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Effect of pasteurized Akkermansia muciniphila MucT on insulin sensitivity, body composition, and GLP-1 production in subjects with metabolic syndrome: impact of low baseline gut Akkermansia levels.

Gut Microbes

Peter Suenaert, Anneleen Segers, Leen Rymenans +4 more

Pasteurized Akkermansia muciniphila MucT was found to improve barrier function in preclinical models and a proof-of-concept study in obese and prediabetic adults. Here, we describe the results of a double-blind placebo-controlled multicenter (Ireland and Germany) trial in 142 adults with metabolic syndrome, with or without prediabetes. The primary endpoint of whole-body insulin sensitivity (Matsuda index) did not differ after 4-months of daily administration of capsules containing 30 billion cells of pasteurized A. muciniphila MucT compared to placebo in the intention-to-treat subjects. Subsequent exploratory analyses showed that 3-months intake of pasteurized A. muciniphila MucT already improved HOMA-based hepatic insulin sensitivity in prediabetic (12%; p = 0.05) and 63-y-or-older-age subgroups (p = 0.05) while increasing post-OGTT excursion of the insulinotropic hormone glucagon-like peptide 1 (GLP-1) over placebo (p < 0.01). Further analysis of the gut microbiota by deep metagenomic analysis showed minor effects of the intervention but revealed that the baseline microbial composition differed from that in matched healthy adults. We found that participants with low baseline Akkermansia gene counts experienced significant health improvements and GLP-1 excursion after 3-months of treatment with pasteurized A. muciniphila MucT over the placebo. These benefits included improved insulin sensitivity (as shown by Matsuda and HOMA-S indices) and GLP-1 excursion (post-OGTT) (p < 0.05), reductions in body weight (p = 0.06) and decreased trunk fat (p < 0.05). In conclusion, daily supplementation with pasteurized A. muciniphila MucT has the potential to improve health markers in overweight or obese normo- or dysglycemic adults with the most significant improvements in subjects with low baseline intestinal Akkermansia levels, who are apparently truly in need of this intervention. Clinical trial registration no.: NCT05114018 clinicaltrials.gov.

[Effect of acupuncture on ovarian function in rats with premature ovarian insufficiency based on kisspeptin/GPR54 pathway].

Zhongguo Zhen Jiu

Boya Chang, Long Chen, Qingkai Jin +2 more

To explore the effect of acupuncture on ovarian function in rats with premature ovarian insufficiency (POI) based on kisspeptin/G protein-coupled receptor 54 (GPR54) pathway.

Ectopic ACTH syndrome caused by pheochromocytoma: diagnostic challenges and surgical outcomes in two cases.

BMC Endocr Disord

Zexuan Lv, Yi Wang, Chuan Zhang +6 more

Ectopic adrenocorticotropic hormone (ACTH) syndrome is a rare form of ACTH-dependent Cushing syndrome, most commonly caused by neuroendocrine tumors. Pheochromocytoma is a rare source of ectopic ACTH secretion. Its clinical presentation is often heterogeneous and may lack the typical features of Cushing syndrome, which can lead to delayed diagnosis or misdiagnosis. Increased awareness of this rare entity is essential for early diagnosis and appropriate management.

A Case of Concurrent Autoimmune Thyroiditis and Adrenal Insufficiency Following Nivolumab Therapy for Advanced Renal Cell Carcinoma.

Cureus

Gillian D Dooley, Henry Li, Ihunanya Agomuoh +2 more

Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor (ICI), improves outcomes in advanced renal cell carcinoma (RCC) by enhancing antitumor T-cell activity. Immune activation may result in immune-related adverse events, including endocrine dysfunction. Thyroid abnormalities are commonly observed, whereas adrenal insufficiency is less frequent but clinically significant. We report a 59-year-old man with metastatic chromophobe RCC who developed autoimmune thyroiditis followed by secondary adrenal insufficiency after treatment with nivolumab. Thyroid dysfunction occurred approximately one month after therapy initiation, and adrenal insufficiency developed eight months later, presenting with orthostatic hypotension and severe hyponatremia. Laboratory evaluation demonstrated undetectable cortisol with inappropriately normal adrenocorticotropic hormone, consistent with ICI-related hypophysitis. The hyponatremia improved after fludrocortisone was added to glucocorticoid therapy due to clinical refractoriness. This case highlights the rare occurrence of concurrent endocrine immune-related adverse events during PD-1 inhibitor therapy and underscores the importance of vigilant longitudinal monitoring of endocrine function in patients receiving ICI. Early recognition and prompt multidisciplinary management are essential to prevent life-threatening complications while allowing continuation of effective oncologic therapy.

Dendrobium huoshanense Ameliorates Sleep Deprivation-Induced Ileal Mucus Barrier Dysfunction by Regulating Steroid Hormone Biosynthesis and the HPA Axis in Rats.

Metabolites

Xue Luo, Shuxiang Jin, Yue Fang +3 more

Background/Objectives: Sleep deprivation (SD) induces the accumulation of reactive oxygen species (ROS) in the intestine, causing inflammation in the intestine, thereby damaging the intestinal epithelial barrier function. As a traditional Chinese medicine, Dendrobium huoshanense (DHS) modulates intestinal flora, maintains the intestinal mucosal barrier, and promotes gastrointestinal motility and digestive secretion. However, the role and mechanism of DHS in improving SD-induced intestinal injury have not been fully studied. Methods: The SD model was established by subjecting rats to complete SD using a specialised SD instrument. Hematoxylin and eosin (HE) staining was performed to evaluate pathological injury in ileal tissues. Enzyme-linked immunosorbent assay (ELISA) and biochemical methods were used to quantify the main inflammatory cytokines, oxidative stress markers, and hypothalamic-pituitary-adrenal (HPA) axis activity. The expression levels of E-cadherin and Occludin proteins in the ileum tissue were analyzed by Western blotting. Additionally, the pH value of ileal mucus, unit secretion, water content, and dry matter weight were measured. Differential metabolites in rat ileum mucus were profiled using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Results: DHS alleviated the pathological injury of the ileum induced by SD. DHS reduced the levels of serotonin (5-HT), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), while increasing interleukin-10 (IL-10) levels, thereby attenuating systemic inflammatory responses. Furthermore, DHS decreased malondialdehyde (MDA) content and elevated glutathione (GSH) and superoxide dismutase (SOD) levels in ileal tissues. DHS also upregulated the protein expression of E-cadherin and Occludin in intestinal tissues. In addition, DHS decreased the pH of ileal mucus, promoted intestinal mucus secretion, and increased dry matter content, facilitating the restoration of the mucus barrier. DHS may alleviate SD-induced ileal injury by modulating steroid hormone biosynthesis. DHS decreased the levels of adrenocorticotropic hormone (ACTH), cortisol (CORT), and corticotropin-releasing hormone (CRH), indicating that DHS suppresses the abnormal activation of the hypothalamic-pituitary-adrenal (HPA) axis. Conclusions: In this study, a comprehensive multi-index evaluation showed that DHS could significantly improve the ileal injury caused by SD in rats. The mechanism involved regulating the balance of serum neurotransmitters and inflammatory factors, reducing oxidative stress in tissues, and improving the physicochemical properties of intestinal mucus. Metabolomic analysis further revealed that these protective effects may be mediated via the regulation of steroid hormone biosynthesis pathways and are associated with the inhibition of abnormal HPA axis activation.

Carcinoid Heart Disease: Surgical Timing, Right Ventricular Risk Stratification and Operative Strategy.

J Cardiovasc Dev Dis

Hani Ali-Ghosh, Jason Kho, Fotios Leventis +3 more

Carcinoid heart disease is a progressive right-sided valvulopathy caused by serotonin and other vasoactive mediators released by metastatic neuroendocrine tumours. As oncological therapies have extended survival, cardiac disease has become a leading determinant of mortality. Operative mortality has decreased to 5-6% in contemporary high-volume centres, and long-term survival appears increasingly determined by tumour biology rather than cardiac disease when surgery is appropriately timed. The principal determinant of operative outcome is preoperative right ventricular function; symptom-based referral alone is insufficient because many patients remain compensated until ventricular dysfunction is advanced. This review synthesises the evidence on surgical timing, operative strategy, prosthesis selection, perioperative endocrine management, and emerging transcatheter options. Tricuspid valve replacement is required in the majority of patients, with concomitant pulmonary valve replacement advocated where concurrent disease is present. Bioprosthetic valves are preferred. Continuous perioperative octreotide infusion has substantially reduced the incidence of carcinoid crisis. Structured multidisciplinary decision-making integrating echocardiographic surveillance, biomarker monitoring, and oncological status assessment is essential.

Glucagon-like peptide-1 receptor agonists as a metabolic optimization strategy in surgical prehabilitation: a translational perspective.

Surg Obes Relat Dis

Michael Rouse, Rory Kokelaar, I-Lynn Lee +1 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), including semaglutide and tirzepatide, are increasingly prescribed for obesity and type 2 diabetes and have demonstrated substantial and rapid weight loss in large randomized trials. At the same time, prehabilitation before major abdominal surgery has become an established perioperative strategy to improve postoperative outcomes. This review explores the potential role of GLP-1RAs as a pharmacological adjunct in multimodal surgical prehabilitation. We discuss the biological rationale for metabolic optimization, the relevance of sarcopenic obesity, potential implications for oncological surgery and neoadjuvant therapy, and emerging data from bariatric and metabolic surgery. We also highlight important perioperative safety considerations, particularly delayed gastric emptying and aspiration risk, and current anesthetic guidance. Although integration of GLP-1RAs into prehabilitation pathways is biologically plausible and clinically attractive, there is currently no direct evidence supporting their use in this setting. We propose that GLP-1RAs represent a promising and testable strategy for metabolic optimization in surgical patients. Prospective studies are required to evaluate feasibility, safety, and impact on clinically meaningful outcomes. This framework is hypothesis-generating and aims to inform future translational research at the interface of metabolic medicine and perioperative care.

GLP-1 receptor agonism reduces PTSD-like anxiety and alters amygdala-hippocampal activity patterns in a Chemogenetic mouse model.

Prog Neuropsychopharmacol Biol Psychiatry

Kubra Akillioglu, Seda Kose Korkmaz, Meltem Donmez Kutlu +2 more

Dysregulated glutamatergic transmission within amygdala-hippocampal circuits has been implicated in the pathophysiology of post-traumatic stress disorder (PTSD), yet pharmacological approaches targeting stress-related behavioral and molecular alterations remain limited. In the present study, we examined the effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide in a single prolonged stress (SPS) mouse model of PTSD combined with chemogenetic activation of basolateral amygdala (BLA) glutamatergic neurons using designer receptors exclusively activated by designer drugs (DREADDs). SPS exposure induced anxiety-like behavior in the open field and elevated plus maze tests and was associated with alterations in hippocampal NMDA receptor subunit expression, CREB signaling, and GLP-1 receptor levels. Liraglutide treatment was associated with improved anxiety-related behavioral measures, with more robust effects observed in the open field test. Chemogenetic activation of BLA glutamatergic neurons produced behavioral effects that differed between control and SPS-exposed animals, suggesting state-dependent modulation of BLA-related circuit output. At the molecular level, SPS increased hippocampal NR2B expression, whereas liraglutide treatment was associated with alterations in NR2B, CREB, and GLP-1 receptor expression. Although differences in c-Fos expression were observed in the BLA and hippocampus, none of the pairwise comparisons remained significant after false discovery rate correction; therefore, these findings are considered exploratory. Collectively, these results suggest that GLP-1 receptor agonism may attenuate PTSD-like behavioral abnormalities and modulate molecular pathways related to glutamatergic signaling and synaptic plasticity. However, these findings do not establish direct circuit-level mechanisms, and further studies incorporating cell-type-specific and real-time circuit analyses are required to clarify the underlying neurobiological substrates.

Effects of exercise and liraglutide on vascular health and inflammation during weight loss maintenance: a prespecified secondary analysis of the S-LiTE trial.

Nat Metab

Rasmus Michael Sandsdal, Joachim Holt, Haithem Ghalib Ali Alkhefagie +17 more

Obesity and inactivity are linked to endothelial dysfunction and atherosclerosis. In this secondary analysis of the S-LiTE trial (ClinicalTrials.gov identifier: NCT04122716 ; EudraCT identifier: 2015-005585-32 ), 130 adults with obesity completed a diet-induced weight loss plan, followed by randomization to weight maintenance with exercise and/or liraglutide for 52 weeks. We show that exercise, alone or in combination with liraglutide, reduces carotid intima-media thickness and systemic pro-inflammatory cytokine levels (interleukin-6 and interferon-γ). Combination treatment also improves endothelial function biomarkers (sICAM-1, sVCAM-1 and tPA). Liraglutide alone shows no such improvements. Overall, regular physical activity, with or without GLP-1R agonists, is essential for promoting vascular health in adults with obesity.

Dihydromyricetin alleviates immunosenescence by modulating the TAK1/MAP3K7 Axis.

Exp Gerontol

Huaiyu Duan, Dongmei Li, Xin Shi +8 more

Aging is frequently associated with a progressive loss of physiological integrity, with immunosenescence and chronic inflammation playing pivotal roles in this process. While natural compounds like Dihydromyricetin (DHM) exhibit significant anti-aging potential, its precise upstream immunomodulatory targets and cross-species conservation remain largely elusive. Through a combination of transcriptomic analyses and cross-species assays, we demonstrated that DHM systematically downregulates basal antimicrobial peptide expression to resolve chronic inflammaging in Drosophila, while simultaneously maintaining robust acute pathogen clearance. Furthermore, DHM significantly suppressed the senescence-associated secretory phenotype (SASP) in a mammalian H₂O₂-induced stress-induced premature senescence (SIPS) model. Crucially, genetic silencing revealed that the immune-regulatory kinase TAK1 (and its mammalian homolog MAP3K7) is fundamentally required for the lifespan-extending benefits of DHM in Drosophila and mediates the suppression of key SASP components, such as IL-1β and IL-8, in mammalian fibroblasts. These findings suggest that the TAK1/MAP3K7 axis serves as a crucial conserved node mediating a significant portion of DHM's cross-species anti-aging effects. This study underscores the therapeutic potential of targeting the TAK1 axis with natural compounds to combat age-related immune dysregulation.

Tirzepatide, a dual GIP/GLP-1 receptor agonist, attenuates endothelial dysfunction and angiotensin II-induced abdominal aortic aneurysm in ApoE-/- mice.

Pharmacol Res

Álvaro Gómez-Martín, Patrice Marques, Cristina Arce-Recatalá +6 more

Endothelial dysfunction is a critical initiating event in abdominal aortic aneurysm (AAA), a condition posing a high risk of a fatal rupture. Dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists have emerged as potent treatments for diabetes and obesity, with clinical evidence suggesting broader cardiovascular benefits. However, the direct impact of tirzepatide (dual GLP-1R/GIPR agonist) on endothelial dysfunction and AAA pathogenesis remains poorly understood. We investigated the effects of dual GLP-1R/GIPR agonism on endothelial dysfunction and AAA development. We employed parallel-plate flow chamber assays to evaluate the effects of tirzepatide on TNFα-induced leukocyte-endothelium interactions. Expression of GLP-1R, GIPR, adhesion molecules (VCAM-1 and ICAM-1), and NF-κB activation was quantified using immunofluorescence and western blotting. The in vivo efficacy of tirzepatide was assessed using an angiotensin-II-infused apoE-/- mouse model of AAA. GLP-1R and GIPR were expressed in human endothelial cells and murine suprarenal aortas. Tirzepatide significantly attenuated TNFα-induced leukocyte-endothelium interactions, downregulated VCAM-1/ICAM-1/CX3CL1 expression, and inhibited the mRNA expression and generation of MCP-1 and RANTES. Mechanistically, these effects were driven by the suppression of NF-κB activation. Chronic subcutaneous administration of tirzepatide over 28 days significantly limited suprarenal aortic expansion and reduced AAA incidence in Ang-II-infused mice. This vasoprotective effect was characterized by preserved elastin integrity, reduced neovessel formation, and diminished macrophage accumulation within the aneurysmal wall. Dual GLP-1R/GIPR agonism mitigates endothelial dysfunction and suppresses inflammatory pathways driving AAA progression. These findings position tirzepatide as a promising therapeutic strategy for the prevention of vascular remodeling and AAA development.

Case Report: Effect of setmelanotide treatment in a young patient with acquired hypothalamic obesity following Escherichia coli sepsis and meningoencephalitis with brain abscess.

Front Endocrinol (Lausanne)

Hajar Dauleh, Khalid Hussain

Acquired hypothalamic obesity (aHO) is a rare and severe condition caused by injury to hypothalamic centers regulating appetite, energy balance, and neuroendocrine function. It is characterized by rapid weight gain, hyperphagia, and significant metabolic complications, and current treatment options remain limited. We report the case of a 22-month-old child who developed severe acquired hypothalamic obesity following neonatal Escherichia coli sepsis complicated by meningoencephalitis and brain abscess. Treatment with the melanocortin-4 receptor agonist setmelanotide was initiated at 0.25 mg daily and gradually titrated to 1.5 mg. Over 13 months of treatment, the patient experienced stabilization and a subsequent reduction in body weight, improvement in liver enzymes and lipid profile, increased motor activity, and marked improvements in interaction and quality of life. The most pronounced clinical response occurred at doses ≥1.25 mg daily. This case represents, to our knowledge, the youngest reported patient treated with setmelanotide and the first case of inflammation-related acquired hypothalamic obesity treated with this therapy. These findings suggest that setmelanotide may represent a promising therapeutic strategy for selected patients with acquired hypothalamic obesity beyond currently approved genetic indications.

Corticotropin-Releasing Factor-Dependent Synaptic Plasticity In Acute Stress: From Rapid Signaling To Circuit Remodeling And Allostatic Load.

Neurosci Biobehav Rev

Dorien Vandael, Natalia V Gounko

Stress enables organisms to adapt to changing environments, but repeated or poorly resolved stress can shift adaptive plasticity toward maladaptive overload. Corticotropin-releasing factor (CRF), also termed corticotropin-releasing hormone (CRH) in endocrine contexts, plays an established role in the hypothalamic-pituitary-adrenal (HPA) axis. Beyond this endocrine role, CRF acts as a neuromodulator in limbic brain circuits, where it can rapidly regulate neuronal communication. Evidence from hippocampal and related limbic circuits shows that CRF can increase neuronal excitability, regulate neurotransmitter release, remodel dendritic spines, and influence long-term synaptic plasticity. These effects suggest that CRF helps establish cellular conditions required for stress-related learning and circuit adaptation. Current models support a temporally layered view of the stress response, in which rapid CRF-dependent signaling interacts with slower glucocorticoid-dependent transcriptional and structural remodeling. Understanding when acute CRF signaling supports adaptive plasticity and when it instead contributes to allostatic load may clarify the transition from resilience to pathology. This review frames CRF not as a generalized stress signal, but as a temporally and spatially organized modulator whose effects depend on circuit architecture, stressor type, receptor context, developmental and experiential history, and interactions with other neuropeptide systems.

Organization and Dynamics of Focal Adhesions: Light Diffraction Analysis of Cellular Adhesion on Nanopatterned Surfaces.

ACS Appl Mater Interfaces

Inna Szekacs, Szabolcs Novák, Boglarka Kovacs +6 more

This study presents the first application of nanophotonic sensing modality for investigating live-cell adhesion, introducing a novel label-free optical method to monitor specific nanoscale structural changes at the cell-substrate interface. Our method utilizes receptor molecules immobilized in a diffraction pattern with a precise submicron periodicity, which provides superior sensing volume confinement through the spatial lock-in amplification principle. This internal nanoscale ruler enables the investigation of otherwise diffraction-limited phenomena with higher specificity and reduced background noise, ultimately providing more insight into nanoscale adhesion organization dynamics. To complement this approach, resonant waveguide grating (RWG) biosensing and holographic microscopy were used to characterize adhesion behavior and morphological changes of HeLa cells on RGD-functionalized substrates. The nanophotonic readout revealed distinct multistep adhesion dynamics associated with integrin clustering, nanoscale redistribution of adhesion-associated molecular assemblies, and focal adhesion remodeling. Quantitative analysis estimated that approximately 1.22 × 106 RGD-specific integrins contributed to the coherent adhesion signal per HeLa cell within 2 h of adhesion, while the measured redistribution dynamics corresponded to an effective velocity of approximately 0.09 μm/h. Enzymatic digestion of the glycocalyx with neuraminidase significantly altered adhesion behavior, highlighting the importance of membrane organization in integrin-mediated adhesion. Furthermore, histamine stimulation modulated adhesion dynamics and induced cytoskeleton-associated remodeling responses that depended on the prior adhesion time. Together, these results demonstrate the sensitivity of this diffraction-engineered sensing strategy to subtle mechanobiologically regulated changes in the cellular microenvironment and establish its potential as a powerful tool for real-time studies of the biophysical regulation of cell adhesion and receptor-mediated signaling.

FGF21 Analogues and MASLD: A Summary of Preclinical and Clinical Data.

Curr Pharm Des

Chrysoula Boutari, Achilleas Triantafyllou, Lavrentis Papalavrentios +2 more

Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) is the most frequent chronic liver disease, which is closely associated with metabolic syndrome and obesity. Although it has now reached epidemic proportions, the treatment of this disease remains a challenge. Currently, there is only one drug approved for metabolic dysfunction-associated steatohepatitis (MASH), and various pharmaceutical agents have reached phase 3 of clinical trials and appear as potential drugs for the disease. Fibroblast Growth Factor (FGF) 21 has been gaining increasing interest as a possible therapeutic target for MASLD. FGF21 analogues, with an improved pharmacodynamic and pharmacokinetic profile, exert pleiotropic, favorable effects on liver function and histology, as well as systemic metabolism. They also appear to be effective in alleviating hepatic steatosis, steatohepatitis, and fibrosis in MASH. Among various others, efruxifermin, pegozafermin, pegbelfermin, and BOS-580 are FGF-21 analogues that have resulted in significant improvements in liver fat, fibrosis, and measures of liver function in the context of phase 2 clinical trials. This review summarizes the preclinical and clinical data from FGF21 analogues for MASLD and MASH.

Accumulation of membrane repair-associated proteins and mature myostatin are novel markers of muscle pathophysiology in Pompe disease.

Acta Neuropathol Commun

Candice Babarit, Sabrina Jagot, Cindy Schleder +25 more

Pompe disease is an autosomal recessive metabolic disorder caused by acid alpha-glucosidase deficiency, characterized by progressive skeletal muscle weakness and respiratory insufficiency. Affected muscles exhibit glycogen-filled lysosomes, autophagic build-up, and mitochondrial abnormalities. Despite global myofibrillar disorganization, satellite cells (SCs) fail to activate, due to mechanisms that remain unclear. This study aimed to further characterize the muscle phenotype in Pompe disease, with particular attention to proteins associated with membrane repair processes, as membrane damage is a primary trigger for SC activation. Longitudinal transcriptomic analysis of skeletal muscle from a Pompe disease mouse model, combined with immunohistochemical and biochemical approaches, showed early and sustained overexpression of dysferlin (DYSF), annexin A2 (ANXA2), and AHNAK2. These membrane repair-associated proteins displayed abnormal localization during disease progression, with sarcoplasmic accumulation associated with T-tubules, lysosomes and autophagosomes, respectively. Analysis of muscle biopsies from some patients with late-onset Pompe disease (LOPD) identified similar expression patterns in moderately affected cases, whereas these patterns were less evident or absent in the most severe samples, suggesting stage-dependent redistribution associated with advanced myoarchitectural disorganization. Furthermore, in the mouse model, we observed persistent post-transcriptional accumulation of mature myostatin (MSTN), a key negative regulator of muscle growth, alongside a decrease in the phospho-SMAD3/SMAD3 ratio and reduced SMAD7 expression, which point toward a more complex modulation of its canonical bioactivity rather than a simple increase. Altogether, these findings identify modified distribution proteins linked to membrane repair and dysregulation of MSTN as features of muscle remodeling in Pompe disease.

Role of NUDT3 in skeletal myogenesis and association of regulatory genetic variants with carcass traits in pigs.

Zool Res

Ya-Long An, Yong-Qi Yue, Yang Li +6 more

Skeletal muscle is central to locomotor function and metabolic regulation in humans and constitutes a primary source of high-quality protein in livestock production. While genome-wide association studies (GWAS) have identified a strong association between Nudix-type hydrolase 3 ( NUDT3) and lean mass in both human ( Homo sapiens) and pig ( Sus scrofa) populations, its functional role in myogenesis remains unclear. In the present study, silencing of NUDT3 in porcine muscle satellite cells (PMSCs) markedly impaired proliferative capacity, as evidenced by G 1 stage accumulation and reduction in EdU + cells. Concomitantly, knockdown of NUDT3 significantly suppressed myogenic differentiation, while NUDT3 overexpression yielded the opposite effects. In vivo, overexpression of NUDT3 in tibialis anterior (TA) muscle of mice ( Mus musculus) significantly increased the abundance of Pax7 + and eMyHC + cells following cardiotoxin-induced injury, thereby promoting regenerative myogenesis. Transcriptomic profiling demonstrated that NUDT3 significantly attenuated NF-κB signaling in a Nudix motif-dependent manner, providing mechanistic insight into its pro-myogenic function. Integrative co-localization of GWAS and expression quantitative trait locus (eQTL) signals identified eight single nucleotide polymorphisms (SNPs) significantly associated with NUDT3 expression in porcine muscle, including four variants located within evolutionarily conserved E6 and E7 enhancer elements supported by HiCuT profiling of H3K27ac and CRISPR interference assays. Among these, rs327612517 within E7 showed significant association with loin muscle area and depth in PigBiobank data and modulated E7 enhancer activity, as demonstrated by dual-luciferase reporter and electrophoretic mobility shift assays. Collectively, these findings establish NUDT3 as a positive regulator of skeletal myogenesis and identify rs327612517 as a functional variant with potential utility for genetic improvement of lean yield in pigs.

The Impact of Missed Doses on Pharmacokinetic Concentrations for Oral Semaglutide in Comparison to Other Glucagon-Like Peptide-1-Based Therapies.

Diabetes Obes Metab

Rune Viig Overgaard, Henrik Agersø, Christian Hollensen +2 more

Hepatic Safety of Orforglipron in Adults With Obesity or Overweight and/or Type 2 Diabetes: A Pooled Analysis of the Orforglipron Phase 3 Clinical Trials.

Diabetes Obes Metab

Sean Wharton, Adam Stefanski, Jiaxun Chen +3 more

Orforglipron is a novel small-molecule, once daily oral non-peptide GLP-1 receptor agonist. The hepatic safety profile in adults with obesity or overweight and/or type 2 diabetes (T2D) across seven orforglipron Phase 3 clinical trials was assessed.

Semaglutide and major adverse cardiovascular events in patients with and without DM: A systematic review and meta-analysis.

Biomed Rep

Yanhua Li, Chunmei Lv, Lianlian Cao +2 more

Semaglutide, a once-weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA), has been associated with cardiovascular benefits, whereas the consistency of its effect across various clinical settings, as well as its safety-economic profile, remains uncertain. MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform were searched up to January 2025 and identified 11 randomized controlled trials (12 comparisons; 25,067 participants) comparing semaglutide with placebo or active control. Using a DerSimonian-Laird random-effects model, semaglutide reduced major adverse cardiovascular events by 32% [pooled odds ratio (OR)=0.68; 95%; confidence interval 0.52-0.91; 95% prediction interval 0.44-1.04]. Point estimates remained unchanged after censoring all STEP obesity trials (OR=0.70) or both heart-failure trials (OR=0.66), indicating a negligible institution-level effect. Mixed-effects meta-regression analysis revealed greater benefit with lower body weight, LDL- and total cholesterol levels, and lesser benefit with higher age, HbA1c and blood pressure (all P<0.01). Safety pooling found higher risks of any gastrointestinal (GI) disorder [relative risk (RR)=1.47], gallbladder events (RR=2.37), and discontinuation due to GI intolerance (RR 2.32). A total of seven out of 11 trials enrolled ≥75% White patients, none of whom were from low-income countries, limiting generalizability. Besides, U.S. cost-utility models published in the literature report incremental cost-effectiveness ratios of US$ 180,000-260,000 per quality-adjusted life-year, above conventional willingness-to-pay thresholds. Overall, semaglutide demonstrated marked cardiovascular risk reduction at all doses and across all populations, with low statistical heterogeneity. However, this benefit must be weighed against GI intolerance, limited racial and geographic representation and uncertain cost-effectiveness outside high-income regions. Future trials must oversample underrepresented minorities, extend to low- and middle-income regions, and include formal economic evaluations to further refine population-specific benefit-risk profiles and value estimates.