Cardiotrophin-1 enhances regeneration of cirrhotic liver remnant after hepatectomy through promotion of angiogenesis and cell proliferation

Department of Surgery, Centre for Cancer Research, Queen Mary Hospital, University of Hong Kong Medical Centre, Pokfulam, Hong Kong, China.
Liver international: official journal of the International Association for the Study of the Liver (Impact Factor: 4.85). 06/2008; 28(5):622-31. DOI: 10.1111/j.1478-3231.2008.01687.x
Source: PubMed


Hepatic resection is not applicable to a certain proportion of hepatocellular carcinoma patients owing to an insufficient liver function reserve. The present study was designed to investigate the effects of cardiotrophin-1 (CT-1) on improving the function of CCl(4)-induced cirrhotic liver remnant after major hepatectomy.
CT-1 was administered to rats after hepatectomy according to different protocols.
A double-dose CT-1 protocol improved liver function, enlarged the volume of liver remnant, upregulated the expression of von Willebrand factor and increased the number of BrdU(+) or Ki-67(+) hepatocytes. Administration of CT-1 enhanced the expression of nuclear factor-kappaB (P65), vascular endothelial growth factor (VEGF), CyclinD1 and p42/44 in the liver remnant. However, the effects of CT-1 were blocked by a VEGF receptor blocker, PTK787. Although the expression of gp130, a receptor of CT-1, was downregulated in the diseased hepatocytes isolated from the cirrhotic liver, CT-1 could still stimulate the cell proliferation. CT-1 administration enhanced the expression of P65 and VEGF in the diseased hepatocytes, but the augmented P65 and VEGF expression was blocked by PTK787 administration.
Short-term administration of CT-1 could improve the function of cirrhotic liver remnant and stimulate liver regeneration through promotion of angiogenesis and cell proliferation.

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    • "CT-1 protects rats and mice from liver damage induced by ischemia/reperfusion, and CT-1 null mice are more sensitive to this type of damage (Iniguez et al., 2006). CT-1 also prevents d-galactosamine-induced fulminant hepatic failure (Ho et al., 2006), whereas administration of CT-1 to cirrhotic rats with major surgical resection of the liver improves survival and liver function (Yang et al., 2008). Treatment with an adenovirus encoding CT-1 efficiently protects rats against fulminant liver failure after subtotal hepatectomy (Bustos et al., 2003). "
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    ABSTRACT: Although generally reversible, contrast media toxicity often induces contrast-induced nephropathy (CIN), which is associated to longer hospitalization time, the need of dialysis, and higher incidence of later cardiovascular events and higher mortality. Preventive co-treatments have been assayed at the preclinical and clinical levels, but recent meta-analysis have not demonstrated a beneficial effect, which supports the search for new nephroprotective strategies. We have assessed if the administration of cardiotrophin-1 (CT-1), an endogenous cytokine with protective properties on the heart and liver, might mitigate CIN in rats. We have developed a model of CIN induced by the administration of the contrast medium gastrographin i.v. (3.7 mg/kg). in rats sensitized by previous administration of sub-nephrotoxic doses of gentamicin (50 mg/kg/day, i.p.) for 6 days. The severity of CIN was assessed by measurement of renal function, renal histological damage, urinary excretion of markers of tubular damage including NAG, KIM-1 and PAI-1, lipid peroxidation and renal apoptosis. Treatment with cardiotrophin-1 almost completely prevented the renal tissue damage as evidenced by almost total prevention of tubular desepithelization and tubular obstruction, reduced caspase activation and cell proliferation. Besides, CT-1 also prevented the increment in renal tissue levels of renal tissue injury markers NAG, KIM-1 and NGAL. Oxidative stress, a hallmark of contrast-induced nephropathy, was also prevented by CT-1. Administration of CT-1 also prevented the derangement in kidney function induced by CIN. Renal hemodynamics, also impaired by the contrast medium, were normal in rats co-treated with CT-1. Cardiotrophin-1 administration significantly prevents the alterations in renal function and structure observed in a rat model of CIN.
    Full-text · Article · Jan 2013 · Toxicological Sciences
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    • "The collagenase perfusion method is a classic method to isolate hepatocytes from liver tissues. This method were used to isolated hepatocyte from normal liver[30], [31], liver cirrhosis[32] and HCC[20], [22], [23], [33] to study molecular mechanisms. Fibrous liver connective tissue was removed through successive perfusion with EDTA, dispase, collagenase type IV, and DNase I. Centrifuged at low speed to eliminate non-parenchymal cells. "
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    ABSTRACT: With the development of high-throughput screening, a variety of genetic alterations has been found in hepatocellular carcinoma (HCC). Although previous studies on HCC methylation profiles have focused on liver tissue, studies using isolated hepatocytes are rare. The heterogeneity of liver composition may impact the genuine methylation status of HCC; therefore, it is important to clarify the methylation profile of hepatocytes to aid in understanding the process of tumorigenesis. The global methylation profile of single hepatocytes isolated from liver tissue of hepatitis B virus (HBV) related HCC (HBHC) was analyzed using Illumina Infinium Human Methylation27 BeadChips, and combined bisulfite restriction analysis (COBRA) and bisulfite sequencing were used to validate the 20 significant hypermethylated genes identified. In this study, we found many noteworthy differences in the genome-wide methylation profiles of single hepatocytes of HBHC. Unsupervised hierarchical clustering analysis showed that hepatocyte methylation profiles could be classified according to three cell types: hepatocytes of HCC, adjacent hepatocytes and normal hepatocytes. Among the 20 most hypermethylated genes in the hepatocytes of HBHC, 7 novel genes (WNK2, EMILIN2, TLX3, TM6SF1, TRIM58, HIST1H4Fand GRASP) were found to be hypermethylated in HBHC and hypomethylated in paired adjacent liver tissues; these findings have not been reported in previous studies on tissue samples. The genome-wide methylation profile of purified single hepatocytes of HBHC was aided in understanding the process of tumorigenesis, and a series of novel methylated genes found in this study have the potential to be biomarkers for the diagnosis and prognosis of HBHC.
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