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Keywords = GHRH antagonists

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22 pages, 1968 KB  
Article
Evaluation of the Therapeutic Potential of Synthetic Growth Hormone-Releasing Hormone Antagonist MIA-690 as a Cognitive Modulator in a Mouse Model of Gulf War Illness
by Luis Manuel Salgueiro-Tosta, Arumugam Radhakrishnan Jayakumar, William Kochen, Renzhi Cai, Wei Sha, Erik Johnson, James O’Callaghan, Miklós Jászberényi, Andrew Victor Schally and Nancy Klimas
Int. J. Mol. Sci. 2025, 26(17), 8516; https://doi.org/10.3390/ijms26178516 - 2 Sep 2025
Viewed by 630
Abstract
Gulf War illness (GWI) is a multi-symptom disorder affecting veterans of the Persian Gulf operations. Persistent neuroendocrine dysregulation contributes to impairing cognitive capacity and generates anxiety-like behavior. Effective treatments for this illness are challenging due to compromised metabolism, increased oxidative stress and neuroinflammation, [...] Read more.
Gulf War illness (GWI) is a multi-symptom disorder affecting veterans of the Persian Gulf operations. Persistent neuroendocrine dysregulation contributes to impairing cognitive capacity and generates anxiety-like behavior. Effective treatments for this illness are challenging due to compromised metabolism, increased oxidative stress and neuroinflammation, perpetuated by chronic stress and hypothalamic–pituitary–adrenal (HPA) axis dysfunction. This neuroinflammation can be alleviated with synthetic antagonistic analogs of the growth hormone-releasing hormone (GHRH) through modulation of the HPA axis. We evaluated the efficacy of the GHRH antagonist analog, MIA-690, against cognitive impairment and anxiety-like behavior in GWI. Mice exposed to an experimental GWI model involving corticosterone (CORT) and diisopropylfluorophosphate (DFP), followed by CORT and lipopolysaccharide (LPS), received a daily subcutaneous dose of 10 μg of MIA-690 for 10 days. Assessments of spatial memory, recognition capacity, somatic health, anxiety and innate survival were carried out, combining the Morris water maze (MWM), novel object recognition (NORT), grip strength (GST), and open field (OFT) tests. Learning efficiency was selectively enhanced in females using the MWM. There were no significant differences in the recall capacity and performance on the OFT, NOR, and GST tasks. Our findings suggest that the MIA-690 dosage is sufficient to improve learning deficits in experimental GWI exposures. Full article
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18 pages, 3029 KB  
Article
Growth Hormone-Releasing Hormone (GHRH) Antagonist Peptides Combined with PI3K Isoform Inhibitors Enhance Cell Death in Prostate Cancer
by Carlos Perez-Stable, Alicia de las Pozas, Medhi Wangpaichitr, Wei Sha, Haibo Wang, Renzhi Cai and Andrew V. Schally
Cancers 2025, 17(10), 1643; https://doi.org/10.3390/cancers17101643 - 13 May 2025
Viewed by 1344
Abstract
Background. Antagonists of GHRH have experimental therapeutic value, but as single agents are not likely to improve clinical outcomes, especially in advanced prostate cancer resistant to androgen deprivation therapy. Our objective is to identify anti-cancer drugs that, in combination with MIA-602 or -690 [...] Read more.
Background. Antagonists of GHRH have experimental therapeutic value, but as single agents are not likely to improve clinical outcomes, especially in advanced prostate cancer resistant to androgen deprivation therapy. Our objective is to identify anti-cancer drugs that, in combination with MIA-602 or -690 GHRH antagonists, increase cell death in all types of prostate cancer. Methods/Results. We identified inhibitors of PI3Kα or PI3Kβ that consistently increased cell death when combined with MIA-602/690. The PI3K family is critical in mediating upstream signals from receptors to downstream AKT/mTOR signaling pathways and has an important role in cancer progression. The results revealed that MIA-602/690 alone decreased androgen receptors and likely enhanced PI3K (negative feedback), which was then countered by the addition of PI3K inhibitors. Furthermore, the MIA-602/690 + PI3K inhibitor combination affected multiple signaling pathways, including apoptosis (anti-apoptotic Mcl-1L switching to pro-apoptotic Mcl-1S), proliferation (E2F1, cyclin A), PI3Kα/β, AKT, and ERK. Similar results were obtained with a more clinically relevant acetate salt form of MIA-602/690. The identification of PI3K as a drug target for prostate cancer is significant because PTEN (negative regulator of PI3K) loss of function occurs in 40–50% and PIK3CA mutation/amplification occurs in 60% of prostate cancer patients, leading to a poor prognosis. Conclusion. The ability of the MIA-602/690 + PI3K inhibitor combination to alter multiple signaling pathways may weaken the activation of adaptive mechanisms resulting from each drug and improve efficacy. Full article
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19 pages, 2545 KB  
Article
Growth Hormone-Releasing Hormone Antagonists Increase Radiosensitivity in Non-Small Cell Lung Cancer Cells
by Iacopo Gesmundo, Francesca Pedrolli, Francesca Romana Giglioli, Florian Jazaj, Giuseppina Granato, Alessia Bertoldo, Federica Bistolfi, Vanesa Gregorc, Anna Sapino, Luisella Righi, Renzhi Cai, Wei Sha, Medhi Wangpaichitr, Mauro Papotti, Ezio Ghigo, Umberto Ricardi, Andrew V. Schally and Riccarda Granata
Int. J. Mol. Sci. 2025, 26(7), 3267; https://doi.org/10.3390/ijms26073267 - 1 Apr 2025
Viewed by 1139
Abstract
Growth hormone-releasing hormone (GHRH) antagonists exert antitumor functions in different experimental cancers. However, their role in combination with radiotherapy in non-small cell lung cancer (NSCLC) remains unknown. Therefore, we investigated the radiosensitizing effect of GHRH antagonists in NSCLC. A549 and H522 NSCLC cell [...] Read more.
Growth hormone-releasing hormone (GHRH) antagonists exert antitumor functions in different experimental cancers. However, their role in combination with radiotherapy in non-small cell lung cancer (NSCLC) remains unknown. Therefore, we investigated the radiosensitizing effect of GHRH antagonists in NSCLC. A549 and H522 NSCLC cell lines were exposed to ionizing radiation (IR) and GHRH antagonists MIA-602 and MIA-690, either individually or in combination. Cell viability and proliferation were evaluated by MTT, BrdU, flow cytofluorimetry, and clonogenic assays; gene and protein expression, signaling pathways, and apoptosis were analyzed by real-time PCR, Western blot, annexin staining, and caspase-3 assay. GHRH antagonists showed antitumor effects alone and potentiated IR-induced inhibition of cell viability and proliferation. The combination of MIA-690 and IR decreased the expression of GHRH receptor, its oncogenic splice variant 1, and IGF1 mRNA levels. Additionally, cell cycle inhibitors and proapoptotic markers were upregulated, whereas cyclins, oncogenic MYC, and the antiapoptotic protein Bcl-2 were downregulated. Radioresistance was prevented by MIA-690, which also blunted epithelial–mesenchymal transition by enhancing E-cadherin and reducing mesenchymal, oxidative, and proangiogenic effectors. Finally, both MIA-602 and MIA-690 enhanced radiosensitivity in primary human NSCLC cells. These findings highlight the potential of GHRH antagonists as radiosensitizers in NSCLC treatment. Full article
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18 pages, 3176 KB  
Article
Antagonist of Growth Hormone-Releasing Hormone Receptor MIA-690 Suppresses the Growth of Androgen-Independent Prostate Cancers
by Laura Muñoz-Moreno, M. Isabel Gómez-Calcerrada, M. Isabel Arenas, M. José Carmena, Juan C. Prieto, Andrew V. Schally and Ana M. Bajo
Int. J. Mol. Sci. 2024, 25(20), 11200; https://doi.org/10.3390/ijms252011200 - 18 Oct 2024
Cited by 1 | Viewed by 1487
Abstract
The development of resistance remains the primary challenge in treating castration-resistant prostate cancer (CRPC). GHRH receptors (GHRH-R), which are coupled to G-proteins (GPCRs), can mediate EGFR transactivation, offering an alternative pathway for tumour survival. This study aimed to evaluate the effects of the [...] Read more.
The development of resistance remains the primary challenge in treating castration-resistant prostate cancer (CRPC). GHRH receptors (GHRH-R), which are coupled to G-proteins (GPCRs), can mediate EGFR transactivation, offering an alternative pathway for tumour survival. This study aimed to evaluate the effects of the GHRH-R antagonist MIA-690, in combination with the EGFR inhibitor Gefitinib, on cell viability, adhesion, gelatinolytic activity, and the cell cycle in advanced prostate cancer PC-3 cells. The findings demonstrate a synergistic effect between MIA-690 and Gefitinib, leading to the inhibition of cell viability, adhesion, and metalloprotease activity. Cell cycle analysis suggests that both compounds induce cell cycle arrest, both individually and in combination. Furthermore, similar effects of the GHRH-R antagonist MIA-690 combined with Gefitinib were observed in PC-3 tumours developed by subcutaneous injection in athymic nude mice 36 days post-inoculation. These results indicate that combined therapy with a GHRH-R antagonist and an EGFR inhibitor exerts a stronger antitumor effect compared to monotherapy by preventing transactivation between EGFR and GHRH-R in CRPC. Full article
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13 pages, 2159 KB  
Article
Effects of GHRH Deficiency and GHRH Antagonism on Emotional Disorders in Mice
by Lucia Recinella, Maria Loreta Libero, Serena Veschi, Anna Piro, Guya Diletta Marconi, Francesca Diomede, Annalisa Chiavaroli, Giustino Orlando, Claudio Ferrante, Rosalba Florio, Alessia Lamolinara, Renzhi Cai, Wei Sha, Andrew V. Schally, Roberto Salvatori, Luigi Brunetti and Sheila Leone
Cells 2023, 12(22), 2615; https://doi.org/10.3390/cells12222615 - 12 Nov 2023
Cited by 6 | Viewed by 2242
Abstract
Growth hormone (GH)-releasing hormone (GHRH) has been suggested to play a crucial role in brain function. We aimed to further investigate the effects of a novel GHRH antagonist of the Miami (MIA) series, MIA-602, on emotional disorders and explore the relationships between the [...] Read more.
Growth hormone (GH)-releasing hormone (GHRH) has been suggested to play a crucial role in brain function. We aimed to further investigate the effects of a novel GHRH antagonist of the Miami (MIA) series, MIA-602, on emotional disorders and explore the relationships between the endocrine system and mood disorders. In this context, the effects induced by MIA-602 were also analyzed in comparison to vehicle-treated mice with GH deficiency due to generalized ablation of the GHRH gene (GHRH knock out (GHRHKO)). We show that the chronic subcutaneous administration of MIA-602 to wild type (+/+) mice, as well as generalized ablation of the GHRH gene, is associated with anxiolytic and antidepressant behavior. Moreover, immunohistochemical and Western blot analyses suggested an evident activation of Nrf2, HO1, and NQO1 in the prefrontal cortex of both +/+ mice treated with MIA-602 (+/+ MIA-602) and homozygous GHRHKO (−/− control) animals. Finally, we also found significantly decreased COX-2, iNOS, NFkB, and TNF-α gene expressions, as well as increased P-AKT and AKT levels in +/+ MIA-602 and −/− control animals compared to +/+ mice treated with vehicle (+/+ control). We hypothesize that the generalized ablation of the GHRH gene leads to a dysregulation of neural pathways, which is mimicked by GHRH antagonist treatment. Full article
(This article belongs to the Special Issue Drug Effects on Neuroendocrine Regulation: New Development)
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11 pages, 2501 KB  
Article
The Application of GHRH Antagonist as a Treatment for Resistant APL
by Ravinder S. Chale, Stephanie M. Almeida, Mario Rodriguez, Ivan Jozic, Simonetta I. Gaumond, Andrew V. Schally and Joaquin J. Jimenez
Cancers 2023, 15(12), 3104; https://doi.org/10.3390/cancers15123104 - 8 Jun 2023
Cited by 6 | Viewed by 2423
Abstract
GHRH is a hypothalamic peptide shown to stimulate the proliferation of malignant cells in humans. We have previously shown that the use of GHRH antagonist MIA-602 successfully suppressed the growth of many human cancer cell lines, spanning more than 20 types of cancers. [...] Read more.
GHRH is a hypothalamic peptide shown to stimulate the proliferation of malignant cells in humans. We have previously shown that the use of GHRH antagonist MIA-602 successfully suppressed the growth of many human cancer cell lines, spanning more than 20 types of cancers. In this study, we demonstrate the presence of GHRH-R in the NB4, NB4-RAA, and K-562 model cell lines. Furthermore, we demonstrate the inhibited proliferation of all three cell lines in vitro after incubation with MIA-602. The treatment of xenografts of human APL cell lines with MIA-602 led to a significant reduction in tumor growth. Additionally, combination therapy with both doxorubicin (DOX) and MIA-602 showed a marked synergistic effect in reducing the proliferation of the K-562 AML cell line. These findings suggest that MIA-602 could be utilized to address resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) therapies, as well as in augmenting anthracycline-based regimens. Full article
(This article belongs to the Collection Acute Myeloid Leukemia (AML))
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8 pages, 1075 KB  
Article
Growth Hormone-Releasing Hormone Antagonist JV-1-36 Suppresses Reactive Oxygen Species Generation in A549 Lung Cancer Cells
by Khadeja-Tul Kubra, Mohammad S. Akhter, Kaitlyn Apperley and Nektarios Barabutis
Endocrines 2022, 3(4), 813-820; https://doi.org/10.3390/endocrines3040067 - 9 Dec 2022
Cited by 13 | Viewed by 2892
Abstract
Growth hormone-releasing hormone (GHRH) and its receptors are expressed in a variety of human cancers, and have been involved in malignancies. GHRH antagonists (GHRHAnt) were developed to suppress tumor progression and metastasis. Previous studies demonstrate the involvement of reactive oxygen species (ROS) in [...] Read more.
Growth hormone-releasing hormone (GHRH) and its receptors are expressed in a variety of human cancers, and have been involved in malignancies. GHRH antagonists (GHRHAnt) were developed to suppress tumor progression and metastasis. Previous studies demonstrate the involvement of reactive oxygen species (ROS) in cancer progression. Herein, we investigate the effect of a commercially available GHRH antagonist, namely JV-1-36, in the redox status of the A549 human cancer cell line. Our results suggest that this peptide significantly reduces ROS production in those cells in a time-dependent manner and counteracts H2O2-induced ROS. Our study supports the anti-oxidative effects of JV-1-36 and contributes in our knowledge towards the in vitro effects of GHRHAnt in cancers. Full article
(This article belongs to the Special Issue Feature Papers in Endocrines)
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16 pages, 2000 KB  
Article
Antagonist of Growth Hormone-Releasing Hormone Potentiates the Antitumor Effect of Pemetrexed and Cisplatin in Pleural Mesothelioma
by Iacopo Gesmundo, Francesca Pedrolli, Nicoletta Vitale, Alessia Bertoldo, Giulia Orlando, Dana Banfi, Giuseppina Granato, Ramesh Kasarla, Federico Balzola, Silvia Deaglio, Renzhi Cai, Wei Sha, Mauro Papotti, Ezio Ghigo, Andrew V. Schally and Riccarda Granata
Int. J. Mol. Sci. 2022, 23(19), 11248; https://doi.org/10.3390/ijms231911248 - 24 Sep 2022
Cited by 13 | Viewed by 3131
Abstract
Pleural mesothelioma (PM) is an aggressive cancer with poor prognosis and no effective therapies, mainly caused by exposure to asbestos. Antagonists of growth hormone-releasing hormone (GHRH) display strong antitumor effects in many experimental cancers, including lung cancer and mesothelioma. Here, we aimed to [...] Read more.
Pleural mesothelioma (PM) is an aggressive cancer with poor prognosis and no effective therapies, mainly caused by exposure to asbestos. Antagonists of growth hormone-releasing hormone (GHRH) display strong antitumor effects in many experimental cancers, including lung cancer and mesothelioma. Here, we aimed to determine whether GHRH antagonist MIA-690 potentiates the antitumor effect of cisplatin and pemetrexed in PM. In vitro, MIA-690, in combination with cisplatin and pemetrexed, synergistically reduced cell viability, restrained cell proliferation and enhanced apoptosis, compared with drugs alone. In vivo, the same combination resulted in a strong growth inhibition of MSTO-211H xenografts, decreased tumor cell proliferation and increased apoptosis. Mechanistically, MIA-690, particularly with chemotherapeutic drugs, inhibited proliferative and oncogenic pathways, such as MAPK ERK1/2 and cMyc, and downregulated cyclin D1 and B1 mRNAs. Inflammatory pathways such as NF-kB and STAT3 were also reduced, as well as oxidative, angiogenic and tumorigenic markers (iNOS, COX-2, MMP2, MMP9 and HMGB1) and growth factors (VEGF and IGF-1). Overall, these findings strongly suggest that GHRH antagonists of MIA class, such as MIA-690, could increase the efficacy of standard therapy in PM. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Malignant Mesothelioma)
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13 pages, 738 KB  
Article
Expression of Growth Hormone-Releasing Hormone and Its Receptor Splice Variants in Primary Human Endometrial Carcinomas: Novel Therapeutic Approaches
by Zsuzsanna Szabo, Eva Juhasz, Andrew V. Schally, Balazs Dezso, Sandor Huga, Zoltan Hernadi, Gabor Halmos and Csongor Kiss
Molecules 2022, 27(9), 2671; https://doi.org/10.3390/molecules27092671 - 21 Apr 2022
Cited by 14 | Viewed by 2617
Abstract
Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of various tumors, including endometrial carcinomas (EC). However, tumoral receptors that mediate the antiproliferative effects of GHRH antagonists in human ECs have not been fully characterized. In this study, we investigated the expression of [...] Read more.
Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of various tumors, including endometrial carcinomas (EC). However, tumoral receptors that mediate the antiproliferative effects of GHRH antagonists in human ECs have not been fully characterized. In this study, we investigated the expression of mRNA for GHRH and splice variants (SVs) of GHRH receptors (GHRH-R) in 39 human ECs and in 7 normal endometrial tissue samples using RT-PCR. Primers designed for the PCR amplification of mRNA for the full length GHRH-R and SVs were utilized. The PCR products were sequenced, and their specificity was confirmed. Nine ECs cancers (23%) expressed mRNA for SV1, three (7.7%) showed SV2 and eight (20.5%) revealed mRNA for SV4. The presence of SVs for GHRH-Rs could not be detected in any of the normal endometrial tissue specimens. The presence of specific, high affinity GHRH-Rs was also demonstrated in EC specimens using radioligand binding studies. Twenty-four of the investigated thirty-nine tumor samples (61.5%) and three of the seven corresponding normal endometrial tissues (42.9%) expressed mRNA for GHRH ligand. Our findings suggest the possible existence of an autocrine loop in EC based on GHRH and its tumoral SV receptors. The antiproliferative effects of GHRH antagonists on EC are likely to be exerted in part by the local SVs and GHRH system. Full article
(This article belongs to the Special Issue Recent Advances in Anticancer Drugs III)
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20 pages, 2521 KB  
Article
Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of Pituitary Adenoma Cells by Hampering Oncogenic Pathways and Promoting Apoptotic Signaling
by Iacopo Gesmundo, Giuseppina Granato, Antonio C. Fuentes-Fayos, Clara V. Alvarez, Carlos Dieguez, Maria Chiara Zatelli, Noemi Congiusta, Dana Banfi, Nunzia Prencipe, Sheila Leone, Luigi Brunetti, Justo P. Castaño, Raúl M. Luque, Renzhi Cai, Wei Sha, Ezio Ghigo, Andrew V. Schally and Riccarda Granata
Cancers 2021, 13(16), 3950; https://doi.org/10.3390/cancers13163950 - 5 Aug 2021
Cited by 12 | Viewed by 3491
Abstract
Pituitary adenomas (PAs) are intracranial tumors, often associated with excessive hormonal secretion and severe comorbidities. Some patients are resistant to medical therapies; therefore, novel treatment options are needed. Antagonists of growth hormone-releasing hormone (GHRH) exert potent anticancer effects, and early GHRH antagonists were [...] Read more.
Pituitary adenomas (PAs) are intracranial tumors, often associated with excessive hormonal secretion and severe comorbidities. Some patients are resistant to medical therapies; therefore, novel treatment options are needed. Antagonists of growth hormone-releasing hormone (GHRH) exert potent anticancer effects, and early GHRH antagonists were found to inhibit GHRH-induced secretion of pituitary GH in vitro and in vivo. However, the antitumor role of GHRH antagonists in PAs is largely unknown. Here, we show that the GHRH antagonists of MIAMI class, MIA-602 and MIA-690, inhibited cell viability and growth and promoted apoptosis in GH/prolactin-secreting GH3 PA cells transfected with human GHRH receptor (GH3-GHRHR), and in adrenocorticotropic hormone ACTH-secreting AtT20 PA cells. GHRH antagonists also reduced the expression of proteins involved in tumorigenesis and cancer progression, upregulated proapoptotic molecules, and lowered GHRH receptor levels. The combination of MIA-690 with temozolomide synergistically blunted the viability of GH3-GHRHR and AtT20 cells. Moreover, MIA-690 reduced both basal and GHRH-induced secretion of GH and intracellular cAMP levels. Finally, GHRH antagonists inhibited cell viability in human primary GH- and ACTH-PA cell cultures. Overall, our results suggest that GHRH antagonists, either alone or in combination with pharmacological treatments, may be considered for further development as therapy for PAs. Full article
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14 pages, 1511 KB  
Review
Growth Hormone-Releasing Hormone in Lung Physiology and Pulmonary Disease
by Chongxu Zhang, Tengjiao Cui, Renzhi Cai, Medhi Wangpaichitr, Mehdi Mirsaeidi, Andrew V. Schally and Robert M. Jackson
Cells 2020, 9(10), 2331; https://doi.org/10.3390/cells9102331 - 21 Oct 2020
Cited by 28 | Viewed by 5875
Abstract
Growth hormone-releasing hormone (GHRH) is secreted primarily from the hypothalamus, but other tissues, including the lungs, produce it locally. GHRH stimulates the release and secretion of growth hormone (GH) by the pituitary and regulates the production of GH and hepatic insulin-like growth factor-1 [...] Read more.
Growth hormone-releasing hormone (GHRH) is secreted primarily from the hypothalamus, but other tissues, including the lungs, produce it locally. GHRH stimulates the release and secretion of growth hormone (GH) by the pituitary and regulates the production of GH and hepatic insulin-like growth factor-1 (IGF-1). Pituitary-type GHRH-receptors (GHRH-R) are expressed in human lungs, indicating that GHRH or GH could participate in lung development, growth, and repair. GHRH-R antagonists (i.e., synthetic peptides), which we have tested in various models, exert growth-inhibitory effects in lung cancer cells in vitro and in vivo in addition to having anti-inflammatory, anti-oxidative, and pro-apoptotic effects. One antagonist of the GHRH-R used in recent studies reviewed here, MIA-602, lessens both inflammation and fibrosis in a mouse model of bleomycin lung injury. GHRH and its peptide agonists regulate the proliferation of fibroblasts through the modulation of extracellular signal-regulated kinase (ERK) and Akt pathways. In addition to downregulating GH and IGF-1, GHRH-R antagonist MIA-602 inhibits signaling pathways relevant to inflammation, including p21-activated kinase 1-signal transducer and activator of transcription 3/nuclear factor-kappa B (PAK1-STAT3/NF-κB and ERK). MIA-602 induces fibroblast apoptosis in a dose-dependent manner, which is an effect that is likely important in antifibrotic actions. Taken together, the novel data reviewed here show that GHRH is an important peptide that participates in lung homeostasis, inflammation, wound healing, and cancer; and GHRH-R antagonists may have therapeutic potential in lung diseases. Full article
(This article belongs to the Special Issue GH and GHR Signaling in Disease and Health)
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