ABSTRACT
Recent data indicates that kisspeptin, encoded by the KISS1 gene, could play a role in transducing metabolic information into the hypothalamic-pituitary-gonadal (HPG) axis, the mechanism that controls reproductive functions. Numerous studies have shown that in a state of negative energy balance, the hypothalamic kisspeptin system is impaired. However, data concerning positive energy balance (e.g. diabetes and obesity) and the role of kisspeptin in the peripheral tissues is scant. We hypothesized that: 1) in diet-induced obese (DIO) male rats and/or rats with diabetes type 1 (DM1) and type 2 (DM2), altered reproductive functions are related to an imbalance in Kiss1 and GPR54 mRNA in the HPG axis; and 2) in DIO and/or DM1 and/or DM2 rats, Kiss1 and GPR 54 expression are altered in the peripheral tissues involved in metabolic functions (fat, pancreas and liver). Animals were fed a high-fat or control diets and STZ (streptozotocin - toxin, which destroys the pancreas) was injected in high or low doses to induce diabetes type 1 (DM1) or diabetes type 2 (DM2), respectively. RT-PCR and Western blot techniques were used to assess the expression of Kiss1 and GRP54 in tissues. At the level of mRNA, we found that diabetic but not obese rats have alterations in Kiss1 and/or GPR54 mRNA levels in the HPG axis as well as in peripheral tissues involved in metabolic functions (fat, pancreas and liver). The most severe changes were seen in DM1 rats. However, in the case of protein levels in the peripheral tissues (fat, pancreas and liver), changes in Kiss1/GPR54 expression were noticed in DIO, DM1 and DM2 animals and were tissue-specific. Our data support the hypothesis that alterations in Kiss1/GPR54 balance may account for both reproductive and metabolic abnormalities reported in obese and diabetic rats.
Subject(s)
Diabetes Mellitus, Experimental/metabolism , Gonads/metabolism , Hypothalamus/metabolism , Kisspeptins/metabolism , Obesity/metabolism , Pituitary Gland/metabolism , Receptors, G-Protein-Coupled/metabolism , Animals , Diet, High-Fat , Male , RNA, Messenger/metabolism , Rats , Rats, Wistar , Receptors, Kisspeptin-1ABSTRACT
BACKGROUND: With an increasing number of patients with hepatocellular carcinoma (HCC) undergoing liver transplantation (OLT), HCC recurrence remains the main limiting factor for long-term survival. We herein report our experience with sorafenib treatment for HCC recurrence post-OLT. PATIENTS AND METHODS: We reviewed data on transplanted HCC patients receiving sorafenib for HCC recurrence. RESULTS: Fourteen patients were included for the period November 2006 to February 2011. There were 9 men and 5 women of median age of 57 years. Twelve patients (86%) received rescue grafts through Eurotransplant allocation. Median values for alpha fetoprotein levels, Model for End-Stage Liver Disease score, sorafenib daily dose, and length of treatment were 97 ng/mL, 10, 400 mg, and 6.5 months, respectively. Sorafenib side effects led to discontinuation (n = 4) or reduction (n = 2) of the daily dose. Four patients experienced tumor progression during treatment. Seven patients are currently alive, 3 patients died of tumor progression, and 4 patients of non-tumor-related causes of death. Median survival was 25 months. CONCLUSION: Sorafenib treatment for HCC recurrence in transplant recipients represents a challenging oncologic approach that requires further validation in prospective, multicenter studies.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/surgery , Liver Neoplasms/drug therapy , Liver Neoplasms/surgery , Liver Transplantation/adverse effects , Neoplasm Recurrence, Local/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Antineoplastic Agents/adverse effects , Carcinoma, Hepatocellular/mortality , Female , Humans , Liver Neoplasms/mortality , Liver Transplantation/mortality , Male , Middle Aged , Neoplasm Recurrence, Local/mortality , Niacinamide/adverse effects , Niacinamide/therapeutic use , Phenylurea Compounds/adverse effects , Protein Kinase Inhibitors/adverse effects , Retrospective Studies , Sorafenib , Time Factors , Treatment OutcomeABSTRACT
The effects of neuromedin-K (NMK) on the rat hypothalamo-pituitary-adrenal (HPA) axis were studied both in vivo and in vitro. A subcutaneous injection of 1 nmol/100 g NMK evoked a rise in plasma ACTH level at 30 min, increased plasma corticosterone (B) concentration (PBC) at 60 and 120 min, and did not alter plasma aldosterone (ALDO) concentration (PAC). The administration of 3 nmol/100 g NMK induced a rise in plasma ACTH level at 120 min and a drop of PBC at 30 min; it increased PBC and PAC at 60 and 120 min. NMK did not affect basal B secretion of dispersed zona fasciculata/reticularis (ZF/R) cells, but markedly enhanced basal ALDO production by dispersed zona glomerulosa (ZG) cells (minimal and maximal effective concentrations were 10(-9) M and 10(-7) M). Video-imaging analysis showed that NMK (10(-8) M) increased intracellular Ca2+ concentration in dispersed ZG cells, but not in ZF/R ones. These findings indicate that NMK exerts a complex modulatory action on the rat HPA axis: low doses of NMK appear to evoke a transient stimulation of ACTH release, while high doses seem to exert a short-term inhibition of glucocorticoid synthesis followed by the compensatory hypersecretion of ACTH; moreover, elevated doses of NMK also exert a strong ALDO secretagogue action by acting directly on the ZG cells.