Effects of [Norleucine27]Growth Hormone-Releasing Hormone (GHRH) (1–29)-NH2Administration on the Immune System of Aging Men and Women1

Khorram, Omid; Yeung, Michael C.; Vu, Lan Phuong; Yen, S. S. C.

doi:10.1210/jcem.82.11.4363

Cited by 10 publications

(3 citation statements)

References 43 publications

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“…In agreement with these results, in cattle, myogenic expression of GHRH led to more abundant T cell lineages of CD2 + , CD4 + CD25 + , and CD4 + CD45R + 27 . In humans, administration of the GHRH analog resulted in a significant increase of cells expressing various T cell receptors, while no difference was observed in T cells expressing CD3, CD4, or CD8 28 . In addition, GHRH-R was found in human sarcoidosis granuloma, a Th17 cell-mediated inflammatory disorder resulting in multisystemic granuloma, which can be alleviated by GHRH antagonist with a reduced level of IL-17A in an in vitro granuloma model 29 .…”

Section: Introductionmentioning

confidence: 93%

Growth hormone releasing hormone signaling promotes Th17 cell differentiation and autoimmune inflammation

Zhou

et al. 2023

Nat Commun

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Dysregulation of Th17 cell differentiation and pathogenicity contributes to multiple autoimmune and inflammatory diseases. Previously growth hormone releasing hormone receptor (GHRH-R) deficient mice have been reported to be less susceptible to the induction of experimental autoimmune encephalomyelitis. Here, we show GHRH-R is an important regulator of Th17 cell differentiation in Th17 cell-mediated ocular and neural inflammation. We find that GHRH-R is not expressed in naïve CD4+ T cells, while its expression is induced throughout Th17 cell differentiation in vitro. Mechanistically, GHRH-R activates the JAK-STAT3 pathway, increases the phosphorylation of STAT3, enhances both non-pathogenic and pathogenic Th17 cell differentiation and promotes the gene expression signatures of pathogenic Th17 cells. Enhancing this signaling by GHRH agonist promotes, while inhibiting this signaling by GHRH antagonist or GHRH-R deficiency reduces, Th17 cell differentiation in vitro and Th17 cell-mediated ocular and neural inflammation in vivo. Thus, GHRH-R signaling functions as a critical factor that regulates Th17 cell differentiation and Th17 cell-mediated autoimmune ocular and neural inflammation.

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Section: Introductionmentioning

confidence: 93%

Growth hormone releasing hormone signaling promotes Th17 cell differentiation and autoimmune inflammation

Zhou

et al. 2023

Nat Commun

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“…2,3 Biological tests of GHRH revealed that the structural requirements for growth hormone–stimulating activity resided in the N-terminal 1–29 residues of this peptide (Figure S1b). 4 The GHRH peptide and GHRH-R are also expressed in various normal human tissues, including breast, colon, esophagus, kidney, liver, lung, ovary, pancreas, prostate, testis, and thymus, 5−7 and in many human cancer cell lines and tumors. 1,8−11 A major drawback in using native GHRH as a therapeutic agent is its short in vivo half-life due to degradation by proteolytic enzymes.…”

Section: Introductionmentioning

confidence: 99%

“…Since the characterization of the sequence of GHRH (Figure S1a), this hypothalamic neuropeptide has been the focus of intense studies. , Biological tests of GHRH revealed that the structural requirements for growth hormone–stimulating activity resided in the N-terminal 1–29 residues of this peptide (Figure S1b). The GHRH peptide and GHRH-R are also expressed in various normal human tissues, including breast, colon, esophagus, kidney, liver, lung, ovary, pancreas, prostate, testis, and thymus, − and in many human cancer cell lines and tumors. ,− A major drawback in using native GHRH as a therapeutic agent is its short in vivo half-life due to degradation by proteolytic enzymes . Understanding the action of GHRH on its target cells is important for the development of various degradation-resistant synthetic GHRH analogues, which may provide a promising approach for drug design.…”

Section: Introductionmentioning

confidence: 99%

Structural Motif Descriptors as a Way To Elucidate the Agonistic or Antagonistic Activity of Growth Hormone–Releasing Hormone Peptide Analogues

et al. 2018

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The synthesis of analogues of hypothalamic neuropeptide growth hormone–releasing hormone (GHRH) is an efficient strategy for designing new therapeutic agents. Several promising synthetic agonist and antagonist analogues of GHRH have been developed based on amino acid mutations of the GHRH (1–29) sequence. Because structural information on the activity of the GHRH agonists or antagonists is limited, there is a need for more effective analytical workflows capable of correlating the peptide sequence with biological activity. In the present work, three GHRH agonists—MR-356, MR-406, and MR-409—and three GHRH antagonists—MIA-602, MIA-606, and MIA-690—were investigated to assess the role of substitutions in the amino acid sequence on structural motifs and receptor binding affinities. The use of high resolution trapped ion mobility spectrometry coupled to mass spectrometry allowed the observation of a large number of peptide-specific mobility bands (or structural motif descriptors) as a function of the amino acid sequence and the starting solution environment. A direct correlation was observed between the amino acid substitutions (i.e., basic residues and d / l -amino acids), the structural motif descriptors, and the biological function (i.e., receptor binding affinities of the GHRH agonists and antagonists). The simplicity, ease, and high throughput of the proposed workflow based on the structural motif descriptors can significantly reduce the cost and time during screening of new synthetic peptide analogues.

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Activity of the growth hormone‐releasing hormone antagonist MIA602 and its underlying mechanisms of action in sarcoidosis‐like granuloma

et al. 2021

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Objectives. Growth hormone-releasing hormone (GHRH) is a potent stimulator of growth hormone (GH) secretion from the pituitary gland. Although GHRH is essential for the growth of immune cells, the regulatory effects of its antagonist in granulomatous disease remain unknown. Methods. Here, we report expression of GHRH receptor (R) in human tissue with sarcoidosis granuloma and demonstrate the anti-inflammatory effects of MIA602 (a GHRH antagonist) in two in vitro human granuloma models and an in vivo granuloma model using different methods including ELISA, immunohistochemistry, RNAseq analysis and flow cytometry. Results. MIA602 decreases the levels of IL-2, IL-2R, IL-7, IL-12, IL-17A and TNF-a in an in vitro granuloma model. Further, we show that the anti-inflammatory effect of MIA602 appears to be mediated by a reduction in CD45 + CD68 + cells in granulomatous tissue and upregulation in PD-1 expression in macrophages. Analysis of the expression of proteins involved in the mitochondrial stage of apoptosis showed that MIA602 increases the levels of caspase-3, BCL-xL/BAK dimer and MCl-1/Bak dimer in the granuloma. These findings indicate that MIA602 may not induce apoptosis. Conclusions. Our findings further suggest that GHRH-R is potentially a clinical target for the treatment of granulomatous disease and that MIA602 may be used as a novel therapeutic agent for sarcoidosis.

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Effects of [Norleucine²⁷]Growth Hormone-Releasing Hormone (GHRH) (1–29)-NH₂Administration on the Immune System of Aging Men and Women¹

Cited by 10 publications

References 43 publications

Growth hormone releasing hormone signaling promotes Th17 cell differentiation and autoimmune inflammation

Growth hormone releasing hormone signaling promotes Th17 cell differentiation and autoimmune inflammation

Structural Motif Descriptors as a Way To Elucidate the Agonistic or Antagonistic Activity of Growth Hormone–Releasing Hormone Peptide Analogues

Activity of the growth hormone‐releasing hormone antagonist MIA602 and its underlying mechanisms of action in sarcoidosis‐like granuloma

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