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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.
Positron emission tomography to assess drug occupancy at peripheral and central incretin receptors.
EBioMedicine
Amina Khalil, Irina Velikyan, Mengfei Xiong +3 more
Incretin mimetics, especially dual/triple agonists, are effective for type 2 diabetes and obesity, though mechanisms remain unclear. This study applied PET using [68Ga]Ga-DO3A-Exendin-4 and [68Ga]S02-GIP-T4 to assess GLP-1R and GIPR occupancy of SAR441255 (a GLP-1R, GIPR, and GCGR agonist) and tirzepatide in pig pancreas and CNS.
Aging and Thymosin Alpha-1.
Int J Mol Sci
Maria A Simonova, Igor Ivanov, Natalia S Shoshina +9 more
Aging is characterized by immune decline, mainly due to thymic involution-the age-related shrinkage of the thymus gland. This leads to reduced T-cell production, chronic inflammation, and increased susceptibility to age-related diseases. Thymosin alpha-1 (Tα1), a peptide hormone produced by the thymus, exhibits potent immunomodulatory, anti-inflammatory, and antioxidant properties. It helps restore immune function by stimulating T-cell differentiation, enhancing thymic output, and modulating dendritic cell and macrophage activity. Preclinical and clinical studies show that Tα1 can improve vaccine response in the elderly and mitigate immunosenescence. The hybrid drug Refnot (a fusion of tumor necrosis factor alpha (TNFα) and Tα1) combines Tα1's immunomodulation with TNF's antitumor activity but has reduced toxicity. It represents a promising therapeutic approach to counteract age-related immune dysfunction and inflammation, potentially by slowing the aging process. Further research is needed to validate its long-term efficacy and safety in geriatrics.
Persistent renin-angiotensin system and inflammatory dysregulation following COVID-19 impairs ischemic stroke recovery.
Exp Mol Pathol
Amy May Lin Quek, Ooiean Teng, Ju-Hea Park +3 more
Previous studies indicate that stroke recovery is worse in patients with prior COVID-19, suggesting persistent biological perturbations. We investigated lingering renin-angiotensin system (RAS) and inflammatory alterations after COVID-19 to uncover mechanisms driving impaired ischemic stroke recovery. We conducted a prospective observational cohort study comparing clinical and molecular profiles of ischemic stroke patients with and without recent COVID-19 infection to age-matched healthy controls. Plasma angiotensin-(1-7), angiotensin II, and soluble ACE2 were quantified, high-throughput proteomic profiling was performed using the Olink® Explore platform, and RNA sequencing was conducted to identify molecular mechanisms related to COVID-19-associated stroke and stroke outcomes (90-day modified Rankin Scale (mRS)). A total of 189 participants (38 COVID-19-associated stroke, 77 non-COVID-19 stroke, and 74 healthy controls) were enrolled. COVID-19-associated stroke patients exhibited significantly higher proportions of cryptogenic strokes (21.1 % vs 10.4 %), earlier hospital presentation (mean 185 vs 310 min), greater use of endovascular thrombectomy (97.4 % vs. 52.6 %), yet poorer functional outcomes (mRS ≥3) at 3 months (73 % vs. 47 %, all p < 0.05). Both stroke groups showed elevated angiotensin-(1-7) levels compared to controls, but angiotensin II levels were notably higher only in non-COVID-19 stroke patients. Proteomic analysis revealed sustained elevation of interferon-gamma (IFN-γ) signaling in COVID-19-associated stroke patients. Reduced AKT3 levels emerged as a significant predictor of poor outcomes, independent of renin-angiotensin biomarkers (adjusted OR 0.40; 95 % CI 0.16-0.94). Stroke patients with low AKT3 levels and poor outcomes exhibited significant upregulation of ribosomal proteins (RPS15, RPS4X, RPS7, RPS18, RPSA, RPS27A, RPS13, RPS23), reflecting heightened translational stress. Persistent RAS and inflammatory dysregulation following COVID-19 may contribute to worse stroke recovery. Future studies should validate and investigate the therapeutic implications of these findings.
Haemostasis and beyond: The expanding role of desmopressin in intensive care.
World J Crit Care Med
Saketh Vinjamuri, Ekta Tiwari, Sahil Kataria +1 more
Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is a synthetic analogue of arginine vasopressin, the body's natural antidiuretic hormone. It acts selectively on V2 receptors, promoting renal water reabsorption and stimulating the release of von Willebrand factor (vWF) and factor VIII, while exerting minimal vasoconstrictive effects through V1 receptors. Developed in the late 1960s and introduced clinically in the early 1970s for the management of central diabetes insipidus, desmopressin was engineered to provide a longer duration of action and reduced cardiovascular side effects compared to native vasopressin. Its haemostatic potential was later recognized when it was observed to enhance endogenous levels of vWF and factor VIII, leading to its incorporation into the treatment of mild haemophilia A and von Willebrand disease (vWD). This unique combination of antidiuretic and prohemostatic properties has broadened its therapeutic role across various clinical settings. In critical care, desmopressin has emerged as a potentially valuable agent in managing complex scenarios such as uremic platelet dysfunction, trauma-associated coagulopathy, intracranial hemorrhage, vWD, and central diabetes insipidus. However, despite its mechanistic appeal and broad pharmacologic utility, the full scope of desmopressin's applications in the intensive care unit (ICU) remains underrecognized. This review aims to provide a comprehensive examination of desmopressin's pharmacological characteristics, evidence-based indications in critically ill patients, therapeutic efficacy, safety profile, and practical considerations for dosing in the ICU setting.
Chronic Stress Segregates Mice into Distinct Behavioral Phenotypes Based on Glucocorticoid Sensitivity.
Int J Mol Sci
Polina Ritter, Rasha Salman, Yuliya Ryabushkina +1 more
Chronic stress alters hypothalamic-pituitary-adrenal (HPA) axis function, affecting corticosterone regulation and adaptive responses. Understanding individual variability in stress adaptation requires identifying distinct HPA axis response patterns. Here, we assessed HPA axis sensitivity in male C57BL6 mice exposed to 30 days of chronic social defeat stress (CSDS). Negative feedback integrity was evaluated using the dexamethasone suppression test (DST), with corticosterone measured after saline or low-dose dexamethasone administration at days 10 and 30. Behavioral testing (open field, elevated plus maze, social interaction test, partition, social defeat, forced swimming test, sucrose preference test) and qPCR analysis of HPA-axis-related genes in the hypothalamus (Crh, Crhr1, Crhbp, Fkbp5, Nr3c1), pituitary (Pomc, Crhr1, Nr3c1, Nr3c2), and adrenal glands (Cyp11a1, Cyp11b1, Hsd11b1, Mc2r, Star, Fkbp5, Nr3c1) were performed. K-means cluster analysis identified three distinct response profiles differing in baseline and dexamethasone-suppressed corticosterone levels. Clusters also exhibited differences in behavioral phenotypes and HPA axis gene expression. Cluster 1 showed low basal corticosterone and an abnormal dexamethasone suppression response, without significant Crh or Crhbp dysregulation in the hypothalamus. Cluster 2 exhibited elevated basal corticosterone, a blunted dexamethasone response, anhedonia, and reduced immobility in the forced swim test; increased Crh and reduced Fkbp5 suggested enhanced glucocorticoid receptor sensitivity and sustained hypercortisolemia. Cluster 3, characterized by normal basal corticosterone and normal dexamethasone response, displayed upregulation of Crh and Crhbp, consistent with balanced and potentially adaptive HPA axis regulation under chronic stress. These results demonstrate that corticosterone response heterogeneity reflects distinct adaptive trajectories under chronic stress. Identifying behavioral and molecular markers of these strategies may advance understanding of stress vulnerability and resilience mechanisms, with implications for stress-related disorders.
Structural and mechanistic divergence in LL-37, HNP-1, and Magainin-2: An integrated computational and biophysical analysis.
Curr Res Struct Biol
Sinethemba H Yakobi, Uchechukwu U Nwodo
Escalating antimicrobial resistance necessitates the development of alternative therapeutics that circumvent conventional enzymatic and efflux-based defence systems. Antimicrobial peptides (AMPs) represent a compelling class of innate immune effectors, however, their clinical translation is hindered by incomplete mechanistic understanding of how structural organization and conformational dynamics shape antimicrobial function. In this study, we performed an integrated comparative analysis of three mechanistically representative AMPs-LL-37, HNP-1, and magainin-2-to resolve how maturation pathways, fold topology, amphipathic architecture, and dynamic target engagement govern antimicrobial action. Consensus secondary-structure prediction, AlphaFold2/PEP-FOLD modelling, and physicochemical profiling revealed three distinct structural signatures. LL-37 exhibited a flexible disorder-to-helix transition enabling adaptive, curvature-driven membrane dissolution, HNP-1 adopted a rigid cysteine-stabilized β-sheet that promotes lipid clustering and entropic inhibition of membrane-associated enzymes, and magainin-2 formed a stable amphipathic α-helix optimized for toroidal pore initiation. Machine-learning classification corroborated strong antimicrobial likelihood for HNP-1 and magainin-2, with LL-37 displaying context-dependent activation. Protein-peptide docking and normal-mode elastic network modelling further demonstrated the possibility of LL-37 allosterically dampening conformational cycling of the MexB efflux pump, HNP-1 restricting catalytic-loop mobility in LpxC, and magainin-2 enhancing correlated β-barrel breathing in OprF to promote pore formation. These findings delineate three mechanistically distinct antimicrobial strategies-adaptive membrane dissolution, rigid pore-stacking inhibition, and dynamic pore initiation-linked directly to peptide structural organization. This framework provides a rational basis for mechanism-guided AMP optimization and the engineering of next-generation membrane-active therapeutics with reduced resistance susceptibility.
Consumption of Unprocessed and Ultraprocessed Foods in Adolescents with Obesity: Associations with Neuroendocrine Mediators of Appetite Regulation and Binge Eating Symptoms.
Nutrients
Patrícia Sousa Neres, Aline de Piano Ganen, Raquel Munhoz da Silveira Campos +4 more
Background/Objectives: Obesity is a multifactorial disease associated with increased consumption of ultraprocessed foods and reduced intake of unprocessed foods. Binge eating, one of the most prevalent eating disorders among adolescents, is closely linked to obesity. Food intake is regulated by both the hedonic system, responsible for reward responses, and the physiological system, which controls hunger and satiety through hormones, such as ghrelin and leptin. The present study aimed to investigate associations between the intake of unprocessed and ultraprocessed foods, neuroendocrine mediators of appetite regulation, and binge eating in adolescents with obesity. Methods: This cross-sectional study included 96 adolescents with obesity who were recruited in São Paulo, Brazil, between 2010 and 2012. Anthropometric and body composition assessments were performed. Binge eating symptoms were evaluated using the binge eating scale (BES), and dietary intake was assessed with a validated Food Frequency Questionnaire, with items classified according to the Nova system. Frequency data were converted into annual consumption scores. Serum levels of ghrelin, leptin, neuropeptide Y (NPY), agouti-related peptide (AgRP), melanin-concentrating hormone (MCH), and alpha-melanocyte-stimulating hormone (α-MSH) were analyzed. Results: Lower consumption of unprocessed foods was associated with higher ghrelin concentrations (p = 0.023), accompanied by a greater percentage of body fat (p = 0.047) and a reduced percentage of lean mass (p = 0.047) compared with adolescents in the second tertile. AgRP was a positive predictor of annual consumption score of ultraprocessed food (β = 0.30; p = 0.04), independent of age, body fat, and binge eating symptoms. Conclusions: In conclusion, lower intake of unprocessed foods was associated with alterations in orexigenic and anorexigenic mediators, suggesting that dietary patterns in adolescents with obesity may influence the neuroendocrine mediators of appetite regulation.
Organokine-Mediated Crosstalk: A Systems Biology Perspective on the Pathogenesis of MASLD-A Narrative Review.
Int J Mol Sci
Sandra Maria Barbalho, Lucas Fornari Laurindo, Vitor Engracia Valenti +3 more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic condition with a complex pathophysiology involving multiple organs. Organokines, including hepatokines, myokines, cardiokines, renokines, osteokines, and adipokines, play central roles in lipid metabolism, glucose homeostasis, inflammation, and fibrosis. Dysregulation of these signaling molecules contributes to the progression of MASLD and its systemic complications. This review examines the role of organokine-mediated crosstalk between the liver and peripheral organs (e.g., muscle, heart, kidneys, bone, and adipose tissue) in the pathogenesis of MASLD. Key molecules, such as myostatin, FGF-21, IL-6, and adiponectin, influence insulin sensitivity, lipid metabolism, and inflammation. Some organokines have protective effects (e.g., FGF-21, irisin, and klotho), while others, such as myostatin and fetuin-A, exacerbate insulin resistance and fibrosis. These findings suggest that targeting organokines could provide potential biomarkers and therapeutic strategies for MASLD. Future research should focus on elucidating the molecular mechanisms and assessing the role of organokines in the prevention and treatment of MASLD.