Effect of inhibitor and activator of ghrelin receptor (GHS-R1a) on porcine ovarian granulosa cell functions

Sirotkin, Alexander V.; Meszarosova, Monika; Großmann, Roland; Benco, Andrej; Valenzuela, Francisco

doi:10.1016/j.ygcen.2011.05.001

Cited by 20 publications

(13 citation statements)

References 24 publications

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“…Our findings are in accordance with previous studies that intense GHSR-1a immunoreactivity was noted in the granulosa cells of developing follicles [16,46], suggesting an important role for ghrelin and GHSR-1a in the ovary [47]. Some previous studies have indicated that ghrelin has an anti-inflammation effect.…”

Section: Discussionsupporting

confidence: 93%

Growth Hormone Releasing Peptide-2 Attenuation of Protein Kinase C-Induced Inflammation in Human Ovarian Granulosa Cells

Chao

Sun

Peng

et al. 2016

IJMS

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Cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) are two important inflammatory mediators in ovulation. Ghrelin may modulate inflammatory signaling via growth hormone secretagogue receptors. We investigated the role of ghrelin in KGN human ovarian granulosa cells using protein kinase C (PKC) activator phorbol 12, 13-didecanoate (PDD) and synthetic ghrelin analog growth hormone releasing peptide-2 (GHRP-2). GHRP-2 attenuated PDD-induced expression of protein and mRNA, the promoter activity of COX-2 and IL-8 genes, and the secretion of prostaglandin E2 (PGE2) and IL-8. GHRP-2 promoted the degradation of PDD-induced COX-2 and IL-8 proteins with the involvement of proteasomal and lysosomal pathways. PDD-mediated COX-2 production acts via the p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways; PDD-mediated IL-8 production acts via the p38, JNK and ERK pathways. GHRP-2 reduced the PDD-induced phosphorylation of p38 and JNK and activator protein 1 (AP-1) reporter activation and PDD-induced NF-κB nuclear translocation and reporter activation. The inhibitors of mitogen-activated protein kinase phosphatase-1 (MKP-1) and protein phosphatase 2 (PP2A) reduced the inhibitory effect of GHRP-2 on PDD-induced COX-2 and IL-8 expression. Our findings demonstrate an anti-inflammatory role for ghrelin (GHRP-2) in PKC-mediated inflammation of granulosa cells, at least in part, due to its inhibitory effect on PKC-induced activation of p38, JNK and NF-κB, possibly by targeting to MKP-1 and PP2A.

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Section: Discussionsupporting

confidence: 93%

Growth Hormone Releasing Peptide-2 Attenuation of Protein Kinase C-Induced Inflammation in Human Ovarian Granulosa Cells

Chao

Sun

Peng

et al. 2016

IJMS

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“…Elegant studies recently suggest that p53 is a key mediator of ghrelin's orexigenic actions in the hypothalamus, where it acts as a nutrient sensor, but not of its GH-secretagogue activity that involves direct action on GH releasing hormone neurons in the arcuate nucleus [9,47]. On the other hand, in vitro experiments on porcine ovarian granulosa cell cultures and in neurons suggest that ghrelin decreases activation of p53 and its downstream proapoptotic mediator Bax [48,49]. Ghrelin prevents the increase in Bax expression following heat-induced testicular damage [50], but increases Bax expression in spermatocytes during normal spermatogenesis in rats [51].…”

Section: Discussionmentioning

confidence: 99%

Ghrelin Prevents Cisplatin-Induced Testicular Damage by Facilitating Repair of DNA Double Strand Breaks Through Activation of p53 in Mice1

García

Chen

Guillory

et al. 2015

Biology of Reproduction

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Cisplatin administration induces DNA damage resulting in germ cell apoptosis and subsequent testicular atrophy. Although 50 percent of male cancer patients receiving cisplatin-based chemotherapy develop long-term secondary infertility, medical treatment to prevent spermatogenic failure after chemotherapy is not available. Under normal conditions, testicular p53 promotes cell cycle arrest, which allows time for DNA repair and reshuffling during meiosis. However, its role in the setting of cisplatin-induced infertility has not been studied. Ghrelin administration ameliorates the spermatogenic failure that follows cisplatin administration in mice, but the mechanisms mediating these effects have not been well established. The aim of the current study was to characterize the mechanisms of ghrelin and p53 action in the testis after cisplatin-induced testicular damage. Here we show that cisplatin induces germ cell damage through inhibition of p53-dependent DNA repair mechanisms involving gamma-H2AX and ataxia telangiectasia mutated protein kinase. As a result, testicular weight and sperm count and motility were decreased with an associated increase in sperm DNA damage. Ghrelin administration prevented these sequelae by restoring the normal expression of gamma-H2AX, ataxia telangiectasia mutated, and p53, which in turn allows repair of DNA double stranded breaks. In conclusion, these findings indicate that ghrelin has the potential to prevent or diminish infertility caused by cisplatin and other chemotherapeutic agents by restoring p53-dependent DNA repair mechanisms.

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“…The treatment of [D-Lys3]-GHRP-6 has been shown to inhibit ERK1/2 activation induced by acylated ghrelin in primary oligodendrocytes (31). Nonetheless, the expression of ERK1/2 was demonstrated to be increased in porcine ovarian granulosa cell after being treated with [D-Lys3]-GHRP-6 (44). In the present study, the observed inhibition of ERK1/2 phosphorylation by [D-Lys3]-GHRP-6 suggests that the desacyl ghrelin-induced restoration of ERK1/2 phosphorylation in doxorubicin-treated cardiomyocytes might be associated with GHSR-dependent mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Desacyl ghrelin prevents doxorubicin-induced myocardial fibrosis and apoptosis via the GHSR-independent pathway

Pei

Yung

Yip

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Effect of inhibitor and activator of ghrelin receptor (GHS-R1a) on porcine ovarian granulosa cell functions

Cited by 20 publications

References 24 publications

Growth Hormone Releasing Peptide-2 Attenuation of Protein Kinase C-Induced Inflammation in Human Ovarian Granulosa Cells

Growth Hormone Releasing Peptide-2 Attenuation of Protein Kinase C-Induced Inflammation in Human Ovarian Granulosa Cells

Ghrelin Prevents Cisplatin-Induced Testicular Damage by Facilitating Repair of DNA Double Strand Breaks Through Activation of p53 in Mice1

Desacyl ghrelin prevents doxorubicin-induced myocardial fibrosis and apoptosis via the GHSR-independent pathway

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