oxyntomodulin and Reperfusion-Injury

Testicular torsion is a serious emergency and a well-known cause of male infertility. It represents 10 %-15 % of scrotal diseases in children. Kisspeptin (KISS1) is a hormone secreted from the hypothalamic nuclei and testis, but its role in testis is not fully understood. Semaglutide is a novel antidiabetic glucagon-like peptide 1 (GLP-1) analog. Hence, we designed the current study to elucidate the possible ameliorative effect of semaglutide on ischemia/reperfusion-induced testicular dysfunction in rats and highlight the role of the testicular GLP-1/PCG-1α-PPAR-α-KISS1 signaling pathway. We randomly divided 50 male Sprague Dawley into five equal groups (10 rats each): SHAM, exendin 9-39 -treated (EX), testicular torsion/detorsion (T/D), testicular torsion/detorsion and semaglutide-treated (SEM + T/D), and testicular torsion/detorsion, exendin, and semaglutide-treated (EX + SEM + T/D). We quantified serum follicle-stimulating hormone, luteinizing hormone, total testosterone, testicular oxidative stress markers, testicular gene expression of GLP-1/KISS1 pathway-related genes (KISS1, KISS1R, GLP-1, GLP-1R, PGC-1α, PPAR-α), steroidogenesis pathway-related genes (STAR, CYP11A1, CYP17A1, HSD17B3, CYP19A1), HO-1, Nrf-2, and testicular protein expression of HIF-1α, TNF-α, NF-κβ, Caspase-3, FAS, proliferating cell nuclear antigen, and KISS1 through testicular histopathology and immunohistochemistry assays. Testicular torsion/detorsion markedly elevated proapoptotic, proinflammatory, and oxidative stress marker levels, noticeably downregulating the expression of GLP-1/KISS1 and steroidogenesis pathway-related proteins. Semaglutide administration significantly ameliorated all these deleterious effects. Nevertheless, injecting exendin, a GLP1-R antagonist, before semaglutide abolished all the documented improvements. We concluded that semaglutide ameliorated ischemia/reperfusion-induced testicular dysfunction by modulating the GLP-1/PGC-1α-PPAR-α/KISS1/steroidogenesis signaling pathway, improving testicular oxidative state, and suppressing testicular inflammation and apoptosis.

Topics: Animals; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Ischemia; Kisspeptins; Male; Oxidative Stress; PPAR alpha; Rats; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury; Signal Transduction; Testis

A substantial number of ischaemic stroke patients who receive reperfusion therapy in the acute phase do not ever fully recover. This reveals the urgent need to develop new adjunctive neuroprotective treatment strategies alongside reperfusion therapy. Previous experimental studies demonstrated the potential of glucagon-like peptide-1 (GLP-1) to reduce acute ischaemic damage in the brain. Here, we examined the neuroprotective effects of two GLP-1 analogues, liraglutide and semaglutide.. A non-diabetic rat model of acute ischaemic stroke involved 90, 120 or 180 min of middle cerebral artery occlusion (MCAO). Liraglutide or semaglutide was administered either i.v. at the onset of reperfusion or s.c. 5 min before the onset of reperfusion. Infarct size and functional status were evaluated after 24 h or 72 h of reperfusion.. Liraglutide, administered as a bolus at the onset of reperfusion, reduced infarct size by up to 90% and improved neuroscore at 24 h in a dose-dependent manner, following 90-min, but not 120-min or 180-min ischaemia. Semaglutide and liraglutide administered s.c. reduced infarct size by 63% and 48%, respectively, and improved neuroscore at 72 h following 90-min MCAO. Neuroprotection by semaglutide was abolished by GLP1-R antagonist exendin(9-39).. Infarct-limiting and functional neuroprotective effects of liraglutide are dose-dependent. Neuroprotection by semaglutide is at least as strong as by liraglutide and is mediated by GLP-1Rs.

Topics: Animals; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Incretins; Infarction, Middle Cerebral Artery; Liraglutide; Male; Neuroprotective Agents; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury; Time Factors

Glucagon-like peptide 2 (GLP-2) is an intestinal epithelium-specific growth factor. However, its protective effects and related mechanism on the small intestine injured by ischemia-reperfusion (I/R) in mice remain unclear. This study aimed to reveal the effects of GLP-2 and its functional relationship with uncoupling protein 2 (UCP2) on the small intestine after I/R injury in mice. Male Balb/c mice were given GLP-2 (250 microg/kg/day, ip) for 3 days and underwent 30 min of superior mesenteric artery occlusion followed by 1 hr of reperfusion on day 4. Histological damage, bacterial translocation, diamine oxidase, and malondialdehyde level were assessed, and UCP2 expression was measured by immunohistochemistry and Western blot. GLP-2 attenuated the intestinal histological damage caused by I/R and increased the villous height by 28% and the crypt depth by 10%, respectively. Compared to the I/R group, diamine oxidase activity was increased, the incidence of bacterial translocation and malondialdehyde level were decreased, and UCP2 expression was increased in GLP-2-treated mice. GLP-2 protected the small intestine from I/R injury and increased UCP2 expression. These results suggested that effects of GLP-2 should be related to the upregulation of mitochondrial UCP2, which antagonized reactive oxygen species production.

Topics: Animals; Biopsy, Needle; Blotting, Western; Disease Models, Animal; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Immunohistochemistry; Injections, Intraperitoneal; Intestinal Mucosa; Intestine, Small; Male; Mice; Mice, Inbred BALB C; Peptides; Probability; Random Allocation; Reference Values; Reperfusion Injury; Sensitivity and Specificity

Glucagon-like peptide-1 (7-36) amide (GLP-1) has been studied as a treatment option in diabetic patients. We investigated the effect of recombinant GLP-1 infusion on hemodynamic parameters, myocardial metabolism, and infarct size during normoxic conditions as well as during ischemia and reperfusion using an open-chest porcine heart model. In the presence of rGLP-1, interstitial levels of pyruvate and lactate decreased during ischemia and reperfusion both in ischemic and non-ischemic tissue. Moreover, rGLP-1 infusion resulted in increased plasma insulin levels and decreased blood glucose levels. Neither hemodynamic variables nor the consequent infarct size were influenced by rGLP-1 infusion. We conclude that rGLP-1 altered myocardial glucose utilization during ischemia and reperfusion. It did not exert any untoward hemodynamic effects.

Topics: Animals; Area Under Curve; Blood Glucose; Cardiovascular System; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Ischemia; Lactic Acid; Microdialysis; Myocardial Infarction; Myocardium; Peptide Fragments; Protein Precursors; Pyruvic Acid; Reperfusion Injury; Swine; Time Factors

Glucagonlike peptide-2 (GLP-2), a product of the posttranslational processing of proglucagon, has been shown to enhance mucosal mass and function in both normal intestine and in the residual intestine after massive small bowel resection. This study was designed to determine if a synthetic, protease-resistant analogue of GLP-2 (GLP-2alpha) can enhance mucosal mass in small intestine after ischemia and reperfusion (I/R) injury.. Ten young adult male Sprague-Dawley rats underwent laparotomy and superior mesenteric artery occlusion for a period of 40 minutes. During this period of ischemia, each rat underwent placement of a jugular venous catheter that was connected to a subcutaneously placed osmotic pump designed to deliver its contents over 3 days. The rats were divided into 2 groups based on the contents of the pumps: group 1, saline at 1 microL/h (n = 6) and group 2, GLP-2alpha at 100 microg/kg/d (n = 4). Three days after insertion of the pumps the small intestine was harvested from the surviving rats for determination of mucosal DNA and protein content. Statistical analysis was performed using unpaired Student's t test.. After I/R injury to the small intestine, a 3-day systemic infusion of GLP-2alpha significantly increased mucosal DNA content 41% (P<.05) and mucosal protein content 60% (P<.05) when compared with saline-treated controls. In addition, infusion of GLP-2alpha reduced mortality from 50% to 25%.. These data show for the first time that GLP-2alpha enhances mucosal mass following I/R injury to the small intestine. GLP-2alpha may be of benefit to patients with intestinal ischemia syndromes such as necrotizing enterocolitis and midgut volvulus.

Topics: Animals; Gastrointestinal Hormones; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Intestinal Mucosa; Male; Organ Size; Peptides; Rats; Rats, Sprague-Dawley; Reperfusion Injury

This study was designed to explore the efficacy of a synthetic analogue of glucagonlike peptide-2 (GLP-2a) in enhancing mucosal mass and absorptive function in a rat model of intestinal ischemia-reperfusion (I-R) injury.. Each of 20 Sprague-Dawley rats underwent placement of a jugular venous catheter connected to a subcutaneous osmotic pump designed to deliver its contents over 3 days. Rats were divided into 4 groups (n = 5 per group): (1) normal intestine/saline infusion; (2) 30-minute superior mesenteric artery occlusion/saline infusion, (3) normal intestine/ GLP-2alpha infusion, and (4) 30-minute superior mesenteric artery occlusion/GLP-2alpha infusion. Subsequently, mean mucosal 14C-galactose and 14C-glycine absorption and DNA content were determined for each group.. In saline-treated rats, 30 minutes of mesenteric ischemia decreased mean mucosal galactose absorption by 29% (P < .05), glycine absorption by 22% (P = .12), and DNA content by 28% (P < .01) when compared with rats with uninjured intestine. In rats subjected to 30 minutes of intestinal ischemia, GLP-2alpha significantly improved galactose absorption by 46% (P < .05), glycine absorption by 84% (P < .01), and DNA content by 63% (P < .01) when compared with saline-treated control rats. In rats with mesenteric I-R injury treated with GLP-2a, galactose absorption was returned to normal. Glycine absorption and DNA content were increased significantly by 44% (P < .01) and 18% (P < .05), respectively, beyond the baseline for normal intestine.. Thirty minutes of intestinal ischemia followed by immediate reperfusion significantly decreased mucosal mass and absorptive function, validating this rat model of I-R injury. After mesenteric I-R, GLP-2a significantly increased mucosal DNA content and absorption of 14C-galactose and 14C-glycine when compared with untreated control rats. After I-R injury, GLP-2a restored mucosal mass and absorptive function to normal or above-normal levels.

Topics: Animals; Disease Models, Animal; DNA; Galactose; Glucagon-Like Peptides; Glycine; Infusions, Intravenous; Intestinal Absorption; Intestinal Mucosa; Male; Peptides; Probability; Rats; Rats, Sprague-Dawley; Reference Values; Reperfusion Injury