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Thyroid dysfunction and diabetes mellitus are prevalent endocrine disorders that often coexist and influence each other. The role of spexin (SPX) in diabetes and obesity is well documented, but its connection to thyroid function is less understood. This study investigates the influence of exercise (EX) and SPX on thyroid hypofunction in obese type 2 diabetic rats. Rats were divided into normal control, obese diabetic sedentary, obese diabetic EX, and obese diabetic SPX groups, with subdivisions for M871 and HT-2157 treatment in the latter two groups. High-fat diet together with streptozotocin (STZ) injection induced obesity and diabetes. The EX group underwent swimming, and the SPX group received SPX injections for 8 wk. Results showed significant improvements in thyroid function and metabolic, oxidative, and inflammatory states with EX and SPX treatment. The study also explored the involvement of galanin receptor isoforms (GALR)2/3 in SPX effects on thyroid function. Blocking GALR2/3 receptors partially attenuated the beneficial effects, indicating their interaction. These findings underscore the importance of EX and SPX in modulating thyroid function in obesity and diabetes. Comprehending this interplay could enable the development of new treatment approaches for thyroid disorders associated with obese type 2 diabetes. Additional research is necessary to clarify the exact mechanisms connecting SPX, EX activity, and thyroid function. NEW & NOTEWORTHY This study proves, for the first time, the beneficial effects of SPX on thyroid dysfunction in obese diabetic rats and suggests that SPX mediates the EX effect on thyroid gland and exerts its effect mainly via GALR2.

This study declared effect of spexin (SPX) on renal dysfunction in obese rats and its potential mitigating mechanisms which could mediated via galanin receptor-2 (GALR-2). Thirty two 32 Wistar male rats were arranged into four groups: control, high fat/fructose diet (HFFD), HFFD + SPX and HFFD + M871 (galanin receptor 2 antagonist)+SPX. At the termination of the experiment, urine volume, body mass index, Lee index and mean arterial blood pressure were assessed. Renal function was evaluated. Lipid profile, fasting glucose, insulin, insulin resistance and SPX levels were estimated. Also, renal histopathological, immunohistochemical and relative gene expression of renal tissue were done. Also, renal protein carbonyl, reduced glutathione, interferon gamma, monocyte chemoattractant protein-1, interleukin-10 and hydroxyproline were determined.Our results explored that SPX treatment prominently mitigated the metabolic changes and renal dysfunction induced by HFFD via GALR-2. SPX improved insulin resistance, dyslipidemia, renal oxidative stress, inflammation, apoptosis, and fibrosis. So, SPX can be considered as prospective therapeutic agent for treating renal dysfunction.

This study evaluated possible mitigating effect of adropin on lung injury in diabetic rats, targeting role of Rho A/Rho-associated kinase pathway. Rats were allocated into four groups: control, adropin, diabetic, and diabetic+adropin groups. At the termination of the experiment, serum fasting glucose, insulin and adropin levels and insulin resistance were calculated. Wet/dry ratio, histopathological, immunohistochemical analyses, and relative real time gene expression of lung tissue was determined. Interleukin-6, tumor necrosis factor alpha, malondialdehyde, 8-Oxo-2'-deoxyguanosine, reduced glutathione, superoxide dismutase, Bcl-2, BAX, myeloperoxidase, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and transforming growth factor-β were determined in lung tissue. Adropin treatment in diabetic rats notably attenuated hyperglycemia and insulin resistance. Also, it mitigated diabetic lung injury via suppressing effect on Rho A/ROCK pathway, apoptosis, inflammatory reactions, oxidative stress, and fibrosis of lung tissue. Adropin can be considered as a promising therapeutic agent for treating diabetic lung injury., (© 2023 International Union of Biochemistry and Molecular Biology.)

The prevalence of obesity and its associated metabolic disorders, along with their healthcare costs, is rising exponentially. Irisin, an adipomyokine, may serve as a critical cross-organ messenger, linking skeletal muscle with adipose tissue and the liver to integrate the energy homeostasis under diet-induced obesity. We aimed to explore the putative role of irisin in the protection against obesity in a postmenopausal rat model by modulating energy expenditure (EE). Bilateral ovariectomy (OVX) was performed. After 3 weeks of recovery, the OVX rats were classified according to their dietary protocol into rats maintained on normal diets (ND) (OVX) or high-fat diet (HFD) groups. The HFD-fed animals were equally divided into OVX/HFD, or irisin-treated OVX/HFD groups. Sham rats, maintained on ND, were selected as the control group. We evaluated anthropometric, EE, and molecular biomarkers of browning and thermogenesis in inguinal white adipose tissue and skeletal muscle, and the activity of the proteins related to mitochondrial long chain fatty acid transport, oxidation, and glycolysis. HFD of OVX further deteriorated the disturbed glucose homeostasis, lipid profile, and the reduced irisin, thermogenic parameters in adipose tissue and skeletal muscle, and EE. Irisin treatment improved the lipid profile and insulin resistance. That was associated with reduced hepatic gluconeogenic enzyme activities and restored hepatic glycogen content. Irisin reduced ectopic lipid infiltration. Irisin augmented EE by activating non-shivering thermogenesis in muscle and adipose tissues and decreasing metabolic efficiency. Our experimental evidence suggests irisin's use as a potential thermogenic agent, therapeutically targeting obesity in postmenopausal patients. Irisin modulates the non-shivering thermogenesis in skeletal muscle and adipose tissue in postmenopausal model., (© 2022. The Author(s).)

Background and Purpose: Varicocele is a leading cause of male infertility. Melatonin is a highly pleiotropic neurohormone. We aimed to characterize the melatonin epigenetic potential in varicocele and the involved molecular mechanisms., Experimental Approach: Fifty-two male albino rats were randomly divided into four groups (13 rats each): control (I), melatonin (II), varicocele (III) and melatonin treated varicocele (IV) groups. Left varicocele was induced by partial left renal vein ligation. Reproductive hormones, epididymal sperm functional parameters, testicular 3/17 β-hydroxysteroid dehydrogenases, antioxidant enzymes, malondialdehyde, nicotinamide adenine dinucleotide phosphate oxidase, 8-hydroxy-2'-deoxyguanosine and histopathological/Johnsen's score were evaluated. Flow cytometry and Comet were carried out to explore extent of sperm and testicular DNA damage. Testicular expression of silent information regulator 1 (SIRT1), forkhead transcription factors-class O (type1) (FOXO1), tumour suppressor gene, P53, cation channels of sperm (CatSper) and steroidogenic acute regulatory protein was evaluated by western blot technique. Testicular expression of Bcl-2 and its associated X protein and nuclear factor kappa-light-chain-enhancer of activated B cells were assayed by immunohistochemical staining. Testicular miR-34a expression was quantified by quantitative reverse transcription-polymerase chain reaction., Key Results: The varicocele induced testicular histological injury, enhanced oxidative stress, P53-mediated apoptosis, DNA damage and increased testicular miR-34a expression paralleled with down-regulated SIRT1/FOXO axis. Melatonin treatment of varicocele rats displayed antioxidant/anti-apoptotic efficacy and improved reproductive hormones axis, CatSper expression and fertility parameters. MiR-34a/SIRT1/FOXO1 epigenetic axis integrates testicular melatonin mediated intracellular transduction cascades in varicocele., Conclusion and Implications: Melatonin can be used as an adjuvant therapy to improve varicocele and its complication., (© 2022 The British Pharmacological Society.)

Doxorubicin (DOX) is an important chemotherapeutic drug. Cardiotoxicity diminishes its clinical efficacy. We aimed to focus on the mechanism of DOX-induced cardiotoxicity, in addition, to evaluate curcumin's protective effect against it. Twenty-eight rats were divided into the normal control group I, curcumin-treated (200 mg/kg body weight [b.w.]) group II, DOX-treated (4 mg/kg b.w.) group III, and DOX + curcumin group IV. Cardiac injury markers, heart tissue oxidative stress indices, interferon-gamma (INF-γ), tumor necrosis factor-like weak inducer of apoptosis (TWEAK), upregulated modulator of apoptosis (PUMA), p53 and nuclear factor kappa-B p65 (NF-κB p65) levels as well as messenger RNA gene expression of Rac1 and fibroblast growth factor-inducible protein 14 (Fn14) were assayed, besides the assay of DNA damage, histopathological changes, survivin immunohistochemistry and electron microscopic examination. Curcumin significantly downregulated Rac1 and Fn14 gene expression and significantly decreased p53, NF-κB p65, INF-γ, and PUMA levels in the cardiac tissue. In addition, curcumin improved oxidative stress indices, DNA damage, and cardiac toxicity markers in the form of lactate dehydrogenase (LD), creatine kinase isoenzyme-MB (CK-MB), and cardiac troponin-I (cTn-I). Meanwhile, upregulated antiapoptotic marker survivin was observed. Light and electron microscopic findings confirmed our biochemical and molecular outcomes. The current study established the antioxidant, anti-inflammatory, and antiapoptotic roles of curcumin against DOX cardiotoxicity., (© 2021 Wiley Periodicals LLC.)

This study was conducted to explore the beneficial impact of nesfatin-1 on reproductive dysfunction induced by nicotine (NT) in male rats with possible modulation of autophagy and pyroptosis signaling pathways. This research was performed on 40 Wistar male rats. They were distributed into four groups: control, normal+nesfatin-1, NT, and NT+nesfatin-1. At the end of the experimental period, the serum was separated for assay of testosterone, FSH and LH. Also, sperm parameters were determined. Histopathological examination of testicular tissue and immunohistochemical analysis was done for mammalian target of rapamycin, AMP-activated protein kinase, and mitogen-activated protein kinases including phosphorylated extracellular signal regulated kinase and phosphorylated cJun N-terminal kinase. Relative gene expression was determined for testicular nucleotide oligomerization domain (NOD)-like receptors proteins and Caspase-1, and autophagy markers including microtubule-associated protein 1 light chain 3 alpha and Beclin-1. Also, the following testicular parameters were assayed: 3β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase, malondialdehyde, superoxide dismutase activity, catalase, glucose-6 phosphate dehydrogenase, reactive oxygen species, caspase-3 activity, IL-1β, IL-18, mitochondrial transmembrane potential and Complex-I activity. The results revealed that the normal+nesfatin-1 group showed insignificant changes as compared to the control group. Meanwhile, the NT group exhibited prominent reproductive dysfunction in male rats. On the other hand, in the NT+nesfatin-1 group nesfatin-1 notably attenuated this reproductive dysfunction as evidenced by improvement of hormonal assay, sperm parameters, histopathological picture, immunohistochemical evaluation and real time relative gene expressions. In conclusion: Nesfatin-1 alleviated the impairment of male reproductive functions induced by NT via enhancement of autophagy pathways, suppression of pyroptosis, apoptosis, mitochondrial dysfunction and ROS production. Thus nesfatin-1 may offer a novel protective or therapeutic access for treating male infertility.

Diabetic retinopathy (DR) is the most common diabetic neurovascular complication, and the leading cause of preventable blindness among working-age individuals. Recently, agmatine, the endogenous decarboxylated L-arginine, has gained attention as a pleiotropic agent that modulates the diabetes-associated decline in quality of life, and exhibited varied protective biological effects. Diabetes was induced by a single streptozotocin (STZ, 50 mg/kg, i.p.) injection. When diabetes was verified, the animals were randomly allocated into three groups (16 rat each); diabetic, agmatine-treated diabetic (1 mg/kg, daily, for 12 weeks), and control group. Blood glucose homeostasis, retinal redox status, apoptotic parameters, nitric oxide synthase (NOS), nitric oxide (NO), vascular endothelial growth factor (VEGF), glutamate, glutamine, glutamine synthase (GS) activity, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and mitogen-activated protein kinase (MAPKs) pathways were assayed biochemically. Retinal vascular permeability was measured. Retinal morphology was evaluated by hematoxylin and eosin staining. Retinal N-methyl-D-aspartic acid receptor1 (NMDAR1) and glutamate aspartate transporter (GLAST) mRNA were quantified. Glucose transporter 1, pro-caspase3, and glial fibrillary acidic protein (GFAP) expression were quantified by immunohistochemistry. Chronic agmatine treatment abrogated STZ-induced retinal neurodegeneration features including gliosis, and neuronal apoptosis, restored retinal vascular permeability, mostly through antioxidant, anti-apoptotic capacity, abolishing glutamate excitotoxicity, modulating the activity of NMDARs, MAPKs/NFκB, and NOS/NO pathways. By restoring the molecular and functional background of retinal neurovascular homeostatic balance, agmatine would be appropriate therapeutic option acting upstream of the DR, impeding its progression.

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., (© 2021 Wiley Periodicals LLC.)

This study purposed to examine the prospective curative role of lipoxin A 4 (LXA 4 ) in induced gastric ulcer in rats and explore the possible involvement of mitochondrial dynamics signaling pathway. Forty-eight male Wistar rats were divided into four groups: control, indomethacin (IND), IND + omeprazole (IND + Omez), and IND+ LXA 4 groups. At the end of the experiment, the gastric pH, gastric fluid volume, total gastric acidity, ulcer index, and curative index were estimated. The gene expression of mitochondrial related protein 1 and mitofusin 2 were determined. In addition, some mitochondrial parameters include mitochondrial transmembrane potential, complex-I activity and reactive oxygen species were measured. Also, some gastric biochemical parameters, histopathological, and immunohistochemical analyses of the gastric mucosa were determined. We found that IND induced gastric ulcer, as manifested by the biochemical, histopathological, and immunohistochemical analyses. Both Omez and LXA 4 treatment for 15 days alleviated the IND-induced gastric ulcer as explored by ameliorating the biochemical, histopathological, and immunohistochemical findings. We concluded that LXA 4 mitigated the IND-induced gastric ulcer via improving the mitochondrial dynamic imbalance and mitochondrial dysfunction, in addition to its anti-apoptotic, anti-inflammatory, and antioxidant properties., (© 2020 International Union of Biochemistry and Molecular Biology.)

This study was designed to explore the effect of angiotensin 1-7 (Ang 1-7) on experimentally induced-preeclampsia in Wistar rats targeting the role of peroxisome proliferator-activated receptors gamma expression (PPARs-γ) & asymmetric dimethylarginine (ADMA). 30 female Wistar rats were divided into three groups: Normal pregnant (NP), preeclampsia (PE), and preeclampsia treated with Ang 1-7 (PE + Ang 1-7) groups. Reduced uterine perfusion pressure (RUPP) model was induced on GD14. On GD18, protein in urine, urine volume and urinary sodium excretion were determined. On GD19, the systolic blood pressure (SBP) was measured, and the gene expression of PPARs-γ were determined. The serum samples were separated for determination of Ang 1-7, ADMA, soluble fms-like tyrosine kinase (sFlt-1), vascular endothelial growth factor (VEGF), nitric oxide (NO) products, endothelial nitric oxide synthase (eNOS) activity, interleukin-6 (IL-6), interleukin-10 (IL-10), malondialdehyde (MDA), and total anti-oxidant capacity (T-AOC). Compared to NP group, SBP, urine protein, serum levels of ADMA, sFlt-1, IL-6 and MDA significantly increased, while expression of PPARs-γ, serum levels of Ang 1-7, VEGF, NO products, eNOS, IL-10 and T-AOC significantly decreased in PE group, while treatment of Ang 1-7 significantly ameliorated all these studied parameters as compared to PE group. We concluded that Ang 1-7 attenuated the symptoms of preeclampsia, which might be via increasing the expression of PPARs-γ and reduction of ADMA levels which could explain its anti-hypertensive, anti-angiogenic, anti-inflammatory and antioxidant effects., (Copyright © 2019 Elsevier Inc. All rights reserved.)