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Involvement of substance P/NK1 receptor system in central sensitization in chronic pain.
Neurosci Lett
Juan Chen, Yimin Lai, Wei Li
Chronic pain has become a serious health issue, affecting more than 30% of people worldwide. One of the main mechanisms of chronic pain is central sensitization. It is well known that substance P (SP) and its receptor, Neurokinin 1 receptor (NK1R), play an important role in transmission of nociceptive signals. However, whether SP/NK1R system is involved in central sensitization in chronic pain remains controversial. In the present study, we adopted spared nerve injury (SNI) mouse model to induce neuropathic pain and assessed the role of SP/NK1R system in the development of hyperalgesia and central sensitization. We observed that hyperalgesia occurred in non-injured body part of SNI mice in tail withdrawal test. We also demonstrated hyperexcitability of S1 apical dendrites in SNI mice. Notably, the hyperalgesia behavior and hyperactivity of S1 apical dendrites were alleviated by NK1R antagonist L-703606. These results indicate that SP/NK1R system is involved in central sensitization in chronic pain.
Uridine-Cytidine Kinase 2 (UCK2)/Uridine-Cytidine Kinase Like 1 (UCKL1) complex exacerbates the differentiation of myocardial fibroblasts via TRIM21/Smurf2/Smad3 pathway after myocardial infarction.
Mol Biomed
Xiao Zhou, Yu Zhang, Hao Wang +5 more
Cardiac fibrosis following myocardial infarction (MI) is a pivotal driver of ventricular dysfunction and heart failure, yet the molecular checkpoints orchestrating the persistent activation of cardiac fibroblasts remain incompletely defined. Here, we uncover a non-canonical, metabolism-independent function of Uridine-Cytidine Kinase 2 (UCK2) and Uridine-Cytidine Kinase Like-1 (UCKL1) as synergistic regulators of pathological remodeling. We demonstrate that both proteins are robustly upregulated in the border zone of ischemic murine hearts and transforming growth factor-β (TGF-β)-activated human cardiac fibroblasts (HCFs). Mechanistically, UCK2 and UCKL1 physically assemble into an obligate functional complex that acts as a molecular scaffold rather than a metabolic enzyme. This complex recruits the E3 ubiquitin ligase Tripartite Motif Containing 21 (TRIM21) to orchestrate the specific ubiquitination and degradation of the negative regulator SMAD Specific E3 Ubiquitin Protein Ligase 2 (Smurf2), thereby sustaining SMAD Family Member 3 (Smad3) phosphorylation and amplifying fibrogenic TGF-β signaling. Disruption of this axis via combined genetic silencing exerts a synergistic protective effect by abrogating myofibroblast differentiation and extracellular matrix production. Furthermore, therapeutic intervention using adeno-associated virus (AAV)-mediated knockdown of UCK2/UCKL1 significantly attenuates adverse ventricular remodeling, limits scar expansion, and preserves cardiac function in a murine MI model. Collectively, these findings identify the UCK2/UCKL1-TRIM21-Smurf2-Smad3 axis as a novel, druggable signalosome linking kinase "moonlighting" functions to transcriptional reprogramming, offering a transformative therapeutic strategy to arrest the progression of post-ischemic heart failure.
Neuroimmune Crosstalk in Psoriasis: Mechanisms and Therapeutic Implications.
Inflammation
Hanlin Gao, Yi Fang, Yue Zhang +3 more
Psoriasis is a chronic, immune-mediated inflammatory skin disorder characterized by keratinocyte hyperproliferation, dermal vascular remodeling, and dense immune cell infiltration. While the conventional immunopathological model emphasizes the IL-23/Th17 axis and aberrant T-cell responses, growing evidence highlights the central role of neuroimmune crosstalk in the initiation, amplification, and persistence of disease. This review systematically dissects the cellular and molecular mechanisms underpinning neuroimmune interactions in psoriasis, focusing on the dynamic interplay between peripheral nerve fibers, keratinocytes, and immune cells. Key neuropeptides—such as calcitonin gene-related peptide (CGRP), substance P (SP), nerve growth factor (NGF), and vasoactive intestinal peptide (VIP)/PACAP—emerge as critical mediators that activate proinflammatory signaling cascades and perpetuate a positive feedback loop involving IL-23, IL-17, and other cytokines. Concurrently, neurotransmitters including norepinephrine (NE), acetylcholine (ACh), and dopamine (DA) modulate dendritic cell activation, Th17 polarization, and epidermal inflammation via adrenergic, cholinergic, and dopaminergic pathways. Importantly, both central and peripheral nervous systems are implicated in neuroinflammatory sensitization, with IL-17 A, IL-1β, and TNF-α disrupting neuronal homeostasis and contributing to pruritus, pain, and stress-induced relapse. We further summarize emerging therapeutic strategies targeting the neuroimmune axis—such as TRPV1 antagonists, botulinum neurotoxins, NK1R inhibitors, and vagus nerve stimulation—which offer promising avenues for personalized and mechanism-based interventions. By reframing psoriasis as a neuroimmune disorder, this review provides new conceptual insights into disease heterogeneity and points toward innovative treatment paradigms.
Exogenous hydrogen sulfide inhibits the progression of vascular dysfunction and hypertension mediated by the renin-angiotensin system in chronic kidney disease.
Biochem Pharmacol
Jorge A Tapia-Martínez, Diana L Silva-Velasco, Jesus H Beltran-Ornelas +3 more
Chronic kidney disease (CKD) overactivates the renin-angiotensin system (RAS), causing vascular dysfunction and hypertension. Additionally, hydrogen sulfide (H2S) is a gasotransmitter that modulates the cardiovascular system by attenuating the RAS. Therefore, this study aimed to investigate the effects of chronic administration of sodium hydrosulfide (NaHS, an exogenous H2S donor) on RAS-mediated vascular responses, oxidative stress, and progression of hypertension in rats with CKD. Thirty-two normotensive male Wistar rats were divided into four groups (n = 8): 1) sham + vehicle (1 mL/kg/d, 100 mM of phosphate buffer, PBS), 2) sham + NaHS (5.6 mg/kg/d), 3) CKD induced by 5/6 nephrectomy + vehicle, and 4) CKD + NaHS. One week after surgery, pharmacological treatments began and were administered intraperitoneally daily for six weeks. Hemodynamic variables, renal function, and H2S serum levels were assessed. Additionally, H2S formation, oxidative stress, and the expression of AT1, AT2, Mas receptors, and H2S-synthesizing enzymes, along with vascular responses to angiotensin (1-7), angiotensin II and H2S were assessed in the thoracic aorta. CKD impairs: 1) RAS-mediated vascular responses; 2) downregulates Mas receptor expression; 3) upregulates AT1 and AT2 receptor expression; 4) increases H2S-mediated vascular response, 5) decreases H2S levels, tissue production of H2S and the expression of the producing enzymes; and 6) induces oxidative stress. Interestingly, NaHS treatment prevented CKD-induced impairments. In conclusion, NaHS administration protects against RAS-mediated vascular dysfunction and progression of hypertension by preventing alterations in AT1, AT2, Mas receptors, H2S-synthesizing enzymes, and oxidative stress.
Elevated plasma cancer antigen-125 level is associated with increased risk of new-onset atrial fibrillation after acute myocardial infarction.
Front Cardiovasc Med
Yuan Fu, Kun Zuo, Mulei Chen +2 more
New-onset atrial fibrillation (NOAF) is the most commonly encountered arrhythmia during the course of acute myocardial infarction (AMI) and is independently associated with a worse prognosis.
Interleukin-35 alleviates pulmonary arterial hypertension by suppressing the VEGFA/VEGFR2 signaling pathway.
Life Sci
Jie Feng, Kai Li, Leilei Han +2 more
Pulmonary arterial hypertension (PAH) is a serious circulatory disorder defined by elevated pulmonary arterial pressure (PAP) with normal pulmonary capillary wedge pressure (PCWP), driven by pathological remodeling of pulmonary arterioles. If left untreated, it can lead to severe health complications and death. Current treatments, such as endothelin receptor antagonists and phosphodiesterase-5 inhibitors, prostacyclin analogs, and soluble guanylate cyclase stimulators-these agents relieve symptoms, improve exercise capacity, and delay disease progression but do not target the underlying vascular pathology. Because these therapies fail to improve long-term prognosis, they impose a heavy burden on patients, families, and society. Thus, there is an urgent need to develop new therapeutic agents that can treat PAH more effectively. Interleukin-35 (IL-35), which is primarily produced by regulatory T cells, is a potent molecule exhibiting significant anti-inflammatory and immunomodulatory properties. Recent research suggests that IL-35 shows promise as a novel therapeutic agent for PAH. However, the precise mechanism by which IL-35 influences pulmonary hypertension remains to be elucidated through further experimentation. To address this, we established animal and cellular models and analyzed molecular, functional, and structural changes using western blotting, PAP measurements, flow cytometry, EdU staining, scratch assay, blood biochemistry, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), hematoxylin and eosin (H&E), Immunohistochemistry (IHC) and Masson's trichrome staining. Our results suggest that IL-35 alleviates PAH-induced inflammation, apoptosis, and smooth muscle cell proliferation, reduces PAP, and restores vascular remodeling, thereby mitigating both structural and functional damage in PAH.
Use of Sotatercept to Facilitate Transition From Intravenous to Oral Prostacyclin Therapy.
Clin Respir J
Chebly Dagher, Maria Akiki, Kristen Swanson +4 more
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary vascular resistance (PVR) leading to right ventricular failure and high mortality. Parenteral prostacyclin therapy remains the cornerstone for high-risk patients but is limited by complications and reduced quality of life. Sotatercept, an activin signaling inhibitor, has recently emerged as an effective adjunct therapy in PAH, improving functional and hemodynamic outcomes. This case series evaluated whether the addition of sotatercept could facilitate the transition from intravenous (IV) to oral prostacyclin in eight high-risk PAH patients who had previously failed transition attempts. All patients received background dual therapy with endothelin receptor antagonists and phosphodiesterase-5 inhibitors and were transitioned from IV to oral treprostinil following the fifth dose of sotatercept. At 24 weeks, all eight patients successfully maintained oral therapy without re-initiation of IV prostacyclin. Significant improvements were observed in 6-min walk distance, WHO functional class, right ventricular systolic pressure, and PVR. No treatment discontinuations or serious adverse events occurred. These findings suggest that adjunctive sotatercept may enable safe and effective transition from parenteral to oral prostacyclin therapy, expanding treatment flexibility and improving quality of life in high-risk PAH patients. Prospective studies are warranted to confirm long-term outcomes.
Unusual Development of Central Diabetes Insipidus after Endovascular Treatment for a Medial Tentorial Dural Arteriovenous Fistula.
J Neuroendovasc Ther
Yuta Oka, Yoshinobu Horio, Munenari Matsuishi +7 more
Medial tentorial dural arteriovenous fistulas (DAVFs) are rare lesions that may cause intracranial hemorrhage or non-hemorrhagic symptoms due to venous congestion from retrograde deep venous drainage. We report a case of a medial tentorial DAVF presenting with cognitive decline and impaired consciousness, successfully treated with transvenous embolization (TVE) and straight sinus angioplasty, and complicated postoperatively by central diabetes insipidus (CDI).
An Online Prescription for Hospitalisation: Euglycaemic Ketoacidosis Caused by an Online Tirzepatide Prescription.
Cureus
Thibagaran Sathambihai, Kushagra Mathur, Seshnag Siddavaram
Obesity affects a significant proportion of the UK population, and tirzepatide, a dual glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP) receptor agonist, is increasingly being prescribed by online services as well as primary care for weight loss in both diabetic and non-diabetic patients. We present the case of a 61-year-old woman with no past medical history, who developed euglycaemic ketoacidosis following six weeks of tirzepatide (Mounjaro®) therapy, which was initiated via an online consultation for weight loss. Despite normal blood glucose levels, she exhibited significant ketonaemia and metabolic acidosis, which resolved with intravenous fluid resuscitation and replacement. This case brings to light the importance of treating clinicians being aware of the potential adverse side effects of euglycaemic ketoacidosis in patients using tirzepatide, and highlights the risk when these medications are prescribed via novel care pathways, which have less rigid monitoring paradigms than traditional prescribing models. Early recognition of, and prompt management, are important to ensure the mitigation of morbidity associated with this under-recognised adverse effect.
Unraveling the Cycle: A Scoping Review Exploring the Impact of Antidepressants on the Female Reproductive Cycle.
Cureus
Shannon Weatherly, Carly D Garazi, Emma Woldenberg +2 more
Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are widely prescribed for mood disorders, including in individuals of reproductive age. While their psychiatric effects are well-documented, emerging evidence suggests these medications may influence hormonal regulation, ovulation, and menstrual cycle patterns. Potential mechanisms include disruption of the hypothalamic-pituitary-ovarian (HPO) axis, alterations in serotonergic signaling, and medication-specific hormonal fluctuations. These interactions raise important questions about the understudied reproductive impact of commonly prescribed antidepressants. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines, a comprehensive search of Ovid MEDLINE, Excerpta Medica Database (EMBASE), and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were performed to identify studies examining the effects of antidepressants on ovarian function, menstrual regularity, ovulation, or hormone levels. Eligible studies included those involving individuals assigned female at birth (AFAB) of reproductive age, as well as animal models with comparable reproductive physiology. Both human and preclinical studies were considered, covering a range of antidepressant classes: SSRIs, SNRIs, atypical antidepressants, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and newer agents such as vortioxetine and vilazodone.  Out of 34 eligible studies, 16 were included in the final synthesis. SSRIs, especially fluoxetine, sertraline, paroxetine, escitalopram, and citalopram, were most frequently studied. Observational studies reported increased rates of menstrual irregularity and sexual dysfunction, particularly with chronic SSRI use. Antidepressant use was associated with reduced fecundability, even after adjusting for depression severity. Bupropion, venlafaxine, and other SNRIs showed cycle-phase-dependent pharmacokinetics and variable hormonal interactions. Antidepressant use was associated with changes in menstrual cycle length and increased cardiometabolic risk; however, they may normalize low testosterone levels in depressed women, with improvements in sexual function post-treatment. Clinical and preclinical findings indicate that SSRIs may impair ovulation through serotonergic inhibition of gonadotropin-releasing hormone (GnRH) as well as downstream suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), with some studies also noting elevated prolactin and follicular atresia. Taken together, these findings suggest a biologic basis for the observed menstrual irregularities and reduced fecundability reported in observational and cohort studies. Across studies, reproductive effects varied by antidepressant class, duration of use, and underlying mood pathology. Observed trends support a drug- and class-dependent impact on estrogen, progesterone, prolactin, and reproductive function, with additional implications for systemic health.
The Human-Like Collagen Alpha-1 Type V Peptides Strengthen the Dermal Fiber Network and Improve the Regeneration Ability of Cells.
J Cosmet Dermatol
Ye Hyang Kim, Byung Kuk Kim, Yeon Kyung Nam +5 more
Collagen, a major structural component of the skin, decreases with age and is associated with wrinkles, reduced elasticity, sagging, and dryness. While hydrolyzed or marine-derived collagens are widely used in cosmetics, advances in biotechnology have enabled the development of bio-collagen peptides. However, the role of collagen type V-derived peptides in skin biology remains largely unexplored.
Myostatin Function during In Vitro Myogenesis: Considerations for Knockout-Based Mechanistic Analysis.
J Bone Metab
Joonho Suh, Jongmin Baik, Yun-Sil Lee
Myostatin (MSTN) is a well-known negative regulator of skeletal muscle growth, and its pharmacological blockade, such as with follistatin (FST), an endogenous MSTN inhibitor, is under active investigation as a treatment for muscle-wasting conditions. However, the dynamics of MSTN signaling during in vitro myogenesis and its modulation by culture conditions remain incompletely understood.
Amylin and the renin-angiotensin system: risk or opportunity in amylin-based therapy?
Lancet
Marcel H A Muskiet, Massimo Nardone, Patrick C N Rensen +2 more
We hypothesise that amylin receptor agonists (eg, pramlintide) and dual amylin and calcitonin-receptor agonists (eg, cagrilintide), which are emerging treatments for obesity and type 2 diabetes, can activate the renin-angiotensin system (RAS) and potentially undermine the cardiorenal benefits of these therapies. Paradoxically, new-generation amylin-based therapies, such as CagriSema, showed substantial blood pressure reductions in phase 3 trials. Beyond amylin's weight loss-mediated effects, we hypothesise that concurrent use of RAS inhibitors (angiotensin-converting enzyme [ACE] inhibitors or angiotensin-receptor blockers) redirects amylin-induced RAS activation towards the protective alternative RAS pathway, which is characterised by vasodilatory, anti-inflammatory, and antiproliferative effects via Mas receptors, potentially explaining part of their therapeutic benefit and cardioprotective and renoprotective potential. To test this, we propose: (1) preclinical studies investigating amylin-RAS interactions with or without RAS blockade; (2) post-hoc analyses of phase 2/3 trials stratified by RAS inhibitor use; (3) biomarker studies monitoring renin, aldosterone, angiotensin-(1-7), and ACE2; and (4) mechanistic human studies prospectively assessing cardiovascular-kidney metabolic effects by RAS inhibitor status. These suggestions aim to determine whether RAS inhibition enhances the overall efficacy of amylin-based therapies, and whether RAS blockers should be strongly recommended in patients receiving them.
Disrupting the MC1R/α-MSH-pCREB-MITF Axis: Rhein-based PROTAC D16 as a Potent Melanogenesis Inhibitor.
Chem Biodivers
Meng Xu, Ziqing Zhang, Peixi Zhang +12 more
Melanin protects skin from ultraviolet rays, but excessive or misdistributed synthesis can cause issues like melasma, freckles, or melanoma. Rhein from traditional Chinese herbs shows various bioactivities, with recent structural modifications enhancing its derivatives, but its effect on melanogenesis is unreported. The study reports synthesizing and evaluating D16, Rhein-based proteolysis targeting chimera (PROTACs) utilizing pomalidomide as an E3 ligand. D16 exhibited significantly reduced cytotoxicity, with half-maximal inhibitory concentration values exceeding 100 µM in both B16-F10 melanoma and human immortalized keratinocyte cells, indicating a low level of toxicity. In addition, mechanistic studies revealed that D16 suppresses melanin production primarily through the melanocortin 1 receptor/α-melanocyte-stimulating hormone signaling pathway, with further analysis suggesting phosphorylated cyclic adenosine monophosphate-response element binding protein (pCREB) as a key target. Through pCREB degradation, D16 disrupts microphthalmia-associated transcription factor transcription, leading to reduced levels of tyrosine. Molecular docking studies further confirmed strong binding between D16 and pCREB. Animal experiment results indicated that D16 effectively suppressed melanogenesis in mice. These findings underscore the potential of D16 to treat melanin-related disorders by targeting pCREB, advancing both the therapeutic utility of PROTACs and the application of pCREB modulation in pigmentation treatments.
Comprehensive insights into emerging advances in the Neurobiology of anorexia.
J Adv Res
Liwei Mao, Lian Wang, Zhihai Huang +3 more
Anorexia is a complex eating disorder influenced by genetic, environmental, psychological, and socio-cultural factors. Research into its molecular mechanisms and neural circuits has deepened our understanding of its pathogenesis. Recent advances in neuroscience, molecular biology, and genetics have revealed key molecular and neural circuit mechanisms underlying anorexia.
Human fetal circulating factors from pregnancies complicated by obesity upregulate genes associated with pathological hypertrophy in neonatal rat cardiomyocytes.
Am J Physiol Heart Circ Physiol
Owen R Vaughan, Andrew Goodspeed, Carmen C Sucharov +2 more
Obesity in pregnant women increases offspring cardiovascular risk and causes fetal cardiac dysfunction. The underpinning mechanisms remain unclear. We hypothesized that circulating factors in serum from fetuses of women with obesity induce pathological cardiomyocyte hypertrophy. Pregnant women with obesity or healthy weight were recruited at term and provided umbilical cord serum and placentas, which were used for isolation of primary trophoblast cells. Primary cardiomyocytes were isolated from neonatal rats. Compared with cord serum from healthy weight women, cord serum from women with obesity upregulated cardiomyocyte mRNA expression of atrial natriuretic factor (Anf) and brain natriuretic peptide (Bnp) and increased the ratio of β-to α-myosin heavy chain expression (Myh7:Myh6), when it was supplemented into the culture medium. This effect was prevented by treating the cord serum with heat-freeze cycling and DNase or RNase digestion. Separately, conditioned medium from trophoblast cells from women with obesity increased cardiomyocyte Anf expression without altering Bnp or Myh7:Myh6. MicroRNAs miR-142 and miR-17, which are associated with cardiac function, were increased in abundance in extracellular vesicles isolated from cord serum from women with obesity. However, miR-142-3p, miR-142-5p, and miR-17-5p did not increase Anf, Bnp, or Myh7:Myh6 expression when they were transfected into cardiomyocytes. Neither cord serum nor the upregulated microRNAs from women with obesity altered cardiomyocyte size. The results show that human fetal circulating and placenta-derived factors induce gene expression hallmarks of pathological hypertrophy in cardiomyocytes and may mediate cardiac dysfunction in children of women with obesity.NEW & NOTEWORTHY Obesity in pregnant women increases risk for heart problems in their children. This study treated heart cells growing in a dish with blood plasma from the umbilical cords of newborn babies. Plasma from babies of women with obesity activated genes linked to heart failure. This means we could design treatments targeting plasma molecules, like microRNAs, or the way the placenta releases them. This could improve children's heart health if the mother has obesity.
Role and therapeutic potential of elabela in renal disease: from molecular mechanisms to clinical applications.
Endocr Connect
Anni Li, Yuxuan Ye, Huimin Cao +5 more
Elabela (ELA) is a relatively newly identified bioactive micropeptide that functions as the second endogenous ligand for the apelin receptor (APJ). It plays a critical role in diverse physiological processes, including cardiovascular development, blood pressure regulation, and fluid homeostasis. Growing evidence underscores its significance in the pathophysiology of various organ systems, particularly the kidneys. This review aims to comprehensively explore the role of ELA in renal physiology and pathology. We focus on its molecular mechanisms, such as modulating renal hemodynamics, inhibiting fibrosis and inflammation, promoting cellular survival, and its therapeutic potential in acute kidney injury, chronic kidney disease, and hypertensive and diabetic nephropathy. Building upon our research group's previous work, this article places special emphasis on the role of ELA in renal metabolism and its promising application in the treatment of diabetic kidney disease. By synthesizing recent advancements, we seek to elucidate the connection between ELA and kidney health, assessing its potential as a novel therapeutic target for renal diseases.
Synaptotagmin-1 regulates egg production by con trolling luteinizing hormone secretion in chickens.
Poult Sci
Zhimin Cheng, Yangyang Wang, Yang Wang +7 more
Egg production represents one of the most economically critical traits in commercial poultry production, orchestrated primarily by the hypothalamus-pituitary-ovarian (HPO) axis. Synaptotagmin 1 (SYT1), a ubiquitous component of the nervous and endocrine systems, functions as a key mediator of calcium-dependent neurotransmitter release and hormone secretion. However, the functional role of SYT1 in avian reproductive performance has remained elusive. In this study, we present evidence that single nucleotide polymorphisms (SNPs) within the SYT1 gene effectively distinguish commercial laying hens from local wild breeds, as demonstrated through principal component analysis (PCA), suggesting the gene's pivotal role in selective breeding for enhanced egg production. Through genotype-phenotype correlation analyses, we identified two SNPs, rs39497549 and rs39477032, that exhibit strong associations with egg laying performance. Furthermore, tissue-specific expression levels showed profiling analysis revealed SYT1 transcript levels in pituitary and ovarian tissues of high-producing hens relative to their low-producing counterparts, and these expression levels showed strong positive correlations with circulating concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2). In addition, fluorescence in situ hybridization analyses further confirmed spatial co-localization of SYT1 and LH within anterior pituitary cells, suggesting a direct involvement of SYT1 in gonadotroph activity. Functional validation through in cultured pituitary cells revealed that gonadotropin-releasing hormone (GnRH) agonist stimulation significantly upregulated SYT1, follicle stimulating hormone beta subunit (FSHβ), and luteinizing hormone beta subunit (LHβ) mRNA, along with enhanced secretion of FSH and LH. Conversely, SYT1 knockdown attenuated GnRH-induced expression and secretion of gonadotropins, while SYT1 overexpression potentiated these effects. Additionally, SYT1 modulated steroidogenesis in ovarian granulosa cells by regulating the expression of steroidogenic enzymes and progesterone production. Taken together, our findings establish SYT1 as a master regulator of chicken egg production performance via modulation of reproductive hormone synthesis and secretion within the HPO axis. These results position SYT1 polymorphisms as promising genetic markers for selective breeding programs in commercial laying hens improving egg production traits in indigenous chicken breeds.
Medical Management of Obesity: A Comprehensive Review of Food and Drug Administration (FDA)-Approved and Investigational Therapies.
Cureus
Syed S Raza, Zarshal Zakir, Ahmad Hashmat +2 more
The global rise in obesity has accelerated both clinical and pharmaceutical innovation in antiobesity pharmacotherapy. This narrative review synthesizes current evidence on Food and Drug Administration-approved medications and emerging investigational agents that are shaping clinical practice. We summarize mechanisms of action, pivotal efficacy data, safety profiles, indications, prescribing guidance, and key uncertainties. Approved long-term agents, orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, semaglutide, and tirzepatide, differ in mechanism, weight-loss magnitude, and safety considerations. Semaglutide and tirzepatide have redefined expectations for pharmacological weight loss, while next-generation drugs, such as oral glucagon-like peptide 1 receptor agonists (e.g., orforglipron) and multireceptor agonists (e.g., retatrutide), show even greater efficacy in early studies. Common safety concerns include gastrointestinal effects, gallbladder events, pancreatitis risk, thyroid C-cell tumor warnings, teratogenicity, and cost barriers. Appropriate patient selection depends on body mass index, comorbidities, contraindications, and treatment goals, with close monitoring throughout therapy. Long-term data on cardiovascular outcomes and posttreatment weight durability are emerging. Future research should prioritize direct comparative trials, real-world effectiveness, long-term safety, and strategies to improve access and adherence. This review offers clinicians a concise, evidence-based guide for obesity pharmacotherapy and outlines key research priorities as the treatment landscape rapidly evolves.
Incretin impact on gastric function in obesity: physiology, and pharmacological, surgical and endoscopic treatments.
J Physiol
Michael Camilleri
The aims of this review are to appraise the role of the stomach in satiation, the effects of incretin and other hormone agonists on weight loss and the role of altered gastric functions in their effects on obesity or glycaemic control. In addition to the gut in its role in enzymatic digestion and hormonal responses to nutrient ingestion, gastric motor functions include accommodation, trituration and emptying [gastric emptying (GE)] of food and elicitation of postprandial satiation and satiety. The postprandially released hormones most extensively studied and utilized therapeutically are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Their mechanisms of action include stimulation of pancreatic β cells to produce insulin. However, GLP-1 reduces glucagon and slows GE, whereas GIP increases glucagon and does not alter GE. Molecular modifications of GLP-1 (which has a T1/2 of 3 min) led to the development of long-acting subcutaneous or oral pharmacological agents that have been approved for the treatment of obesity, and their effects on gastric function are documented. Other medications in development target other molecular mechanisms, including glucagon and amylin. Small-molecule GLP-1 receptor agonists are promising for the treatment of obesity and may also slow GE. Bariatric surgery and endoscopy increase satiation by restricting gastric size; in addition Roux-en-Y gastric bypass and to a lesser extent sleeve gastrectomy (but not endoscopic gastroplasty) increase postprandial circulating incretins, reducing appetite. In conclusion the stomach's function is integral to the impact of the most effective pharmacological and procedural reversal of obesity related to the incretin revolution.