European journal of pharmacology

The increasing prevalence of obesity and type 2 diabetes mellitus has resulted in a significant challenge to public health throughout the globe. It required the development of novel therapeutic approaches. Retatrutide is a groundbreaking triple agonist that targets glucagon receptors, gastric inhibitory polypeptide, and glucagon-like peptide-1. Retatrutide's complex mechanism of action involves a synergistic interaction among these receptors, resulting in increased insulin secretion, improved glucose homeostasis, and refined appetite modulation. Clinical trials in phases 1 to 3 have demonstrated significant efficacy, highlighted by significant reductions in body weight and favorable glycemic control outcomes. Additionally, retatrutide shows promise in mitigating cardiovascular risk factors and addressing metabolic dysfunction-associated steatotic liver disease. However, careful attention is required to delineate its long-term safety profile, explore its potential in special populations, unravel its adjunctive therapeutic roles, and elucidate its mechanisms in pediatric cohorts. As a transformative therapeutic modality, retatrutide represents a beacon of hope, signifying transformative changes in the management landscape of obesity and type 2 diabetes mellitus (T2DM), and warranting continued exploration and refinement in clinical practice. This narrative review examines the therapeutic potential of retatrutide in the management of obesity and T2DM.

Sepsis-induced cardiomyopathy (SICM) is a prevalent cardiac complication of sepsis that is characterized by inflammatory dysregulation, mitochondrial dysfunction, metabolic disturbance, and changes in the myocardial microenvironment. Mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) is a mitochondrial-derived microprotein with metabolic regulatory and stress-responsive properties. Existing studies have linked MOTS-c to AMP-activated protein kinase-related energy metabolism, antioxidant responses, inflammatory restraint, endothelial and microvascular protection, and mitochondrial quality control. These processes are relevant to SICM; however, there is limited direct SICM-specific evidence for MOTS-c, and several proposed mechanisms, such as stress-responsive nuclear signaling, have been established primarily in non-SICM settings. This review summarizes the biological characteristics and stress-responsive regulation of MOTS-c, evaluates its potential involvement in pathological processes related to SICM, and distinguishes direct SICM evidence from findings extrapolated from other cardiovascular, metabolic, and inflammatory disease models. We also discuss the exploratory value and current limitations of MOTS-c as a stress-related adjunctive biomarker and potential therapeutic candidate, with particular attention to biomarker specificity, post-treatment efficacy, target-cell mechanisms, and pharmacokinetic or biodistribution issues under septic conditions. Overall, MOTS-c represents a plausible but insufficiently validated molecule in SICM research, and its translational relevance will depend on disease-specific mechanistic and pharmacological validation.

Esophagocutaneous fistulas are a failure of the NO-system, due to NO-synthase blockage by the NOS-blocker L-NAME consequently counteracted by l-arginine and gastric pentadecapeptide BPC 157 (l-arginine <BPC 157), precipitating a therapeutic benefit. Previously, there was an established BPC 157-NO-system interaction. BPC 157 GEPPPGKPADDAGLV, MW 1419 (LD1 not achieved), is a safe and stable anti-ulcer peptide, successful in inflammatory bowel disease trials, counteracting esophagitis, sphincter failure, gastrointestinal and skin ulcers, gastrocutaneous or colocutaneous fistulas. We treated rats with established cervical esophagocutaneous fistulas throughout four days (both open skin and esophageal defects, with significant leakage) with BPC 157 (parenterally and perorally) and L-NAME (blocking NO genesis) and l-arginine (NO-substrate) alone or in combination. RT-PCR investigated eNOS, iNOS, COX-2 mRNA levels in the fistulas. We evidenced a closely inter-related process of unhealed skin, esophageal defects, unhealed fistulas (up regulated eNOS, iNOS and COX2 mRNA levels), usually lethal, particularly NO-system related and therapy dependent. Generally, the course of fistula healing was accelerated either to a greater extent (with BPC 157 (in particular, less eNOS gene expression) completely counteracting L-NAME effects, in L-NAME+BPC 157 and L-NAME+l-arginine+BPC 157 groups), or to a lesser extent (with l-arginine). Conversely, the process was aggravated, rapidly and prominently (with L-NAME). In particular, BPC 157 was effective either given per-orally/intraperitoneally, in &#x3bc;g- and ng-regimens. Shortly, defects started to heal, with less fistula leakage and no mortality at day 4. Failure of pyloric and lower esophageal sphincter pressure was restored, with practically no esophagitis.

Previous studies have reported the effects of melatonin mainly in male rodents. However, the effect of sex on the effect of melatonin remains unknown. The purpose of this study was to evaluate the role of sex in the antiallodynic effect of melatonin under neuropathic pain conditions. Intrathecal melatonin reduced both evoked and spontaneous pain in female and male neuropathic mice, with a significantly greater effect in female mice. Selective blockade of spinal melatonin MT 2 , but not MT 1 , receptors abated the antiallodynic effect of melatonin in both sexes. In contrast, blockade of spinal opioid receptors abated the antiallodynic effect of melatonin in male mice and partially in female mice. Notably, ovariectomy eliminated the antiallodynic effect of melatonin in female mice. Additionally, 17&#x3b2;-estradiol or estrogen receptor-&#x3b1; agonist PPT treatment, but not estrogen receptor-&#x3b2; agonist DPN, restored the antiallodynic effect of melatonin in ovariectomized female mice. Furthermore, blocker of estrogen receptor-&#x3b1;/&#x3b2; ICI-182,780 or estrogen receptor-&#x3b1; MPP prevented the effect of 17&#x3b2;-estradiol on melatonin-induced antiallodynia in ovariectomized female mice. Our results indicate a sex-dependent mechanism in melatonin-induced antiallodynic effect in mice. While the activation of melatonin MT 2 receptors mediates the effect of melatonin in both female and male mice, activation of spinal opioid receptors plays a more relevant role in male mice. Additionally, the effects of melatonin in females depend on the activation of spinal estrogen receptor-&#x3b1;.