during the first couple transfers. Remarkably, the final cell number of six populations crashed to levels 60- to 400-fold smaller than their cohorts. Five of these populations recovered to full density soon after, but one population remained an order of magnitude smaller for over one hundred generations. These variable dynamics appeared to be due to a density threshold for growth that was specific to both this particular ancestral strain and to growth on methanol. When tested at full density, this population had become less fit than its ancestor. Simply increasing the initial dilution 16-fold reversed this result, revealing that this population had more than a 3-fold advantage when tested at this lower density. As this population evolved and ultimately recovered to the same final density range as the other populations this low-density advantage waned. Conclusions These results demonstrate surprisingly strong tradeoffs during adaptation to growth at low absolute densities that manifest over just a 16-fold change in density. Capturing laboratory examples of transitions to and from growth at low density may help us understand the physiological and evolutionary forces that have led to the unusual properties of natural bacteria that have specialized to low-density environments such as the open ocean.

Recovering from a bad start: rapid adaptation and tradeoffs to growth below a threshold density.

Science.gov (United States)

Marx, Christopher J

2012-07-04

Bacterial growth in well-mixed culture is often assumed to be an autonomous process only depending upon the external conditions under control of the investigator. However, increasingly there is awareness that interactions between cells in culture can lead to surprising phenomena such as density-dependence in the initiation of growth. Here I report the unexpected discovery of a density threshold for growth of a strain of Methylobacterium extorquens AM1 used to inoculate eight replicate populations that were evolved in methanol. Six of these populations failed to grow to the expected full density during the first couple transfers. Remarkably, the final cell number of six populations crashed to levels 60- to 400-fold smaller than their cohorts. Five of these populations recovered to full density soon after, but one population remained an order of magnitude smaller for over one hundred generations. These variable dynamics appeared to be due to a density threshold for growth that was specific to both this particular ancestral strain and to growth on methanol. When tested at full density, this population had become less fit than its ancestor. Simply increasing the initial dilution 16-fold reversed this result, revealing that this population had more than a 3-fold advantage when tested at this lower density. As this population evolved and ultimately recovered to the same final density range as the other populations this low-density advantage waned. These results demonstrate surprisingly strong tradeoffs during adaptation to growth at low absolute densities that manifest over just a 16-fold change in density. Capturing laboratory examples of transitions to and from growth at low density may help us understand the physiological and evolutionary forces that have led to the unusual properties of natural bacteria that have specialized to low-density environments such as the open ocean.

CT Perfusion Characteristics Identify Metastatic Sites in Liver

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Yuan Wang

2015-01-01

Full Text Available Tissue perfusion plays a critical role in oncology because growth and migration of cancerous cells require proliferation of new blood vessels through the process of tumor angiogenesis. Computed tomography (CT perfusion is an emerging functional imaging modality that measures tissue perfusion through dynamic CT scanning following intravenous administration of contrast medium. This noninvasive technique provides a quantitative basis for assessing tumor angiogenesis. CT perfusion has been utilized on a variety of organs including lung, prostate, liver, and brain, with promising results in cancer diagnosis, disease prognostication, prediction, and treatment monitoring. In this paper, we focus on assessing the extent to which CT perfusion characteristics can be used to discriminate liver metastases from neuroendocrine tumors from normal liver tissues. The neuroendocrine liver metastases were analyzed by distributed parameter modeling to yield tissue blood flow (BF, blood volume (BV, mean transit time (MTT, permeability (PS, and hepatic arterial fraction (HAF, for tumor and normal liver. The result reveals the potential of CT perfusion as a tool for constructing biomarkers from features of the hepatic vasculature for guiding cancer detection, prognostication, and treatment selection.

The interaction between regulatory T cells and NKT cells in the liver: a CD1d bridge links innate and adaptive immunity.

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Hua, Jing; Liang, Shuwen; Ma, Xiong; Webb, Tonya J; Potter, James P; Li, Zhiping

2011-01-01

Regulatory T cells (Tregs) and natural killer T (NKT) cells are two distinct lymphocyte subsets that independently regulate hepatic adaptive and innate immunity, respectively. In the current study, we examine the interaction between Tregs and NKT cells to understand the mechanisms of cross immune regulation by these cells. The frequency and function of Tregs were evaluated in wild type and NKT cell deficient (CD1dko) mice. In vitro lymphocyte proliferation and apoptosis assays were performed with NKT cells co-cultured with Tregs. The ability of Tregs to inhibit NKT cells in vivo was examined by adoptive transfer of Tregs in a model of NKT cell mediated hepatitis. CD1dko mice have a significant reduction in hepatic Tregs. Although, the Tregs from CD1dko mice remain functional and can suppress conventional T cells, their ability to suppress activation induced NKT cell proliferation and to promote NKT cell apoptosis is greatly diminished. These effects are CD1d dependent and require cell to cell contact. Adoptive transfer of Tregs inhibits NKT cell-mediated liver injury. NKT cells promote Tregs, and Tregs inhibit NKT cells in a CD1d dependent manner requiring cell to cell contact. These cross-talk immune regulations provide a linkage between innate and adaptive immunity.

Key physiological properties contributing to rhizosphere adaptation and plant growth promotion abilities of Azospirillum brasilense.

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Fibach-Paldi, Sharon; Burdman, Saul; Okon, Yaacov

2012-01-01

Azospirillum brasilense is a plant growth promoting rhizobacterium (PGPR) that is being increasingly used in agriculture in a commercial scale. Recent research has elucidated key properties of A. brasilense that contribute to its ability to adapt to the rhizosphere habitat and to promote plant growth. They include synthesis of the auxin indole-3-acetic acid, nitric oxide, carotenoids, and a range of cell surface components as well as the ability to undergo phenotypic variation. Storage and utilization of polybetahydroxyalkanoate polymers are important for the shelf life of the bacteria in production of inoculants, products containing bacterial cells in a suitable carrier for agricultural use. Azospirillum brasilense is able to fix nitrogen, but despite some controversy, as judging from most systems evaluated so far, contribution of fixed nitrogen by this bacterium does not seem to play a major role in plant growth promotion. In this review, we focus on recent advances in the understanding of physiological properties of A. brasilense that are important for rhizosphere performance and successful interactions with plant roots. © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Liver regeneration and restoration of liver function after partial hepatectomy in patients with liver tumors

International Nuclear Information System (INIS)

Jansen, P.L.M.; Chamuleau, R.A.F.; Leeuwen, D.J. van; Schippor, H.G.; Busemann-Sokole, E.; Heyde, M.N. van der

1990-01-01

Liver regeneration and restoration of liver function were studied in six patients who underwent partial hepatectomy with removal of 30-70% of the liver. Liver volume and liver regeneration were studied by single photon computed tomography (SPECT), using 99m Tc-colloid as tracer. The method was assessed in 11 patients by comparing the pre- and post-operative volume measurement with the volume of the resected liver mass. Liver function was determined by measuring the galactose elimination capacity and the caffeine clearance. After a postoperative follow-up period of 50 days, the liver had regenerated maximally to a volume of 75 ± 2% of the preoperative liver mass. Maximal restoration of liver function was achieved 120 days after operation and amounted to 75 ± 10% for the caffeine clearance and to 100 ± 25% for the galactose elimination capacity. This study shows that SPECT is a useful method for assessing liver regeneration in patients after partial hepatectomy. The study furthermore shows that caffeine clearance correlates well with total liver volume, whereas the galactose elimination capacity overestimates total liver volume after partial hepatectomy. 22 refs

Liver hypertrophy in winter flounder following exposure to experimentally oiled sediments

Energy Technology Data Exchange (ETDEWEB)

Fletcher, G L; King, M J; Kiceniuk, J W; Addison, R F

1982-01-01

1. Male winter flounder were exposed to sediments contaminated with Venezuelan crude oil in 3 laboratory experiments of 4-5 months duration. 2. Oil exposure resulted in significant increases in liver weight. This was particularly evident in fish weighing less than 400 g. 3. The enlarged livers of the oil-exposed flounder had reduced concentrations of DNA, protein, Na/sup +/ and Zn2/sup +/, and increased concentrations of lipid and phospholipid. 4. The reduced DNA and Na/sup +/ concentrations suggested liver hypertrophy rather than hyperplasia. 5. The increased phospholipid concentrations suggested growth of membrane structures such as endoplasmic reticulum.

[Epidemiology, risk factors and molecular pathogenesis of primary liver cancer].

Science.gov (United States)

Hagymási, Krisztina; Tulassay, Zsolt

2008-03-23

Primary liver cancer is the fifth most common cancer worldwide. Hepatocellular carcinoma accounts for 85-90% of primary liver cancers. Distribution of hepatocellular carcinoma shows variations among geographic regions and ethnic groups. Males have higher liver cancer rates than females. Hepatocellular carcinoma occurs within an established background of chronic liver disease and cirrhosis (70-90%). Major causes (80%) of hepatocellular carcinoma are hepatitis B, C virus infection, and aflatoxin exposition. Its development is a multistep process. We have a growing understanding on the molecular pathogenesis. Genetic and epigenetic changes activate oncogenes, inhibit tumorsuppressor genes, which result in autonomous cell proliferation. The chromosomal instability caused by telomere dysfunction, the growth-retrained environment and the alterations of the micro- and macroenvironment help the expansion of the malignant cells. Understanding the molecular mechanisms could improve the screening of patients with chronic liver disease, or cirrhosis, and the prevention as well as treatment of hepatocellular carcinoma.

Therapeutic effect of angiogenesis inhibitor combined with radiotherapy on liver metastasis model of colon cancer

International Nuclear Information System (INIS)

Jin Liugen; Zhou Shifu

2005-01-01

Objective: To observe the therapeutic effect of angiogenesis inhibitor combined with radiotherapy on liver metastasis model of colon cancer. Methods: Nude mice liver metastasis model of colon cancer was established with human colon cancer cells line (LS174T) inoculated into mice' spleen and followed by splenectomy. Angiogenesis inhibitor 2-ME and radiotherapy were administered after-wads. The growth inhibition effect on metastases and neovessel was examined. Results: The incidences of liver metastasis were 100% in this intrasplenic injection model. The mean weight and microvessel density 4 weeks after inoculation were 53.6 ± 4.7 mg, 8.4 ± 1.7 in treatment group as compared to 173.9 ± 11.6 mg, 41.2 ± 6.3 in control group respectively. Conclusion: 2-ME combined with radiotherapy has significant inhibition on the growth of liver metastases. Angiogenesis inhibition is one of the mechanisms of its efficiency. (authors)

Microanatomical and histological features in the long bones of Mosasaurine mosasaurs (Reptilia, Squamata)--implications for aquatic adaptation and growth rates.

Science.gov (United States)

Houssaye, Alexandra; Lindgren, Johan; Pellegrini, Rodrigo; Lee, Andrew H; Germain, Damien; Polcyn, Michael J

2013-01-01

During their evolution in the Late Cretaceous, mosasauroids attained a worldwide distribution, accompanied by a marked increase in body size and open ocean adaptations. This transition from land-dwellers to highly marine-adapted forms is readily apparent not only at the gross anatomic level but also in their inner bone architecture, which underwent profound modifications. The present contribution describes, both qualitatively and quantitatively, the internal organization (microanatomy) and tissue types and characteristics (histology) of propodial and epipodial bones in one lineage of mosasauroids; i.e., the subfamily Mosasaurinae. By using microanatomical and histological data from limb bones in combination with recently acquired knowledge on the inner structure of ribs and vertebrae, and through comparisons with extant squamates and semi-aquatic to fully marine amniotes, we infer possible implications on mosasaurine evolution, aquatic adaptation, growth rates, and basal metabolic rates. Notably, we observe the occurrence of an unusual type of parallel-fibered bone, with large and randomly shaped osteocyte lacunae (otherwise typical of fibrous bone) and particular microanatomical features in Dallasaurus, which displays, rather than a spongious inner organization, bone mass increase in its humeri and a tubular organization in its femora and ribs. The dominance of an unusual type of parallel-fibered bone suggests growth rates and, by extension, basal metabolic rates intermediate between that of the extant leatherback turtle, Dermochelys, and those suggested for plesiosaur and ichthyosaur reptiles. Moreover, the microanatomical features of the relatively primitive genus Dallasaurus differ from those of more derived mosasaurines, indicating an intermediate stage of adaptation for a marine existence. The more complete image of the various microanatomical trends observed in mosasaurine skeletal elements supports the evolutionary convergence between this lineage of

Microanatomical and histological features in the long bones of Mosasaurine mosasaurs (Reptilia, Squamata--implications for aquatic adaptation and growth rates.

Directory of Open Access Journals (Sweden)

Alexandra Houssaye

Full Text Available BACKGROUND: During their evolution in the Late Cretaceous, mosasauroids attained a worldwide distribution, accompanied by a marked increase in body size and open ocean adaptations. This transition from land-dwellers to highly marine-adapted forms is readily apparent not only at the gross anatomic level but also in their inner bone architecture, which underwent profound modifications. METHODOLOGY/PRINCIPAL FINDINGS: The present contribution describes, both qualitatively and quantitatively, the internal organization (microanatomy and tissue types and characteristics (histology of propodial and epipodial bones in one lineage of mosasauroids; i.e., the subfamily Mosasaurinae. By using microanatomical and histological data from limb bones in combination with recently acquired knowledge on the inner structure of ribs and vertebrae, and through comparisons with extant squamates and semi-aquatic to fully marine amniotes, we infer possible implications on mosasaurine evolution, aquatic adaptation, growth rates, and basal metabolic rates. Notably, we observe the occurrence of an unusual type of parallel-fibered bone, with large and randomly shaped osteocyte lacunae (otherwise typical of fibrous bone and particular microanatomical features in Dallasaurus, which displays, rather than a spongious inner organization, bone mass increase in its humeri and a tubular organization in its femora and ribs. CONCLUSIONS/SIGNIFICANCE: The dominance of an unusual type of parallel-fibered bone suggests growth rates and, by extension, basal metabolic rates intermediate between that of the extant leatherback turtle, Dermochelys, and those suggested for plesiosaur and ichthyosaur reptiles. Moreover, the microanatomical features of the relatively primitive genus Dallasaurus differ from those of more derived mosasaurines, indicating an intermediate stage of adaptation for a marine existence. The more complete image of the various microanatomical trends observed in mosasaurine

Complete remission of liver metastasis in a lung cancer patient with epidermal growth factor mutation achieved with Icotinib.

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Zhu, Zhouyu; Chai, Ying

2016-11-01

A 65-year-old Chinese male was referred to our hospital for epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Aggressive combined therapy with surgical resection of the right upper lung lesion and chemotherapy was performed. One month later, continued Icotinib treatment was used as magnetic resonance imaging revealed liver metastasis (LM). Interestingly, complete remission of the patient's LM lesions was achieved in six months. To our knowledge, this is the first report documenting a successful case of an NSCLC patient with LM treated with Icotinib after receiving a radical resection for pulmonary carcinoma. Our experience could provide a treatment strategy for patients with similar disease. © 2016 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Metabolic Disturbances in Children with Chronic Liver Disease

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A Rezaeian

2014-04-01

Full Text Available Introduction: Liver disease results in complex pathophysiologic disturbances affecting nutrient digestion, absorption, distribution, storage, and use. This article aimed to present a classification of metabolic disturbances in chronic liver disease in children?   Materials and Methods: In this review study databases including proquest, pubmedcentral, scincedirect, ovid, medlineplus were been searched with keyword words such as” chronic liver disease"  ” metabolic disorder””children” between 1999 to 2014. Finally, 8 related articles have been found.   Results: Metabolic disorder in this population could be categorized in four set: 1carbohydrates, 2proteins,3 fats and 4vitamins. 1 Carbohydrates: Children with CLD are at increased risk for fasting hypoglycemia, because the capacity for glycogen storage and gluconeogenesis is reduced as a result of abnormal hepatocyte function and loss of hepatocyte mass. 2 Proteins: The liver’s capacity for plasma protein synthesis is impaired by reduced substrate availability, impaired hepatocyte function, and increased catabolism. This results in hypoalbuminemia, leading to peripheral edema and contributing to ascites. Reduced synthesis of insulin-like growth factor (IGF-1 and its binding protein IGF-BP3 by the chronically diseased liver results in growth hormone resistance and may contribute to the poor growth observed in these children. 3 Fats: There is increased fat oxidation in children with end-stage liver disease in the fed and fasting states compared with controls, which is probably related to reduced carbohydrate availability. The increased lipolysis results in a decrease in fat stores, which may not be easily replenished in the setting of the fat malabsorption that accompanies cholestasis. Reduced bile delivery to the gut results in impaired fat emulsification, and hence digestion. The products of fat digestion are also poorly absorbed, because bile is also required for micelle formation

Adaptation of the QoL-AGHDA scale for adults with growth hormone deficiency in four Slavic languages

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McKenna Stephen P

2011-08-01

Full Text Available Abstract Purpose The Quality of Life in Adult Growth Hormone Deficiency Assessment (QoL-AGHDA is a disease-specific quality of life measure specific to individuals who are growth hormone deficient. The present study describes the adaptation of the QoL-AGHDA for use in the following four Slavic languages; Czech, Polish, Serbian and Slovakian. Methods The study involved three stages in each language; translation, cognitive debriefing and validation. The validation stage assessed internal consistency (Cronbach's alpha, reproducibility (test-retest reliability using Spearman's rank correlations, convergent and divergent validity (Correlations with the NHP and known group validity. Results The QoL-AGHDA was successfully translated into the target languages with minimal problems. Cognitive debriefing interviewees (n = 15-18 found the measures easy to complete and identified few problems with the content. Internal consistency (Czech Republic = 0.91, Poland = 0.91, Serbia = 0.91 and Slovakia = 0.89 and reproducibility (Czech Republic = 0.91, Poland = 0.91, Serbia = 0.88 and Slovakia = 0.93 were good in all adaptations. Convergent and divergent validity and known group validity data were not available for Slovakia. The QoL-AGHDA correlated as expected with the NHP scales most relevant to GHD. The QoL-AGHDA was able to distinguish between participants based on a range of variables. Conclusions The QoL-AGHDA was successfully adapted for use in the Czech Republic, Poland, Serbia and Slovakia. Further validation of the Slovakian version would be beneficial. The addition of these new lanaguage versions will prove valuable to multinational clinical trials and to clinical practice in the respective countries.

Insulin resistance and delayed clearance of peptide hormones in cirrhotic rat liver

International Nuclear Information System (INIS)

Shankar, T.P.; Drake, S.; Solomon, S.S.

1987-01-01

Clearance of porcine insulin, glucagon, and human growth hormone was measured in intact perfused cirrhotic and normal rat livers. Binding and degradation of 125 I-insulin by hepatocytes isolated from cirrhotic and normal livers were also studied. The half-lives (t/sub 1/2/) of immunoreactive insulin and glucagon were 14.0 +/- 3.1 and 9.6 +/- 2.1 min in normal livers and 26.0 +/- 6.1 and 25.0 +/- 7.1 min in cirrhotic livers. Insulin binding and degradation by hepatocytes from control and cirrhotic livers showed no significant differences. Intraportal insulin infusion in perfusion studies suppressed glucagon-stimulated increases in glucose output from control livers but failed to suppress glucose production by cirrhotic livers, suggesting the presence of hepatic insulin resistance in cirrhosis. Impaired clearance of insulin and glucagon by the intact cirrhotic liver and normal binding and degradation of insulin by isolated hepatocytes suggest that factors such as intrahepatic fibrosis and shunting and postbinding defects may be responsible for the impaired hormone clearance and hepatic insulin resistance

Thrombospondin-1 expression may be implicated in liver atrophic mechanism due to obstructed portal venous flow.

Science.gov (United States)

Hayashi, Hiromitsu; Kuroki, Hideyuki; Higashi, Takaaki; Takeyama, Hideaki; Yokoyama, Naomi; Okabe, Hirohisa; Nitta, Hidetoshi; Beppu, Toru; Takamori, Hiroshi; Baba, Hideo

2017-07-01

Liver is an amazing organ that can undergo regenerative and atrophic changes inversely, depending on blood flow conditions. Although the regenerative mechanism has been extensively studied, the atrophic mechanism remains to be elucidated. To assess the molecular mechanism of liver atrophy due to reduced portal blood flow, we analyzed the gene expressions between atrophic and hypertrophic livers induced by portal vein embolization in three human liver tissues using microarray analyses. Thrombospondin (TSP)-1 is an extracellular protein and a negative regulator of liver regeneration through its activation of the transforming growth factor-β/Smad signaling pathway. TSP-1 was extracted as the most upregulated gene in atrophic liver compared to hypertrophic liver due to portal flow obstruction in human. Liver atrophic and hypertrophic changes were confirmed by HE and proliferating cell nuclear antigen staining and terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling. In an in vivo model with portal ligation, TSP-1 and phosphorylated Smad2 expression were continuously induced at 6 h and thereafter in the portal ligated liver, whereas the induction was transient at 6 h in the portal non-ligated liver. Indeed, while cell proliferation represented by proliferating cell nuclear antigen expression at 48 h was induced in the portal ligated liver, the sinusoidal dilatation and hepatocyte cell death with terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling was detectable at 48 h in the portal ligated liver. Obstructed portal flow induces persistent TSP-1 expression and transforming growth factor-β/Smad signal activation in atrophic liver. Thrombospondin-1 may be implicated in the liver atrophic change due to obstructed portal flow as a pro-atrophic factor. © 2016 The Japan Society of Hepatology.

Chemical and Hormonal Effects on STAT5b-Dependent Sexual Dimorphism of the Liver Transcriptome.

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Keiyu Oshida

Full Text Available The growth hormone (GH-activated transcription factor signal transducer and activator of transcription 5b (STAT5b is a key regulator of sexually dimorphic gene expression in the liver. Suppression of hepatic STAT5b signaling is associated with lipid metabolic dysfunction leading to steatosis and liver cancer. In the companion publication, a STAT5b biomarker gene set was identified and used in a rank-based test to predict both increases and decreases in liver STAT5b activation status/function with high (≥ 97% accuracy. Here, this computational approach was used to identify chemicals and hormones that activate (masculinize or suppress (feminize STAT5b function in a large, annotated mouse liver and primary hepatocyte gene expression compendium. Exposure to dihydrotestosterone and thyroid hormone caused liver masculinization, whereas glucocorticoids, fibroblast growth factor 15, and angiotensin II caused liver feminization. In mouse models of diabetes and obesity, liver feminization was consistently observed and was at least partially reversed by leptin or resveratrol exposure. Chemical-induced feminization of male mouse liver gene expression profiles was a relatively frequent phenomenon: of 156 gene expression biosets from chemically-treated male mice, 29% showed feminization of liver STAT5b function, while <1% showed masculinization. Most (93% of the biosets that exhibited feminization of male liver were also associated with activation of one or more xenobiotic-responsive receptors, most commonly constitutive activated receptor (CAR or peroxisome proliferator-activated receptor alpha (PPARα. Feminization was consistently associated with increased expression of peroxisome proliferator-activated receptor gamma (Pparg but not other lipogenic transcription factors linked to steatosis. GH-activated STAT5b signaling in mouse liver is thus commonly altered by diverse chemicals, and provides a linkage between chemical exposure and dysregulated gene

Microvessel density and endothelial cell proliferation levels in colorectal liver metastases from patients given neo-adjuvant cytotoxic chemotherapy and bevacizumab

DEFF Research Database (Denmark)

Eefsen, Rikke Løvendahl; Engelholm, Lars Henning; Willemoe, Gro L.

2016-01-01

with chemotherapy or chemotherapy plus bevacizumab. The resected liver metastases were characterised with respect to growth pattern, endothelial and tumour cell proliferation as well as microvessel density and tumour regression. Tumour regression grade of liver metastases differed significantly between untreated/chemotherapy......The treatment of patients with colorectal liver metastasis has improved significantly and first line therapy is often combined chemotherapy and bevacizumab, although it is unknown who responds to this regimen. Colorectal liver metastases grow in different histological growth patterns showing...... treated patients in comparison to chemotherapy plus bevacizumab treated patients (both p chemotherapy-treated patients (p = 0.006/p = 0.002). Tumour cell...

Estrogens regulate the hepatic effects of growth hormone, a hormonal interplay with multiple fates

DEFF Research Database (Denmark)

Fernández-Pérez, Leandro; Guerra, Borja; Díaz-Chico, Juan C

2013-01-01

The liver responds to estrogens and growth hormone (GH) which are critical regulators of body growth, gender-related hepatic functions, and intermediate metabolism. The effects of estrogens on liver can be direct, through the direct actions of hepatic ER, or indirect, which include the crosstalk...

Liver-Derived Insulin-Like Growth Factor-I is Involved in the Regulation of Blood Pressure in Mice

DEFF Research Database (Denmark)

Tivesten, Asa; Bollano, Entela; Andersson, Irene

2002-01-01

IGF-I has been suggested to be of importance for cardiovascular structure and function, but the relative role of locally produced and liver-derived endocrine IGF-I remains unclear. Using the Cre-LoxP recombination system, we have previously created transgenic mice with a liver-specific, inducible...... IGF-I knockout (LI-IGF-I-/-). To examine the role of liver-derived IGF-I in cardiovascular physiology, liver-derived IGF-I was inactivated at 4 wk of age, resulting in a 79% reduction of serum IGF-I levels. At 4 months of age, systolic blood pressure (BP) was increased in LI-IGF-I-/- mice...... to endothelial dysfunction associated with increased expression of endothelin-1 and impaired vasorelaxation of resistance vessels. In conclusion, our findings suggest that liver-derived IGF-I is involved in the regulation of BP in mice....

A three-dimensional in vitro HepG2 cells liver spheroid model for genotoxicity studies.

Science.gov (United States)

Shah, Ume-Kulsoom; Mallia, Jefferson de Oliveira; Singh, Neenu; Chapman, Katherine E; Doak, Shareen H; Jenkins, Gareth J S

2018-01-01

The liver's role in metabolism of chemicals makes it an appropriate tissue for toxicity testing. Current testing protocols, such as animal testing and two-dimensional liver cell systems, offer limited resemblance to in vivo liver cell behaviour, in terms of gene expression profiles and metabolic competence; thus, they do not always accurately predict human toxicology. In vitro three-dimensional liver cell models offer an attractive alternative. This study reports on the development of a 3D liver model, using HepG2 cells, by a hanging-drop technique, with a focus on evaluating spheroid growth characteristics and suitability for genotoxicity testing. The cytokinesis-blocked micronucleus assay protocol was adapted to enable micronucleus (MN) detection in the 3D spheroid models. This involved evaluating the difference between hanging vs non-hanging drop positions for dosing of the test agents and comparison of automated Metafer scoring with manual scoring for MN detection in HepG2 spheroids. The initial seeding density, used for all experiments, was 5000 cells/20 μl drop hanging spheroids, harvested on day 4, with >75% cell viability. Albumin secretion (7.8 g/l) and both CYP1A1 and CYP1A2 gene expression were highest in the 3D environment at day 4. Exposure to metabolically activated genotoxicants for 24 h resulted in a 6-fold increase in CYP1A1 enzyme activity (3 μM B[a]P) and a 30-fold increase in CYP1A2 enzyme activity (5 μM PhIP) in 3D hanging spheroids. MN inductions in response to B[a]P or PhIP were 2-fold and 3-fold, respectively, and were greater in 3D hanging spheroids than in 2D format, showing that hanging spheroids are more sensitive to genotoxic agents. HepG2 hanging-drop spheroids are an exciting new alternative system for genotoxicity studies, due to their improved structural and physiological properties, relative to 2D cultures. Copyright © 2017 Elsevier B.V. All rights reserved.

Gait in ducks (Anas platyrhynchos and chickens (Gallus gallus – similarities in adaptation to high growth rate

Directory of Open Access Journals (Sweden)

B. M. Duggan

2016-08-01

Full Text Available Genetic selection for increased growth rate and muscle mass in broiler chickens has been accompanied by mobility issues and poor gait. There are concerns that the Pekin duck, which is on a similar selection trajectory (for production traits to the broiler chicken, may encounter gait problems in the future. In order to understand how gait has been altered by selection, the walking ability of divergent lines of high- and low-growth chickens and ducks was objectively measured using a pressure platform, which recorded various components of their gait. In both species, lines which had been selected for large breast muscle mass moved at a slower velocity and with a greater step width than their lighter conspecifics. These high-growth lines also spent more time supported by two feet in order to improve balance when compared with their lighter, low-growth conspecifics. We demonstrate that chicken and duck lines which have been subjected to intense selection for high growth rates and meat yields have adapted their gait in similar ways. A greater understanding of which components of gait have been altered in selected lines with impaired walking ability may lead to more effective breeding strategies to improve gait in poultry.

High hydrostatic pressure influences the in vitro response to xenobiotics in Dicentrarchus labrax liver

Energy Technology Data Exchange (ETDEWEB)

Lemaire, Benjamin; Mignolet, Eric; Debier, Cathy [Institut des Sciences de la Vie, Université Catholique de Louvain, Croix du Sud 2, B-1348 Louvain-la-Neuve (Belgium); Calderon, Pedro Buc [Louvain Drug Research Institute, Université Catholique de Louvain, Avenue Mounier 73, B-1200 Woluwé-Saint-Lambert (Belgium); Thomé, Jean Pierre [Laboratoire d’Ecologie Animale et Ecotoxicologie, Université de Liège, Allée du 6 août 15, B-4000 Liège (Belgium); Rees, Jean François, E-mail: jf.rees@uclouvain.be [Institut des Sciences de la Vie, Université Catholique de Louvain, Croix du Sud 2, B-1348 Louvain-la-Neuve (Belgium)

2016-04-15

Highlights: • The methodology of precision-cut liver slices was applied to the European seabass. • Liver slices remained viable and functional in short-term co-exposure studies. • CYP1A induction was blocked in slices exposed to an AhR agonist at high pressure. • HSP70 induction was lower in slices exposed to an AhR agonist at high pressure. • Oxidative stress responses to tBHP were less pronounced at high pressure. - Abstract: Hydrostatic pressure (HP) increases by about 1 atmosphere (0.1 MPa) for each ten-meter depth increase in the water column. This thermodynamical parameter could well influence the response to and effects of xenobiotics in the deep-sea biota, but this possibility remains largely overlooked. To grasp the extent of HP adaptation in deep-sea fish, comparative studies with living cells of surface species exposed to chemicals at high HP are required. We initially conducted experiments with precision-cut liver slices of a deep-sea fish (Coryphaenoides rupestris), co-exposed for 15 h to the aryl hydrocarbon receptor (AhR) agonist 3-methylcholanthrene at HP levels representative of the surface (0.1 MPa) and deep-sea (5–15 MPa; i.e., 500–1500 m depth) environments. The transcript levels of a suite of stress-responsive genes, such as the AhR battery CYP1A, were subsequently measured (Lemaire et al., 2012; Environ. Sci. Technol. 46, 10310–10316). Strikingly, the AhR agonist-mediated increase of CYP1A mRNA content was pressure-dependently reduced in C. rupestris. Here, the same co-exposure scenario was applied for 6 or 15 h to liver slices of a surface fish, Dicentrarchus labrax, a coastal species presumably not adapted to high HP. Precision-cut liver slices of D. labrax were also used in 1 h co-exposure studies with the pro-oxidant tert-butylhydroperoxide (tBHP) as to investigate the pressure-dependence of the oxidative stress response (i.e., reactive oxygen production, glutathione and lipid peroxidation status). Liver cells remained

High hydrostatic pressure influences the in vitro response to xenobiotics in Dicentrarchus labrax liver

International Nuclear Information System (INIS)

Lemaire, Benjamin; Mignolet, Eric; Debier, Cathy; Calderon, Pedro Buc; Thomé, Jean Pierre; Rees, Jean François

2016-01-01

Highlights: • The methodology of precision-cut liver slices was applied to the European seabass. • Liver slices remained viable and functional in short-term co-exposure studies. • CYP1A induction was blocked in slices exposed to an AhR agonist at high pressure. • HSP70 induction was lower in slices exposed to an AhR agonist at high pressure. • Oxidative stress responses to tBHP were less pronounced at high pressure. - Abstract: Hydrostatic pressure (HP) increases by about 1 atmosphere (0.1 MPa) for each ten-meter depth increase in the water column. This thermodynamical parameter could well influence the response to and effects of xenobiotics in the deep-sea biota, but this possibility remains largely overlooked. To grasp the extent of HP adaptation in deep-sea fish, comparative studies with living cells of surface species exposed to chemicals at high HP are required. We initially conducted experiments with precision-cut liver slices of a deep-sea fish (Coryphaenoides rupestris), co-exposed for 15 h to the aryl hydrocarbon receptor (AhR) agonist 3-methylcholanthrene at HP levels representative of the surface (0.1 MPa) and deep-sea (5–15 MPa; i.e., 500–1500 m depth) environments. The transcript levels of a suite of stress-responsive genes, such as the AhR battery CYP1A, were subsequently measured (Lemaire et al., 2012; Environ. Sci. Technol. 46, 10310–10316). Strikingly, the AhR agonist-mediated increase of CYP1A mRNA content was pressure-dependently reduced in C. rupestris. Here, the same co-exposure scenario was applied for 6 or 15 h to liver slices of a surface fish, Dicentrarchus labrax, a coastal species presumably not adapted to high HP. Precision-cut liver slices of D. labrax were also used in 1 h co-exposure studies with the pro-oxidant tert-butylhydroperoxide (tBHP) as to investigate the pressure-dependence of the oxidative stress response (i.e., reactive oxygen production, glutathione and lipid peroxidation status). Liver cells remained

Liver Transplant

Science.gov (United States)

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Determinate primary root growth as an adaptation to aridity in Cactaceae: towards an understanding of the evolution and genetic control of the trait.

Science.gov (United States)

Shishkova, Svetlana; Las Peñas, María Laura; Napsucialy-Mendivil, Selene; Matvienko, Marta; Kozik, Alex; Montiel, Jesús; Patiño, Anallely; Dubrovsky, Joseph G

2013-07-01

Species of Cactaceae are well adapted to arid habitats. Determinate growth of the primary root, which involves early and complete root apical meristem (RAM) exhaustion and differentiation of cells at the root tip, has been reported for some Cactoideae species as a root adaptation to aridity. In this study, the primary root growth patterns of Cactaceae taxa from diverse habitats are classified as being determinate or indeterminate, and the molecular mechanisms underlying RAM maintenance in Cactaceae are explored. Genes that were induced in the primary root of Stenocereus gummosus before RAM exhaustion are identified. Primary root growth was analysed in Cactaceae seedlings cultivated in vertically oriented Petri dishes. Differentially expressed transcripts were identified after reverse northern blots of clones from a suppression subtractive hybridization cDNA library. All species analysed from six tribes of the Cactoideae subfamily that inhabit arid and semi-arid regions exhibited determinate primary root growth. However, species from the Hylocereeae tribe, which inhabit mesic regions, exhibited mostly indeterminate primary root growth. Preliminary results suggest that seedlings of members of the Opuntioideae subfamily have mostly determinate primary root growth, whereas those of the Maihuenioideae and Pereskioideae subfamilies have mostly indeterminate primary root growth. Seven selected transcripts encoding homologues of heat stress transcription factor B4, histone deacetylase, fibrillarin, phosphoethanolamine methyltransferase, cytochrome P450 and gibberellin-regulated protein were upregulated in S. gummosus root tips during the initial growth phase. Primary root growth in Cactoideae species matches their environment. The data imply that determinate growth of the primary root became fixed after separation of the Cactiodeae/Opuntioideae and Maihuenioideae/Pereskioideae lineages, and that the genetic regulation of RAM maintenance and its loss in Cactaceae is

Liver transplantation for metastatic neuroendocrine tumor: A case report and review of the literature

Institute of Scientific and Technical Information of China (English)

Wojciech C Blonski; K Rajender Reddy; Abraham Shaked; Evan Siegelman; David C Metz

2005-01-01

Neuroendocrine tumors are divided into gastrointestinal carcinoids and pancreatic neuroendocrine tumors. The WHO has updated the classification of these lesions and has abandoned the term "carcinoid". Both types of tumors are divided into functional and non-functional tumors. They are characterized by slow growth and frequent metastasis to the liver and may be limited to the liver for long periods. The therapeutic approach to hepatic metastases should consider the number and distribution of the liver metastases as well as the severity of symptoms related to hormone production and tumor bulk. Surgery is generally considered as the first line therapy. In patients with unresectable liver metastases,alternative treatments are dependent on the type and the growth rate. Initial treatments consist of long acting somatostatin analogs and/or interferon. Streptozocinbased chemotherapy is usually reserved for symptomatic patients with rapidly advancing disease, but generally the therapy is poorly tolerated and its effects are short-lived.Locoregional therapy directed such as hepatic-artery embolization and chemoembolization, radiofrequency thermal ablation and cryosurgery, is often used instead of systemic therapy, if the disease is limited to the liver.However, liver transplantation should be considered in patients with neuroendocrine metastases to the liver that are not accessible to curative or cytoreductive surgery and if medical or locoregional treatment has failed and if there are life threatening hormonal symptoms. We report a case of liver transplantation for metastatic neuroendocrine tumor of unknown primary source and provide a detailed review of the world literature on this controversial topic.

Posttraumatic growth measures: translation and adaptation of three self-report instruments to Brazilian Portuguese

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Thiago Loreto Garcia da Silva

2016-06-01

Full Text Available Abstract Background Posttraumatic growth is one of the most commonly used concepts to evaluate positive changes after trauma. The principal scales used internationally to evaluate this phenomenon have not yet a Brazilian Portuguese version. Objectives This study aimed to translate and adapt to the Brazilian context the Posttraumatic Growth Inventory (PTGI, the Core Beliefs Inventory (CBI, and the Event Related Rumination Inventory (ERRI. Methods The procedures included translation, back translation, expert committee’s evaluation, and pilot testing in the target population. Results All items of all three instruments had a good content validity index after evaluation by four experts and three reformulations. The back translation of the final version also demonstrated that all Brazilian Portuguese versions convey the same meaning as the original English version. The final version was pilot tested with 30 undergraduate students, and all the items were above the cut-off point. Discussion This study was able to produce Brazilian versions of the PTGI, CBI, and ERRI. Further studies are underway to determine the reliability, factorial validity, and convergent validity of the subscales of the instruments.

Liver regeneration and restoration of liver function after partial hepatectomy in patients with liver tumors

NARCIS (Netherlands)

Jansen, P. L.; Chamuleau, R. A.; van Leeuwen, D. J.; Schipper, H. G.; Busemann-Sokole, E.; van der Heyde, M. N.

1990-01-01

Liver regeneration and restoration of liver function were studied in six patients who underwent partial hepatectomy with removal of 30-70% of the liver. Liver volume and liver regeneration were studied by single-photon computed tomography (SPECT), using 99mTc-colloid as tracer. The method was

The Effect of Elephantopus scaber L. on Liver Regeneration after Partial Hepatectomy

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Chin-Chuan Tsai

2013-01-01

Full Text Available Liver regeneration after partial hepatectomy (PHx is a physiological response for maintaining homeostasis. The aim of this study is to investigate effects of Elephantopus scaber L.- (ESL- induced liver regeneration on growth factors (HGF and IGF-1, cell cycle regulation, and apoptosis suppressed. In this study, we fed five Chinese medicinal herbs (1 g/kg/day, Codonopsis pilosula (CP, Dangshen, Salvia miltiorrhiza Bunge (SMB, Danshen,, Bupleurum kasi (BK, Chaihu, Elephantopus scaber L. (ESL, Teng-Khia-U, and Silymarin (Sm, 25 mg/kg for 7 days to male Spraue-Dawley rats. Then surgical 2/3 PHx was conducted and liver regeneration mechanisms were estimated on the following 24 hrs and 72 hrs. The activities of growth factors (HGF and IGF-I and cell cycle proteins were measured by Western blot and RT-PCR. Histological analysis and apoptosis were detected by H&E stain and TUNEL. The results showed that extraction of Elephantopus scaber L. (ESL and Silymarin (Sm, positive control were increased protein expression levels of HGF and IGF-1 which leads into cell cycle. These results suggest that the ESL plays a crucial role in cell cycle-induced liver regeneration and apoptosis. These results suggested that the ESL plays a crucial role in cell cycle-induced liver regeneration and suppressed hepatocytes apoptosis.

Semisolid liver infusion tryptose supplemented with human urine allows growth and isolation of Trypanosoma cruzi and Trypanosoma rangeli clonal lineages

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Emanuella Francisco Fajardo

2016-06-01

Full Text Available Abstract: INTRODUCTION This work shows that 3% (v/v human urine (HU in semisolid Liver Infusion Tryptose (SSL medium favors the growth of Trypanosoma cruzi and T. rangeli. METHODS Parasites were plated as individual or mixed strains on SSL medium and on SSL medium with 3% human urine (SSL-HU. Isolate DNA was analyzed using polymerase chain reaction (PCR and pulsed-field gel electrophoresis (PFGE. RESULTS SSL-HU medium improved clone isolation. PCR revealed that T. cruzi strains predominate on mixed-strain plates. PFGE confirmed that isolated parasites share the same molecular karyotype as parental cell lines. CONCLUSIONS SSL-HU medium constitutes a novel tool for obtaining T. cruzi and T. rangeli clonal lineages.

Clinical significance of changes of serum insulin-like growth factors contents in patients with cirrhosis of liver

International Nuclear Information System (INIS)

Hu Haiqiang; Lei Qiufang; Ye Peihong; Li Xiaohong; Gao Wenjin; Wang Mingtao

2006-01-01

Objective: To investigate the association between the serum contents of IGF-I, IGF-II and liver dysfunction (as classified with Child-Pugh grades). Methods: Liver function test profiles as well as serum IGF-I, IGF-II contents ( with IRMA) were studied in 46 patients with liver cirrhosis and 32 controls. Results: According to the degree of liver dysfunction, these 46 patients with cirrhosis could be classified as: Child Grade A, n=17; Child B, n=20; and Child C, n=9. The serum IGF-I and IGF-II contents in the cirrhotic patients were significantly lower than those in the controls (P<0.001). The levels dropped along with the progression of child classification grades. Changes of IGF-II were more sensitive than those of IGF-I. Conclusion: Serum IGF-I and IGF-II contents were closely associated with degree of liver dysfunction and might be of prognostic significance. (authors)

Bone Mineral Density and Growth in Children Having Undergone Liver Transplantation With Corticosteroid-Free Immunosuppressive Protocol.

Science.gov (United States)

Mager, Diana; Al-Zaben, Abeer Salman; Robert, Cheri; Gilmour, Susan; Yap, Jason

2017-05-01

Children post-liver transplantation (post-LTX) are at risk of growth delay and decreased bone mineral density (BMD) secondary to corticosteroid (CS) therapy and suboptimal intake of nutrients important for bone health. The pediatric LTX program at Stollery Children's Hospital introduced a CS-free LTX regimen in 2003. This retrospective study investigated whether the implementation of a CS-free protocol resulted in improvements in BMD (dual x-ray absorptiometry) and growth following LTX. A retrospective chart review of all children undergoing LTX was conducted. The parameters included repeated measures of anthropometric (weight, weight z score, height, height z score), BMD/bone mineral content (BMC), laboratory variables, graft function (number/severity of rejection), and CS therapy (dose, duration). A total of 39 patients met study inclusion (20 male; n = 28 on CS; n = 11 CS-free). Mean duration of follow-up was 5.5 ± 3.3 years. The mean weight and height z scores were -0.31 ± 0.14 (CS) and 0.22 ± 0.23 (CS-free; P = .09) and -0.71 ± 0.13 (CS) and 0.23 ± 0.22 (CS-free; P = .002), respectively. Lumbar and whole-body BMD z score less than -2 were present in 15% and 8% of the cohort, respectively. There were no significant differences between CS and CS-free in lumbar BMC (22.2 ± 1.4 and 23.4 ± 2.02 g; P = .165) and lumbar BMD (0.57 ± 0.02 and 0.80 ± 0.22 g/cm 2 ; P = .152), respectively. Lumbar BMC ( r 2 = 0.89, P 0.2 mg/kg/d and positively related to bone age ( P bone health is important to optimizing growth and bone health in children post-LTX.

Method of propagation, stimulation of rhizomes growth in vitro culture and adaptation in the open ground for the genus Miscanthus representatives

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С. М. Гонтаренко

2017-09-01

Full Text Available Purpose. To develop a method of propagation, stimulation of rhizomes growth in vitro culture for the genus Miscanthus representatives and their adaptation in the open field without the use of greenhouse complexes for acclimatization and completion of growing. Methods. Biotechnological procedures, mathematical and statistical analyses. Results. Prescription of nutrient medium was developed for explants inoculation, sprouts propagation, rhizomes growth stimulation in vitro. Such sterile explants as seeds, buds to be removed from rhizomes, parts of  stems with bud were placed on modified media with mineral portion by Murashige and Skoog (MS that contained 0,5–1 dose of macroelements and one dose of microelements,  vitamins (10 mg/l of thia­minum, 1,0 mg/l of pyridoxine, 1,0 mg/l of nicotinic acid and 1,0 mg/l of ascorbic acid supplemented with amino acids (250 mg/l of glutamic acid, 3 mg/l of tyrosine, 3 mg/l of arginine, 2 mg/l of hydroxyproline, plant growth regulators [0,5–1,0 mg/l of GA (gibberelline acid, 0,2 mg/l of 6-BAP (6-Benzylaminopurine, 0,1 mg/l of NAA (α-naphtylacetic acid] in different variations. After seed germination, buds emerging and sprouts formation 1–2 cm in height, for propagation purpose they were passivated on the medium of other composition that differed from previous one by the content and ratio of growth regulators, especially by a high concentration of cytokinins [6-BAP (0,4–0,5 mg/l, kinetin (0,5 mg/l, adenine (0,5 mg/k] in different variations in presence of GA (0,2 mg/l. In order to stimulate rhizomes growth, microclones were transferred on media with other composition and ratio growth regulators (6-BAP (0,2–0,3 mg/l + GA (0,5–1,0 mg/l or 6-BAP (0,2–0,3 mg/l + GA (0,5–1,0 mg/l + NAA (0,1 mg/l,  in other words,  with a high content of gibberellins. After the formation of rhizomes 10–15 cm in length, miscanthus plants were planted out in the open ground. Stimulation of

Effect of Salinity Adaptation Technique on Survival and Growth Rate of Patin Catfish, Pangasius sp.

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K. Nirmala

2007-01-01

Full Text Available This study was carried out to determine the effect of salinity adaptation techniques on growth and survival of patin catfish Pangasius sp. fry.  Fry of 1.5-2.0 inch in length were reared in the water with different of the initial salinity of 1, 2, 3, 4 and 5 ppt.  Salinity was then daily increased by duplicated the initial water salinity until fish died.  The results of study showed that fry could survive by initial salinity adaptation of 1 ppt and then increasing the salinity by 1 ppt/day to reach 27 ppt.  In the other treatments, all fry died after the salinity reach 18-25 ppt. Keywords: patin catfish, Pangasius, adaptation, salinity   ABSTRAK Penelitian ini bertujuan untuk mengetahui pengaruh teknik adaptasi salinitas terhadap pertumbuhan dan kelangsungan hidup benih ikan patin Pangasius sp.  Benih patin ukuran 1,5-2 inci dipelihara pada salinitas awal berbeda, yaitu 1, 2, 3, 4 dan 5 ppt. Salinitas air pemeliharaan ditingkatkan kelipatan dari salinitas awal setiap hari hingga ikan mati.  Hasil penelitian menunjukkan bahwa adaptasi salinitas awal 1 ppt dan peningkatan sebesar 1ppt/hari menyebabkan ikan dapat bertahan hidup sampai pada salinitas 27 ppt. Pada perlakuan lainnya, benih ikan mengalami kematian masal ketika salinitas mencapai 18-25 ppt. Kata kunci: ikan patin, Pangasius, adaptasi, salinitas

Case Characterization, Clinical Features and Risk Factors in Drug-Induced Liver Injury

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Aida Ortega-Alonso

2016-05-01

Full Text Available Idiosyncratic drug-induced liver injury (DILI caused by xenobiotics (drugs, herbals and dietary supplements presents with a range of both phenotypes and severity, from acute hepatitis indistinguishable of viral hepatitis to autoimmune syndromes, steatosis or rare chronic vascular syndromes, and from asymptomatic liver test abnormalities to acute liver failure. DILI pathogenesis is complex, depending on the interaction of drug physicochemical properties and host factors. The awareness of risk factors for DILI is arising from the analysis of large databases of DILI cases included in Registries and Consortia networks around the world. These networks are also enabling in-depth phenotyping with the identification of predictors for severe outcome, including acute liver failure and mortality/liver transplantation. Genome wide association studies taking advantage of these large cohorts have identified several alleles from the major histocompatibility complex system indicating a fundamental role of the adaptive immune system in DILI pathogenesis. Correct case definition and characterization is crucial for appropriate phenotyping, which in turn will strengthen sample collection for genotypic and future biomarkers studies.

Force-induced bone growth and adaptation: A system theoretical approach to understanding bone mechanotransduction

International Nuclear Information System (INIS)

Maldonado, Solvey; Findeisen, Rolf

2010-01-01

The modeling, analysis, and design of treatment therapies for bone disorders based on the paradigm of force-induced bone growth and adaptation is a challenging task. Mathematical models provide, in comparison to clinical, medical and biological approaches an structured alternative framework to understand the concurrent effects of the multiple factors involved in bone remodeling. By now, there are few mathematical models describing the appearing complex interactions. However, the resulting models are complex and difficult to analyze, due to the strong nonlinearities appearing in the equations, the wide range of variability of the states, and the uncertainties in parameters. In this work, we focus on analyzing the effects of changes in model structure and parameters/inputs variations on the overall steady state behavior using systems theoretical methods. Based on an briefly reviewed existing model that describes force-induced bone adaptation, the main objective of this work is to analyze the stationary behavior and to identify plausible treatment targets for remodeling related bone disorders. Identifying plausible targets can help in the development of optimal treatments combining both physical activity and drug-medication. Such treatments help to improve/maintain/restore bone strength, which deteriorates under bone disorder conditions, such as estrogen deficiency.

Liver Hemangioma

Science.gov (United States)

Liver hemangioma Overview A liver hemangioma (he-man-jee-O-muh) is a noncancerous (benign) mass in the liver. A liver hemangioma is made up of a tangle of blood vessels. Other terms for a liver hemangioma are hepatic hemangioma and cavernous hemangioma. Most ...

High hydrostatic pressure influences the in vitro response to xenobiotics in Dicentrarchus labrax liver.

Science.gov (United States)

Lemaire, Benjamin; Mignolet, Eric; Debier, Cathy; Calderon, Pedro Buc; Thomé, Jean Pierre; Rees, Jean François

2016-04-01

Hydrostatic pressure (HP) increases by about 1 atmosphere (0.1MPa) for each ten-meter depth increase in the water column. This thermodynamical parameter could well influence the response to and effects of xenobiotics in the deep-sea biota, but this possibility remains largely overlooked. To grasp the extent of HP adaptation in deep-sea fish, comparative studies with living cells of surface species exposed to chemicals at high HP are required. We initially conducted experiments with precision-cut liver slices of a deep-sea fish (Coryphaenoides rupestris), co-exposed for 15h to the aryl hydrocarbon receptor (AhR) agonist 3-methylcholanthrene at HP levels representative of the surface (0.1MPa) and deep-sea (5-15MPa; i.e., 500-1500m depth) environments. The transcript levels of a suite of stress-responsive genes, such as the AhR battery CYP1A, were subsequently measured (Lemaire et al., 2012; Environ. Sci. Technol. 46, 10310-10316). Strikingly, the AhR agonist-mediated increase of CYP1A mRNA content was pressure-dependently reduced in C. rupestris. Here, the same co-exposure scenario was applied for 6 or 15h to liver slices of a surface fish, Dicentrarchus labrax, a coastal species presumably not adapted to high HP. Precision-cut liver slices of D. labrax were also used in 1h co-exposure studies with the pro-oxidant tert-butylhydroperoxide (tBHP) as to investigate the pressure-dependence of the oxidative stress response (i.e., reactive oxygen production, glutathione and lipid peroxidation status). Liver cells remained viable in all experiments (adenosine triphosphate content). High HP precluded the AhR agonist-mediated increase of CYP1A mRNA expression in D. labrax, as well as that of glutathione peroxidase, and significantly reduced that of heat shock protein 70. High HP (1h) also tended per se to increase the level of oxidative stress in liver cells of the surface fish. Trends to an increased resistance to tBHP were also noted. Whether the latter observation truly

Proteomic analysis of physiological function response to hot summer in liver from lactating dairy cows.

Science.gov (United States)

Wang, Qiangjun; Zhao, Xiaowei; Zhang, Zijun; Zhao, Huiling; Huang, Dongwei; Cheng, Guanglong; Yang, Yongxin

2017-04-01

Lactation performance of dairy cattle is susceptible to heat stress. The liver is one of the most crucial organs affected by high temperature in dairy cows. However, the physiological adaption by the liver to hot summer conditions has not been well elucidated in lactating dairy cows. In the present study, proteomic analysis of the liver in dairy cows in spring and hot summer was performed using a label-free method. In total, 127 differentially expressed proteins were identified; most of the upregulated proteins were involved in protein metabolic processes and responses to stimuli, whereas most of the downregulated proteins were related to oxidation-reduction. Pathway analysis indicated that 3 upregulated heat stress proteins (HSP90α, HSP90β, and endoplasmin) were enriched in the NOD-like receptor signaling pathway, whereas several downregulated NADH dehydrogenase proteins were involved in the oxidative phosphorylation pathway. The protein-protein interaction network indicated that several upregulated HSPs (HSP90α, HSP90β, and GRP78) were involved in more interactions than other proteins and were thus considered as central hub nodes. Our findings provide novel insights into the physiological adaption of liver function in lactating dairy cows to natural high temperature. Copyright © 2017. Published by Elsevier Ltd.

Effects of Diclofenac, L-NAME, L-Arginine, and Pentadecapeptide BPC 157 on Gastrointestinal, Liver, and Brain Lesions, Failed Anastomosis, and Intestinal Adaptation Deterioration in 24 Hour-Short-Bowel Rats.

Science.gov (United States)

Lojo, Nermin; Rasic, Zarko; Zenko Sever, Anita; Kolenc, Danijela; Vukusic, Darko; Drmic, Domagoj; Zoricic, Ivan; Sever, Marko; Seiwerth, Sven; Sikiric, Predrag

2016-01-01

Stable gastric pentadecapeptide BPC 157 was previously used to ameliorate wound healing following major surgery and counteract diclofenac toxicity. To resolve the increasing early risks following major massive small bowel resectioning surgery, diclofenac combined with nitric oxide (NO) system blockade was used, suggesting therapy with BPC 157 and the nitric oxide synthase (NOS substrate) L-arginine, is efficacious. Immediately after anastomosis creation, short-bowel rats were untreated or administered intraperitoneal diclofenac (12 mg/kg), BPC 157 (10 μg/kg or 10 ng/kg), L-NG-nitroarginine methyl ester (L-NAME, 5 mg/kg), L-arginine (100 mg/kg) alone or combined, and assessed 24 h later. Short-bowel rats exhibited poor anastomosis healing, failed intestine adaptation, and gastrointestinal, liver, and brain lesions, which worsened with diclofenac. This was gradually ameliorated by immediate therapy with BPC 157 and L-arginine. Contrastingly, NOS-blocker L-NAME induced further aggravation and lesions gradually worsened. Specifically, rats with surgery alone exhibited mild stomach/duodenum lesions, considerable liver lesions, and severe cerebral/hippocampal lesions while those also administered diclofenac showed widespread severe lesions in the gastrointestinal tract, liver, cerebellar nuclear/Purkinje cells, and cerebrum/hippocampus. Rats subjected to surgery, diclofenac, and L-NAME exhibited the mentioned lesions, worsening anastomosis, and macro/microscopical necrosis. Thus, rats subjected to surgery alone showed evidence of deterioration. Furtheremore, rats subjected to surgery and administered diclofenac showed worse symptoms, than the rats subjected to surgery alone did. Rats subjected to surgery combined with diclofenac and L-NAME showed the worst deterioration. Rats subjected to surgery exhibited habitual adaptation of the remaining small intestine, which was markedly reversed in rats subjected to surgery and diclofenac, and those with surgery, diclofenac, and

Endocrine causes of nonalcoholic fatty liver disease.

Science.gov (United States)

Marino, Laura; Jornayvaz, François R

2015-10-21

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world. The prevalence of NAFLD is increasing, becoming a substantial public health burden. NAFLD includes a broad spectrum of disorders, from simple conditions such as steatosis to severe manifestations such as fibrosis and cirrhosis. The relationship of NAFLD with metabolic alterations such as type 2 diabetes is well described and related to insulin resistance, with NAFLD being recognized as the hepatic manifestation of metabolic syndrome. However, NAFLD may also coincide with endocrine diseases such as polycystic ovary syndrome, hypothyroidism, growth hormone deficiency or hypercortisolism. It is therefore essential to remember, when discovering altered liver enzymes or hepatic steatosis on radiological exams, that endocrine diseases can cause NAFLD. Indeed, the overall prognosis of NAFLD may be modified by treatment of the underlying endocrine pathology. In this review, we will discuss endocrine diseases that can cause NALFD. Underlying pathophysiological mechanisms will be presented and specific treatments will be reviewed.

Successful Sequential Liver and Hematopoietic Stem Cell Transplantation in a Child With CD40 Ligand Deficiency and Cryptosporidium-Induced Liver Cirrhosis.

Science.gov (United States)

Quarello, Paola; Tandoi, Francesco; Carraro, Francesca; Vassallo, Elena; Pinon, Michele; Romagnoli, Renato; David, Ezio; Dell Olio, Dominic; Salizzoni, Mauro; Fagioli, Franca; Calvo, Pier Luigi

2018-05-01

Hematopoietic stem cell transplantation (HSCT) is curative in patients with primary immunodeficiencies. However, pre-HSCT conditioning entails unacceptably high risks if the liver is compromised. The presence of a recurrent opportunistic infection affecting the biliary tree and determining liver cirrhosis with portal hypertension posed particular decisional difficulties in a 7-year-old child with X-linked CD40-ligand deficiency. We aim at adding to the scanty experience available on such rare cases, as successful management with sequential liver transplantation (LT) and HSCT has been reported in detail only in 1 young adult to date. A closely sequential strategy, with a surgical complication-free LT, followed by reduced-intensity conditioning, allowed HSCT to be performed only one month after LT, preventing Cryptosporidium parvum recolonization of the liver graft. Combined sequential LT and HSCT resolved the cirrhotic evolution and corrected the immunodeficiency so that the infection responsible for the progressive sclerosing cholangitis did not recur. Hopefully, this report of the successful resolution of a potentially fatal combination of immunodeficiency and chronic opportunistic infection with end-stage organ damage in a child will encourage others to adapt a sequential transplant approach to this highly complex pathology. However, caution is to be exercised to carefully balance the risks intrinsic to transplant surgery and immunosuppression in primary immunodeficiencies.

Identification and Characterization of Mesenchymal-Epithelial Progenitor-Like Cells in Normal and Injured Rat Liver

Science.gov (United States)

Liu, Daqing; Yovchev, Mladen I.; Zhang, Jinghang; Alfieri, Alan A.; Tchaikovskaya, Tatyana; Laconi, Ezio; Dabeva, Mariana D.

2016-01-01

In normal rat liver, thymocyte antigen 1 (Thy1) is expressed in fibroblasts/myofibroblasts and in some blood progenitor cells. Thy1-expressing cells also accumulate in the liver during impaired liver regeneration. The origin and nature of these cells are not well understood. By using RT-PCR analysis and immunofluorescence microscopy, we describe the presence of rare Thy1+ cells in the liver lobule of normal animals, occasionally forming small collections of up to 20 cells. These cells constitute a small portion (1.7% to 1.8%) of nonparenchymal cells and reveal a mixed mesenchymal-epithelial phenotype, expressing E-cadherin, cytokeratin 18, and desmin. The most potent mitogens for mesenchymal-epithelial Thy1+ cells in vitro are the inflammatory cytokines interferon γ, IL-1, and platelet-derived growth factor-BB, which are not produced by Thy1+ cells. Thy1+ cells express all typical mesenchymal stem cell and hepatic progenitor cell markers and produce growth factor and cytokine mRNA (Hgf, Il6, Tgfa, and Tweak) for proteins that maintain oval cell growth and differentiation. Under appropriate conditions, mesenchymal-epithelial cells differentiate in vitro into hepatocyte-like cells. In this study, we show that the adult rat liver harbors a small pool of endogenous mesenchymal-epithelial cells not recognized previously. In the quiescent state, these cells express both mesenchymal and epithelial cell markers. They behave like hepatic stem cells/progenitors with dual phenotype, exhibiting high plasticity and long-lasting proliferative activity. PMID:25447047

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

Administration of multipotent mesenchymal stromal cells restores liver regeneration and improves liver function in obese mice with hepatic steatosis after partial hepatectomy.

Science.gov (United States)

Ezquer, Fernando; Bahamonde, Javiera; Huang, Ya-Lin; Ezquer, Marcelo

2017-01-28

The liver has the remarkable capacity to regenerate in order to compensate for lost or damaged hepatic tissue. However, pre-existing pathological abnormalities, such as hepatic steatosis (HS), inhibits the endogenous regenerative process, becoming an obstacle for liver surgery and living donor transplantation. Recent evidence indicates that multipotent mesenchymal stromal cells (MSCs) administration can improve hepatic function and increase the potential for liver regeneration in patients with liver damage. Since HS is the most common form of chronic hepatic illness, in this study we evaluated the role of MSCs in liver regeneration in an animal model of severe HS with impaired liver regeneration. C57BL/6 mice were fed with a regular diet (normal mice) or with a high-fat diet (obese mice) to induce HS. After 30 weeks of diet exposure, 70% hepatectomy (Hpx) was performed and normal and obese mice were divided into two groups that received 5 × 10 5 MSCs or vehicle via the tail vein immediately after Hpx. We confirmed a significant inhibition of hepatic regeneration when liver steatosis was present, while the hepatic regenerative response was promoted by infusion of MSCs. Specifically, MSC administration improved the hepatocyte proliferative response, PCNA-labeling index, DNA synthesis, liver function, and also reduced the number of apoptotic hepatocytes. These effects may be associated to the paracrine secretion of trophic factors by MSCs and the hepatic upregulation of key cytokines and growth factors relevant for cell proliferation, which ultimately improves the survival rate of the mice. MSCs represent a promising therapeutic strategy to improve liver regeneration in patients with HS as well as for increasing the number of donor organs available for transplantation.

Therapeutic effects of protein kinase N3 small interfering RNA and doxorubicin combination therapy on liver and lung metastases

Science.gov (United States)

Hattori, Yoshiyuki; Kikuchi, Takuto; Nakamura, Mari; Ozaki, Kei-Ichi; Onishi, Hiraku

2017-01-01

It has been reported that suppression of protein kinase N3 (PKN3) expression in vascular and lymphatic endothelial cells results in the inhibition of tumor progression and lymph node metastasis formation. The present study investigated whether combination therapy of small interfering RNA (siRNA) against PKN3 and doxorubicin (DXR) could increase therapeutic efficacy against liver and lung metastases. In vitro transfection of PKN3 siRNA into PKN3-positive MDA-MB-231, LLC, and Colon 26 cells and PKN3-negative MCF-7 cells did not inhibit cell growth and did not increase sensitivity to DXR. However, following in vivo treatment, PKN3 siRNA suppressed the growth of liver MDA-MB-231 and lung LLC and MCF-7 metastases, although combination therapy with DXR did not increase the therapeutic efficacy. By contrast, in liver MCF-7 metastases, PKN3 siRNA or DXR alone did not exhibit significant inhibition of tumor growth, but their combination significantly improved therapeutic efficacy. Treatment of liver MDA-MB-231 metastases with PKN3 siRNA induced a change in vasculature structure via suppression of PKN3 mRNA expression. PKN3 siRNA may induce antitumor effects in lung and liver metastases by suppression of PKN3 expression in stroma cells, such as endothelial cells. From these findings, PKN3 siRNA alone or in combination with DXR may reduce the tumor growth of liver and lung metastases regardless of PKN3 expression in tumor cells. PMID:29098022

Inhibition of tumor necrosis factor alpha reduces the outgrowth of hepatic micrometastasis of colorectal tumors in a mouse model of liver ischemia-reperfusion injury.

Science.gov (United States)

Jiao, Shu-Fan; Sun, Kai; Chen, Xiao-Jing; Zhao, Xue; Cai, Ning; Liu, Yan-Jun; Xu, Long-Mei; Kong, Xian-Ming; Wei, Li-Xin

2014-01-08

Patients with colorectal cancer (CRC) often develop liver metastases, in which case surgery is considered the only potentially curative treatment option. However, liver surgery is associated with a risk of ischemia-reperfusion (IR) injury, which is thought to promote the growth of colorectal liver metastases. The influence of IR-induced tumor necrosis factor alpha (TNF-α) elevation in the process still is unknown. To investigate the role of TNF-α in the growth of pre-existing micrometastases in the liver following IR, we used a mouse model of colorectal liver metastases. In this model, mice received IR treatment seven days after intrasplenic injections of colorectal CT26 cells. Prior to IR treatment, either TNF-α blocker Enbrel or low-dose TNF-α, which could inhibit IR-induced TNF-α elevation, was administered by intraperitoneal injection. Hepatic IR treatment significantly promoted CT26 tumor growth in the liver, but either Enbrel or low-dose TNF-α pretreatment reversed this trend. Further studies showed that the CT26 + IR group prominently increased the levels of ALT and AST, liver necrosis, inflammatory infiltration and the expressions of hepatic IL-6, MMP9 and E-selectin compared to those of CT26 group. Inhibition of TNF-α elevation remarkably attenuated the increases of these liver inflammatory damage indicators and tumor-promoting factors. These findings suggested that inhibition of TNF-α elevation delayed the IR-enhanced outgrowth of colorectal liver metastases by reducing IR-induced inflammatory damage and the formation of tumor-promoting microenvironments. Both Enbrel and low-dose TNF-α represented the potential therapeutic approaches for the protection of colorectal liver metastatic patients against IR injury-induced growth of liver micrometastases foci.

Cilostazol attenuates cholestatic liver injury and its complications in common bile duct ligated rats.

Science.gov (United States)

Abdel Kawy, Hala S

2015-04-05

Cilostazol is a phosphodiesterase III inhibitor increases adenosine 3', 5'-cyclic monophosphate (cyclic AMP) level which inhibits hepatic stellate cell activation. Its pharmacological effects include vasodilation, inhibition of vascular smooth muscle cell growth, inhibition of platelet activation and aggregation. The aim of the current study was to determine the effects of early administration of low dose cilostazol on cholestatic liver injury induced by common bile duct ligation (CBDL) in rat. Male Wistar rats (180-200g) were divided into three groups: Group A; simple laparotomy group (sham). Group B; CBDL, Group C; CBDL rats treated with cilostazol (9mg/kg daily for 21 days). Six rats from each group were killed by the end of weeks one and three after surgery, livers and serum were collected for biochemical and histopathological studies. Aspartate aminotransferase, alanine aminotransferase, gama glutamyl transferase, alkaline phosphatase and total bilirubin serum levels decreased in the cilostazol treated rats, when compared with CBDL rats. The hepatic levels of tumor necrosis factor-alpha, transforming growth factor-beta, and platelet derived growth factor-B were significantly lower in cilostazol treated rats than that in CBDL rats. Cilostazol decreased vascular endothelial growth factor level and hemoglobin content in the livers. Cilostazol significantly lowered portal pressure, inhibited ductular proliferation, portal inflammation, hepatic fibrosis and decreased hepatic hydroxyproline contents. Administration of cilostazol in CBDL rats improved hepatic functions, decreased ductular proliferation, ameliorated portal inflammation, lowered portal hypertension and reduced fibrosis. These effects of cilostazol may be useful in the attenuation of liver injury in cholestasis. Copyright © 2015 Elsevier B.V. All rights reserved.

Prioritizing Popular Proteins in Liver Cancer: Remodelling One-Carbon Metabolism.

Science.gov (United States)

Mora, María Isabel; Molina, Manuela; Odriozola, Leticia; Elortza, Félix; Mato, José María; Sitek, Barbara; Zhang, Pumin; He, Fuchu; Latasa, María Uxue; Ávila, Matías Antonio; Corrales, Fernando José

2017-12-01

Primary liver cancer (HCC) is recognized as the fifth most common neoplasm and the second leading cause of cancer death worldwide. Most risk factors are known, and the molecular pathogenesis has been widely studied in the past decade; however, the underlying molecular mechanisms remain to be unveiled, as they will facilitate the definition of novel biomarkers and clinical targets for more effective patient management. We utilize the B/D-HPP popular protein strategy. We report a list of popular proteins that have been highly cocited with the expression "liver cancer". Several enzymes highlight the known metabolic remodeling of liver cancer cells, four of which participate in one-carbon metabolism. This pathway is central to the maintenance of differentiated hepatocytes, as it is considered the connection between intermediate metabolism and epigenetic regulation. We designed a targeted selective reaction monitoring (SRM) method to follow up one-carbon metabolism adaptation in mouse HCC and in regenerating liver following exposure to CCl 4 . This method allows systematic monitoring of one-carbon metabolism and could prove useful in the follow-up of HCC and of chronically liver-diseased patients (cirrhosis) at risk of HCC. The SRM data are available via ProteomeXchange in PASSEL (PASS01060).

Fish gut-liver immunity during homeostasis or inflammation revealed by integrative transcriptome and proteome studies

Science.gov (United States)

Wu, Nan; Song, Yu-Long; Wang, Bei; Zhang, Xiang-Yang; Zhang, Xu-Jie; Wang, Ya-Li; Cheng, Ying-Yin; Chen, Dan-Dan; Xia, Xiao-Qin; Lu, Yi-Shan; Zhang, Yong-An

2016-11-01

The gut-associated lymphoid tissue, connected with liver via bile and blood, constructs a local immune environment of both defense and tolerance. The gut-liver immunity has been well-studied in mammals, yet in fish remains largely unknown, even though enteritis as well as liver and gallbladder syndrome emerged as a limitation in aquaculture. In this study, we performed integrative bioinformatic analysis for both transcriptomic (gut and liver) and proteomic (intestinal mucus and bile) data, in both healthy and infected tilapias. We found more categories of immune transcripts in gut than liver, as well as more adaptive immune in gut meanwhile more innate in liver. Interestingly reduced differential immune transcripts between gut and liver upon inflammation were also revealed. In addition, more immune proteins in bile than intestinal mucus were identified. And bile probably providing immune effectors to intestinal mucus upon inflammation was deduced. Specifically, many key immune transcripts in gut or liver as well as key immune proteins in mucus or bile were demonstrated. Accordingly, we proposed a hypothesized profile of fish gut-liver immunity, during either homeostasis or inflammation. Current data suggested that fish gut and liver may collaborate immunologically while keep homeostasis using own strategies, including potential unique mechanisms.

Dendritic cells regulate angiogenesis associated with liver fibrogenesis.

Science.gov (United States)

Blois, Sandra M; Piccioni, Flavia; Freitag, Nancy; Tirado-González, Irene; Moschansky, Petra; Lloyd, Rodrigo; Hensel-Wiegel, Karin; Rose, Matthias; Garcia, Mariana G; Alaniz, Laura D; Mazzolini, Guillermo

2014-01-01

During liver fibrogenesis the immune response and angiogenesis process are fine-tuned resulting in activation of hepatic stellate cells that produce an excess of extracellular matrix proteins. Dendritic cells (DC) play a central role modulating the liver immunity and have recently been implicated to favour fibrosis regression; although their ability to influence the development of fibrogenesis is unknown. Therefore, we explored whether the depletion of DC during early stages of liver injury has an impact in the development of fibrogenesis. Using the CD11c.DTR transgenic mice, DC were depleted in two experimental models of fibrosis in vivo. The effect of anti-angiogenic therapy was tested during early stages of liver fibrogenesis. DC depletion accelerates the development of fibrosis and as a consequence, the angiogenesis process is boosted. We observed up-regulation of pro-angiogenic factors together with an enhanced vascular endothelial growth factor (VEGF) bioavailability, mainly evidenced by the decrease of anti-angiogenic VEGF receptor 1 (also known as sFlt-1) levels. Interestingly, fibrogenesis process enhanced the expression of Flt-1 on hepatic DC and administration of sFlt-1 was sufficient to abrogate the acceleration of fibrogenesis upon DC depletion. Thus, DC emerge as novel players during the development of liver fibrosis regulating the angiogenesis process and thereby influencing fibrogenesis.

Cancer Stem Cells in Primary Liver Cancers: Pathological Concepts and Imaging Findings

Energy Technology Data Exchange (ETDEWEB)

Joo, Ijin [Department of Radiology, Seoul National University Hospital, Seoul 110-744 (Korea, Republic of); Kim, Haeryoung [Department of Pathology, Seoul National University Bundang Hospital, Seongnam 463-707 (Korea, Republic of); Lee, Jeong Min [Department of Radiology, Seoul National University Hospital, Seoul 110-744 (Korea, Republic of)

2015-11-01

There is accumulating evidence that cancer stem cells (CSCs) play an integral role in the initiation of hepatocarcinogenesis and the maintaining of tumor growth. Liver CSCs derived from hepatic stem/progenitor cells have the potential to differentiate into either hepatocytes or cholangiocytes. Primary liver cancers originating from CSCs constitute a heterogeneous histopathologic spectrum, including hepatocellular carcinoma, combined hepatocellular-cholangiocarcinoma, and intrahepatic cholangiocarcinoma with various radiologic manifestations. In this article, we reviewed the recent concepts of CSCs in the development of primary liver cancers, focusing on their pathological and radiological findings. Awareness of the pathological concepts and imaging findings of primary liver cancers with features of CSCs is critical for accurate diagnosis, prediction of outcome, and appropriate treatment options for patients.

Cancer Stem Cells in Primary Liver Cancers: Pathological Concepts and Imaging Findings

International Nuclear Information System (INIS)

Joo, Ijin; Kim, Haeryoung; Lee, Jeong Min

2015-01-01

There is accumulating evidence that cancer stem cells (CSCs) play an integral role in the initiation of hepatocarcinogenesis and the maintaining of tumor growth. Liver CSCs derived from hepatic stem/progenitor cells have the potential to differentiate into either hepatocytes or cholangiocytes. Primary liver cancers originating from CSCs constitute a heterogeneous histopathologic spectrum, including hepatocellular carcinoma, combined hepatocellular-cholangiocarcinoma, and intrahepatic cholangiocarcinoma with various radiologic manifestations. In this article, we reviewed the recent concepts of CSCs in the development of primary liver cancers, focusing on their pathological and radiological findings. Awareness of the pathological concepts and imaging findings of primary liver cancers with features of CSCs is critical for accurate diagnosis, prediction of outcome, and appropriate treatment options for patients

Antepartal insulin-like growth factor concentrations indicating differences in the metabolic adaptive capacity of dairy cows

Science.gov (United States)

Holzhausen, Lars; Araujo, Marcelo Gil; Heppelmann, Maike; Sipka, Anja; Pfarrer, Chistiane; Schuberth, Hans-Joachim; Bollwein, Heinrich

2014-01-01

Cows with different Insulin-like Growth Factor-I (IGF-I) concentrations showed comparable expression levels of hepatic growth hormone receptor (GHR). Suppressor of cytokine signaling 2 (SOCS2), could be responsible for additional inhibition of the GHR signal cascade. The aims were to monitor cows with high or low antepartal IGF-I concentrations (IGF-Ihigh or IGF-Ilow), evaluate the interrelationships of endocrine endpoints, and measure hepatic SOCS2 expression. Dairy cows (n = 20) were selected (240 to 254 days after artificial insemination (AI)). Blood samples were drawn daily (day -17 until calving) and IGF-I, GH, insulin, thyroid hormones, estradiol, and progesterone concentrations were measured. Liver biopsies were taken (day 264 ± 1 after AI and postpartum) to measure mRNA expression (IGF-I, IGFBP-2, IGFBP-3, IGFBP-4, acid labile subunit (ALS), SOCS2, deiodinase1, GHR1A). IGF-I concentrations in the two groups were different (p 0.05). Thyroxine levels and ALS expression were higher in the IGF-Ihigh cows compared to IGF-Ilow cows. Estradiol concentration tended to be greater in the IGF-Ilow group (p = 0.06). It was hypothesized that low IGF-I levels are associated with enhanced SOCS2 expression although this could not be decisively confirmed by the present study. PMID:24962413

Isocaloric high-fat feeding directs hepatic metabolism to handling of nutrient imbalance promoting liver fat deposition

KAUST Repository

Diaz Rua, Ruben; Van Schothorst, E. M.; Keijer, J.; Palou, A.; Oliver, P.

2016-01-01

Background/Objectives: Consumption of fat-rich foods is associated with obesity and related alterations. However, there is a group of individuals, the metabolically obese normal-weight (MONW) subjects, who present normal body weight but have metabolic features characteristic of the obese status, including fat deposition in critical tissues such as liver, recognized as a major cause for the promotion of metabolic diseases. Our aim was to better understand metabolic alterations present in liver of MONW rats applying whole genome transcriptome analysis. Methods: Wistar rats were chronically fed a high-fat diet isocaloric relative to Control animals to avoid the hyperphagia and overweight and to mimic MONW features. Liver transcriptome analysis of both groups was performed. Results: Sustained intake of an isocaloric high-fat diet had a deep impact on the liver transcriptome, mainly affecting lipid metabolism. Although serum cholesterol levels were not affected, circulating triacylglycerols were lower, and metabolic adaptations at gene expression level indicated adaptation toward handling the increased fat content of the diet, an increased triacylglycerol and cholesterol deposition in liver of MONW rats was observed. Moreover, gene expression pointed to increased risk of liver injury. One of the top upregulated genes in this tissue was Krt23, a marker of hepatic disease in humans that was also increased at the protein level.Conclusion:Long-term intake of a high-fat diet, even in the absence of overweight/obesity or increase in classical blood risk biomarkers, promotes a molecular environment leading to hepatic lipid accumulation and increasing the risk of suffering from hepatic diseases.

Isocaloric high-fat feeding directs hepatic metabolism to handling of nutrient imbalance promoting liver fat deposition

KAUST Repository

Diaz Rua, Ruben

2016-03-22

Background/Objectives: Consumption of fat-rich foods is associated with obesity and related alterations. However, there is a group of individuals, the metabolically obese normal-weight (MONW) subjects, who present normal body weight but have metabolic features characteristic of the obese status, including fat deposition in critical tissues such as liver, recognized as a major cause for the promotion of metabolic diseases. Our aim was to better understand metabolic alterations present in liver of MONW rats applying whole genome transcriptome analysis. Methods: Wistar rats were chronically fed a high-fat diet isocaloric relative to Control animals to avoid the hyperphagia and overweight and to mimic MONW features. Liver transcriptome analysis of both groups was performed. Results: Sustained intake of an isocaloric high-fat diet had a deep impact on the liver transcriptome, mainly affecting lipid metabolism. Although serum cholesterol levels were not affected, circulating triacylglycerols were lower, and metabolic adaptations at gene expression level indicated adaptation toward handling the increased fat content of the diet, an increased triacylglycerol and cholesterol deposition in liver of MONW rats was observed. Moreover, gene expression pointed to increased risk of liver injury. One of the top upregulated genes in this tissue was Krt23, a marker of hepatic disease in humans that was also increased at the protein level.Conclusion:Long-term intake of a high-fat diet, even in the absence of overweight/obesity or increase in classical blood risk biomarkers, promotes a molecular environment leading to hepatic lipid accumulation and increasing the risk of suffering from hepatic diseases.

Levels of mercury in muscle and liver of star-spotted dogfish (Mustelus manazo) from the northern region of Japan: a comparison with spiny dogfish (Squalus acanthias).

Science.gov (United States)

Endo, Tetsuya; Hisamichi, Yohsuke; Kimura, Osamu; Ogasawara, Hideki; Ohta, Chiho; Koga, Nobuyuki; Kato, Yoshihisa; Haraguchi, Koichi

2013-04-01

We analyzed mercury (Hg) concentrations in muscle and liver samples of star-spotted dogfish (Mustelus manazo) caught off the northern region of Japan and compared them with those of spiny dogfish (Squalus acanthias) caught in the same region. The average body length of male star-spotted dogfish specimens was significantly smaller than that of female specimens, reflecting the slower growth rate of male fish. Hg concentrations in liver and muscle increased with increases in body length and estimated age of both male and female star-spotted dogfish specimens. However, the relationships between Hg concentration in liver or muscle and body length or estimated age of male specimens differed markedly from those of female specimens, reflecting differences in growth rate and cessation of growth on reaching maturity. Marked increases in Hg concentration in liver of male and female star-spotted dogfish specimens were observed slightly later than increases in Hg concentration in muscle of those specimens due to growth cessation. These marked increases in Hg in liver may reflect increases in Hg due to the formation of mercury selenide. Similar results were previously reported in spiny dogfish specimens, except spiny dogfish showed only trace levels of Hg in liver (Endo et al., Chemosphere 77:1333-1337, 2009). The greater lipid content in liver and the larger liver size in spiny dogfish may explain the much lower levels of Hg observed in liver of spiny dogfish compared with those in the star-spotted dogfish.

A cellular automaton - finite volume method for the simulation of dendritic and eutectic growth in binary alloys using an adaptive mesh refinement

Science.gov (United States)

Dobravec, Tadej; Mavrič, Boštjan; Šarler, Božidar

2017-11-01

A two-dimensional model to simulate the dendritic and eutectic growth in binary alloys is developed. A cellular automaton method is adopted to track the movement of the solid-liquid interface. The diffusion equation is solved in the solid and liquid phases by using an explicit finite volume method. The computational domain is divided into square cells that can be hierarchically refined or coarsened using an adaptive mesh based on the quadtree algorithm. Such a mesh refines the regions of the domain near the solid-liquid interface, where the highest concentration gradients are observed. In the regions where the lowest concentration gradients are observed the cells are coarsened. The originality of the work is in the novel, adaptive approach to the efficient and accurate solution of the posed multiscale problem. The model is verified and assessed by comparison with the analytical results of the Lipton-Glicksman-Kurz model for the steady growth of a dendrite tip and the Jackson-Hunt model for regular eutectic growth. Several examples of typical microstructures are simulated and the features of the method as well as further developments are discussed.

Efficacy of liver parenchymal enhancement and liver volume to standard liver volume ratio on Gd-EOB-DTPA-enhanced MRI for estimation of liver function

Energy Technology Data Exchange (ETDEWEB)

Yoneyama, Tomohide; Fukukura, Yoshihiko; Kamimura, Kiyohisa; Takumi, Koji; Umanodan, Aya; Nakajo, Masayuki [Kagoshima University Graduate School of Medical and Dental Sciences, Department of Radiology, Kagoshima City (Japan); Ueno, Shinichi [Kagoshima University Graduate School of Medical and Dental Sciences, Department of Surgical Oncology and Digestive Surgery, Kagoshima City (Japan)

2014-04-15

We aimed to develop and assess the efficacy of a liver function index that combines liver enhancement and liver volume to standard liver volume (LV/SLV) ratio on gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced MRI. In all, 111 patients underwent a Gd-EOB-DTPA-enhanced MRI, including T1 mapping, before and 20 min after Gd-EOB-DTPA administration. We calculated the following Gd-EOB-DTPA-enhanced MRI-based liver function indices: relative enhancement of the liver, corrected enhancement of the liver-to-spleen ratio, LSC{sub N}20, increase rate of the liver-to-muscle ratio, reduction rate of T1 relaxation time of the liver, ΔR1 of the liver and K{sub Hep}; the indices were multiplied by the LV/SLV ratio. We calculated the correlations between an indocyanine green (ICG) clearance and the Gd-EOB-DTPA-enhanced MRI-based liver function indices multiplied by the LV/SLV ratio, by using Pearson correlation analysis. There were significant correlations between all Gd-EOB-DTPA-enhanced MRI-based liver function indices and ICG clearance (r = -0.354 to -0.574, P < 0.001). All Gd-EOB-DTPA-enhanced MRI-based liver function indices multiplied by the LV/SLV ratio (r = -0.394 to -0.700, P < 0.001) were more strongly correlated with the ICG clearance than those without multiplication by the LV/SLV ratio. Gd-EOB-DTPA-enhanced MRI-based liver function indices that combine liver enhancement and the LV/SLV ratio may more reliably estimate liver function. (orig.)

Effects of intrauterine growth restriction during late pregnancy on the cell apoptosis and related gene expression in ovine fetal liver.

Science.gov (United States)

Liu, Yingchun; Ma, Chi; Li, Hui; Li, Lingyao; Gao, Feng; Ao, Changjin

2017-03-01

This study investigated the effect of intrauterine growth restriction (IUGR) during late pregnancy on the cell apoptosis and related gene expression in ovine fetal liver. Eighteen time-mated Mongolian ewes with singleton fetuses were allocated to three groups at d 90 of pregnancy: Restricted Group 1 (RG1, 0.18 MJ ME kg BW -0.75  d -1 , n = 6), Restricted Group 2 (RG2, 0.33 MJ ME kg BW -0.75  d -1 , n = 6) and a Control Group (CG, ad libitum, 0.67 MJ ME kg BW -0.75  d -1 , n = 6). Fetuses were recovered at slaughter on d 140. Fetal liver weight, DNA content and protein/DNA ratio, proliferation index, cytochrome c, activities of Caspase-3, 8, and 9 were examined, along with relative expression of genes related to apoptosis. Fetuses in both restricted groups exhibited decreased BW, hepatic weight, DNA content, and protein/DNA ratio when compared to CG (P restricted groups (P  0.05). Hepatic expression of gene related to apoptosis showed reduced protein 21 (P21), B-cell lymphoma 2 (Bcl-2) and apoptosis antigen 1 ligand (FasL) expression in RG1 and RG2 (P < 0.05). In contrast, the increased hepatic expression of protein 53 (P53), Bcl-2 associated X protein (Bax) and apoptosis antigen 1 (Fas) in both IUGR fetuses were found (P < 0.05). These results indicate that the fetal hepatocyte proliferation were arrested in G1 cell cycle, and the fetal hepatocyte apoptosis was sensitive to the IUGR resulted from maternal undernutrition. The cell apoptosis in IUGR fetal liver were the potential mechanisms for its retarded proliferation and impaired development. Copyright © 2016 Elsevier Inc. All rights reserved.

Endoscopic stenting in bile duct cancer increases liver volume.

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Lee, Chang Hun; Kim, Seong Hun; Kim, In Hee; Kim, Sang Wook; Lee, Soo Teik; Kim, Dae Ghon; Yang, Jae Do; Yu, Hee Chul; Cho, Baik Hwan; Lee, Seung Ok

2014-09-01

Objective evaluation tools for assessing the effectiveness of stenting in palliative treatment of malignant biliary obstruction are not satisfactory. Effects of biliary stenting on liver volume change have never been studied. We aimed to use volumetry to analyze liver volume changes after endoscopic stenting in bile duct cancer according to the location and number of stents. Retrospective review. University hospital. Patients with a diagnosis of hilar or distal bile duct cancer and who underwent biliary metal stenting. ERCP with self-expandable metal stent placement. Liver volume change after biliary stenting and its comparison according to the location (hilar vs distal common bile duct) and number (hilar bilateral vs hilar unilateral). There were 60 patients; 31 were treated for hilar bile duct cancer (13 for bilateral stent and 18 for unilateral stent) and 29 for distal bile duct cancer. Overall mean follow-up duration was 11.7 ± 4.9 weeks. Liver volume increased 17.4 ± 24.1%. The rate of liver growth was rapid during the early period from 4 to 8 weeks. Stenting in hilar bile duct cancer tended to increase liver volume more than distal biliary stents (22.5% vs 11.9%, P = .091). In hilar bile duct cancer, unilateral and bilateral stents showed similar liver volume increases (20.1% and 25.8%, respectively; P = .512). Single center, retrospective. Biliary stenting markedly increased liver volume in both hilar and distal bile duct cancer. Our data suggest that liver volume assessment could be a useful tool for evaluating stent efficacy. Copyright © 2014 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.

Liver transplantation in polycystic liver disease

DEFF Research Database (Denmark)

Krohn, Paul S; Hillingsø, Jens; Kirkegaard, Preben

2008-01-01

OBJECTIVE: Polycystic liver disease (PLD) is a rare, hereditary, benign disorder. Hepatic failure is uncommon and symptoms are caused by mass effects leading to abdominal distension and pain. Liver transplantation (LTX) offers fully curative treatment, but there is still some controversy about...... whether it is a relevant modality considering the absence of liver failure, relative organ shortage, perioperative risks and lifelong immunosuppression. The purpose of this study was to review our experience of LTX for PLD and to compare the survival with the overall survival of patients who underwent LTX...... from 1992 to 2005. MATERIAL AND METHODS: A retrospective study of the journals of 440 patients, who underwent 506 LTXs between 1992 and 2005, showed that 14 patients underwent LTX for PLD. All patients had normal liver function. Three were receiving haemodialysis and thus underwent combined liver...

Perioperative management of liver surgery-review on pathophysiology of liver disease and liver failure.

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Gasteiger, Lukas; Eschertzhuber, Stephan; Tiefenthaler, Werner

2018-01-01

An increasing number of patients present for liver surgery. Given the complex pathophysiological changes in chronic liver disease (CLD), it is pivotal to understand the fundamentals of chronic and acute liver failure. This review will give an overview on related organ dysfunction as well as recommendations for perioperative management and treatment of liver failure-related symptoms.

[Effect of hepatic resection on development of liver metastasis].

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García-Alonso, I; Palomares, T; Alonso, A; Portugal, V; Castro, B; Caramés, J; Méndez, J

2003-11-01

In the early stages of metastasis, development of the disease is dependent on growth factors produced by the host. There are clinical situations associated with an increase in these factors, such as partial resection of metastasized liver. Given the important role of hepatotrophic factors in liver regeneration, we have studied the effect of partial hepatectomy on the development of residual micrometastases in the liver, and on the neoplastic process as a whole. We used a murine model in which a rabdomiosarcoma was established by subcutaneous inoculation of syngeneic tumor cells in male Wag rats. Subsequently, the primary tumor was resected and/or a 40% hepatectomy was performed. The effect of these two surgical procedures on the tumor process was analyzed on the 25th and 35th days post-inoculation, and the percentage of regenerating hepatocytes was assessed. Both the tumorectomy and liver resection, when not combined, produced an increase in regional adenopathies without modifying the evolution of metastasis in the liver. However, when tumor excision and partial hepatectomy were performed simultaneously, there was a net increase in the metastatic process. In addition to a rapid spread of the disease (lung, mediastinum, retroperitoneum), the number of liver metastases increased by 300%. This development coincided with a steep rise in the percentage of regenerating hepatocytes, which nearly doubled that of the group subjected only to liver resection. We conclude that liver resection, alone or combined with excision of the primary tumor, may enhance tumor progression, both locally and at the metastasic level.

Mesenchymal Stem Cells Enhance Liver Regeneration via Improving Lipid Accumulation and Hippo Signaling

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Yang Liu

2018-01-01

Full Text Available The liver has the potential to regenerate after injury. It is a challenge to improve liver regeneration (LR after liver resection in clinical practice. Bone morrow-derived mesenchymal stem cells (MSCs have shown to have a role in various liver diseases. To explore the effects of MSCs on LR, we established a model of 70% partial hepatectomy (PHx. Results revealed that infusion of MSCs could improve LR through enhancing cell proliferation and cell growth during the first 2 days after PHx, and MSCs could also restore liver synthesis function. Infusion of MSCs also improved liver lipid accumulation partly via mechanistic target of rapamycin (mTOR signaling and enhanced lipid β-oxidation support energy for LR. Rapamycin-induced inhibition of mTOR decreased liver lipid accumulation at 24 h after PHx, leading to impaired LR. And after infusion of MSCs, a proinflammatory environment formed in the liver, evidenced by increased expression of IL-6 and IL-1β, and thus the STAT3 and Hippo-YAP pathways were activated to improve cell proliferation. Our results demonstrated the function of MSCs on LR after PHx and provided new evidence for stem cell therapy of liver diseases.

Enhancement of liver regeneration and liver surgery

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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

Behavior of HepG2 liver cancer cells using microfluidic-microscopy: a preliminary study

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Karamahmutoglu, Hande; ćetin, Metin; Yaǧcı, Tamer; Elitaş, Meltem

2018-02-01

Hepatocellular carcinoma is one of the most common types of liver cancer causing death all over the world. Although early-stage liver cancer can sometimes be treated with partial hepatectomy, liver transplantation, ablation, and embolization, sorafenib treatment is the only approved systemic therapy for advanced HCC. The aim of this research is to develop tools and methods to understand the individuality of hepatocellular carcinoma. Microfluidic cell-culture platform has been developed to observe behavior of single-cells; fluorescence microscopy has been implemented to investigate phenotypic changes of cells. Our preliminary data proved high-level heterogeneity of hepatocellular carcinoma while verifying limited growth of liver cancer cell lines on the silicon wafer.

Reducing iodine load in hepatic CT for patients with chronic liver disease with a combination of low-tube-voltage and adaptive statistical iterative reconstruction

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Noda, Yoshifumi [Department of Radiology and Services, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194 (Japan); Kanematsu, Masayuki, E-mail: masa_gif@yahoo.co.jp [Department of Radiology and Services, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194 (Japan); Department of Radiology Services, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194 (Japan); Goshima, Satoshi; Kondo, Hiroshi; Watanabe, Haruo; Kawada, Hiroshi; Kawai, Nobuyuki; Tanahashi, Yukichi [Department of Radiology and Services, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194 (Japan); Miyoshi, Toshiharu R.T. [Department of Radiology Services, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194 (Japan); Bae, Kyongtae T. [Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, PA (United States)

2015-01-15

Highlights: • 80 kVp CT scanning was successfully applied to the hepatic imaging. • Iodine contrast material load was reduced to 400 mg iodine/kg. • Image quality and the detectability of HCCs were maintained. - Abstract: Purpose: To prospectively assess the effect of reduced iodine load to contrast enhancement, image quality, and detectability of hepatocellular carcinomas (HCCs) in hepatic CT with a combination of 80 kVp tube voltage setting and adaptive statistical iterative reconstruction (ASIR) technique in patients with chronic liver disease. Materials and methods: This HIPAA-compliant study was approved by our institutional review board and written informed consent was obtained in all patients. During a recent 9-month period, 170 consecutive patients (114 men and 56 women; age range, 40–85 years; mean, 67.7 years) with suspected chronic liver diseases were randomized into three CT groups according to the following iodine-load and tube-voltage protocols: 600 milligram per kilogram body weight (mg/kg) iodine load and 120 peak kilovolt (kVp) tube voltage setting (600-120 group), 500 mg/kg and 80 kVp (500-80 group), and 400 mg/kg and 80 kVp (400-80 group). Analysis of variance was conducted to evaluate differences in CT number, background noise, signal-to-noise ratio (SNR), effective dose, HCC-to-liver contrast-to-noise ratio (CNR), and figure of merit (FOM). Sensitivity, specificity, and area under the receiver-operating-characteristic curve (AUC) were compared to assess the detectability of HCCs. Results: Vascular and hepatic enhancement in the 400-80 and 500-80 groups was comparable to or greater than that in the 600-120 group (P < .05). Subjective image quality was comparable among the three groups. Sensitivity, specificity, and AUC for detecting HCCs were comparable among the groups. The effective dose was kept low (3.3–4.1 mSv) in all three groups. Conclusion: Iodine load can be reduced by 33% in CT of the liver with a combination of 80 kVp tube

Adaptation of the fish juvenile growth test (OECD TG 215, 2000) to the marine species Dicentrarchus labrax.

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Tornambè, A; Manfra, L; Canepa, S; Oteri, F; Martuccio, G; Cicero, A M; Magaletti, E

2018-02-01

The OECD TG 215 method (2000) (C.14 method of EC Regulation 440/2008) was developed on the rainbow trout (Oncorynchus mykiss) to assess chronic toxicity (28d) of chemicals on fish juveniles. It contemplates to use other well documented species identifying suitable conditions to evaluate their growth. OECD proposes the European sea bass (Dicentrarchus labrax, L. 1758) as Mediterranean species among vertebrates recommended in the OECD guidelines for the toxicity testing of chemicals. In this context, our study is aimed to proposing the adaptation of the growth test (OECD TG 215, 2000) to D. labrax. For this purpose toxicity tests were performed with sodium dodecyl sulfate, a reference toxicant commonly used in fish toxicity assays. The main aspects of the testing procedure were reviewed: fish size (weight), environmental conditions, dilution water type, experimental design, loading rate and stocking density, feeding (food type and ration), test validity criteria. The experience gained from growth tests with the sea bass allows to promote its inclusion among the species to be used for the C.14 method. Copyright © 2016. Published by Elsevier Inc.

Somatostatin is required for masculinization of growth hormone–regulated hepatic gene expression but not of somatic growth

Science.gov (United States)

Low, Malcolm J.; Otero-Corchon, Veronica; Parlow, Albert F.; Ramirez, Jose L.; Kumar, Ujendra; Patel, Yogesh C.; Rubinstein, Marcelo

2001-01-01

Pulsatile growth hormone (GH) secretion differs between males and females and regulates the sex-specific expression of cytochrome P450s in liver. Sex steroids influence the secretory dynamics of GH, but the neuroendocrine mechanisms have not been conclusively established. Because periventricular hypothalamic somatostatin (SST) expression is greater in males than in females, we generated knockout (Smst–/–) mice to investigate whether SST peptides are necessary for sexually differentiated GH secretion and action. Despite marked increases in nadir and median plasma GH levels in both sexes of Smst–/– compared with Smst+/+ mice, the mutant mice had growth curves identical to their sibling controls and retained a normal sexual dimorphism in weight and length. In contrast, the liver of male Smst–/– mice was feminized, resulting in an identical profile of GH-regulated hepatic mRNAs between male and female mutants. Male Smst-/- mice show higher expression of two SST receptors in the hypothalamus and pituitary than do females. These data indicate that SST is required to masculinize the ultradian GH rhythm by suppressing interpulse GH levels. In the absence of SST, male and female mice exhibit similarly altered plasma GH profiles that eliminate sexually dimorphic liver function but do not affect dimorphic growth. PMID:11413165

NKT cell subsets as key participants in liver physiology and pathology

Science.gov (United States)

Bandyopadhyay, Keya; Marrero, Idania; Kumar, Vipin

2016-01-01

Natural killer T (NKT) cells are innate-like lymphocytes that generally recognize lipid antigens and are enriched in microvascular compartments of the liver. NKT cells can be activated by self- or microbial-lipid antigens and by signaling through toll-like receptors. Following activation, NKT cells rapidly secrete pro-inflammatory or anti-inflammatory cytokines and chemokines, and thereby determine the milieu for subsequent immunity or tolerance. It is becoming clear that two different subsets of NKT cells—type I and type II—have different modes of antigen recognition and have opposing roles in inflammatory liver diseases. Here we focus mainly on the roles of both NKT cell subsets in the maintenance of immune tolerance and inflammatory diseases in liver. Furthermore, how the differential activation of type I and type II NKT cells influences other innate cells and adaptive immune cells to result in important consequences for tissue integrity is discussed. It is crucial that better reagents, including CD1d tetramers, be used in clinical studies to define the roles of NKT cells in liver diseases in patients. PMID:26972772

NKT cell subsets as key participants in liver physiology and pathology.

Science.gov (United States)

Bandyopadhyay, Keya; Marrero, Idania; Kumar, Vipin

2016-05-01

Natural killer T (NKT) cells are innate-like lymphocytes that generally recognize lipid antigens and are enriched in microvascular compartments of the liver. NKT cells can be activated by self- or microbial-lipid antigens and by signaling through toll-like receptors. Following activation, NKT cells rapidly secrete pro-inflammatory or anti-inflammatory cytokines and chemokines, and thereby determine the milieu for subsequent immunity or tolerance. It is becoming clear that two different subsets of NKT cells-type I and type II-have different modes of antigen recognition and have opposing roles in inflammatory liver diseases. Here we focus mainly on the roles of both NKT cell subsets in the maintenance of immune tolerance and inflammatory diseases in liver. Furthermore, how the differential activation of type I and type II NKT cells influences other innate cells and adaptive immune cells to result in important consequences for tissue integrity is discussed. It is crucial that better reagents, including CD1d tetramers, be used in clinical studies to define the roles of NKT cells in liver diseases in patients.

Comparing the effects of different dietary organic acids on the growth, intestinal short-chain fatty acids, and liver histopathology of red hybrid tilapia (Oreochromis sp.) and potential use of these as preservatives.

Science.gov (United States)

Ebrahimi, Mahdi; Daeman, Nor Hafizah; Chong, Chou Min; Karami, Ali; Kumar, Vikas; Hoseinifar, Seyed Hossein; Romano, Nicholas

2017-08-01

Dietary organic acids are increasingly being investigated as a potential means of improving growth and nutrient utilization in aquatic animals. A 9-week study was performed to compare equal amounts (2%) of different organic acids (sodium butyrate, acetate, propionate, or formate) on the growth, muscle proximate composition, fatty acid composition, cholesterol and lipid peroxidation, differential cell counts, plasma biochemistry, intestinal short-chain fatty acid (SCFA) level, and liver histopathology to red hybrid tilapia (Oreochromis sp.) (initial mean weight of 2.87 g). A second experiment was performed to determine their effects on lipid peroxidation and trimethylamine (TMA) when added at 1% to tilapia meat and left out for 24 h. The results of the first experiment showed no treatment effect to growth, feeding efficiencies, or muscle fatty acid composition, but all dietary organic acids significantly decreased intestinal SCFA. Dietary butyrate and propionate significantly decreased muscle lipid peroxidation compared to the control group, but the dietary formate treatment had the lowest lipid peroxidation compared to all treatments. Muscle crude protein and lipid in tilapia fed the formate diet were significantly lower and higher, respectively, and showed evidence of stress based on the differential cell counts, significantly higher plasma glucose and liver glycogen, as well as inflammatory responses in the liver. Although a potential benefit of dietary organic acids was a reduction to lipid peroxidation, this could be accomplished post-harvest by direct additions to the meat. In addition, inclusions of butyrate and propionate to tilapia meat significantly decreased TMA, which might be a more cost-effective option to improve the shelf life of tilapia products.

Animal models for the study of hepatitis C virus infection and related liver disease

DEFF Research Database (Denmark)

Bukh, Jens

2012-01-01

Hepatitis C virus (HCV) causes liver-related death in more than 300,000 people annually. Treatments for patients with chronic HCV are suboptimal, despite the introduction of directly acting antiviral agents. There is no vaccine that prevents HCV infection. Relevant animal models are important...... for HCV research and development of drugs and vaccines. Chimpanzees are the best model for studies of HCV infection and related innate and adaptive host immune responses. They can be used in immunogenicity and efficacy studies of HCV vaccines. The only small animal models of robust HCV infection are T......- and B- cell deficient mice with human chimeric livers. Although these mice cannot be used in studies of adaptive immunity, they have provided new insights into HCV neutralization, interactions between virus and receptors, innate host responses, and therapeutic approaches. Recent progress in developing...

Identity disorder and social-psychological adaptation in patients with hepatobiliary disease

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V. V. Khramtsova

2017-12-01

Full Text Available Negative bodily experience due to health complications and disability is perceived as a difficult life situation. The success of adaptation, commitment to treatment and cooperation with a doctor depend on the personality characteristics that define behavioral representations. Aim. Investigate the structure of identity and mechanisms of social-psychological adaptation of patients with the hepatobiliary system disease. Contingent and methods. 75 patients with a diffuse liver disease - chronic hepatitis, mostly of viral etiology (36 people and liver cirrhosis (39 patients have been examined. We have applied clinical, clinical-psychological, mathematical and empirical methods, semi-structured cross-interviews ("patient-doctor", "patient-psychologist", diagnostics of personal characteristics, identity structure, social-psychological components of adaptation. Three leading personality profiles have been highlighted. Results. Persons with a disharmonious personality development are characterized by disorders in the area of identity formation and development. Fragmentation, the impossibility of personal integration and severe penetrability from the environment contribute to social-psychological maladjustment. The coping is aimed at preserving the problem situation and intensifying the intrapersonal conflict. For persons with difficulties in the adaptation of the personality, a violation of activity interaction with the surrounding world is characteristic, a ban on one's self-identity. Social adaptation is often disrupted due to instability in the emotional-volitional sphere and choosing low-adaptive coping strategies. Genuine "I" and identity formation is impeded for the individuals suppressing aggressive impulses. Adaptability tends to be discrete. With mental stress increasing, the likelihood of choosing low-adaptive coping strategies increases. Conclusions. When drafting psycho-correction programs and medical treatment of people with a hepatobiliary

Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR)

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Cheng, Xingguo, E-mail: chengx@stjohns.edu [Department of Pharmaceutical Sciences, St. John' s University, 8000 Utopia Parkway, Queens, NY 11439 (United States); Vispute, Saurabh G. [Department of Pharmaceutical Sciences, St. John' s University, 8000 Utopia Parkway, Queens, NY 11439 (United States); Liu, Jie [Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160 (United States); Cheng, Christine; Kharitonenkov, Alexei [Lilly Research Laboratories, Division of Eli Lilly and Co., Indianapolis, IN 46285 (United States); Klaassen, Curtis D., E-mail: curtisklaassenphd@gmail.com [Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160 (United States)

2014-07-01

The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (− 105/+ 1 base pair). Fgf21-null mice administered 200 μg/kg of TCDD died within 20 days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver. - Highlights: • TCDD induced Fgf21 expression at both mRNA and protein levels. • Fgf21 induction by TCDD is AhR-dependent. • DEHP attenuated TCDD-induced Fgf21 expression.

Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR)

International Nuclear Information System (INIS)

Cheng, Xingguo; Vispute, Saurabh G.; Liu, Jie; Cheng, Christine; Kharitonenkov, Alexei; Klaassen, Curtis D.

2014-01-01

The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (− 105/+ 1 base pair). Fgf21-null mice administered 200 μg/kg of TCDD died within 20 days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver. - Highlights: • TCDD induced Fgf21 expression at both mRNA and protein levels. • Fgf21 induction by TCDD is AhR-dependent. • DEHP attenuated TCDD-induced Fgf21 expression

Identification of Pathways in Liver Repair Potentially Targeted by Secretory Proteins from Human Mesenchymal Stem Cells

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Sandra Winkler

2016-07-01

Full Text Available Background: The beneficial impact of mesenchymal stem cells (MSC on both acute and chronic liver diseases has been confirmed, although the molecular mechanisms behind it remain elusive. We aim to identify factors secreted by undifferentiated and hepatocytic differentiated MSC in vitro in order to delineate liver repair pathways potentially targeted by MSC. Methods: Secreted factors were determined by protein arrays and related pathways identified by biomathematical analyses. Results: MSC from adipose tissue and bone marrow expressed a similar pattern of surface markers. After hepatocytic differentiation, CD54 (intercellular adhesion molecule 1, ICAM-1 increased and CD166 (activated leukocyte cell adhesion molecule, ALCAM decreased. MSC secreted different factors before and after differentiation. These comprised cytokines involved in innate immunity and growth factors regulating liver regeneration. Pathway analysis revealed cytokine-cytokine receptor interactions, chemokine signalling pathways, the complement and coagulation cascades as well as the Januskinase-signal transducers and activators of transcription (JAK-STAT and nucleotide-binding oligomerization domain-like receptor (NOD-like receptor signalling pathways as relevant networks. Relationships to transforming growth factor β (TGF-β and hypoxia-inducible factor 1-α (HIF1-α signalling seemed also relevant. Conclusion: MSC secreted proteins, which differed depending on cell source and degree of differentiation. The factors might address inflammatory and growth factor pathways as well as chemo-attraction and innate immunity. Since these are prone to dysregulation in most liver diseases, MSC release hepatotropic factors, potentially supporting liver regeneration.

Perioperative ischaemia-induced liver injury and protection strategies: An expanding horizon for anaesthesiologists

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Chandra Kant Pandey

2013-01-01

Full Text Available Liver resection is an effective modality of treatment in patients with primary liver tumour, metastases from colorectal cancers and selected benign hepatic diseases. Its aim is to resect the grossly visible tumour with clear margins and to ensure that the remnant liver mass has sufficient function which is adequate for survival. With the advent of better preoperative imaging, surgical techniques and perioperative management, there is an improvement in the outcome with decreased mortality. This decline in postoperative mortality after hepatic resection has encouraged surgeons for more radical liver resections, leaving behind smaller liver remnants in a bid to achieve curative surgeries. But despite advances in diagnostic, imaging and surgical techniques, postoperative liver dysfunction of varied severity including death due to liver failure is still a serious problem in such patients. Different surgical and non-surgical techniques like reducing perioperative blood loss and consequent decreased transfusions, vascular occlusion techniques (intermittent portal triad clamping and ischaemic preconditioning, administration of pharmacological agents (dextrose, intraoperative use of methylprednisolone, trimetazidine, ulinastatin and lignocaine and inhaled anaesthetic agents (sevoflurane and opioids (remifentanil have demonstrated the potential benefit and minimised the adverse effects of surgery. In this article, the authors reviewed the surgical and non-surgical measures that could be adopted to minimise the risk of postoperative liver failure following liver surgeries with special emphasis on ischaemic and pharmacological preconditioning which can be easily adapted clinically.

Salinity Effects on Strategies of Glycogen Utilization in Livers of Euryhaline Milkfish (Chanos chanos under Hypothermal Stress

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Chia-Hao Chang

2018-02-01

Full Text Available The fluctuation of temperature affects many physiological responses in ectothermic organisms, including feed intake, growth, reproduction, and behavior. Changes in environmental temperatures affect the acquisition of energy, whereas hepatic glycogen plays a central role in energy supply for the homeostasis of the entire body. Glycogen phosphorylase (GP, which catalyzes the rate-limiting step in glycogenolysis, is also an indicator of environmental stress. Here, we examined the effects of salinity on glycogen metabolism in milkfish livers under cold stress. A reduction of feed intake was observed in both freshwater (FW and seawater (SW milkfish under cold adaptation. At normal temperature (28°C, compared to the FW milkfish, the SW milkfish exhibited greater mRNA abundance of the liver isoform of GP (Ccpygl, higher GP activity, and less glycogen content in the livers. Upon hypothermal (18°C stress, hepatic Ccpygl mRNA expression of FW milkfish surged at 3 h, declined at 6 and 12 h, increased again at 24 h, and increased significantly after 96 h. Increases in GP protein, GP activity, and the phosphorylation state and the breakdown of glycogen were also found in FW milkfish livers after 12 h of exposure at 18°C. Conversely, the Ccpygl transcript levels in SW milkfish were downregulated after 1 h of exposure at 18°C, whereas the protein abundance of GP, GP activity, and glycogen content were not significantly altered. Taken together, under 18°C cold stress, FW milkfish exhibited an acute response with the breakdown of hepatic glycogen for maintaining energy homeostasis of the entire body, whereas no change was observed in the hepatic glycogen content and GP activity of SW milkfish because of their greater tolerance to cold conditions.

Thermal manipulation during embryogenesis has long-term effects on muscle and liver metabolism in fast-growing chickens.

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Thomas Loyau

Full Text Available Fast-growing chickens have a limited ability to tolerate high temperatures. Thermal manipulation during embryogenesis (TM has previously been shown to lower chicken body temperature (Tb at hatching and to improve thermotolerance until market age, possibly resulting from changes in metabolic regulation. The aim of this study was to evaluate the long-term effects of TM (12 h/d, 39.5°C, 65% RH from d 7 to 16 of embryogenesis vs. 37.8°C, 56% RH continuously and of a subsequent heat challenge (32°C for 5 h at 34 d on the mRNA expression of metabolic genes and cell signaling in the Pectoralis major muscle and the liver. Gene expression was analyzed by RT-qPCR in 8 chickens per treatment, characterized by low Tb in the TM groups and high Tb in the control groups. Data were analyzed using the general linear model of SAS considering TM and heat challenge within TM as main effects. TM had significant long-term effects on thyroid hormone metabolism by decreasing the muscle mRNA expression of deiodinase DIO3. Under standard rearing conditions, the expression of several genes involved in the regulation of energy metabolism, such as transcription factor PGC-1α, was affected by TM in the muscle, whereas for other genes regulating mitochondrial function and muscle growth, TM seemed to mitigate the decrease induced by the heat challenge. TM increased DIO2 mRNA expression in the liver (only at 21°C and reduced the citrate synthase activity involved in the Krebs cycle. The phosphorylation level of p38 Mitogen-activated-protein kinase regulating the cell stress response was higher in the muscle of TM groups compared to controls. In conclusion, markers of energy utilization and growth were either changed by TM in the Pectoralis major muscle and the liver by thermal manipulation during incubation as a possible long-term adaptation limiting energy metabolism, or mitigated during heat challenge.

Staphylococcus aureus Alters Growth Activity, Autolysis, and Antibiotic Tolerance in a Human Host-Adapted Pseudomonas aeruginosa Lineage

DEFF Research Database (Denmark)

Frydenlund Michelsen, Charlotte; Christensen, Anne-Mette; Bojer, Martin Saxtorph

2014-01-01

Interactions among members of polymicrobial infections or between pathogens and the commensal flora may determine disease outcomes. Pseudomonas aeruginosa and Staphylococcus aureus are important opportunistic human pathogens and are both part of the polymicrobial infection communities in human...... hosts. In this study, we analyzed the in vitro interaction between S. aureus and a collection of P. aeruginosa isolates representing different evolutionary steps of a dominant lineage, DK2, that have evolved through decades of growth in chronically infected patients. While the early adapted P....... aeruginosa DK2 strains outcompeted S. aureus during coculture on agar plates, we found that later P. aeruginosa DK2 strains showed a commensal-like interaction, where S. aureus was not inhibited by P. aeruginosa and the growth activity of P. aeruginosa was enhanced in the presence of S. aureus. This effect...

Abdominal MR: liver and pancreas

International Nuclear Information System (INIS)

Bartolozzi, C.; Lencioni, R.; Donati, F.; Cioni, D.

1999-01-01

Following the introduction of rapid, high-quality scan techniques and the development of new, tissue-specific contrast agents, the applications of MRI for abdominal imaging are experiencing unprecedented growth. This article examines the current status of liver and pancreatic MRI, highlighting technical and methodological approach, use of contrast agents, and main clinical applications. The MRI technique appears to be the ideal diagnostic tool for detection and characterization of benign and malignant liver neoplasms, and for evaluating tumor response after nonsurgical treatments. Dynamic imaging after bolus injection of a gadolinium chelate is currently a fundamental component of an MRI examination of the liver in many instances. Optimal dynamic scanning depends on the use of a multisection spoiled gradient-echo technique that allows one to image the entire region of interest during a single suspended respiration. Images are obtained during four phases relative to the injection of the contrast agent: precontrast, arterial (pre-sinusoidal), portal (sinusoidal), and delayed (extracellular) phase. Liver-specific contrast agents, including hepatobiliary agents and reticuloendothelial system-targeted iron oxide particles, however, may offer advantages over gadolinium chelates in some clinical settings. Computed tomography is still preferred to MRI for imaging the pancreas. However, state-of-the-art MRI may currently be at least as accurate as spiral CT for depiction of inflammatory and neoplastic pancreatic diseases. Moreover, MRI has the advantage of allowing simultaneous investigation of the biliary tree, owing to cholangiopancreatography techniques. Hence, a comprehensive assessment of most pancreatic diseases can be achieved with a single examination. (orig.)

Role of histone deacetylases(HDACs) in progression and reversal of liver fibrosis

Energy Technology Data Exchange (ETDEWEB)

Li, Xing; Wu, Xiao-Qin; Xu, Tao; Li, Xiao-Feng; Yang, Yang; Li, Wan-Xia; Huang, Cheng; Meng, Xiao-Ming; Li, Jun, E-mail: lijun@ahmu.edu.cn

2016-09-01

Liver fibrosis refers to a reversible wound healing process response to chronic liver injuries. Activation of hepatic stellate cells (HSCs) is closely correlated with the development of liver fibrosis. Histone deacetylases(HDACs) determine the acetylation levels of core histones to modulate expression of genes. To demonstrate the link between HDACs and liver fibrosis, CCl4-induced mouse liver fibrosis model and its spontaneous reversal model were established. Results of the current study demonstrated that deregulation of liver HDACs may involved in the development of liver fibrosis. Among 11 HDACs tested in our study (Class I, II, and IV HDACs), expression of HDAC2 was maximally increased in CCl4-induced fibrotic livers but decreased after spontaneous recovery. Moreover, expression of HDAC2 was elevated in human liver fibrotic tissues. In this regard, the potential role of HDAC2 in liver fibrosis was further evaluated. Our results showed that administration of HSC-T6 cells with transforming growth factor-beta1 (TGF-β1) resulted in an increase of HDAC2 protein expression in dose- and time-dependent manners. Moreover, HDAC2 deficiency inhibited HSC-T6 cell proliferation and activation induced by TGF-β1. More importantly, the present study showed HDAC2 may regulate HSCs activation by suppressing expression of Smad7, which is a negative modulator in HSCs activation and liver fibrosis. Collectively, these observations revealed that HDAC2 may play a pivotal role in HSCs activation and liver fibrosis while deregulation of HDACs may serve as a novel mechanism underlying liver fibrosis. - Highlights: • This is the first report to systematically examine expressions of HDACs during liver fibrosis and fibrosis reversal. • Aberrant expression of HDAC2 contributes to the development of liver fibrosis. • Provided important foundation for further liver fibrosis conversion studies.

Preparation and evaluation of chicken embryo-adapted fowl adenovirus serotype 4 vaccine in broiler chickens.

Science.gov (United States)

Mansoor, Muhammad Khalid; Hussain, Iftikhar; Arshad, Muhammad; Muhammad, Ghulam

2011-02-01

The current study was planned to develop an efficient vaccine against hydropericardium syndrome virus (HSV). Currently, formalin-inactivated liver organ vaccines failed to protect the Pakistan broiler industry from this destructive disease of economic importance. A field isolate of the pathogenic hydropericardium syndrome virus was adapted to chicken embryos after four blind passages. The chicken embryo-adapted virus was further serially passaged (12 times) to get complete attenuation. Groups of broiler chickens free from maternal antibodies against HSV at the age of 14 days were immunized either with 16th passage attenuated HSV vaccine or commercially formalized liver organ vaccine. The antibody response, measured by enzyme-linked immunosorbent assay was significantly higher (P attenuated HSV vaccine compared to the group immunized with liver organ vaccine at 7, 14, and 21 days post-immunization. At 24 days of age, the broiler chickens in each group were challenged with 10(3.83) embryo infectious dose(50) of pathogenic HSV and were observed for 7 days post-challenge. Vaccination with the 16th passage attenuated HSV gave 94.73% protection as validated on the basis of clinical signs (5.26%), gross lesions in the liver and heart (5.26%), histopathological lesions in the liver (1.5 ± 0.20), and mortality (5.26%). The birds inoculated with liver organ vaccine showed significantly low (p vaccine proved to be immunogenic and has potential for controlling HSV infections in chickens.

Relationship between liver lipid and liver dry matter in slaughtered ruminants

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Zohreh Eftekhari

2012-12-01

Full Text Available Lipids in liver wet and dry matter, liver moist and dry matter and their relationships were investigated based on species, sex and age in cows, buffaloes, sheep and goats. Mean percentage of lipids in liver wet and dry matter and liver dry matter in cows were 3.60%, 1.10%, 29.70%, and for buffaloes were 5.30%, 1.55%, 29.20%, sheep 3.00%, 0.83%, 27.90%, and goats 2.910%, 1.55% and 28.40%, respectively. The highest and lowest percentage of lipids in liver wet and dry matter was observed in buffaloes and sheep, and for the liver dry matter was recorded in cows and sheep, respectively. Analyses showed significant differences in liver parameters among ruminants (p < 0.01. Gender, except for goats, did not affect the animals' liver parameters. In overall 15.00% of buffaloes and 3.50% of cows showed over 10.00% lipids in liver, while none of small ruminants appeared to have over 6.00% lipids in liver. There was no correlation between liver lipid and liver dry matter. In conclusion mean percentage of lipid in liver dry matter in small ruminants was less than large ruminants. Liver dry matter was high in cows and low in sheep. Mean differences in liver parameters was significant, while the age and sex of the animals were not. Liver lipidosis in buffaloes seems greater than in cows, and in small ruminants it was negligible. No correlation was expected between liver parameters. Finally, on the basis of liver dry matter, the liver in ruminants ranked from cows to buffaloes, goats and sheep.

PGC-1α in aging and lifelong exercise training-mediated regulation of UPR in mouse liver

DEFF Research Database (Denmark)

Maag Kristensen, Caroline; Brandt, Christina Tingbjerg; Jørgensen, Stine Ringholm

2017-01-01

of specific UPR pathways and increased activity of the ATF6 pathway in the liver with aging. Lifelong exercise training prevented the age-associated change in BiP and IRE1α protein, but not cleaved ATF6 protein and resulted in further decreased PERK protein. Taken together, the present study provides evidence...... that the capacity and activity of the three UPR pathways are differentially regulated in the liver with aging and lifelong exercise training. In addition, PGC-1α does not seem to regulate the activity of hepatic UPR in response to exercise training, but to influence the capacity of the liver to induce UPR......Aging is associated with changes in several metabolic pathways affecting liver function including the adaptive unfolded protein response (UPR). On the other hand, exercise training has been shown to exert beneficial effects on metabolism in the liver and exercise training has been reported...

Compound list: transforming growth factor beta 1 [Open TG-GATEs

Lifescience Database Archive (English)

Full Text Available transforming growth factor beta 1 TGFB1 00182 ftp://ftp.biosciencedbc.jp/archive/op...en-tggates/LATEST/Human/in_vitro/transforming_growth_factor_beta_1.Human.in_vitro.Liver.zip ...

Fatty Liver

International Nuclear Information System (INIS)

Filippone, A.; Digiovandomenico, V.; Digiovandomenico, E.; Genovesi, N.; Bonomo, L.

1991-01-01

The authors report their experience with the combined use of US and CT in the study of diffuse and subtotal fatty infiltration of the liver. An apparent disagreement was initially found between the two examinations in the study of fatty infiltration. Fifty-five patients were studied with US and CT of the upper abdomen, as suggested by clinics. US showed normal liver echogenicity in 30 patients and diffuse increased echogenicity (bright liver) in 25 cases. In 5 patients with bright liver, US demonstrated a solitary hypoechoic area, appearing as a 'skip area', in the quadrate lobe. In 2 patients with bright liver, the hypoechoic area was seen in the right lobe and exhibited no typical US features of 'Skip area'. Bright liver was quantified by measuring CT density of both liver and spleen. The relative attenuation values of spleen and liver were compared on plain and enhanced CT scans. In 5 cases with a hypoechoic area in the right lobe, CT findings were suggestive of hemangioma. A good correlation was found between broght liver and CT attenuation values, which decrease with increasing fat content of the liver. Moreover, CT attenuation values confirmed US findings in the study of typical 'skip area', by demonstrating normal density - which suggests that CT can characterize normal tissue in atypical 'skip area'

Excellent survival after liver transplantation for isolated polycystic liver disease : an European Liver Transplant Registry study

NARCIS (Netherlands)

van Keimpema, Loes; Nevens, Frederik; Adam, Rene; Porte, Robert J.; Fikatas, Panagiotis; Becker, Thomas; Kirkegaard, Preben; Metselaar, Herold J.; Drenth, Joost P. H.

2011-01-01

Patients with end-stage isolated polycystic liver disease (PCLD) suffer from incapacitating symptoms because of very large liver volumes. Liver transplantation (LT) is the only curative option. This study assesses the feasibility of LT in PCLD. We used the European Liver Transplant Registry (ELTR)

Levosimendan: a cardiovascular drug to prevent liver ischemia-reperfusion injury?

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Peter Onody

Full Text Available INTRODUCTION: Temporary occlusion of the hepatoduodenal ligament leads to an ischemic-reperfusion (IR injury in the liver. Levosimendan is a new positive inotropic drug, which induces preconditioning-like adaptive mechanisms due to opening of mitochondrial KATP channels. The aim of this study was to examine possible protective effects of levosimendan in a rat model of hepatic IR injury. MATERIAL AND METHODS: Levosimendan was administered to male Wistar rats 1 hour (early pretreatment or 24 hours (late pretreatment before induction of 60-minute segmental liver ischemia. Microcirculation of the liver was monitored by laser Doppler flowmeter. After 24 hours of reperfusion, liver and blood samples were taken for histology, immuno- and enzyme-histochemistry (TUNEL; PARP; NADH-TR as well as for laboratory tests. Furthermore, liver antioxidant status was assessed and HSP72 expression was measured. RESULTS: In both groups pretreated with levosimendan, significantly better hepatic microcirculation was observed compared to respective IR control groups. Similarly, histological damage was also reduced after levosimendan administration. This observation was supported by significantly lower activities of serum ALT (p early = 0.02; p late = 0.005, AST (p early = 0.02; p late = 0.004 and less DNA damage by TUNEL test (p early = 0.05; p late = 0.034 and PAR positivity (p early = 0.02; p late = 0.04. Levosimendan pretreatment resulted in significant improvement of liver redox homeostasis. Further, significantly better mitochondrial function was detected in animals receiving late pretreatment. Finally, HSP72 expression was increased by IR injury, but it was not affected by levosimendan pretreatment. CONCLUSION: Levosimendan pretreatment can be hepatoprotective and it could be useful before extensive liver resection.

Growth-hormone-induced signal transducer and activator of transcription 5 signaling causes gigantism, inflammation, and premature death but protects mice from aggressive liver cancer.

Science.gov (United States)

Friedbichler, Katrin; Themanns, Madeleine; Mueller, Kristina M; Schlederer, Michaela; Kornfeld, Jan-Wilhelm; Terracciano, Luigi M; Kozlov, Andrey V; Haindl, Susanne; Kenner, Lukas; Kolbe, Thomas; Mueller, Mathias; Snibson, Kenneth J; Heim, Markus H; Moriggl, Richard

2012-03-01

Persistently high levels of growth hormone (GH) can cause liver cancer. GH activates multiple signal-transduction pathways, among them janus kinase (JAK) 2-signal transducer and activator of transcription (STAT) 5 (signal transducer and activator of transcription 5). Both hyperactivation and deletion of STAT5 in hepatocytes have been implicated in the development of hepatocellular carcinoma (HCC); nevertheless, the role of STAT5 in the development of HCC as a result of high GH levels remains enigmatic. Thus, we crossed a mouse model of gigantism and inflammatory liver cancer caused by hyperactivated GH signaling (GH(tg) ) to mice with hepatic deletion of STAT5 (STAT5(Δhep) ). Unlike GH(tg) mice, GH(tg) STAT5(Δhep) animals did not display gigantism. Moreover, the premature mortality, which was associated with chronic inflammation, as well as the pathologic alterations of hepatocytes observed in GH(tg) mice, were not observed in GH(tg) animals lacking STAT5. Strikingly, loss of hepatic STAT5 proteins led to enhanced HCC development in GH(tg) mice. Despite reduced chronic inflammation, GH(tg) STAT5(Δhep) mice displayed earlier and more advanced HCC than GH(tg) animals. This may be attributed to the combination of increased peripheral lipolysis, hepatic lipid synthesis, loss of hepatoprotective mediators accompanied by aberrant activation of tumor-promoting c-JUN and STAT3 signaling cascades, and accumulation of DNA damage secondary to loss of cell-cycle control. Thus, HCC was never observed in STAT5(Δhep) mice. As a result of their hepatoprotective functions, STAT5 proteins prevent progressive fatty liver disease and the formation of aggressive HCC in the setting of hyperactivated GH signaling. At the same time, they play a key role in controlling systemic inflammation and regulating organ and body size. Copyright © 2011 American Association for the Study of Liver Diseases.

Growth hormone-insuline-like growth factor-I system in pejerrey Odontesthes bonariensis (Atheriniformes

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S.E. Arranz

2008-07-01

Full Text Available Using biotechnology to increase the growth rates of fish is likely to reduce production costs per unit of food. Among vertebrates, fish appear to occupy a unique position, when growth patterns are considered. With few exceptions, fish species tend to grow indeterminately, implying that size is never fixed. Both hyperplasia and hypertrophy contribute to post-larval muscle growth in fish. Growth hormone (GH - Insulin-like Growth Factor I (IGF-I is the most important growth axis in fish. Our experimental model, the pejerrey, Odontesthes bonariensis (Ateriniformes is a South American inland water fish considered to be a promising species for intensive aquaculture. However, one major drawback to achieve this goal is its slow growth in captivity. In order to understand how growth is regulated in this species, our first objective was to characterized pejerrey GH- IGF-I axis. We first cloned and characterized pejerrey (pj GH, IGF-I and the growth hormone receptors (GHRs I and II. In addition to providing valuable data for evolutionary comparison of GH, investigation of GH action in teleosts is particularly important because of its potential application in aquaculture. GH can not only promote the somatic growth in fish but also lower dietary protein requirements. A prerequisite for providing sufficient amounts of GH for basic research and aquaculture application is a large-scale production of GH. For that purpose, recombinant pjGH was expressed in a bacterial system. Protocols for solubilization and proper folding were achieved. Activity of recombinant pjGH was assessed in fish by measuring the liver IGF-I response to different doses of GH. IGF-I transcript was measured in the liver after pjGHr in vivo stimulation by means of quantitative real-time PCR assays. A dose-dependent response of IGF-I mRNA was observed after pjGHr administration, and reached a 6 fold IGF-I maximum increase over control group when 2.5 µg pjGH /g-body weight were injected

Local and Global Function Model of the Liver

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Wang, Hesheng, E-mail: hesheng@umich.edu [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Feng, Mary [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Jackson, Andrew [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Ten Haken, Randall K.; Lawrence, Theodore S. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Cao, Yue [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States); Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan (United States)

2016-01-01

Purpose: To develop a local and global function model in the liver based on regional and organ function measurements to support individualized adaptive radiation therapy (RT). Methods and Materials: A local and global model for liver function was developed to include both functional volume and the effect of functional variation of subunits. Adopting the assumption of parallel architecture in the liver, the global function was composed of a sum of local function probabilities of subunits, varying between 0 and 1. The model was fit to 59 datasets of liver regional and organ function measures from 23 patients obtained before, during, and 1 month after RT. The local function probabilities of subunits were modeled by a sigmoid function in relating to MRI-derived portal venous perfusion values. The global function was fitted to a logarithm of an indocyanine green retention rate at 15 minutes (an overall liver function measure). Cross-validation was performed by leave-m-out tests. The model was further evaluated by fitting to the data divided according to whether the patients had hepatocellular carcinoma (HCC) or not. Results: The liver function model showed that (1) a perfusion value of 68.6 mL/(100 g · min) yielded a local function probability of 0.5; (2) the probability reached 0.9 at a perfusion value of 98 mL/(100 g · min); and (3) at a probability of 0.03 [corresponding perfusion of 38 mL/(100 g · min)] or lower, the contribution to global function was lost. Cross-validations showed that the model parameters were stable. The model fitted to the data from the patients with HCC indicated that the same amount of portal venous perfusion was translated into less local function probability than in the patients with non-HCC tumors. Conclusions: The developed liver function model could provide a means to better assess individual and regional dose-responses of hepatic functions, and provide guidance for individualized treatment planning of RT.

Adapting the Surgical Apgar Score for Perioperative Outcome Prediction in Liver Transplantation: A Retrospective Study

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Amy C. S. Pearson, MD

2017-11-01

Conclusions. The SAS-LT utilized simple intraoperative metrics to predict early morbidity and mortality after liver transplant with similar accuracy to other scoring systems at an earlier postoperative time point.

Benign Liver Tumors

Science.gov (United States)

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Liver Function Tests

Science.gov (United States)

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

An Update on Drug-induced Liver Injury.

Science.gov (United States)

Devarbhavi, Harshad

2012-09-01

Idiosyncratic drug-induced liver injury (DILI) is an important cause of morbidity and mortality following drugs taken in therapeutic doses. Hepatotoxicity is a leading cause of attrition in drug development, or withdrawal or restricted use after marketing. No age is exempt although adults and the elderly are at increased risk. DILI spans the entire spectrum ranging from asymptomatic elevation in transaminases to severe disease such as acute hepatitis leading to acute liver failure. The liver specific Roussel Uclaf Causality Assessment Method is the most validated and extensively used for determining the likelihood that an implicated drug caused DILI. Asymptomatic elevation in liver tests must be differentiated from adaptation. Drugs producing DILI have a signature pattern although no single pattern is characteristic. Antimicrobial and central nervous system agents including antiepileptic drugs are the leading causes of DILI worldwide. In the absence of a diagnostic test or a biomarker, the diagnosis rests on the evidence of absence of competing causes such as acute viral hepatitis, autoimmune hepatitis and others. Recent studies show that antituberculosis drugs given for active or latent disease are still a major cause of drug-induced liver injury in India and the West respectively. Presence of jaundice signifies a severe disease and entails a worse outcome. The pathogenesis is unclear and is due to a mix of host, drug metabolite and environmental factors. Research has evolved from incriminating candidate genes to genome wide analysis studies. Immediate cessation of the drug is key to prevent or minimize progressive damage. Treatment is largely supportive. N-acetylcysteine is the antidote for paracetamol toxicity. Carnitine has been tried in valproate injury whereas steroids and ursodeoxycholic acid may be used in DILI associated with hypersensitivity or cholestatic features respectively. This article provides an overview of the epidemiology, the patterns of

Antepartal insulin-like growth factor concentrations indicating differences in the metabolic adaptive capacity of dairy cows.

Science.gov (United States)

Piechotta, Marion; Holzhausen, Lars; Araujo, Marcelo Gil; Heppelmann, Maike; Sipka, Anja; Pfarrer, Chistiane; Schuberth, Hans-Joachim; Bollwein, Heinrich

2014-01-01

Cows with different Insulin-like Growth Factor-I (IGF-I) concentrations showed comparable expression levels of hepatic growth hormone receptor (GHR). Suppressor of cytokine signaling 2 (SOCS2), could be responsible for additional inhibition of the GHR signal cascade. The aims were to monitor cows with high or low antepartal IGF-I concentrations (IGF-I(high) or IGF-I(low)), evaluate the interrelationships of endocrine endpoints, and measure hepatic SOCS2 expression. Dairy cows (n = 20) were selected (240 to 254 days after artificial insemination (AI)). Blood samples were drawn daily (day -17 until calving) and IGF-I, GH, insulin, thyroid hormones, estradiol, and progesterone concentrations were measured. Liver biopsies were taken (day 264 ± 1 after AI and postpartum) to measure mRNA expression (IGF-I, IGFBP-2, IGFBP-3, IGFBP-4, acid labile subunit (ALS), SOCS2, deiodinase1, GHR1A). IGF-I concentrations in the two groups were different (p 0.05). Thyroxine levels and ALS expression were higher in the IGF-I(high) cows compared to IGF-I(low) cows. Estradiol concentration tended to be greater in the IGF-I(low) group (p = 0.06). It was hypothesized that low IGF-I levels are associated with enhanced SOCS2 expression although this could not be decisively confirmed by the present study.

Land management on soil physical properties and maize (Zea mays L. var. BIMA) growth (An adaptation strategy of climate change)

Science.gov (United States)

Zaki, M. K.; Komariah; Pujiasmanto, B.; Noda, K.

2018-03-01

Water deficit is a problem on rainfed maize production but can be solved by proper land management. The objective of the study to determine the soil physical properties and maize yield affected by land management to adapt to drought. The experimental design was a randomized complete block using 5 treatments with 4 repetitions, including: (i) Control (KO), (ii) Rice Straw Mulched (MC), (iii) Compost Fertilizer (CF), (iv) In-Organic Fertilizer (AF), (v) Legume Cover crop (CC). Soil physical and maize growth properties namely soil moisture, soil texture, soil bulk density, plant height, biomass, and yield were investigated. The results showed that composting land increased soil water availability and provided nutrient to crops and thus increase soil physical properties, maize growth and yield. Although inorganic fertilizer also increased plant growth and yield, but it did not improve soil physical properties.

The clinical significance of determination of serum CTGF, PDGF and TGF-β1 levels in patients with post-hepatitis B liver cirrhosis

International Nuclear Information System (INIS)

Li Qingru; Sang Shibiao; Zhao Zhenhua; Jiang Jiwei

2010-01-01

Objective: To explore the clinical significance of changes of serum connective tissue growth factor (CTGF), Platelet-derived growth factor (PDGF) and transforming growth factor-β 1 (TGF-β 1 )levels in patients with post-hepatitis B liver cirrhosis. Methods: Serum TGF-β 1 (with RIA), CTGF and PDGF (with ELISA) levels were determined in 50 patients with liver cirrhosis (mild, n=15 moderate n=16 severe, n=19) and 45 controls. Results: The serum level of CTGF in patients with mild post-hepatitis B liver cirrhosis were in significantly higher than those in the controls (P>0.05). The serum level of CTGF were significantly higher in patients with moderate (P 1 were also significantly higher in all the patients than those in the controls (P<0.05, P<0.01, P<0.01). Conclusion: The changes of those 3 markers serum levels were related to the progress of post-hepatitis B liver cirrhosis and the determination was helpful for outcome prediction. (authors)

A Pathway to Personalizing Therapy for Metastases Using Liver-on-a-Chip Platforms.

Science.gov (United States)

Khazali, A S; Clark, A M; Wells, A

2017-06-01

Metastasis accounts for most cancer-related deaths. The majority of solid cancers, including those of the breast, colorectum, prostate and skin, metastasize at significant levels to the liver due to its hemodynamic as well as tumor permissive microenvironmental properties. As this occurs prior to detection and treatment of the primary tumor, we need to target liver metastases to improve patients' outcomes. Animal models, while proven to be useful in mechanistic studies, do not represent the heterogeneity of human population especially in drug metabolism lack proper human cell-cell interactions, and this gap between animals and humans results in costly and inefficient drug discovery. This underscores the need to accurately model the human liver for disease studies and drug development. Further, the occurrence of liver metastases is influenced by the primary tumor type, sex and race; thus, modeling these specific settings will facilitate the development of personalized/targeted medicine for each specific group. We have adapted such all-human 3D ex vivo hepatic microphysiological system (MPS) (a.k.a. liver-on-a-chip) to investigate human micrometastases. This review focuses on the sources of liver resident cells, especially the iPS cell-derived hepatocytes, and examines some of the advantages and disadvantages of these sources. In addition, this review also examines other potential challenges and limitations in modeling human liver.

Multi-layer cube sampling for liver boundary detection in PET-CT images.

Science.gov (United States)

Liu, Xinxin; Yang, Jian; Song, Shuang; Song, Hong; Ai, Danni; Zhu, Jianjun; Jiang, Yurong; Wang, Yongtian

2018-06-01

Liver metabolic information is considered as a crucial diagnostic marker for the diagnosis of fever of unknown origin, and liver recognition is the basis of automatic diagnosis of metabolic information extraction. However, the poor quality of PET and CT images is a challenge for information extraction and target recognition in PET-CT images. The existing detection method cannot meet the requirement of liver recognition in PET-CT images, which is the key problem in the big data analysis of PET-CT images. A novel texture feature descriptor called multi-layer cube sampling (MLCS) is developed for liver boundary detection in low-dose CT and PET images. The cube sampling feature is proposed for extracting more texture information, which uses a bi-centric voxel strategy. Neighbour voxels are divided into three regions by the centre voxel and the reference voxel in the histogram, and the voxel distribution information is statistically classified as texture feature. Multi-layer texture features are also used to improve the ability and adaptability of target recognition in volume data. The proposed feature is tested on the PET and CT images for liver boundary detection. For the liver in the volume data, mean detection rate (DR) and mean error rate (ER) reached 95.15 and 7.81% in low-quality PET images, and 83.10 and 21.08% in low-contrast CT images. The experimental results demonstrated that the proposed method is effective and robust for liver boundary detection.

Hedging Medical Spending Growth: An Adaptive Expectations Approach.

Science.gov (United States)

Lieberthal, Robert D

2016-08-01

Long-term health insurance provides consumers with protection against persistent, negative health shocks. While the stochastic rise in medical spending growth may make some health risks harder to insure, financial assets could act as a hedge for medical spending growth risk. The purpose of this research was to determine whether such hedges exist. The results of this study were two-fold. First, the asset classes with the strongest statistical evidence as hedges were bonds, not stocks. Second, any strategy to hedge medical spending growth involved shorting assets i.e. betting against the bond or stock market. Health insurers writing long-term contracts should combine the use of hedges in the bond market with of portfolio diversification, and may benefit from health policies to moderate the uncertainty of medical spending growth.

Liver

International Nuclear Information System (INIS)

Bernardino, M.E.; Sones, P.J. Jr.; Barton Price, R.; Berkman, W.A.

1984-01-01

Evaluation of the liver for focal lesions is extremely important because the liver is one of the most common sites for metastatic disease. Most patients with metastatic deposits to the liver have a survival rate of about 6 months. Thus, metastatic disease to the liver has an extremely grave prognosis. In the past patients with hepatic lesions had no therapeutic recourse. However, with recent aggressive surgical advances (such as partial hepatectomies) and hepatic artery embolization, survival of patients with hepatic metastases has increased. Thus it is important for noninvasive imaging not only to detect lesions early in their course, but also to give their true hepatic involvement and the extent of the neoplastic process elsewhere in the body. Recent advances in imaging have been rapidly changing over the past 5 years. These changes have been more rapid in computed tomography (CT) and ultrasound than in radionuclide imaging. Thus, the question addressed in this chapter is: What is the relationship of hepatic ultrasound to the other current diagnostic modalities in detecting metastatic liver disease and other focal liver lesions? Also, what is its possible future relationship to nuclear magnetic resonance?

Genotypic variation in growth and physiological response to drought stress and re-watering reveals the critical role of recovery in drought adaptation in maize seedlings

Directory of Open Access Journals (Sweden)

Daoqian eChen

2016-01-01

Full Text Available Non-irrigated crops in temperate climates and irrigated crops in arid climates are subjected to continuous cycles of water stress and re-watering. Thus, fast and efficient recovery from water stress may be among the key determinants of plant drought adaptation. The present study was designed to comparatively analyze the roles of drought resistance and drought recovery in drought adaptation and to investigate the physiological basis of genotypic variation in drought adaptation in maize (Zea mays seedlings. As the seedlings behavior in growth associate with yield under drought, it could partly reflect the potential of drought adaptability. Growth and physiological responses to progressive drought stress and recovery were observed in seedlings of ten maize lines. The results showed that drought adaptability is closely related to drought recovery (r = 0.714**, but not to drought resistance (r = 0.332. Drought induced decreases in leaf water content, water potential, osmotic potential, gas exchange parameters, chlorophyll content, Fv/Fm and nitrogen content, and increased H2O2 accumulation and lipid peroxidation. After recovery, most of these physiological parameters rapidly returned to normal levels. The physiological responses varied between lines. Further correlation analysis indicated that the physiological bases of drought resistance and drought recovery are definitely different, and that maintaining higher chlorophyll content (r = 0.874*** and Fv/Fm (r = 0.626* under drought stress contributes to drought recovery. Our results suggest that both drought resistance and recovery are key determinants of plant drought adaptation, and that drought recovery may play a more important role than previously thought. In addition, leaf water potential, chlorophyll content and Fv/Fm could be used as efficient reference indicators in the selection of drought-adaptive genotypes.

Lower levels of insulin-like growth factor-1 standard deviation score are associated with histological severity of non-alcoholic fatty liver disease.

Science.gov (United States)

Sumida, Yoshio; Yonei, Yoshikazu; Tanaka, Saiyu; Mori, Kojiroh; Kanemasa, Kazuyuki; Imai, Shunsuke; Taketani, Hiroyoshi; Hara, Tasuku; Seko, Yuya; Ishiba, Hiroshi; Okajima, Akira; Yamaguchi, Kanji; Moriguchi, Michihisa; Mitsuyoshi, Hironori; Yasui, Kohichiroh; Minami, Masahito; Itoh, Yoshito

2015-07-01

Growth hormone (GH) deficiency may be associated with histological progression of non-alcoholic fatty liver disease (NAFLD) which includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). Insulin-like growth factor 1 (IGF-1) is mainly produced by hepatocytes and its secretion is stimulated by GH. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of IGF-1 in Japanese patients. Serum samples were obtained in 199 Japanese patients with biopsy-proven NAFLD and in 2911 sex- and age-matched healthy people undergoing health checkups. The serum levels of IGF-1 were measured using a commercially available immunoradiometric assay. The standard deviation scores (SDS) of IGF-1 according to age and sex were also calculated in NAFLD patients. The serum IGF-1 levels in NAFLD patients were significantly lower (median, 112 ng/mL) compared with the control population (median, 121 ng/mL, P < 0.0001). IGF-1 SDS less than -2.0 SD from median were found in 11.6% of 199 patients. NASH patients exhibited significantly lower levels of IGF-1 SDS (n = 130; median, -0.7) compared with NAFL patients (n = 69; median, -0.3; P = 0.026). The IGF-1 SDS values decreased significantly with increasing lobular inflammation (P < 0.001) and fibrosis (P < 0.001). In multiple regressions, the association between the IGF-1 SDS values and the severity of NAFLD persisted after adjusting for age, sex and insulin resistance. Low levels of circulating IGF-1 may have a role in the development of advanced NAFLD, independent of insulin resistance. Supplementation with GH/IGF-1 may be a candidate for the treatment of NASH. © 2014 The Japan Society of Hepatology.

Hypervascular liver lesions in radiologically normal liver

Energy Technology Data Exchange (ETDEWEB)

Amico, Enio Campos; Alves, Jose Roberto; Souza, Dyego Leandro Bezerra de; Salviano, Fellipe Alexandre Macena; Joao, Samir Assi; Liguori, Adriano de Araujo Lima, E-mail: ecamic@uol.com.br [Hospital Universitario Onofre Lopes (HUOL/UFRN), Natal, RN (Brazil). Clinica Gastrocentro e Ambulatorios de Cirurgia do Aparelho Digestivo e de Cirurgia Hepatobiliopancreatica

2017-09-01

Background: The hypervascular liver lesions represent a diagnostic challenge. Aim: To identify risk factors for cancer in patients with non-hemangiomatous hypervascular hepatic lesions in radiologically normal liver. Method: This prospective study included patients with hypervascular liver lesions in radiologically normal liver. The diagnosis was made by biopsy or was presumed on the basis of radiologic stability in follow-up period of one year. Cirrhosis or patients with typical imaging characteristics of haemangioma were excluded. Results: Eighty eight patients were included. The average age was 42.4. The lesions were unique and were between 2-5 cm in size in most cases. Liver biopsy was performed in approximately 1/3 of cases. The lesions were benign or most likely benign in 81.8%, while cancer was diagnosed in 12.5% of cases. Univariate analysis showed that age >45 years (p< 0.001), personal history of cancer (p=0.020), presence of >3 nodules (p=0.003) and elevated alkaline phosphatase (p=0.013) were significant risk factors for cancer. Conclusion: It is safe to observe hypervascular liver lesions in normal liver in patients up to 45 years, normal alanine amino transaminase, up to three nodules and no personal history of cancer. Lesion biopsies are safe in patients with atypical lesions and define the treatment to be established for most of these patients. (author)

Tc-99 m-GSA liver scintigraphy in alcoholic liver cirrhosis

International Nuclear Information System (INIS)

Itano, Satoshi; Harada, Masaru; Nagamatsu, Hiroaki

2003-01-01

We compared 15 alcoholic liver cirrhosis patients with 10 viral liver cirrhosis patients using technetium-99 m-galactosyl human serum albumin (Tc-99 m-GSA) liver scintigraphy and could clinically reveal the disorder of metabolism of asialoglycoprotein in alcoholic liver cirrhosis. Receptor index (LHL 15 = liver count divided by the sum of liver and heart counts at 15 minutes) was significantly (p <0.01) lower in patients with alcoholic cirrhosis (median: 0.821), compared with patients with viral cirrhosis (0.915). Grading score, which was an index showed by the difference in the isotope uptake patterns between liver and heart, was significantly (p <0.01) worse in patients with alcoholic cirrhosis, compared with patients with viral cirrhosis. These results suggested that alcoholic liver cirrhosis had a specific disorder of a metabolic function for asialoglycoprotein. (author)

The 2-oxoglutarate carrier promotes liver cancer by sustaining mitochondrial GSH despite cholesterol loading

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Anna Baulies

2018-04-01

Full Text Available Cancer cells exhibit mitochondrial cholesterol (mt-cholesterol accumulation, which contributes to cell death resistance by antagonizing mitochondrial outer membrane (MOM permeabilization. Hepatocellular mt-cholesterol loading, however, promotes steatohepatitis, an advanced stage of chronic liver disease that precedes hepatocellular carcinoma (HCC, by depleting mitochondrial GSH (mGSH due to a cholesterol-mediated impairment in mGSH transport. Whether and how HCC cells overcome the restriction of mGSH transport imposed by mt-cholesterol loading to support mGSH uptake remains unknown. Although the transport of mGSH is not fully understood, SLC25A10 (dicarboxylate carrier, DIC and SLC25A11 (2-oxoglutarate carrier, OGC have been involved in mGSH transport, and therefore we examined their expression and role in HCC. Unexpectedly, HCC cells and liver explants from patients with HCC exhibit divergent expression of these mitochondrial carriers, with selective OGC upregulation, which contributes to mGSH maintenance. OGC but not DIC downregulation by siRNA depleted mGSH levels and sensitized HCC cells to hypoxia-induced ROS generation and cell death as well as impaired cell growth in three-dimensional multicellular HCC spheroids, effects that were reversible upon mGSH replenishment by GSH ethyl ester, a membrane permeable GSH precursor. We also show that OGC regulates mitochondrial respiration and glycolysis. Moreover, OGC silencing promoted hypoxia-induced cardiolipin peroxidation, which reversed the inhibition of cholesterol on the permeabilization of MOM-like liposomes induced by Bax or Bak. Genetic OGC knockdown reduced the ability of tumor-initiating stem-like cells to induce liver cancer. These findings underscore the selective overexpression of OGC as an adaptive mechanism of HCC to provide adequate mGSH levels in the face of mt-cholesterol loading and suggest that OGC may be a novel therapeutic target for HCC treatment. Keywords: Cholesterol

STAT3 activation in monocytes accelerates liver cancer progression

International Nuclear Information System (INIS)

Wu, Wen-Yong; Li, Jun; Wu, Zheng-Sheng; Zhang, Chang-Le; Meng, Xiang-Ling

2011-01-01

Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor ubiquitously expressed in different cell types. STAT3 plays an essential role in cell survival, proliferation, and differentiation. Aberrantly hyper-activated STAT3 signaling in cancer cells and in the tumor microenvironment has been detected in a wide variety of human cancers and is considered an important factor for cancer initiation, development, and progression. However, the role of STAT3 activation in monocytes in the development of HCC has not been well understood. Immunohistochemical analysis of phosphorylated STAT3 was performed on tissue microarray from HCC patients. Using a co-culture system in vivo, HCC cell growth was determined by the MTT assay. In vivo experiments were conducted with mice given diethylinitrosamine (DEN), which induces HCC was used to investigate the role of STAT3 expression in monocytes on tumor growth. Real-time PCR was used to determine the expression of cell proliferation and cell arrest associated genes in the tumor and nontumor tissue from liver. Phosphorylated STAT3 was found in human hepatocellular carcinoma tissue samples and was expressed in tumor cells and also in monocytes. Phosphorylated STAT3 expression in monocyte was significantly correlated to advanced clinical stage of HCC and a poor prognosis. Using a co-culture system in vivo, monocytes promoted HCC cell growth via the IL-6/STAT3 signaling pathway. The STAT3 inhibitor, NSC 74859, significantly suppressed tumor growth in vivo in mice with diethylinitrosamine (DEN)-induced HCC. In this animal model, blockade of STAT3 with NSC 74859 induced tumor cell apoptosis, while inhibiting both tumor cells and monocytes proliferation. Furthermore, NSC 74859 treatment suppressed cancer associated inflammation in DEN-induce HCC. Our data suggest constitutively activated STAT3 monocytes promote liver tumorigenesis in clinical patients and animal experiments. Thus, STAT3 in tumor

Temperature adaptation of bacterial communities in experimentally warmed forest soils.

Science.gov (United States)

Rousk, Johannes; Frey, Serita D; Bååth, Erland

2012-10-01

A detailed understanding of the influence of temperature on soil microbial activity is critical to predict future atmospheric CO 2 concentrations and feedbacks to anthropogenic warming. We investigated soils exposed to 3-4 years of continuous 5 °C-warming in a field experiment in a temperate forest. We found that an index for the temperature adaptation of the microbial community, T min for bacterial growth, increased by 0.19 °C per 1 °C rise in temperature, showing a community shift towards one adapted to higher temperature with a higher temperature sensitivity (Q 10(5-15 °C) increased by 0.08 units per 1 °C). Using continuously measured temperature data from the field experiment we modelled in situ bacterial growth. Assuming that warming did not affect resource availability, bacterial growth was modelled to become 60% higher in warmed compared to the control plots, with the effect of temperature adaptation of the community only having a small effect on overall bacterial growth (bacterial growth, most likely due to substrate depletion because of the initially higher growth in warmed plots. When this was factored in, the result was similar rates of modelled in situ bacterial growth in warmed and control plots after 3 years, despite the temperature difference. We conclude that although temperature adaptation for bacterial growth to higher temperatures was detectable, its influence on annual bacterial growth was minor, and overshadowed by the direct temperature effect on growth rates. © 2012 Blackwell Publishing Ltd.

The Adaptive Endoplasmic Reticulum Stress Response to Lipotoxicity in Progressive Human Nonalcoholic Fatty Liver Disease

Czech Academy of Sciences Publication Activity Database

Lake, A.D.; Novák, Petr; Hardwick, R.N.; Flores-Keown, B.; Zhao, F.; Klimecki, W. T.; Cherrington, N.J.

2014-01-01

Roč. 137, č. 1 (2014), s. 26-35 ISSN 1096-6080 Institutional support: RVO:60077344 Keywords : nonalcoholic fatty liver disease * lipotoxicity * nonalcoholic steatohepatitis Subject RIV: CE - Biochemistry Impact factor: 3.854, year: 2014

Coordinated and interactive expression of genes of lipid metabolism and inflammation in adipose tissue and liver during metabolic overload.

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Wen Liang

Full Text Available BACKGROUND: Chronic metabolic overload results in lipid accumulation and subsequent inflammation in white adipose tissue (WAT, often accompanied by non-alcoholic fatty liver disease (NAFLD. In response to metabolic overload, the expression of genes involved in lipid metabolism and inflammatory processes is adapted. However, it still remains unknown how these adaptations in gene expression in expanding WAT and liver are orchestrated and whether they are interrelated. METHODOLOGY/PRINCIPAL FINDINGS: ApoE*3Leiden mice were fed HFD or chow for different periods up to 12 weeks. Gene expression in WAT and liver over time was evaluated by micro-array analysis. WAT hypertrophy and inflammation were analyzed histologically. Bayesian hierarchical cluster analysis of dynamic WAT gene expression identified groups of genes ('clusters' with comparable expression patterns over time. HFD evoked an immediate response of five clusters of 'lipid metabolism' genes in WAT, which did not further change thereafter. At a later time point (>6 weeks, inflammatory clusters were induced. Promoter analysis of clustered genes resulted in specific key regulators which may orchestrate the metabolic and inflammatory responses in WAT. Some master regulators played a dual role in control of metabolism and inflammation. When WAT inflammation developed (>6 weeks, genes of lipid metabolism and inflammation were also affected in corresponding livers. These hepatic gene expression changes and the underlying transcriptional responses in particular, were remarkably similar to those detected in WAT. CONCLUSION: In WAT, metabolic overload induced an immediate, stable response on clusters of lipid metabolism genes and induced inflammatory genes later in time. Both processes may be controlled and interlinked by specific transcriptional regulators. When WAT inflammation began, the hepatic response to HFD resembled that in WAT. In all, WAT and liver respond to metabolic overload by

Improvement of fetus growth restriction diagnostics in pregnant women by means of biochemical markers that characterize the disorder of stress-adaptation

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N. G. Kolokot

2018-04-01

Full Text Available Object of the work. Regulatory and adaptive processes of the system “mother –placenta – fetus” state determination and detection of pregnant women adaptive capabilities specific features in case of fetus growth restriction based on a number of the blood plasma biochemical indicators. Materials and methods. Markers of oxidative stress were detected spectrophotometrically in the blood plasma according to generally accepted methods: oxidative modification of proteins, stable metabolites of nitrogen oxide, L-arginine, malondialdehyde, thiol compounds and reduced glutathione. Statistical processing of data was made by methods of variational statistics with Microsoft Office Excel 2010, Statistica 6.0. Results. The use applicability of the number of biochemical markers which are predictors of perinatal complications has been scientifically substantiated. Using biochemical diagnostic technique it has been shown that fetus growth restriction syndrome is accompanied by disorders of regulatory and adaptive processes of the system “mother –placenta – fetus”. In particular, the level of proteins and lipids oxidative modification increases, nitric oxide synthase activity decreases and reserves of L-arginine and thiol compounds decrease in the blood plasma. Conclusions. Comparative analysis of a number of biochemical markers determination results of stress-realizing system activity in pregnant women with fetus growth restriction and in women with a physiological pregnancy has revealed a significant (P ≤ 0.05 increase in markers of protein oxidative modification blood levels (the level of dinitrophenylhydrazones of aliphatic aldehyd of basic amino acid residues and dinitrophenylhydrazones of carbonyl compounds of basic amino acid residues in the spontaneous sample increased by 14.2 % and 16.3 %, respectively, and in the stimulated sample by 46.6 % and 43.0 %, the level of malondialdehyde increased by 42.9 %. Reduction of the stress

Excellent survival after liver transplantation for isolated polycystic liver disease: an European Liver Transplant Registry study

DEFF Research Database (Denmark)

van Keimpema, Loes; Nevens, Frederik; Adam, René

2011-01-01

Patients with end-stage isolated polycystic liver disease (PCLD) suffer from incapacitating symptoms because of very large liver volumes. Liver transplantation (LT) is the only curative option. This study assesses the feasibility of LT in PCLD. We used the European Liver Transplant Registry (ELTR......) database to extract demographics and outcomes of 58 PCLD patients. We used Kaplan-Meier survival analysis for survival rates. Severe abdominal pain (75%) was the most prominent symptom, while portal hypertension (35%) was the most common complication in PCLD. The explantation of the polycystic liver...

Inflammatory models drastically alter tumor growth and the immune microenvironment in hepatocellular carcinoma.

Science.gov (United States)

Markowitz, Geoffrey J; Michelotti, Gregory A; Diehl, Anna Mae; Wang, Xiao-Fan

2015-04-01

Initiation and progression of hepatocellular carcinoma (HCC) is intimately associated with a chronically diseased liver tissue. This diseased liver tissue background is a drastically different microenvironment from the healthy liver, especially with regard to immune cell prevalence and presence of mediators of immune function. To better understand the consequences of liver disease on tumor growth and the interplay with its microenvironment, we utilized two standard methods of fibrosis induction and orthotopic implantation of tumors into the inflamed and fibrotic liver to mimic the liver condition in human HCC patients. Compared to non-diseased controls, tumor growth was significantly enhanced under fibrotic conditions. The immune cells that infiltrated the tumors were also drastically different, with decreased numbers of natural killer cells but greatly increased numbers of immune-suppressive CD11b + Gr1 hi myeloid cells in both models of fibrosis. In addition, there were model-specific differences: Increased numbers of CD11b + myeloid cells and CD4 + CD25 + T cells were found in tumors in the bile duct ligation model but not in the carbon tetrachloride model. Induction of fibrosis altered the cytokine production of implanted tumor cells, which could have farreaching consequences on the immune infiltrate and its functionality. Taken together, this work demonstrates that the combination of fibrosis induction with orthotopic tumor implantation results in a markedly different tumor microenvironment and tumor growth kinetics, emphasizing the necessity for more accurate modeling of HCC progression in mice, which takes into account the drastic changes in the tissue caused by chronic liver disease.

COMPARATIVE STUDY OF EMOTIONAL DISORDERS STRUCTURE IN PATIENTS BEFORE AND AFTER ORTHOTOPIC LIVER TRANSPLANTATION

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T. G. Mikhaylichenko

2011-01-01

Full Text Available Being based on a private experience, authors considered necessary to study features of emotional disorders that will allow understanding the mechanism of mental adaptation to disease at patients before and after OLT. In comparative research of structure of emotional frustration at the patients making the most numerous groups of patients before transplantation of a liver (viral hepatitis and autoimmune liver diseases, 129 persons, from them 75 before OLT are included at entering into a waiting list and 54 to through 22 ± 9 days after OLT. Distinctions in structure of emotional frustration are revealed: at patients with autoimmune liver diseases be- fore OLT and viral hepatitis after OLT the semiology combined with disturbing-depressive experiences and hypochondriac fixings is brightly expressed neurotic, them distinguishes high level of personal uneasiness. For patients with autoimmune liver diseases after OLT and viral hepatitis before OLT are characteristic moderately expressed neurotic frustration of an asthenia circle and low level of personal and situational anxiety. 

Dr. Liver: A preoperative planning system of liver graft volumetry for living donor liver transplantation.

Science.gov (United States)

Yang, Xiaopeng; Yang, Jae Do; Yu, Hee Chul; Choi, Younggeun; Yang, Kwangho; Lee, Tae Beom; Hwang, Hong Pil; Ahn, Sungwoo; You, Heecheon

2018-05-01

Manual tracing of the right and left liver lobes from computed tomography (CT) images for graft volumetry in preoperative surgery planning of living donor liver transplantation (LDLT) is common at most medical centers. This study aims to develop an automatic system with advanced image processing algorithms and user-friendly interfaces for liver graft volumetry and evaluate its accuracy and efficiency in comparison with a manual tracing method. The proposed system provides a sequential procedure consisting of (1) liver segmentation, (2) blood vessel segmentation, and (3) virtual liver resection for liver graft volumetry. Automatic segmentation algorithms using histogram analysis, hybrid level-set methods, and a customized region growing method were developed. User-friendly interfaces such as sequential and hierarchical user menus, context-sensitive on-screen hotkey menus, and real-time sound and visual feedback were implemented. Blood vessels were excluded from the liver for accurate liver graft volumetry. A large sphere-based interactive method was developed for dividing the liver into left and right lobes with a customized cutting plane. The proposed system was evaluated using 50 CT datasets in terms of graft weight estimation accuracy and task completion time through comparison to the manual tracing method. The accuracy of liver graft weight estimation was assessed by absolute difference (AD) and percentage of AD (%AD) between preoperatively estimated graft weight and intraoperatively measured graft weight. Intra- and inter-observer agreements of liver graft weight estimation were assessed by intraclass correlation coefficients (ICCs) using ten cases randomly selected. The proposed system showed significantly higher accuracy and efficiency in liver graft weight estimation (AD = 21.0 ± 18.4 g; %AD = 3.1% ± 2.8%; percentage of %AD > 10% = none; task completion time = 7.3 ± 1.4 min) than the manual tracing method (AD = 70

FibroMeters: a family of blood tests for liver fibrosis.

Science.gov (United States)

Calès, P; Boursier, J; Oberti, F; Hubert, I; Gallois, Y; Rousselet, M-C; Dib, N; Moal, V; Macchi, L; Chevailler, A; Michalak, S; Hunault, G; Chaigneau, J; Sawadogo, A; Lunel, F

2008-09-01

FibroMeters are blood tests for liver fibrosis with several specificities: two main diagnostic targets (fibrosis stage and area of fibrosis); adaptation to specific causes; and results confirmed by an expert system. Thus, FibroMeters comprise six different tests: one for staging and one for quantitation of liver fibrosis in each of the three main causes of chronic liver disease-chronic viral hepatitis, alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). FibroMeters display a high overall diagnostic accuracy and are the only tests to correctly classify 100% of HCV patients without fibrosis or with cirrhosis. They have 90% predictive values in a higher proportion of patients than with other usual blood tests. A 90% correct classification is available in 100% of HCV patients with the following reliable diagnostic intervals: F0/1, F1/2, F2+/-1, F3+/-1. In real-life conditions, the reproducibility of FibroMeters is higher than that of liver biopsy or ultrasonographic elastometry. FibroMeters are robust tests with the most stable diagnostic performance across different centers. Optional tests are also available, such as a specific one for cirrhosis, which has a diagnostic accuracy of 93.0% (AUROC: 0.92) and a 100% positive predictive value for diagnosis of HCV cirrhosis. Determination by FibroMeters of the area of fibrosis - the only direct, non-invasive, quantitative measurement of liver fibrosis - are especially useful for following-up cirrhosis as it correlates well with clinical events. FibroMeters are also very accurate in HVB or HIV-HCV co-infected patients. The tests specific for ALD and NAFLD also have a high diagnostic accuracy (AUROCs: 0.96 and 0.94, respectively, for significant fibrosis).

Hepatitis E in liver biopsies from patients with acute hepatitis of clinically unexplained origin.

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Uta eDrebber

2013-12-01

Full Text Available Hepatitis E virus (HEV is a small RNA virus and the infectious agent of hepatitis E that occurs worldwide either as epidemics in Asia caused by genotype 1 and 2 or as sporadic disease in industrialized countries induced by genotype 3 and 4. The frequency might be underestimated in central Europe as a cause of acute hepatitis. Therefore, we analyzed on liver biopsies, if cases of acute hepatitis with clinically unknown or obscure diagnosis were actually caused by the infection with HEV.We included 221 liver biopsies retrieved from the files of the institute of pathology during the years 2000 till 2010 that were taken from patients with acute hepatitis of obscure or doubtful diagnosis. From all biopsies RNA was extracted, prepared, and subjected to RT-PCR with specific primers. Amplified RNA was detected in 7 patients, sequenced and the genotype 3 could be determined in four of the seven of positive specimens from 221 samples. Histopathology of the biopsies revealed a classic acute hepatitis with cholestatic features and in some cases confluent necrosis in zone 3. Histology in a cohort of matched patients was less severe and showed more eosinophils. The analysis of the immune response by subtyping of liver infiltrating lymphocytes showed circumstantial evidence of adaptive immune reaction with CD 8 positive CTLs being the dominant lymphocyte population.In conclusion, in doubtful cases of acute hepatitis of unknown origine hepatitis E virus infection should be considered as etiology in central Europe. We demonstrate for the first time that the diagnosis can be made in paraffin-embedded liver biopsies reliably when no serum is available and also the genotype can be determined. The analysis of the immune response by subtyping of liver infiltrating lymphocytes indicates an adaptive mechanism suggesting in analogy with HAV, HBV and HCV that the virus itself is not cytopathic but liver damage is due to immune reaction.

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 ...

Liver scintigraphy

International Nuclear Information System (INIS)

Tateno, Yukio

1996-01-01

Liver scintigraphy can be classified into 3 major categories according to the properties of the radiopharmaceuticals used, i.e., methods using radiopharmaceuticals which are (1) incorporated by hepatocytes, (2) taken up by reticulo endothelial cells, and (3) distributed in the blood pool of the liver. Of these three categories, the liver scintigraphy of the present research falls into category 2. Radiopharmaceuticals which are taken up by endothelial cells include 198 Au colloids and 99m Tc-labelled colloids. Liver scintigraphy takes advantage of the property by which colloidal microparticles are phagocytosed by Kupffer cells, and reflect the distribution of endothelial cells and the intensity of their phagocytic capacity. This examination is indicated in the following situations: (i) when you suspect a localized intrahepatic lesion (tumour, abscess, cyst, etc.), (ii) when you want to follow the course of therapy of a localized lesion, (iii) when you suspect liver cirrhosis, (iv) when you want to know the severity of liver cirrhosis or hepatitis, (v) when there is hepatomegaly and you want to determine the morphology of the liver, (vi) differential diagnosis of upper abdominal masses, and (vii) when there are abnormalities of the right diaphragm and you want to know their relation to the liver

Schistosoma mansoni infection suppresses the growth of Plasmodium yoelii parasites in the liver and reduces gametocyte infectivity to mosquitoes.

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Taeko Moriyasu

2018-01-01

Full Text Available Malaria and schistosomiasis are major parasitic diseases causing morbidity and mortality in the tropics. Epidemiological surveys have revealed coinfection rates of up to 30% among children in Sub-Saharan Africa. To investigate the impact of coinfection of these two parasites on disease epidemiology and pathology, we carried out coinfection studies using Plasmodium yoelii and Schistosoma mansoni in mice. Malaria parasite growth in the liver following sporozoite inoculation is significantly inhibited in mice infected with S. mansoni, so that when low numbers of sporozoites are inoculated, there is a large reduction in the percentage of mice that go on to develop blood stage malaria. Furthermore, gametocyte infectivity is much reduced in mice with S. mansoni infections. These results have profound implications for understanding the interactions between Plasmodium and Schistosoma species, and have implications for the control of malaria in schistosome endemic areas.

Chitosan-coated doxorubicin nano-particles drug delivery system inhibits cell growth of liver cancer via p53/PRC1 pathway.

Science.gov (United States)

Ye, Bai-Liang; Zheng, Ru; Ruan, Xiao-Jiao; Zheng, Zhi-Hai; Cai, Hua-Jie

2018-01-01

Nano-particles have been widely used in target-specific drug delivery system and showed advantages in cancers treatment. This study aims to evaluate the effect of chitosan coated doxorubicin nano-particles drug delivery system in liver cancer. The chitosan nano-particles were prepared by using the ionic gelation method. The characterizations of the nano-particles were determined by transmission electron microscopy. The cytotoxicity was detected by MTT assay, and the endocytosis, cell apoptosis and cell cycle were examined by flow cytometry. The protein level was analyzed with western blot. The dual luciferase reporter assay was performed to assess the interaction between p53 and the promoter of PRC1, and chromatin immune-precipitation was used to verify the binding between them. The FA-CS-DOX nano-particles were irregular and spherical particles around 30-40 nm, with uniform size and no adhesion. No significant difference was noted in doxorubicin release rate between CS-DOX and FA-CS-DOX. FA-CS-DOX nano-particles showed stronger cytotoxicity than CS-DOX. FA-CS-DOX nano-particles promoted the apoptosis and arrested cell cycle at G2/M phase, and they up-regulated p53. FA-CS-DOX nano-particles inhibited cell survival through p53/PRC1 pathway. Chitosan-coated doxorubicin nano-particles drug delivery system inhibits cell growth of liver cancer by promoting apoptosis and arresting cell cycle at G2/M phase through p53/PRC1 pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

Molecular Cues Guiding Matrix Stiffness in Liver Fibrosis

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Takaoki Saneyasu

2016-01-01

Full Text Available Tissue and matrix stiffness affect cell properties during morphogenesis, cell growth, differentiation, and migration and are altered in the tissue remodeling following injury and the pathological progression. However, detailed molecular mechanisms underlying alterations of stiffness in vivo are still poorly understood. Recent engineering technologies have developed powerful techniques to characterize the mechanical properties of cell and matrix at nanoscale levels. Extracellular matrix (ECM influences mechanical tension and activation of pathogenic signaling during the development of chronic fibrotic diseases. In this short review, we will focus on the present knowledge of the mechanisms of how ECM stiffness is regulated during the development of liver fibrosis and the molecules involved in ECM stiffness as a potential therapeutic target for liver fibrosis.

Accelerated Growth Programme with Polyherbal Formulations for Dairy Calves

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K.Hadiya

2009-04-01

Full Text Available An experimental field study in approximately one month old, forty eight Jaffrabadi buffalo calves was carried out to evaluate efficacy of herbal formulations on growth & average daily gain. Calves were randomly divided into four groups, one control & three treatments. Treated groups were administered herbal formulations; Ruchamax, AV/DAC/16 @5gm/calf/day & Yakrifit @1 bolus/calf/day following treatment regimen of once a week per month for three consecutive months therapy. Growth related parameters were recorded for ninety days of experimental trial. It was observed that supplementation of herbal growth promoter & liver tonic products significantly improved liver function, feed assimilation & digestibility of ration ultimately leading to gain in body weight as compared to untreated control group. [Vet. World 2009; 2(2.000: 62-64

Acoustic radiation force impulse elastography of the liver. Can fat deposition in the liver affect the measurement of liver stiffness?

International Nuclear Information System (INIS)

Motosugi, Utaroh; Ichikawa, Tomoaki; Araki, Tsutomu; Niitsuma, Yoshibumi

2011-01-01

The aim of this study was to compare acoustic radiation force impulse (ARFI) results between livers with and without fat deposition. We studied 200 consecutive healthy individuals who underwent health checkups at our institution. The subjects were divided into three groups according to the echogenicity of the liver on ultrasonography (US) and the liver-spleen attenuation ratio index (LSR) on computed tomography: normal liver group (n=121, no evidence of bright liver on US and LSR >1); fatty liver group (n=46, bright liver on US and LSR 5 days a week (n=18) were excluded from the analysis. The velocities measured by ARFI in the normal and fatty liver groups were compared using the two one-sided test. The mean (SD) velocity measured in the normal and fatty liver groups were 1.03 (0.12) m/s and 1.02 (0.12) m/s, respectively. The ARFI results of the fatty liver group were similar to those of the normal liver group (P<0.0001). This study suggested that fat deposition in the liver does not affect the liver stiffness measurement determined by ARFI. (author)

Disruption of STAT5b-Regulated Sexual Dimorphism of the Liver Transcriptome by Diverse Factors Is a Common Event

Science.gov (United States)

Signal transducer and activator of transcription 5b (STAT5b) is a growth hormone (GH)-activated transcription factor and a master regulator of sexually dimorphic gene expression in the liver. Disruption ofthe GH hypothalamo-pituitary-liver axis controlling STAT5b activation can ...

Human hepatocytes loaded in 3D bioprinting generate mini-liver.

Science.gov (United States)

Zhong, Cheng; Xie, Hai-Yang; Zhou, Lin; Xu, Xiao; Zheng, Shu-Sen

2016-10-01

Because of an increasing discrepancy between the number of potential liver graft recipients and the number of organs available, scientists are trying to create artificial liver to mimic normal liver function and therefore, to support the patient's liver when in dysfunction. 3D printing technique meets this purpose. The present study was to test the feasibility of 3D hydrogel scaffolds for liver engineering. We fabricated 3D hydrogel scaffolds with a bioprinter. The biocompatibility of 3D hydrogel scaffolds was tested. Sixty nude mice were randomly divided into four groups, with 15 mice in each group: control, hydrogel, hydrogel with L02 (cell line HL-7702), and hydrogel with hepatocyte growth factor (HGF). Cells were cultured and deposited in scaffolds which were subsequently engrafted into livers after partial hepatectomy and radiation-induced liver damage (RILD). The engrafted tissues were examined after two weeks. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, total bilirubin, CYP1A2, CYP2C9, glutathione S-transferase (a-GST), and UDP-glucuronosyl transferase (UGT-2) were compared among the groups. Hematoxylin-eosin (HE) staining and immunohistochemistry of cKit and cytokeratin 18 (CK18) of engrafted tissues were evaluated. The survival time of the mice was also compared among the four groups. 3D hydrogel scaffolds did not impact the viability of cells. The levels of ALT, AST, albumin, total bilirubin, CYP1A2, CYP2C9, a-GST and UGT-2 were significantly improved in mice engrafted with 3D scaffold loaded with L02 compared with those in control and scaffold only (P<0.05). HE staining showed clear liver tissue and immunohistochemistry of cKit and CK18 were positive in the engrafted tissue. Mice treated with 3D scaffold+L02 cells had longer survival time compared with those in control and scaffold only (P<0.05). 3D scaffold has the potential of recreating liver tissue and partial liver functions and can be used in the

Liver Progenitor Cell Line HepaRG Differentiated in a Bioartificial Liver Effectively Supplies Liver Support to Rats with Acute Liver Failure

NARCIS (Netherlands)

Nibourg, Geert A. A.; Chamuleau, Robert A. F. M.; van der Hoeven, Tessa V.; Maas, Martinus A. W.; Ruiter, An F. C.; Lamers, Wouter H.; Oude Elferink, Ronald P. J.; van Gulik, Thomas M.; Hoekstra, Ruurdtje

2012-01-01

A major roadblock to the application of bioartificial livers is the need for a human liver cell line that displays a high and broad level of hepatic functionality. The human bipotent liver progenitor cell line HepaRG is a promising candidate in this respect, for its potential to differentiate into

Serum Hepatocyte Growth Factor as A Non-Invasive Marker For Evaluation of Hepatocellular Carcinoma

International Nuclear Information System (INIS)

Abdelgawad, M.R.; Wahba, M.A.

2012-01-01

The change and the prognostic value of serum hepatocyte growth factor and AFP level in patients with cirrhosis and/or primary liver cancer (HCC) were investigated. The level of serum hepatocyte growth factor was determined by using enzyme-linked immunosorbent assay, and AFP was determined by using radioimmunoassay in 29 patients with cirrhosis. Twenty five patients with primary liver cancer (13 patients without nodular cirrhosis and 12 patients with nodular cirrhosis) were categorized according to tumour size (≤ or >5 cm) and the level of AFP (≤ or > 200 ng/dl). The correlation between serum AFP and hepatocyte growth factor were significantly increased (P 0.05). Serum AFP can significantly discriminate between all studied groups (P 0.001) except for the comparison between control and cirrhosis (P>0.05), and also between HCC and HCC without nodular cirrhosis and HCC with cirrhosis (P>0.05). Serum HGF and AFP levels were positively affected by tumour size and nodular cirrhosis (P<0.001). Also, serum HGF level was highly affected by the levels of serum AFP in HCC patients. Non-significant correlation was observed between serum hepatocyte growth factor and AFP in control, cirrhosis, cirrhosis and HCC patients with AFP ? 200 ng/dl. It could be concluded that the over expressions of the hepatocyte growth factor and AFP may indicate an adverse prognosis for patients with cirrhosis and/or liver cancer. The sustained high level of serum hepatocyte growth factor in cirrhosis and/or HCC could be considered a factor related to early tumour diagnosis, so, serum HGF level may be used as a non-invasive marker in diagnosis and prognosis of liver malignancy. However, further studies are highly recommended to evaluate the role of HGF or its constituents in diagnosis and/or therapy in the future in a larger cohort of patients with different stages of liver malignancy

Correlation with liver scintigram, reticuloendothelial function test, plasma endotoxin level and liver function tests in chronic liver diseases. Multivariate analysis

Energy Technology Data Exchange (ETDEWEB)

Ohmoto, Kenji; Yamamoto, Shinichi; Ideguchi, Seiji and others

1989-02-01

Liver scintigrams with Tc-99m phytate were reviewed in a total of 64 consecutive patients, comprising 28 with chronic hepatitis and 36 with liver cirrhosis. Reticuloendothelial (RES) function, plasma endotoxin (Et) levels and findings of general liver function tests were used as reference parameters to determine the diagnostic ability of liver scintigraphy. Multivariate analyses revealed that liver scintigrams had a strong correlation with RES function and Et levels in terms of morphology of the liver and hepatic and bone marrow Tc-99m uptake. General liver function tests revealed gamma globulin to be correlated with hepatic uptake and the degree of splenogemaly on liver scintigrams; and ICG levels at 15 min to be correlated with bone marrow and splenic uptake. Accuracy of liver scintigraphy was 73% for chronic hepatitis, which was inferior to general liver function tests (83%). When both modalities were combined, diangostic accuracy increased to 95%. Liver scintigraphy seems to be useful as a complementary approach. (Namekawa, K).

Adaptation, allometry, and hypertension.

Science.gov (United States)

Weder, A B; Schork, N J

1994-08-01

Essential hypertension is a "disease of civilization" but has a clear genetic component. From an evolutionary perspective, persistence in the human genome of elements capable of raising blood pressure presupposes their adaptive significance. Recently, two hypotheses that explicitly appeal to selectionist arguments, the "slavery" and "thrifty gene" theories, have been forwarded. We find neither completely successful, and we advance an alternative explanation of the adaptive importance of genes responsible for hypertension. We propose that blood pressure rises during childhood and adolescence to subserve homeostatic needs of the organism. Specifically, we contend that blood pressure is a flexible element in the repertoire of renal homeostatic mechanisms serving to match renal function to growth. The effect of modern diet and lifestyle on human growth stimulates earlier and more vigorous development, straining biologically necessary relationships between renal and general somatic growth and requiring compensation via homeostatic mechanisms preserved during evolution. Prime among such mechanisms is blood pressure, which rises as a compensation to maintain renal function in the face of greater growth. Since virtually all members of acculturated societies share in the modern lifestyle, the demands imposed by accelerated growth and development result in a populational shift to higher blood pressures, with a consequent increase in the prevalence of hypertension. We propose that hypertension is the product of maladaptation of highly genetically conserved mechanisms subserving important biological homeostatic needs. Elucidation of the mechanisms underlying hypertension will require approaches that examine the developmental processes linking growth to blood pressure.

Nonalcoholic fatty liver in patients with Laron syndrome and GH gene deletion - preliminary report.

Science.gov (United States)

Laron, Zvi; Ginsberg, Shira; Webb, Muriel

2008-10-01

There is little information on the relationship between growth hormone/insulin-like growth factor-I (GH/IGF-I) deficiency or IGF-I treatment on nonalcoholic fatty liver disease (NAFLD) a disorder linked to obesity and insulin resistance. To find out whether the markedly obese patients with Laron syndrome (LS) and GH gene deletion have fatty livers. We studied 11 untreated adult patients with LS (5M, 6F), five girls with LS treated by IGF-I and five adult patients with GH gene deletion (3M, 3F), four previously treated by hGH in childhood. Fatty liver was quantitatively evaluated by ultrasonography using a phase array US system (HITACHI 6500, Japan). Body adiposity was determined by DEXA, and insulin resistance was estimated by HOMA-IR using the fasting serum glucose and insulin values. Six out of 11 adult patients with LS, two out of the five IGF-I treated girls with LS and three out of five adult hGH gene deletion patients were found to have NAFLD (nonalcoholic fatty liver disease). NAFLD is a frequent complication in untreated and treated congenital IGF-I deficiency. No correlation between NAFLD and age, sex, degree of obesity, blood lipids, or degree of insulin resistance was observed.

The population ecology of contemporary adaptations: what empirical studies reveal about the conditions that promote adaptive evolution.