Risk of Developing Hepatocellular Carcinoma following Depressive Disorder Based on the Expression Level of Oatp2a1 and Oatp2b1

Background. Accumulating evidence from prospective epidemiological studies has showed that depression disorder (DD) is a risk factor for cancer. The aim of this study is to explore the association of DD and the overall occurrence risk of hepatocellular carcinoma (HCC) and the mechanism. Methods. In this study, 60 mice were randomly divided into four groups: Control group, DD group, HCC group, HCC-DD group. Mice received a chronic dose of reserpine to establish depression model, followed by Diethylnitrosamine and Carbon tetrachloride administration to establish HCC models. Behavioral depression was assessed by sucrose preference test (SPT) and the expression of Serotonin 1A (5-HT1A) receptor in the hippocampal. The expression of Oatp2a1 and Oatp2b1 in the digestive system tissues was detected by PCR and western blotting. Results. Reserpine-administrated mice had a reducing sucrose preference at Day 14 compared with blank mice (P<0.05). The expression of 5-HT1A receptor in the hippocampal was decreased in DD mice compared with blank mice. The survival analysis indicated that the HCC mice with DD have poorer survival rate compared with the HCC mice. Compared with HCC mice, the expression of Oatp2a1 and Oatp2b1 was lower in liver and stomach tissue and higher in hepatic carcinoma and colon tissue of HCC-DD mice (P<0.05), and the expression of Oatp2a1 was higher in the spleen tissue of HCC-DD mice while the expression of Oatp2b1 was lower (P<0.05). However, no difference was found in the expression of Oatp2a1 and Oatp2b1 in the small intestine tissue between HCC group and HCC-DD group. Conclusions. DD was the adverse factors for the overall occurrence risk of HCC. Mechanistically, be the downregulation of Oatp2a1 and Oatp2b1 in liver tissue induced by DD might be involved.

CARBON TETRACHLORIDE ADMINISTRATION INDUCES THE EXPRESSION OF HYPOXIA INDUCIBLE FACTOR-1α (HIF-1α) IN RAT LIVER

Background: There is now increasing evidence that HIF-1 is also responsive to a variety of non-hypoxic stimuli. However, the mechanisms by which these non-hypoxic stimuli induce HIF-1α are not completely known, yet, although some evidence points to a role of ROS as messengers regulating HIF activity.Objective: To determine the expression of HIF-1α in liver rat tissue induced by carbon tetrachloride under normoxic conditions, with or without N-acetylcysteine protection.Methods: Twenty five male Sprague-Dawley rats were divided into 5 group: normal control rats, normal rats orally administered with coconut oil (1 mL/200 g body weight) for 1 day, rats orally administered with CCl4 (0.55 mg/g body weight) for 1 day, rats injected i.v. with NAC (0.15 mg/g body weight) for 8 days and then orally administered with CCl4 (0.55 mg/g body weight) for 1 day, rats orally administered with CCl4 (0.55 mg/g body weight) for 1 day and then injected i.v. with NAC (0.15 mg/g body weight) for 2 days. The expression of HIF-1α mRNA was measured by real-time RT-PCR using the Livak method. The expression of HIF-1α protein was measured by ELISA assay. Results: The highest HIF-1α mRNA and protein expression found in the group treated by CCl4 and then was gradually lowered in the pre-NAC group, post-NAC group, control group, and last, in the oil group. Conclusion : Our study shows the effect of CCl4-treated rats under normoxic conditions increased the mRNA and protein HIF-1α. NAC post-treatment provide a better protective effect compared with NAC pre-treatment

Deficiency of BPOZ2 Decreases Liver Fibrosis After Chronic Carbon Tetrachloride Administration in Mice

Bood POZ containing gene type 2 (BPOZ2), a Broad-Complex, Tramtrack, and Bric a brac domain containing protein, is an adaptor protein for the E3 ubiquitin ligase scaffold protein CUL3. It plays an important role in acute carbon tetrachloride (CCl4)-induced liver injury and regeneration in mice. In this study, we investigated the role of BPOZ2 in the process of liver fibrosis induced by chronic CCl4 treatment. The results indicate that BPOZ2 deficiency decreases sustained activation of hepatic stellate cells, attenuates collagen αI(I) and tissue inhibitor of matrix metalloprotease 1 expression, and decreases liver fibrosis after repeated CCl4 administration. These findings suggest BPOZ2 as a new therapeutic target for the prevention and treatment of hepatic fibrosis in chronic liver disease.

Calcium receptors located in fibrotic septa: a new target to reduce portal pressure in liver cirrhosis

In rats with experimental liver cirrhosis, the kidney contains reduced amounts of membrane-bound CaRs (calcium-sensing receptors), and the specific stimulation of CaRs causes the generation of PGE2 (prostaglandin E2), renal vasodilation and increased natriuresis. CaR content and function in the liver of cirrhotic rats are unknown. To assess the activity of this Ca2+-dependent vasomotor system, we evaluated the effects of intravenous administration of PolyAg (poly-L-arginine), a selective CaR agonist, on hormonal status, portal haemodynamics, MAP (mean arterial pressure) in rats with liver cirrhosis induced by chronic CCl4 (carbon tetrachloride) administration. Two groups of eight control rats received intravenously 1 ml of 5% (w/v) glucose solution alone or containing 0.5 mg of PolyAg; two groups of ten cirrhotic rats were administered vehicle or PolyAg. Compared with controls, at baseline cirrhotic rats showed higher portal pressure (P<0.01), lower estimated functional liver plasma flow, measured as CICG (Indocyanine Green clearance) (P<0.03) and reduced hepatic protein content of CaRs (P<0.03), which were located mainly in sub-endothelial layers of portal venules and in myofibroblasts of fibrotic septa (immunohistochemistry and indirect immunofluorescence staining of liver sections). In cirrhotic animals, 0.5 mg of PolyAg decreased portal pressure (P<0.01) and increased CICG (P<0.05), without effects on arterial pressure and hormonal status. In conclusion, the present study provides evidence that in experimental cirrhosis agonists of liver CaRs elicit beneficial portal hypotensive effects by reducing intrahepatic resistance to portal flow. Moreover, these drugs are devoid of effects on systemic haemodynamics.