sermorelin and Inflammation

Optic neuropathies are leading causes of irreversible visual impairment and blindness, currently affecting more than 100 million people worldwide. Glaucoma is a group of optic neuropathies attributed to progressive degeneration of retinal ganglion cells (RGCs). We have previously demonstrated an increase in survival of RGCs by the activation of macrophages, whereas the inhibition of macrophages was involved in the alleviation on endotoxin-induced inflammation by antagonist of growth hormone-releasing hormone (GHRH). Herein, we hypothesized that GHRH receptor (GHRH-R) signaling could be involved in the survival of RGCs mediated by inflammation. We found the expression of GHRH-R in RGCs of adult rat retina. After optic nerve crush, subcutaneous application of GHRH agonist MR-409 or antagonist MIA-602 promoted the survival of RGCs. Both the GHRH agonist and antagonist increased the phosphorylation of Akt in the retina, but only agonist MR-409 promoted microglia activation in the retina. The antagonist MIA-602 reduced significantly the expression of inflammation-related genes

Topics: Animals; Cell Survival; Gene Expression Regulation; Growth Hormone; Growth Hormone-Releasing Hormone; Inflammation; Macrophages; Male; MAP Kinase Signaling System; Microglia; Neuroprotection; Optic Nerve Injuries; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats, Inbred F344; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone; Retinal Ganglion Cells; Sermorelin; Signal Transduction; STAT3 Transcription Factor; Vitreous Body; Zymosan

Topics: Cell Proliferation; Epithelial Cells; Growth Hormone-Releasing Hormone; Humans; Inflammation; Male; Prostate; Sermorelin

Gastric cancer (GC) ranks as the fourth most frequent in incidence and second in mortality among all cancers worldwide. The development of effective treatment approaches is an urgent requirement. Growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) have been found to be present in a variety of tumoral tissues and cell lines. Therefore the inhibition of GHRH-R was proposed as a promising approach for the treatment of these cancers. However, little is known about GHRH-R and the relevant therapy in human GC. By survival analyses of multiple cohorts of GC patients, we identified that increased GHRH-R in tumor specimens correlates with poor survival and is an independent predictor of patient prognosis. We next showed that MIA-602, a highly potent GHRH-R antagonist, effectively inhibited GC growth in cultured cells. Further, this inhibitory effect was verified in multiple models of human GC cell lines xenografted into nude mice. Mechanistically, GHRH-R antagonists target GHRH-R and down-regulate the p21-activated kinase 1 (PAK1)-mediated signal transducer and activator of transcription 3 (STAT3)/nuclear factor-κB (NF-κB) inflammatory pathway. Overall, our studies establish GHRH-R as a potential molecular target in human GC and suggest treatment with GHRH-R antagonist as a promising therapeutic intervention for this cancer.

Topics: Aged; Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Progression; Down-Regulation; Female; Humans; Inflammation; Kaplan-Meier Estimate; Male; Mice; Mice, Nude; Middle Aged; NF-kappa B; p21-Activated Kinases; Prognosis; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone; Sensitivity and Specificity; Sermorelin; Signal Transduction; STAT3 Transcription Factor; Stomach Neoplasms; Treatment Outcome; Xenograft Model Antitumor Assays

We previously showed that growth hormone-releasing hormone (GHRH) agonists are cardioprotective following myocardial infarction (MI). Here, our aim was to evaluate the in vitro and in vivo activities of highly potent new GHRH agonists, and elucidate their mechanisms of action in promoting cardiac repair.. H9c2 cells were cultured in serum-free medium, mimicking nutritional deprivation. GHRH agonists decreased calcium influx and significantly improved cell survival. Rats with cardiac infarction were treated with GHRH agonists or placebo for four weeks. MI size was reduced by selected GHRH agonists (JI-38, MR-356, MR-409); this accompanied an increased number of cardiac c-kit+ cells, cellular mitotic divisions, and vascular density. One week post-MI, MR-409 significantly reduced plasma levels of IL-2, IL-6, IL-10 and TNF-α compared to placebo. Gene expression studies revealed favorable outcomes of MR-409 treatment partially result from inhibitory activity on pro-apoptotic molecules and pro-fibrotic systems, and by elevation of bone morphogenetic proteins.. Treatment with GHRH agonists appears to reduce the inflammatory responses post-MI and may consequently improve mechanisms of healing and cardiac remodeling by regulating pathways involved in fibrosis, apoptosis and cardiac repair. Patients with cardiac dysfunction could benefit from treatment with novel GHRH agonists.

Topics: Alprostadil; Animals; Cell Line; Enzyme-Linked Immunosorbent Assay; Gene Expression Profiling; Gene Expression Regulation; Growth Hormone-Releasing Hormone; Heart Failure; Humans; Inflammation; Interleukin-10; Interleukin-2; Interleukin-6; Microscopy, Fluorescence; Mitosis; Myocardial Infarction; Rats; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone; Sermorelin; Tumor Necrosis Factor-alpha

Growth hormone-releasing hormone (GHRH), a hypothalamic polypeptide, acts as a potent autocrine/paracrine growth factor in many cancers. Benign prostatic hyperplasia (BPH) is a pathologic proliferation of prostatic glandular and stromal tissues; a variety of growth factors and inflammatory processes are inculpated in its pathogenesis. Previously we showed that potent synthetic antagonists of GHRH strongly inhibit the growth of diverse experimental human tumors including prostate cancer by suppressing various tumoral growth factors. The influence of GHRH antagonists on animal models of BPH has not been investigated. We evaluated the effects of the GHRH antagonists JMR-132 given at doses of 40 μg/d, MIA-313 at 20 μg/d, and MIA-459 at 20 μg/d in testosterone-induced BPH in Wistar rats. Reduction of prostate weights was observed after 6 wk of treatment with GHRH antagonists: a 17.8% decrease with JMR-132 treatment; a 17.0% decline with MIA-313 treatment; and a 21.4% reduction with MIA-459 treatment (P < 0.05 for all). We quantified transcript levels of genes related to growth factors, inflammatory cytokines, and signal transduction and identified significant changes in the expression of more than 80 genes (P < 0.05). Significant reductions in protein levels of IL-1β, NF-κβ/p65, and cyclooxygenase-2 (COX-2) also were observed after treatment with a GHRH antagonist. We conclude that GHRH antagonists can lower prostate weight in experimental BPH. This reduction is caused by the direct inhibitory effects of GHRH antagonists exerted through prostatic GHRH receptors. This study sheds light on the mechanism of action of GHRH antagonists in BPH and suggests that GHRH antagonists should be considered for further development as therapy for BPH.

Topics: Alternative Splicing; Animals; Apoptosis; Cell Division; Cyclooxygenase 2; Down-Regulation; Gene Expression Regulation, Neoplastic; Growth Hormone-Releasing Hormone; Humans; Immunohistochemistry; Inflammation; Inflammation Mediators; Insulin-Like Growth Factor I; Interleukin-1beta; Male; NF-kappa B; Organ Size; Prostate; Prostate-Specific Antigen; Prostatic Hyperplasia; Rats; Receptors, Androgen; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone; Sermorelin; Signal Transduction; Transcription, Genetic