cyclin-d1 and Metabolic-Syndrome

Metabolic syndrome (MetS) is a combination of metabolic disorders that can predispose individuals to benign prostatic hyperplasia (BPH). The inhibition of the cannabinoid 1 (CB1) receptor has been used to treat metabolic disorders in animal models. This study reports the use of a peripherally restricted CB1 antagonist (AM6545) and a neutral CB1 antagonist (AM4113) to improve MetS-related BPH in rats. Animals were divided into three control groups to receive either a normal rodent diet, AM6545, or AM4113. MetS was induced in the fourth, fifth, and sixth groups using a concentrated fructose solution and high-salt diet delivered as food pellets for eight weeks. The fifth and sixth groups were further given AM6545 or AM4113 for additional four weeks. Body and prostate weights were measured and prostate sections were stained with hematoxylin eosin. Cyclin D1, markers of oxidative stress and inflammation, and levels of the endocannabinoids were recorded. BPH in rats with MetS was confirmed through increased prostate weight and index, as well as histopathology. Treatment with either AM6545 or AM4113 significantly decreased prostate weight, improved prostate histology, and reduced cyclin D1 expression compared with the MetS group. Groups treated with CB1 antagonists experienced reduced lipid peroxidation, recovered glutathione depletion, restored catalase activity, and had lower inflammatory markers interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α). MetS rats treated with either AM6545 or AM4113 showed reduced concentrations of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the prostate compared with the MetS group. In conclusion, the CB1 antagonists AM6545 and AM4113 protect against MetS-induced BPH through their anti-proliferative, antioxidant, and anti-inflammatory effects.

Topics: Animals; Cannabinoid Receptor Antagonists; Cyclin D1; Humans; Male; Metabolic Syndrome; Piperidines; Prostatic Hyperplasia; Rats; Receptor, Cannabinoid, CB1

Metabolic syndrome (MS) is an emerging risk factor in hepatocellular carcinoma (HCC). HCC related to MS may occur either in advanced fibrosis or before the development of cirrhosis, suggesting involvement of different molecular pathways according to the features of background liver.. To investigate genomic aberrations in HCC related to MS in order to identify new target genes involved in liver carcinogenesis.. Chromosomal aberrations of HCC obtained from 20 patients with MS (HCC/MS) were studied by comparative genomic hybridisation and compared with HCC related to hepatitis C virus (HCV) infection (HCC/HCV, n=10) and, within the group of HCC with MS, according to the condition of the background liver (presence or absence of significant fibrosis).. Among the most frequent chromosomal alterations observed in HCC, 6p21.1 amplification had a higher incidence in HCC/MS than in HCC/HCV (60% vs 20%, p<0.01). Advanced fibrosis/cirrhosis in the peritumoral liver was the only clinicopathological factor associated with the 6p21.1 amplicon in HCC/MS. Increased expression of cullin7 (CUL7), a gene located at the 6p21.1 locus, was demonstrated in HCC with the 6p21.1 amplicon, in parallel with a decrease in cyclin D1 expression. CUL7 downregulation using siRNA transfection in hepatoma cell lines induced significant cyclin D1 expression (by promoting its degradation), decreased cell proliferation and increased apoptosis.. This study demonstrates specific genomic alterations in HCC/MS and points to CUL7 as a novel gene potentially involved in liver carcinogenesis associated with MS, the amplification of which might influence cell proliferation.

Topics: Aged; Aged, 80 and over; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Proliferation; Cell Transformation, Neoplastic; Chromosome Aberrations; Chromosomes, Human, Pair 6; Cullin Proteins; Cyclin D1; Female; Gene Expression; Hepatitis C; Humans; Immunohistochemistry; Liver Cirrhosis; Liver Neoplasms; Male; Metabolic Syndrome; Middle Aged; Nucleic Acid Hybridization; Real-Time Polymerase Chain Reaction