The Experts below are selected from a list of 78 Experts worldwide ranked by ideXlab platform
Michael P Wajnrajch - One of the best experts on this subject based on the ideXlab platform.
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nonsense mutation in the human growth Hormone releasing Hormone Receptor causes growth failure analogous to the little lit mouse
Nature Genetics, 1996Co-Authors: Michael P Wajnrajch, Joseph M Gertner, Madeleine D Harbison, Streamson C Chua, Rudolph L LeibelAbstract:Pituitary growth Hormone release is under dual hypothalamic control, stimulated by growth Hormone releasing Hormone (GHRH) and inhibited by somatostatin. Childhood growth Hormone deficiency (GHD), leading to dwarfism and metabolic dysfunction1, can result from a failure of hypothalamic GHRH production or release, from maldevel-opment of the pituitary somatotrophes, and from genetic disorders of growth Hormone synthesis. Some familial cases of isolated GHD have been attributed to mutations in the growth Hormone gene itself2 but in other families GHD is not linked to this locus2. The mouse dwarfism trait, little, is due to a recessively inherited missense mutation (lit) in the extracellular domain of the GHRH Receptor (Ghrhr)3–6: Pituitary glands of the little mouse are deficient in growth Hormone and are unresponsive to GHRH in vivo and in vitro7. Somatic growth is increased by systemic administration of human growth Hormone8. Human GHPHR shows strong sequence homology to the murine gene. The cDNA contains an open reading frame of 1,269 base pairs (bp) coding for a 423-amino acid protein10. Having mapped the human homologue (GHRHR) to chromosome 7p15 (ref. 9), we undertook to look for mutations in GHRHR in familial GHD. We now report a nonsense mutation in the human GHRHR gene that results in profound GH deficiency in at least two members of a consanguineous family. Mutations of GHRHR may account for other instances of GH deficiency in which the growth Hormone gene is normal
Takashi Yashiro - One of the best experts on this subject based on the ideXlab platform.
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effects of retinoic acid on growth Hormone releasing Hormone Receptor growth Hormone secretagogue Receptor gene expression and growth Hormone secretion in rat anterior pituitary cells
Endocrine Journal, 2016Co-Authors: Rita Maliza, Ken Fujiwara, Takehiro Tsukada, Morio Azuma, Motoshi Kikuchi, Takashi YashiroAbstract:Retinoic acid (RA) is an important signaling molecule in embryonic development and adult tissue. The actions of RA are mediated by the nuclear Receptors retinoic acid Receptor (RAR) and retinoid X Receptor (RXR), which regulate gene expression. RAR and RXR are widely expressed in the anterior pituitary gland. RA was reported to stimulate growth Hormone (GH) gene expression in the anterior pituitary cells. However, current evidence is unclear on the role of RA in gene expression of growth Hormone-releasing Hormone Receptor (Ghrh-r), growth Hormone secretagogue Receptor (Ghs-r) and somatostatin Receptors (Sst-rs). Using isolated anterior pituitary cells of rats, we examined the effects of RA on gene expression of these Receptors and GH release. Quantitative real-time PCR revealed that treatment with all-trans retinoic acid (ATRA; 10(-6) M) for 24 h increased gene expression levels of Ghrh-r and Ghs-r; however, expressions of Sst-r2 and Sst-r5 were unchanged. Combination treatment with the RAR-agonist Am80 and RXR-agonist PA024 mimicked the effects of ATRA on Ghrh-r and Ghs-r gene expressions. Exposure of isolated pituitary cells to ATRA had no effect on basal GH release. In contrast, ATRA increased growth Hormone-releasing Hormone (GHRH)- and ghrelin-stimulated GH release from cultured anterior pituitary cells. Our results suggest that expressions of Ghrh-r and Ghs-r are regulated by RA through the RAR-RXR Receptor complex and that RA enhances the effects of GHRH and ghrelin on GH release from the anterior pituitary gland.
Renzhi Cai - 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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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.
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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, Andrew V. Schally, Renzhi Cai, Joshua M Hare, Rosemeire M Kanashirotakeuchi, Sonia S Majid, Norman L Block, 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.
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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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, Andrew V. Schally, Renzhi Cai, Joshua M Hare, Rosemeire M Kanashirotakeuchi, Sonia S Majid, Norman L Block, 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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differential immunostaining of various types of breast carcinomas for growth Hormone releasing Hormone Receptor apocrine epithelium and carcinomas emerging as uniformly positive
Apmis, 2014Co-Authors: Bence Kővári, Andrew V. Schally, Orsolya Rusz, Zsuzsanna Kahan, Gábor CserniAbstract:Different classes of breast cancers were explored for their positivity for growth Hormone-releasing Hormone Receptors (GHRH-R) in this pilot study, as no systematic evaluation of such tumors has been performed to date. Seventy-two small primary breast carcinomas were evaluated for GHRH-R expression by immunohistochemistry using a polyclonal antibody and a cutoff value of 10% staining. GHRH-R positivity was detected in 58% of all cases, 20/23 (87%) of invasive lobular carcinomas (ILC) and 22/46 (48%) of invasive ductal carcinomas (IDC). GHRH-R positivity was more frequent in grade 2 tumors (86%), as compared to grade 1 (18%) or grade 3 (47%) cancers. GHRH-R expression was not associated with mitotic scores, the Ki-67 labeling indices or nodal status. IDCs with casting-type calcifications on the mammogram showed positivity for GHRH-R in 9/12 (75%) cases. Most importantly, apocrine epithelium, and all 10 apocrine carcinomas added later to the study were GHRH-R-positive. These preliminary results suggest a greater than average GHRH-R expression in ILCs and IDCs associated with casting-type calcifications on the mammogram. Apocrine carcinomas seem uniformly positive for GHRH-R. Whether these findings could indicate a potential role of GHRH-antagonists in targeted treatment of these types of breast cancer requires further studies.
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s nitrosoglutathione reductase gsnor enhances vasculogenesis by mesenchymal stem cells
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Samirah A Gomes, Andrew V. Schally, Erika B Rangel, Courtney Premer, Raul A Dulce, Yenong Cao, Victoria Florea, Wayne Balkan, Claudia O Rodrigues, Joshua M HareAbstract:Although nitric oxide (NO) signaling promotes differentiation and maturation of endothelial progenitor cells, its role in the differentiation of mesenchymal stem cells (MSCs) into endothelial cells remains controversial. We tested the role of NO signaling in MSCs derived from WT mice and mice homozygous for a deletion of S-nitrosoglutathione reductase (GSNOR−/−), a denitrosylase that regulates S-nitrosylation. GSNOR−/− MSCs exhibited markedly diminished capacity for vasculogenesis in an in vitro Matrigel tube–forming assay and in vivo relative to WT MSCs. This decrease was associated with down-regulation of the PDGF Receptorα (PDGFRα) in GSNOR−/− MSCs, a Receptor essential for VEGF-A action in MSCs. Pharmacologic inhibition of NO synthase with L-NG-nitroarginine methyl ester (L-NAME) and stimulation of growth Hormone–releasing Hormone Receptor (GHRHR) with GHRH agonists augmented VEGF-A production and normalized tube formation in GSNOR−/− MSCs, whereas NO donors or PDGFR antagonist reduced tube formation ∼50% by murine and human MSCs. The antagonist also blocked the rescue of tube formation in GSNOR−/− MSCs by L-NAME or the GHRH agonists JI-38, MR-409, and MR-356. Therefore, GSNOR−/− MSCs have a deficient capacity for endothelial differentiation due to downregulation of PDGFRα related to NO/GSNOR imbalance. These findings unravel important aspects of modulation of MSCs by VEGF-A activation of the PDGFR and illustrate a paradoxical inhibitory role of S-nitrosylation signaling in MSC vasculogenesis. Accordingly, disease states characterized by NO deficiency may trigger MSC-mediated vasculogenesis. These findings have important implications for therapeutic application of GHRH agonists to ischemic disorders.
Rudolph L Leibel - One of the best experts on this subject based on the ideXlab platform.
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nonsense mutation in the human growth Hormone releasing Hormone Receptor causes growth failure analogous to the little lit mouse
Nature Genetics, 1996Co-Authors: Michael P Wajnrajch, Joseph M Gertner, Madeleine D Harbison, Streamson C Chua, Rudolph L LeibelAbstract:Pituitary growth Hormone release is under dual hypothalamic control, stimulated by growth Hormone releasing Hormone (GHRH) and inhibited by somatostatin. Childhood growth Hormone deficiency (GHD), leading to dwarfism and metabolic dysfunction1, can result from a failure of hypothalamic GHRH production or release, from maldevel-opment of the pituitary somatotrophes, and from genetic disorders of growth Hormone synthesis. Some familial cases of isolated GHD have been attributed to mutations in the growth Hormone gene itself2 but in other families GHD is not linked to this locus2. The mouse dwarfism trait, little, is due to a recessively inherited missense mutation (lit) in the extracellular domain of the GHRH Receptor (Ghrhr)3–6: Pituitary glands of the little mouse are deficient in growth Hormone and are unresponsive to GHRH in vivo and in vitro7. Somatic growth is increased by systemic administration of human growth Hormone8. Human GHPHR shows strong sequence homology to the murine gene. The cDNA contains an open reading frame of 1,269 base pairs (bp) coding for a 423-amino acid protein10. Having mapped the human homologue (GHRHR) to chromosome 7p15 (ref. 9), we undertook to look for mutations in GHRHR in familial GHD. We now report a nonsense mutation in the human GHRHR gene that results in profound GH deficiency in at least two members of a consanguineous family. Mutations of GHRHR may account for other instances of GH deficiency in which the growth Hormone gene is normal
