Potential effect of adrenomedullin on metabolic and endocrinal dysfunctions in the experimentally induced polycystic ovary: Targeting implication of endoplasmic reticulum stress

Abstract

This study investigated the potential effect of adrenomedullin (ADM) on metabolic and endocrinal dysfunctions in experimentally induced polycystic ovary. Twenty‐four female Wistar rats were allocated into three groups: control; polycystic ovary syndrome (PCOS) in which PCOS was induced by letrozole, orally in a dose of 1 mg/kg once daily for 3 weeks; and ADM group in which ADM was injected intraperitonally in a dose of 3.5/μg/twice daily for 4 weeks. At the end of the experimental period, the serum sex hormone profile, ADM, fasting glucose, insulin, homeostatic model assessment of insulin resistance, and lipid parameters were determined. Ovarian tissue homogenates were used to determine malondialdehyde, total antioxidant capacity, glutathione peroxidase activity, tumor necrosis factor α, interleukin 6, B cell lymphoma‐2 (Bcl‐2), and Bcl‐2 associated X protein. The profibrotic growth factors, including transforming growth factor β1 and connective tissue growth factor, were determined; and also, the relative gene expression of endoplasmic reticulum (ER) stress, including (Xbox‐binding protein‐1 [XBP‐1], activating transcription factor 6 [ATF6], and homologous protein [CHOP]), serine/threonine kinase 1 (Akt1), phosphatidylinositol 3‐kinase (PI3K), and peroxisome proliferator‐activated receptor γ (PPAR‐γ) were determined. Finally, histopathological analysis of the ovaries was evaluated. PCOS group exhibited increased ER stress, suppressing of PI3K/Akt1 and PPAR‐γ pathways, imbalance of sex hormonal profile, hyperglycemia, insulin resistance, dyslipidemia, increased profibrotic factors, and abnormal ovarian histopathological picture, while ADM treatment alleviated these disturbances occurring in the PCOS model. We concluded that ADM mitigated PCOS via attenuating the ER stress, in addition to activation of PI3K/Akt1 and PPAR‐γ pathways, its antioxidant, anti‐inflammatory, antiapoptotic, and antifibrotic properties.

Pathophysiology of polycystic ovary syndrome revisited: Current understanding and perspectives regarding future research

“…Intraovarian factors have regulatory roles during the entire process of follicular growth and play crucial roles in pathological conditions of the ovary, including PCOS 39,53,60,61 . We demonstrated for the first time that ER stress pathways are activated in the granulosa cells of both a mouse model of PCOS induced by the continuous administration of androgen and in humans, and this finding has been confirmed by other groups 48,62–67 . We also found that local hyperandrogenism in the follicular microenvironment of PCOS is an activator of ER stress in human granulosa cells, 52 and this finding has been confirmed in mouse granulosa cells 63 .…”

Adrenomedullin Mitigates Doxorubicin-Induced Nephrotoxicity in Rats: Role of Oxidative Stress, Inflammation, Apoptosis, and Pyroptosis

“…Similarly, Suetomi et al (2020) and Igarashi et al (2014) demonstrated the cytoprotective effect of ADM in pancreatic β-cells [ 24 ], as well as acute and chronic cerebral ischemia [ 35 ]. Accumulating evidence from previous research pointed to the antioxidant mechanism of ADM, which could be accredited to activating the PI3K/Akt pathway and mitigating ER stress [ 36 ].…”

“…However, ADM co-treatment effectively reduced TNF-α, IL-1β, and IL-18 levels compared to their levels in the DOX-only treated group. The ADM-observed anti-inflammatory effect against DOX-induced nephrotoxicity could be accredited to the upregulation of PPAPγ, which has been found to be involved in anti-inflammatory reactions via TNF-α downregulation due to the suppression of ER stress [ 36 ]. These findings are consistent with previous studies by Li et al (2019) and Mahmoodazdeh et al (2020) [ 21 , 39 ].…”

“…This result is in concordance with the findings Wang et al (2021) [ 30 ] and An et al (2017) [ 40 ]. The anti-apoptotic mechanism of ADM might be ascribed to its antioxidant, anti-inflammatory, and ER stress-attenuating effects [ 36 ]. Furthermore, Si et al (2018) reported that ADM protected mesenchymal stem cells against hypoxia-induced apoptosis, which may be mediated through the protein kinase B (Akt)/glycogen synthase kinase (GSK)3β and Bcl-2 signaling pathways [ 41 ].…”

Influence of Optimal Management of Hyperglycemia and Intensive Nursing on Blood Glucose Control Level and Complications in Patients with Postoperative Cerebral Hemorrhage

“…The results suggest that the intensive nursing of hyperglycemia optimization management can effectively improve the degree of nerve defect and the ability of daily living in patients with cerebral hemorrhage after operation. This is due to the optimal management of hyperglycemia intensive nursing inter-vention mode of patients with better blood glucose control can avoid hyperglycemia damage to neurons [27][28][29]. Hyperglycemia can increase the anaerobic metabolism of brain tissue, destroy mitochondria, produce a large number of free radicals, and increase the Ca2 + influx of nerve cells [30][31][32].…”