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Andrew V. Schally - One of the best experts on this subject based on the ideXlab platform.
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Growth Hormone-Releasing Hormone Receptor Antagonist Modulates Lung Inflammation and Fibrosis due to Bleomycin.
Lung, 2019Co-Authors: Chongxu Zhang, Andrew V. Schally, Renzhi Cai, Aaron Lazerson, Gaëtan J.-r. Delcroix, Medhi Wangpaichitr, Mehdi Mirsaeidi, Anthony J. Griswold, Robert M. JacksonAbstract:Purpose Growth Hormone-Releasing Hormone (GHRH) is a 44-amino acid peptide that regulates Growth Hormone (GH) secretion. We hypothesized that a GHRH receptor (GHRH-R) antagonist, MIA-602, would inhibit bleomycin-induced lung inflammation and/or fibrosis in C57Bl/6J mice.
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actions and potential therapeutic applications of Growth Hormone releasing Hormone agonists
Endocrinology, 2019Co-Authors: Andrew V. Schally, Renzhi Cai, Xianyang Zhang, Joshua M Hare, Riccarda Granata, Manuela BartoliAbstract:In this article, we briefly review the identification of GHRH, provide an abridged overview of GHRH antagonists, and focus on studies with GHRH agonists. Potent GHRH agonists of JI and MR class were synthesized and evaluated biologically. Besides the induction of the release of pituitary GH, GHRH analogs promote cell proliferation and exert stimulatory effects on various tissues, which express GHRH receptors (GHRH-Rs). A large body of work shows that GHRH agonists, such as MR-409, improve pancreatic β-cell proliferation and metabolic functions and facilitate engraftment of islets after transplantation in rodents. Accordingly, GHRH agonists offer a new therapeutic approach to treating diabetes. Various studies demonstrate that GHRH agonists promote repair of cardiac tissue, producing improvement of ejection fraction and reduction of infarct size in rats, reduction of infarct scar in swine, and attenuation of cardiac hypertrophy in mice, suggesting clinical applications. The presence of GHRH-Rs in ocular tissues and neuroprotective effects of GHRH analogs in experimental diabetic retinopathy indicates their possible therapeutic applications for eye diseases. Other effects of GHRH agonists, include acceleration of wound healing, activation of immune cells, and action on the central nervous system. As GHRH might function as a Growth factor, we examined effects of GHRH agonists on tumors. In vitro, GHRH agonists stimulate Growth of human cancer cells and upregulate GHRH-Rs. However, in vivo, GHRH agonists inhibit Growth of human cancers xenografted into nude mice and downregulate pituitary and tumoral GHRH-Rs. Therapeutic applications of GHRH analogs are discussed. The development of GHRH analogs should lead to their clinical use.
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agonists of Growth Hormone releasing Hormone ghrh inhibit human experimental cancers in vivo by down regulating receptors for ghrh
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Andrew V. Schally, Irving Vidaurre, Petra Popovics, Roberto Perez, Haibo Wang, Jinlin He, Xianyang ZhangAbstract:The effects of the Growth Hormone-Releasing Hormone (GHRH) agonist MR409 on various human cancer cells were investigated. In H446 small cell lung cancer (SCLC) and HCC827 and H460 (non-SCLC) cells, MR409 promoted cell viability, reduced cell apoptosis, and induced the production of cellular cAMP in vitro. Western blot analyses showed that treatment of cancer cells with MR409 up-regulated the expression of cyclins D1 and D2 and cyclin-dependent kinases 4 and 6, down-regulated p27kip1, and significantly increased the expression of the pituitary-type GHRH receptor (pGHRH-R) and its splice-variant (SV1). Hence, in vitro MR409 exerts agonistic action on lung cancer cells in contrast to GHRH antagonists. However, in vivo, MR409 inhibited Growth of lung cancers xenografted into nude mice. MR409 given s.c. at 5 μg/day for 4 to 8 weeks significantly suppressed Growth of HCC827, H460, and H446 tumors by 48.2%, 48.7%, and 65.6%, respectively. This inhibition of tumor Growth by MR409 was accompanied by the down-regulation of the expression of pGHRH-R and SV1 in the pituitary gland and tumors. Tumor inhibitory effects of MR409 in vivo were also observed in other human cancers, including gastric, pancreatic, urothelial, prostatic, mammary, and colorectal. This inhibition of tumor Growth parallel to the down-regulation of GHRH-Rs is similar and comparable to the suppression of sex Hormone-dependent cancers after the down-regulation of receptors for luteinizing Hormone-Releasing Hormone (LHRH) by LHRH agonists. Further oncological investigations with GHRH agonists are needed to elucidate the underlying mechanisms.
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P53, GHRH, inflammation and cancer
Elsevier, 2018Co-Authors: Nektarios Barabutis, Andrew V. Schally, Agnieszka SiejkaAbstract:P53 is a transcription factor very often mutated in malignancies. It functions towards the regulation of important cellular activities, such as cell cycle, senescence and apoptosis. Since inflammation and cancer are strongly associated through common pathways, P53 can suppress inflammation in a plethora of human tissues. Growth Hormone - Releasing Hormone is a hypothalamic peptide with a great capacity to affect the complex networks of cellular regulation via GHRH - specific receptors. GHRH antagonistic and agonistic analogs have been developed for clinical applications, including treatment of benign prostatic hyperplasia, breast, prostate and lung cancers, diabetes and neurodegenerative diseases. The epicenter of the current manuscript is the protective role of P53 against inflammation and cancer and emphasizes the p53 – mediated beneficial effects of GHRH antagonists in various human diseases. Keywords: Growth factors, Oncology, Barrier functio
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protective effects of agonists of Growth Hormone releasing Hormone ghrh in early experimental diabetic retinopathy
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Menaka Thounaojam, Norman L. Block, Folami L Powell, Sagar Patel, Diana Gutsaeva, Amany Tawfik, Sylvia B Smith, Julian Nussbaum, Pamela M Martin, Andrew V. SchallyAbstract:The potential therapeutic effects of agonistic analogs of Growth Hormone-Releasing Hormone (GHRH) and their mechanism of action were investigated in diabetic retinopathy (DR). Streptozotocin-induced diabetic rats (STZ-rats) were treated with 15 μg/kg GHRH agonist, MR-409, or GHRH antagonist, MIA-602. At the end of treatment, morphological and biochemical analyses assessed the effects of these compounds on retinal neurovascular injury induced by hyperglycemia. The expression levels of GHRH and its receptor (GHRH-R) measured by qPCR and Western blotting were significantly down-regulated in retinas of STZ-rats and in human diabetic retinas (postmortem) compared with their respective controls. Treatment of STZ-rats with the GHRH agonist, MR-409, prevented retinal morphological alteration induced by hyperglycemia, particularly preserving survival of retinal ganglion cells. The reverse, using the GHRH antagonist, MIA-602, resulted in worsening of retinal morphology and a significant alteration of the outer retinal layer. Explaining these results, we have found that MR-409 exerted antioxidant and anti-inflammatory effects in retinas of the treated rats, as shown by up-regulation of NRF-2-dependent gene expression and down-regulation of proinflammatory cytokines and adhesion molecules. MR-409 also significantly down-regulated the expression of vascular endothelial Growth factor while increasing that of pigment epithelium-derived factor in diabetic retinas. These effects correlated with decreased vascular permeability. In summary, our findings suggest a neurovascular protective effect of GHRH analogs during the early stage of diabetic retinopathy through their antioxidant and anti-inflammatory properties.
Renzhi Cai - One of the best experts on this subject based on the ideXlab platform.
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effects of Growth Hormone releasing Hormone agonistic analog mr 409 on insulin secreting cells under cyclopiazonic acid induced endoplasmic reticulum stress
Molecular and Cellular Endocrinology, 2021Co-Authors: Karina Rodriguesdossantos, Renzhi Cai, Gabriela Moreira Soares, Dimitrius Santiago P S F Guimaraes, Thiago R Araujo, Jean F Vettorazzi, Lucas Zangerolamo, Emilio MarconatojuniorAbstract:The endoplasmic reticulum (ER) stress is one of the mechanisms related to decreased insulin secretion and beta cell death, contributing to the progress of type 2 diabetes mellitus (T2D). Thus, investigating agents that can influence this process would help prevent the development of T2D. Recently, the Growth-Hormone-Releasing Hormone (GHRH) action has been demonstrated in INS-1E cells, in which it increases cell proliferation and insulin secretion. As the effects of GHRH and its agonists have not been fully elucidated in the beta cell, we proposed to investigate them by evaluating the role of the GHRH agonist, MR-409, in cells under ER stress. Our results show that the agonist was unable to ameliorate or prevent ER stress. However, cells exposed to the agonist showed less oxidative stress and greater survival even under ER stress. The mechanisms by which GHRH agonist, MR-409, leads to these outcomes require further investigation.
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Growth Hormone-Releasing Hormone Receptor Antagonist Modulates Lung Inflammation and Fibrosis due to Bleomycin.
Lung, 2019Co-Authors: Chongxu Zhang, Andrew V. Schally, Renzhi Cai, Aaron Lazerson, Gaëtan J.-r. Delcroix, Medhi Wangpaichitr, Mehdi Mirsaeidi, Anthony J. Griswold, Robert M. JacksonAbstract:Purpose Growth Hormone-Releasing Hormone (GHRH) is a 44-amino acid peptide that regulates Growth Hormone (GH) secretion. We hypothesized that a GHRH receptor (GHRH-R) antagonist, MIA-602, would inhibit bleomycin-induced lung inflammation and/or fibrosis in C57Bl/6J mice.
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actions and potential therapeutic applications of Growth Hormone releasing Hormone agonists
Endocrinology, 2019Co-Authors: Andrew V. Schally, Renzhi Cai, Xianyang Zhang, Joshua M Hare, Riccarda Granata, Manuela BartoliAbstract:In this article, we briefly review the identification of GHRH, provide an abridged overview of GHRH antagonists, and focus on studies with GHRH agonists. Potent GHRH agonists of JI and MR class were synthesized and evaluated biologically. Besides the induction of the release of pituitary GH, GHRH analogs promote cell proliferation and exert stimulatory effects on various tissues, which express GHRH receptors (GHRH-Rs). A large body of work shows that GHRH agonists, such as MR-409, improve pancreatic β-cell proliferation and metabolic functions and facilitate engraftment of islets after transplantation in rodents. Accordingly, GHRH agonists offer a new therapeutic approach to treating diabetes. Various studies demonstrate that GHRH agonists promote repair of cardiac tissue, producing improvement of ejection fraction and reduction of infarct size in rats, reduction of infarct scar in swine, and attenuation of cardiac hypertrophy in mice, suggesting clinical applications. The presence of GHRH-Rs in ocular tissues and neuroprotective effects of GHRH analogs in experimental diabetic retinopathy indicates their possible therapeutic applications for eye diseases. Other effects of GHRH agonists, include acceleration of wound healing, activation of immune cells, and action on the central nervous system. As GHRH might function as a Growth factor, we examined effects of GHRH agonists on tumors. In vitro, GHRH agonists stimulate Growth of human cancer cells and upregulate GHRH-Rs. However, in vivo, GHRH agonists inhibit Growth of human cancers xenografted into nude mice and downregulate pituitary and tumoral GHRH-Rs. Therapeutic applications of GHRH analogs are discussed. The development of GHRH analogs should lead to their clinical use.
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regulation of vascular calcification by Growth Hormone releasing Hormone and its agonists
Circulation Research, 2018Co-Authors: Jian Shen, Ning Zhang, Yi Nuo Lin, Ping Ping Xiang, Xian Bao Liu, Peng Fei Shan, Wei Zhu, Yao Liang Tang, Keith A Webster, Renzhi CaiAbstract:Rationale: Vascular calcification (VC) is a marker of the severity of atherosclerotic disease. Hormones play important roles in regulating calcification; estrogen and parathyroid Hormones exert opposing effects, the former alleviating VC and the latter exacerbating it. So far no treatment strategies have been developed to regulate clinical VC. Objective: To investigate the effect of Growth Hormone-Releasing Hormone (GHRH) and its agonist (GHRH-A) on the blocking of VC in a mouse model. Methods and Results: Young adult osteoprotegerin deficient (OPG -/- ) mice were given daily subcutaneous injections of GHRH-A (MR409) for 4 weeks. Significant reductions in calcification of the aortas of MR409 treated mice were paralleled by markedly lower alkaline phosphatase (ALP) activity and a dramatic reduction in the expression of transcription factors including the osteogenic marker gene Runx2 and its downstream factors, osteonectin and osteocalcin. The mechanism of action of GHRH-A was dissected in smooth muscle cells (SMCs) isolated from human and mouse aortas. Calcification of SMCs induced by osteogenic medium (OM) was inhibited in the presence of GHRH or MR409, as evidenced by reduced ALP activity and Runx2 expression. Inhibition of calcification by MR409 was partially reversed by MIA602, a GHRH antagonist, or a GHRH receptor selective siRNA. Treatment with MR409 induced elevated cytosolic cAMP and its target, protein kinase A (PKA) which in turn blocked NADPH oxidase activity and reduced production of reactive oxygen species (ROS), thus blocking the phosphorylation of NFκB (p65), a key intermediate in the RANKL-Runx2/ALP osteogenesis program. A PKA-selective siRNA or the chemical inhibitor H89 abolished these beneficial effects of MR409. Conclusions: GHRH-A controls osteogenesis in SMCs by targeting cross talk between PKA and NFκB (p65) and through the suppression of ROS production that induces the Runx2 gene and ALP. Inflammation-mediated osteogenesis is thereby blocked. GHRH-A may represent a new pharmacological strategy to regulate VC.
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Growth Hormone releasing Hormone receptor antagonists inhibit human gastric cancer through downregulation of pak1 stat3 nf κb signaling
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Jinfeng Gan, Jiali Jiang, Hongmei Dong, Zhimeng Yao, Yusheng Lin, Wan Lin, Shumei Yan, Yixuan Zhuang, Wai Kit Chu, Renzhi CaiAbstract: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.
Marta Zarandi - One of the best experts on this subject based on the ideXlab platform.
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preclinical efficacy of Growth Hormone releasing Hormone antagonists for androgen dependent and castration resistant human prostate cancer
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Cale D Fahrenholtz, Ferenc G Rick, Marta Zarandi, Norman L. Block, Andrew V. Schally, Maria I Garcia, Kerry L BurnsteinAbstract:Abstract Advanced Hormone-sensitive prostate cancer responds to androgen-deprivation therapy (ADT); however, therapeutic options for recurrent castration-resistant disease are limited. Because Growth Hormone-Releasing Hormone (GHRH) and GHRH receptor (GHRH-R) are regulated in an autocrine fashion in prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists—MIA-602, MIA-606, and MIA-690—on the Growth of androgen-dependent as well as castration-resistant prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human prostate cancer cell lines. Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared with castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro, MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of MIA-602. In vivo, MIA-602 was more effective than MIA-606 and MIA-690 and decreased 22Rv1 xenograft tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in body weight occurred. In vitro, the VCaP cell line was minimally inhibited by MIA-602, but in vivo, this line showed a substantial reduction in Growth of xenografts in response to MIA-602, indicating both direct and systemic inhibitory effects. MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist MIA-602 for treatment of both androgen-dependent and CRPC.
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potentiation of cytotoxic chemotherapy by Growth Hormone releasing Hormone agonists
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Miklos Jaszberenyi, Ferenc G Rick, Luca Szalontay, Marta Zarandi, Norman L. Block, Irving Vidaurre, Renzhi Cai, Petra Popovics, Arumugam Jayakumar, Andrew V. SchallyAbstract:The dismal prognosis of malignant brain tumors drives the development of new treatment modalities. In view of the multiple activities of Growth Hormone-Releasing Hormone (GHRH), we hypothesized that pretreatment with a GHRH agonist, JI-34, might increase the susceptibility of U-87 MG glioblastoma multiforme (GBM) cells to subsequent treatment with the cytotoxic drug, doxorubicin (DOX). This concept was corroborated by our findings, in vivo, showing that the combination of the GHRH agonist, JI-34, and DOX inhibited the Growth of GBM tumors, transplanted into nude mice, more than DOX alone. In vitro, the pretreatment of GBM cells with JI-34 potentiated inhibitory effects of DOX on cell proliferation, diminished cell size and viability, and promoted apoptotic processes, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, ApoLive-Glo multiplex assay, and cell volumetric assay. Proteomic studies further revealed that the pretreatment with GHRH agonist evoked differentiation decreasing the expression of the neuroectodermal stem cell antigen, nestin, and up-regulating the glial maturation marker, GFAP. The GHRH agonist also reduced the release of humoral regulators of glial Growth, such as FGF basic and TGFβ. Proteomic and gene-expression (RT-PCR) studies confirmed the strong proapoptotic activity (increase in p53, decrease in v-myc and Bcl-2) and anti-invasive potential (decrease in integrin α3) of the combination of GHRH agonist and DOX. These findings indicate that the GHRH agonists can potentiate the anticancer activity of the traditional chemotherapeutic drug, DOX, by multiple mechanisms including the induction of differentiation of cancer cells.
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antagonists of Growth Hormone releasing Hormone ghrh given before whole body radiation lead to modulation of radiation response and organ specific changes in the expression of angiogenesis
Journal of Radiation Oncology, 2012Co-Authors: May Abdelwahab, Omar Mahmoud, Teresita Reiner, Ferenc G Rick, Luca Szalontay, Norman L. Block, Andrew V. Schally, Arnold M. Markoe, Merce Jorda, Marta ZarandiAbstract:Purpose This study seeks to determine if Growth Hormone-Releasing Hormone (GHRH) antagonist, JMR-132, increases survival when given before whole body radiation.
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Combining Growth Hormone-Releasing Hormone Antagonist With Luteinizing Hormone-Releasing Hormone Antagonist Greatly Augments Benign Prostatic Hyperplasia Shrinkage
The Journal of urology, 2012Co-Authors: Ferenc G Rick, Luca Szalontay, Marta Zarandi, Norman L. Block, Andrew V. Schally, Mehrdad Nadji, Karoly Szepeshazi, Irving Vidaurre, Magdolna Kovacs, Zoltan RekasiAbstract:Purpose: Benign prostatic hyperplasia often affects aging men. Antagonists of the neuropeptide Growth Hormone-Releasing Hormone reduced prostate weight in an androgen induced benign prostatic hyperplasia model in rats. Luteinizing Hormone-Releasing Hormone antagonists also produce marked, protracted improvement in lower urinary tract symptoms, reduced prostate volume and an increased urinary peak flow rate in men with benign prostatic hyperplasia. We investigated the influence of a combination of antagonists of Growth Hormone-Releasing Hormone and luteinizing Hormone-Releasing Hormone on animal models of benign prostatic hyperplasia.Materials and Methods: We evaluated the effects of the Growth Hormone-Releasing Hormone antagonist JMR-132, given at a dose of 40 μg daily, the luteinizing Hormone-Releasing Hormone antagonist cetrorelix, given at a dose of 0.625 mg/kg, and their combination on testosterone induced benign prostatic hyperplasia in adult male Wistar rats in vivo. Prostate tissue was examined bio...
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antagonists of Growth Hormone releasing Hormone ghrh reduce prostate size in experimental benign prostatic hyperplasia
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Ferenc G Rick, Marta Zarandi, Norman L. Block, Andrew V. Schally, Mehrdad Nadji, Karoly Szepeshazi, Irving Vidaurre, Roberto Perez, Gabor HalmosAbstract: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.
Norman L. Block - One of the best experts on this subject based on the ideXlab platform.
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protective effects of agonists of Growth Hormone releasing Hormone ghrh in early experimental diabetic retinopathy
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Menaka Thounaojam, Norman L. Block, Folami L Powell, Sagar Patel, Diana Gutsaeva, Amany Tawfik, Sylvia B Smith, Julian Nussbaum, Pamela M Martin, Andrew V. SchallyAbstract:The potential therapeutic effects of agonistic analogs of Growth Hormone-Releasing Hormone (GHRH) and their mechanism of action were investigated in diabetic retinopathy (DR). Streptozotocin-induced diabetic rats (STZ-rats) were treated with 15 μg/kg GHRH agonist, MR-409, or GHRH antagonist, MIA-602. At the end of treatment, morphological and biochemical analyses assessed the effects of these compounds on retinal neurovascular injury induced by hyperglycemia. The expression levels of GHRH and its receptor (GHRH-R) measured by qPCR and Western blotting were significantly down-regulated in retinas of STZ-rats and in human diabetic retinas (postmortem) compared with their respective controls. Treatment of STZ-rats with the GHRH agonist, MR-409, prevented retinal morphological alteration induced by hyperglycemia, particularly preserving survival of retinal ganglion cells. The reverse, using the GHRH antagonist, MIA-602, resulted in worsening of retinal morphology and a significant alteration of the outer retinal layer. Explaining these results, we have found that MR-409 exerted antioxidant and anti-inflammatory effects in retinas of the treated rats, as shown by up-regulation of NRF-2-dependent gene expression and down-regulation of proinflammatory cytokines and adhesion molecules. MR-409 also significantly down-regulated the expression of vascular endothelial Growth factor while increasing that of pigment epithelium-derived factor in diabetic retinas. These effects correlated with decreased vascular permeability. In summary, our findings suggest a neurovascular protective effect of GHRH analogs during the early stage of diabetic retinopathy through their antioxidant and anti-inflammatory properties.
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beneficial effects of Growth Hormone releasing Hormone agonists on rat ins 1 cells and on streptozotocin induced nod scid mice
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Xianyang Zhang, Irving Vidaurre, Renzhi Cai, Petra Popovics, Janine Schmid, Barbara Ludwig, Haibo Wang, Tengjiao Cui, Wei Sha, Norman L. BlockAbstract:Agonists of Growth Hormone-Releasing Hormone (GHRH) have been previously reported to promote Growth, function, and engraftment of islet cells following transplantation. Here we evaluated recently synthesized GHRH agonists on the proliferation and biological functions of rat pancreatic β-cell line (INS-1) and islets. In vitro treatment of INS-1 cells with GHRH agonists increased cell proliferation, the expression of cellular insulin, insulin-like Growth factor-1 (IGF1), and GHRH receptor, and also stimulated insulin secretion in response to glucose challenge. Exposure of INS-1 cells to GHRH agonists, MR-356 and MR-409, induced activation of ERK and AKT pathways. Agonist MR-409 also significantly increased the levels of cellular cAMP and the phosphorylation of cAMP response element binding protein (CREB) in INS-1 cells. Treatment of rat islets with agonist, MR-409 significantly increased cell proliferation, islet size, and the expression of insulin. In vivo daily s.c. administration of 10 μg MR-409 for 3 wk dramatically reduced the severity of streptozotocin (STZ)-induced diabetes in nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice. The maximal therapeutic benefits with respect to the efficiency of engraftment, ability to reach normoglycemia, gain in body weight, response to high glucose challenge, and induction of higher levels of serum insulin and IGF1 were observed when diabetic mice were transplanted with rat islets preconditioned with GHRH agonist, MR-409, and received additional treatment with MR-409 posttransplantation. This study provides an improved approach to the therapeutic use of GHRH agonists in the treatment of diabetes mellitus.
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agonists of Growth Hormone releasing Hormone stimulate self renewal of cardiac stem cells and promote their survival
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Victoria Florea, Norman L. Block, Andrew V. Schally, Renzhi Cai, Rosemeire M Kanashirotakeuchi, Joshua M Hare, Sonia S Majid, Claudia O RodriguesAbstract:The beneficial effects of agonists of Growth Hormone-Releasing Hormone receptor (GHRH-R) in heart failure models are associated with an increase in the number of ckit+ cardiac stem cells (CSCs). The goal of the present study was to determine the presence of GHRH-R in CSCs, the effect of GHRH-R agonists on their proliferation and survival, and the mechanisms involved. We investigated the expression of GHRH-R in CSCs of different species and the effect of GHRH-R agonists on their cell proliferation and survival. GHRH-R is expressed in ckit+ CSCs isolated from mouse, rat, and pig. Treatment of porcine CSCs with the GHRH-R agonist JI-38 significantly increased the rate of cell division. Similar results were observed with other GHRH-R agonists, MR-356 and MR-409. JI-38 exerted a protective effect on survival of porcine CSCs under conditions of oxidative stress induced by exposure to hydrogen peroxide. Treatment with JI-38 before exposure to peroxide significantly reduced cell death. A similar effect was observed with MR-356. Addition of GHRH-R agonists to porcine CSCs induced activation of ERK and AKT pathways as determined by increased expression of phospho-ERK and phospho-AKT. Inhibitors of ERK and AKT pathways completely reversed the effect of GHRH-R agonists on CSC proliferation. Our findings extend the observations of the expression of GHRH-R by CSCs and demonstrate that GHRH-R agonists have a direct effect on proliferation and survival of CSCs. These results support the therapeutic use of GHRH-R agonists for stimulating endogenous mechanisms for myocardial repair or for preconditioning of stem cells before transplantation.
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preclinical efficacy of Growth Hormone releasing Hormone antagonists for androgen dependent and castration resistant human prostate cancer
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Cale D Fahrenholtz, Ferenc G Rick, Marta Zarandi, Norman L. Block, Andrew V. Schally, Maria I Garcia, Kerry L BurnsteinAbstract:Abstract Advanced Hormone-sensitive prostate cancer responds to androgen-deprivation therapy (ADT); however, therapeutic options for recurrent castration-resistant disease are limited. Because Growth Hormone-Releasing Hormone (GHRH) and GHRH receptor (GHRH-R) are regulated in an autocrine fashion in prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists—MIA-602, MIA-606, and MIA-690—on the Growth of androgen-dependent as well as castration-resistant prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human prostate cancer cell lines. Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared with castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro, MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of MIA-602. In vivo, MIA-602 was more effective than MIA-606 and MIA-690 and decreased 22Rv1 xenograft tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in body weight occurred. In vitro, the VCaP cell line was minimally inhibited by MIA-602, but in vivo, this line showed a substantial reduction in Growth of xenografts in response to MIA-602, indicating both direct and systemic inhibitory effects. MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist MIA-602 for treatment of both androgen-dependent and CRPC.
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potentiation of cytotoxic chemotherapy by Growth Hormone releasing Hormone agonists
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Miklos Jaszberenyi, Ferenc G Rick, Luca Szalontay, Marta Zarandi, Norman L. Block, Irving Vidaurre, Renzhi Cai, Petra Popovics, Arumugam Jayakumar, Andrew V. SchallyAbstract:The dismal prognosis of malignant brain tumors drives the development of new treatment modalities. In view of the multiple activities of Growth Hormone-Releasing Hormone (GHRH), we hypothesized that pretreatment with a GHRH agonist, JI-34, might increase the susceptibility of U-87 MG glioblastoma multiforme (GBM) cells to subsequent treatment with the cytotoxic drug, doxorubicin (DOX). This concept was corroborated by our findings, in vivo, showing that the combination of the GHRH agonist, JI-34, and DOX inhibited the Growth of GBM tumors, transplanted into nude mice, more than DOX alone. In vitro, the pretreatment of GBM cells with JI-34 potentiated inhibitory effects of DOX on cell proliferation, diminished cell size and viability, and promoted apoptotic processes, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, ApoLive-Glo multiplex assay, and cell volumetric assay. Proteomic studies further revealed that the pretreatment with GHRH agonist evoked differentiation decreasing the expression of the neuroectodermal stem cell antigen, nestin, and up-regulating the glial maturation marker, GFAP. The GHRH agonist also reduced the release of humoral regulators of glial Growth, such as FGF basic and TGFβ. Proteomic and gene-expression (RT-PCR) studies confirmed the strong proapoptotic activity (increase in p53, decrease in v-myc and Bcl-2) and anti-invasive potential (decrease in integrin α3) of the combination of GHRH agonist and DOX. These findings indicate that the GHRH agonists can potentiate the anticancer activity of the traditional chemotherapeutic drug, DOX, by multiple mechanisms including the induction of differentiation of cancer cells.
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preclinical efficacy of Growth Hormone releasing Hormone antagonists for androgen dependent and castration resistant human prostate cancer
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Cale D Fahrenholtz, Ferenc G Rick, Marta Zarandi, Norman L. Block, Andrew V. Schally, Maria I Garcia, Kerry L BurnsteinAbstract:Abstract Advanced Hormone-sensitive prostate cancer responds to androgen-deprivation therapy (ADT); however, therapeutic options for recurrent castration-resistant disease are limited. Because Growth Hormone-Releasing Hormone (GHRH) and GHRH receptor (GHRH-R) are regulated in an autocrine fashion in prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists—MIA-602, MIA-606, and MIA-690—on the Growth of androgen-dependent as well as castration-resistant prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human prostate cancer cell lines. Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared with castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro, MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of MIA-602. In vivo, MIA-602 was more effective than MIA-606 and MIA-690 and decreased 22Rv1 xenograft tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in body weight occurred. In vitro, the VCaP cell line was minimally inhibited by MIA-602, but in vivo, this line showed a substantial reduction in Growth of xenografts in response to MIA-602, indicating both direct and systemic inhibitory effects. MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist MIA-602 for treatment of both androgen-dependent and CRPC.
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potentiation of cytotoxic chemotherapy by Growth Hormone releasing Hormone agonists
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Miklos Jaszberenyi, Ferenc G Rick, Luca Szalontay, Marta Zarandi, Norman L. Block, Irving Vidaurre, Renzhi Cai, Petra Popovics, Arumugam Jayakumar, Andrew V. SchallyAbstract:The dismal prognosis of malignant brain tumors drives the development of new treatment modalities. In view of the multiple activities of Growth Hormone-Releasing Hormone (GHRH), we hypothesized that pretreatment with a GHRH agonist, JI-34, might increase the susceptibility of U-87 MG glioblastoma multiforme (GBM) cells to subsequent treatment with the cytotoxic drug, doxorubicin (DOX). This concept was corroborated by our findings, in vivo, showing that the combination of the GHRH agonist, JI-34, and DOX inhibited the Growth of GBM tumors, transplanted into nude mice, more than DOX alone. In vitro, the pretreatment of GBM cells with JI-34 potentiated inhibitory effects of DOX on cell proliferation, diminished cell size and viability, and promoted apoptotic processes, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, ApoLive-Glo multiplex assay, and cell volumetric assay. Proteomic studies further revealed that the pretreatment with GHRH agonist evoked differentiation decreasing the expression of the neuroectodermal stem cell antigen, nestin, and up-regulating the glial maturation marker, GFAP. The GHRH agonist also reduced the release of humoral regulators of glial Growth, such as FGF basic and TGFβ. Proteomic and gene-expression (RT-PCR) studies confirmed the strong proapoptotic activity (increase in p53, decrease in v-myc and Bcl-2) and anti-invasive potential (decrease in integrin α3) of the combination of GHRH agonist and DOX. These findings indicate that the GHRH agonists can potentiate the anticancer activity of the traditional chemotherapeutic drug, DOX, by multiple mechanisms including the induction of differentiation of cancer cells.
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antagonists of Growth Hormone releasing Hormone ghrh given before whole body radiation lead to modulation of radiation response and organ specific changes in the expression of angiogenesis
Journal of Radiation Oncology, 2012Co-Authors: May Abdelwahab, Omar Mahmoud, Teresita Reiner, Ferenc G Rick, Luca Szalontay, Norman L. Block, Andrew V. Schally, Arnold M. Markoe, Merce Jorda, Marta ZarandiAbstract:Purpose This study seeks to determine if Growth Hormone-Releasing Hormone (GHRH) antagonist, JMR-132, increases survival when given before whole body radiation.
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Combining Growth Hormone-Releasing Hormone Antagonist With Luteinizing Hormone-Releasing Hormone Antagonist Greatly Augments Benign Prostatic Hyperplasia Shrinkage
The Journal of urology, 2012Co-Authors: Ferenc G Rick, Luca Szalontay, Marta Zarandi, Norman L. Block, Andrew V. Schally, Mehrdad Nadji, Karoly Szepeshazi, Irving Vidaurre, Magdolna Kovacs, Zoltan RekasiAbstract:Purpose: Benign prostatic hyperplasia often affects aging men. Antagonists of the neuropeptide Growth Hormone-Releasing Hormone reduced prostate weight in an androgen induced benign prostatic hyperplasia model in rats. Luteinizing Hormone-Releasing Hormone antagonists also produce marked, protracted improvement in lower urinary tract symptoms, reduced prostate volume and an increased urinary peak flow rate in men with benign prostatic hyperplasia. We investigated the influence of a combination of antagonists of Growth Hormone-Releasing Hormone and luteinizing Hormone-Releasing Hormone on animal models of benign prostatic hyperplasia.Materials and Methods: We evaluated the effects of the Growth Hormone-Releasing Hormone antagonist JMR-132, given at a dose of 40 μg daily, the luteinizing Hormone-Releasing Hormone antagonist cetrorelix, given at a dose of 0.625 mg/kg, and their combination on testosterone induced benign prostatic hyperplasia in adult male Wistar rats in vivo. Prostate tissue was examined bio...
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agonist of Growth Hormone releasing Hormone reduces pneumolysin induced pulmonary permeability edema
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Rudolf Lucas, Ferenc G Rick, Supriya Sridhar, Boris A Gorshkov, Nagavedi S Umapathy, Guang Yang, Aluya Oseghale, Alexander D Verin, Trinad Chakraborty, Michael A MatthayAbstract:Aggressive treatment with antibiotics in patients infected with Streptococcus pneumoniae induces release of the bacterial virulence factor pneumolysin (PLY). Days after lungs are sterile, this pore-forming toxin can still induce pulmonary permeability edema in patients, characterized by alveolar/capillary barrier dysfunction and impaired alveolar liquid clearance (ALC). ALC is mainly regulated through Na+ transport by the apically expressed epithelial sodium channel (ENaC) and the basolaterally expressed Na+/K+-ATPase in type II alveolar epithelial cells. Because no standard treatment is currently available to treat permeability edema, the search for novel therapeutic candidates is of high priority. We detected mRNA expression for the active receptor splice variant SV1 of the hypothalamic polypeptide Growth Hormone-Releasing Hormone (GHRH), as well as for GHRH itself, in human lung microvascular endothelial cells (HL-MVEC). Therefore, we have evaluated the effect of the GHRH agonist JI-34 on PLY-induced barrier and ALC dysfunction. JI-34 blunts PLY-mediated endothelial hyperpermeability in monolayers of HL-MVEC, in a cAMP-dependent manner, by means of reducing the phosphorylation of myosin light chain and vascular endothelial (VE)-cadherin. In human airway epithelial H441 cells, PLY significantly impairs Na+ uptake, but JI-34 restores it to basal levels by means of increasing cAMP levels. Intratracheal instillation of PLY into C57BL6 mice causes pulmonary alveolar epithelial and endothelial hyperpermeability as well as edema formation, all of which are blunted by JI-34. These findings point toward a protective role of the GHRH signaling pathway in PLY-induced permeability edema.
