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Neudesin modulates IGF1 and insulin signaling pathways by regulating the surface expression of IGF1R through a conserved WPE motif.
FEBS J
Yoshiaki Nakayama, Motohiro Nonaka, Yuki Masuda +13 more
Neudesin, a secreted protein implicated in diverse physiological processes, such as metabolism and immunity, lacks an identified receptor, which has prevented a detailed understanding of its molecular mechanisms. In this study, we aimed to elucidate the function of neudesin by identifying its cognate receptor and investigating its effects on cellular signaling. Using a combination of phage display, bioinformatics, and biochemical analysis, we identified insulin-like growth factor 1 receptor (IGF1R) as a high-affinity receptor for neudesin, with a binding affinity of 1.78 ± 1.87 nm. This interaction was mediated by a conserved tryptophan-proline-glutamic acid (WPE) motif in the IGF1R extracellular domain. Our cellular assays revealed that, while neudesin binding to IGF1R induces basal phosphorylation of the downstream signaling molecules extracellular signal-regulated kinase (ERK) and AKT (also known as Protein Kinase B, or PKB) in a cell-line-specific manner, it consistently acts as a negative modulator, attenuating both IGF1- and insulin-induced signaling. Mechanistically, neudesin promoted the downregulation of cell surface IGF1R, thereby reducing the receptor pool available for ligand stimulation. Furthermore, neudesin inhibited insulin signaling, likely through the co-internalization of IGF1R/insulin receptor (INSR) hybrid complexes. The physiological significance of this role was underscored in 3 T3-L1 adipocytes, where neudesin knockdown enhanced insulin-induced signaling and accelerated triglyceride accumulation. These results establish a novel molecular link between neudesin and the IGF1/insulin signaling axis, suggesting that neudesin may serve as an endogenous modulator of IGF1R/insulin activity, with potential implications for metabolic and growth-related diseases.
Defective transcription of AAGAG satellite DNA causes sex-ratio meiotic drive in Drosophila.
Nat Commun
Tomohiro Kumon, Mami Nakamizo-Dojo, Amelie A Raz +3 more
Male germ cells have complex transcriptomes, with a large fraction of the genome being transcribed. This includes protein-coding genes (often not translated), non-coding DNA, and repetitive DNA, such as transposons and satellite DNA, which are normally silenced as heterochromatin. The significance of such widespread transcription remains unknown. Here, we show that a heterochromatin protein, HP2, is required for the transcription of AAGAG satellite DNA in Drosophila spermatocytes. HP2 depletion leads to abnormal retention of heterochromatin histone marks (H3K9me3) and spermatid death during sperm DNA packaging, leading to a model that transcription of AAGAG satellite DNA facilitates the remodeling of its heterochromatic nature in preparation for sperm DNA packaging. Strikingly, the severity of the spermatid death correlates with the amount of AAGAG satellite DNA carried by the spermatids, leading to preferential death of Y-chromosome-containing spermatids over X-containing spermatids, and hence sex-ratio meiotic drive phenotype. We propose that widespread spermatocyte transcription may reflect the process of chromatin remodeling to allow sperm DNA packaging. We further propose that differential composition and amount of satellite DNA on chromosomes may underlie naturally occurring male meiotic drive.
Cardiovascular outcomes of glucagon-like peptide-1 receptor agonists: A systematic review.
Am J Health Syst Pharm
Nicoline Bihelek, Sarah Burke, Arden R Barry
To identify and evaluate cardiovascular outcome trials for glucagon-like peptide-1 receptor agonists (GLP1RAs) in various patient populations, including those with or without type 2 diabetes (T2D).
Mapping Global Research on Adverse Effects of GLP-1 Receptor Agonists (2006-2025): A Scopus-Based Bibliometric and Thematic Analysis.
Inquiry
Riad Mohammed Abdelrahman, Taha Hussein Musa, Ismail Adam Arbab +5 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for managing type 2 diabetes and obesity. As their clinical applications expand, interest in their safety and adverse effects has grown. This study provides a comprehensive bibliometric analysis of global research trends, collaboration patterns, and thematic evolution on GLP-1RA-related adverse effects from 2006 to 2025. This study is a bibliometric analysis. Data were extracted from the Scopus database and analyzed using Bibliometrix (R package) and VOS viewer. Indicators assessed included publication and citation metrics, institutional productivity, and keyword co-occurrence and mapping. Correlations were evaluated using Pearson and Spearman tests, and the Durbin-Watson statistic was applied to assess the independence of residuals. A total of 1075 articles published in 389 journals were identified, authored by 6068 researchers across 85 countries. The annual growth rate was 32.06%, with no single-author papers and 34.23% international co-authorship, indicating strong global collaboration. The United States (30.5%), the United Kingdom (10.6%), and Denmark (7.8%) led in publication output and total citations. Institutional analysis identified Novo Nordisk A/S (60 papers, 11 207 citations) and Eli Lilly & Co. (45 papers, 9948 citations) as the most influential contributors. Diabetes, Obesity and Metabolism published the most articles (n = 106), followed by Diabetes Care and The Lancet Diabetes & Endocrinology. Significant correlations were found between article count and h-index (r = .677, P < .001) and total citations (r = .779, P < .001). Keyword analysis revealed 2 main thematic clusters-one pharmacological (drug safety, efficacy, liraglutide, semaglutide) and 1 clinical (human, male, female, adult)-with an emerging focus on population-specific safety since 2021. Research on GLP-1RA-related adverse effects has expanded rapidly, shaped by strong international collaboration and industry-academic partnerships. Future efforts should prioritize balanced global participation, real-world safety data, and mechanistic insights to inform clinical practice and pharmacovigilance.
GLP-1 agonists and changes in body mass and composition in adults with overweight or obesity with or without type 2 diabetes mellitus: a systematic review and meta-analysis.
Int J Obes (Lond)
Nadia Sawicka-Gutaj, Dawid Gruszczyński, Kacper Nijakowski +5 more
The systematic review aimed to assess the effects of GLP-1 receptor agonists (GLP-1 RA) and dual GLP-1/GIP agonists on weight loss and body composition in individuals with overweight or obesity, with or without type 2 diabetes mellitus.
From Skin to Brain: Antagonism and Parallelism in the MCH and MSH Systems.
Ann N Y Acad Sci
Amal Alachkar, Olivier Civelli
The melanin-concentrating hormone (MCH) and melanocyte-stimulating hormone (MSH, α-MSH) systems are examples of functional antagonism built upon mechanistic parallelism. Evolved from light-responsive pigment mechanisms, these peptides were repurposed into hypothalamic circuits regulating energy balance, circadian rhythms, and complex behaviors. Their antagonism manifests across multiple biological scales. In the skin, MCH induces melanosome aggregation in low light, whereas MSH promotes their dispersion for ultraviolet protection. In the brain, this pigmentary logic was repurposed into circadian and metabolic regulation: MCH promotes feeding, energy conservation, and sleep, while MSH drives satiety, thermogenesis, and wakefulness. Strikingly, their antagonism extends to subcellular organelles. MCH shortens neuronal primary cilia, whereas MSH elongates them, paralleling their opposite actions on melanosomes. Both processes depend on cAMP-PKA-regulated microtubule transport, reflecting a conserved cellular architecture probably rooted in the shared neural crest origins of melanocytes and neurons. Importantly, these pathways remain tightly entrained to the circadian clock, translating external light-dark cycles into rhythmic control of skin pigmentation and the body's internal metabolic state. Disruptions of these systems contribute to diverse metabolic and neuropsychiatric disorders, often through opposite imbalances of signaling, and understanding this deep evolutionary continuity reveals new therapeutic targets, from receptor ligands to circadian interventions and cilia-targeted therapies.
Immunosenescence and Inflammaging: From Pathological Hallmarks to Rejuvenation Strategies.
J Gerontol A Biol Sci Med Sci
Yaoli Hou, Zhiying Zeng, Sheng He +8 more
Immunosenescence-the age-related decline of immune function-drives a state of chronic, sterile inflammation termed inflammaging. Far from passive deterioration, this process is actively orchestrated by distinct but interconnected hallmarks: erosion of lymphoid organs, myeloid-biased hematopoiesis, accumulation of immune-evasive senescent cells, and metabolic-epigenetic reprogramming that locks cells into dysfunctional states. These core nodes form a self-perpetuating cycle that propagates pathology across multiple organ systems, fueling neurodegeneration, cancer, musculoskeletal decline, and gut dysbiosis. Critically, the field has transitioned from descriptive phenomenology to mechanism-based intervention. This review synthesizes emerging therapeutic strategies targeting specific nodes of the immunosenescence network. We examine senotherapeutics that sensitize senescent cells for immune clearance, HSC and thymic rejuvenation to restore lymphocyte production, and metabolic-epigenetic interventions to correct intracellular deficits. By integrating these insights, we propose a precision medicine framework that moves beyond broad immunosuppression toward rational combinatorial regimens. This roadmap aims to decouple protective immunity from pathological drivers, extending healthspan and redefining the paradigm of geriatric care.
The sleeping threat: targeting cancer dormancy to transform metastasis therapy.
Nat Rev Cancer
Julio A Aguirre-Ghiso, Jose Javier Bravo-Cordero, Wenjun Guo +2 more
Metastatic cancer cell dormancy, wherein disseminated cancer cells (DCCs) persist in a quiescent state before reactivating to fuel metastasis, has emerged as a critical determinant of cancer relapse. In this Review, we synthesize recent advances in understanding the microenvironmental drivers of dormancy, including the role of niche-derived signals and extracellular matrix composition in maintaining DCC quiescence, as well as the epigenetic and transcriptional programmes, and chromatin remodelling that enforce and sustain dormancy. We also cover the mechanisms by which dormant DCCs evade immune surveillance, highlighting both innate and adaptive immune interactions, and the strategies tumours use to escape immune-mediated clearance. Although most data come from solid cancers, we also examine the biology of residual cells in haematologic malignancies that share key dormancy and relapse mechanisms with solid tumours. We also discuss how, despite these mechanistic insights, clinical translation remains limited, as available biomarkers or therapies targeting dormancy have yet to be effectively implemented. We conclude that by outlining the challenges and opportunities for leveraging dormancy biology, we may be able to prevent metastatic recurrence and improve patient outcomes.
Apelin-13 alleviates post-infarction injury by modulating macrophage inflammation via APJ-dependent inhibition of NLRP3-mediated pyroptosis.
Int Immunopharmacol
Xian-Jie Xu, Kuo Shen, Yu-Jie Ma +10 more
Sustained macrophage-driven inflammation critically exacerbates post-infarction myocardial injury and remodeling. While Apelin-13 (A13) is known for its cardiovascular benefits, its direct immunomodulatory role on macrophages after myocardial infarction (MI) remains undefined.
Mechanisms and Efficacy of Massage Therapy for Post-Exercise Muscle Repair: A Narrative Review.
Muscles
Peter M Tiidus
Although widely used, massage has not been reported to be effective in enhancing recovery from exercise-induced muscle damage in humans. Studies using massage-like interventions in animal models have, in contrast, consistently demonstrated a significant enhancement of muscle repair, reduction in muscle inflammation and enhanced return of muscle force following muscle damage. The physiology of muscle damage and repair and the putative physiological mechanisms of potential massage-induced muscle repair and post-damage recovery, including soreness sensation, edema, inflammation, protein synthesis and other related mechanisms, are reviewed in this context. Animal models have demonstrated that massage effectiveness in enhancing post-damage muscle repair is dictated by the timing, duration, force and technique of its application and may also be modified by age and sex effects. The potentially very narrow "window of effectiveness" of massage application for the enhancement of post-damage muscle repair in humans has yet to be defined. And the lack of demonstrated effectiveness for massage on post-damage muscle recovery may be due to the wide range and inconsistency of massage techniques, timing and methodologies applied in human studies. Until a specific massage application protocol is defined for massage efficacy in post-damage human muscle recovery, therapists will continue to work blind, using a variety of techniques which lack empirical validity and have an undemonstrated effectiveness for enhancing muscle repair.
Efficacy and safety of semaglutide injection in Indian patients with type 2 diabetes mellitus inadequately controlled on metformin: a phase 3, randomized, active-controlled trial (SIZE-DM study).
Cardiovasc Diabetol Endocrinol Rep
Nitin Kapoor, Shehla Shaikh, Saptarshi Bhattacharya +26 more
This study evaluated the efficacy and safety of generic semaglutide compared with innovator Semaglutide in Indian adults with type 2 diabetes mellitus (T2DM).
Persistence-Dependent Effectiveness of Tirzepatide on the Cardio-Metabolic-Kidney Syndrome Outcomes in Obesity: Real-World Evidence from the United Arab Emirates.
Diabetes Ther
Imran Rashid Rangraze, Mohamed El-Tanani, Andrej Janez +9 more
Tirzepatide has been associated with significant reductions in body weight in randomized clinical trials. However, real-world evidence evaluating the multisystemic effects of tirzepatide across the cardio-metabolic-kidney (CKM) continuum remains limited. The aim of this study was to assess the real-world persistence-driven cumulative benefits of tirzepatide beyond weight reduction in adults with obesity but without type 2 diabetes mellitus (T2DM).
Real-World Comparison of Short-Term Adverse Events, Treatment Persistence, and Efficacy of Semaglutide and Tirzepatide: A Nationwide Multicenter Study.
Obes Facts
Sema Hepşen, Cem Haymana, Gizem Ertepe Küçükgöde +78 more
Real-world data directly comparing the safety, tolerability, and effectiveness of semaglutide and tirzepatide in patients with obesity remain limited. This nationwide multicenter observational study compared short-term adverse events, treatment discontinuation, body weight loss (BWL), and metabolic outcomes between the two treatments.
Mechanistic Insights Into OSM and IL-31 in Primary Localized Cutaneous Amyloidosis: A Narrative Review.
Int J Dermatol
Yi Teng, Xingli Zhou, Yue Xiao +3 more
Primary localized cutaneous amyloidosis (PLCA) is a chronic pruritic dermatological disorder characterized by amyloid deposits in the papillary dermis, significantly impairing patients' quality of life. Although the pathogenesis of PLCA is multifaceted, emerging evidence highlights the pivotal role of dysregulated cytokines, particularly the members of interleukin-6 (IL-6) cytokines family in PLCA. Oncostatin M (OSM) mediates keratinocyte proliferation through the STAT5-KLF7 axis upon OSMRβ engagement. Pathogenic variants in OSMR disrupt receptor dimerization, thereby suppressing signal transduction. These alterations together with cytokine dysregulation concomitantly elevate the expression of AHNAK and suppress that of Bcl-xL, which accelerate keratinocyte differentiation and apoptosis respectively, leading to the thickening of the stratum corneum and amyloid fibril deposition. Furthermore, dysregulated expression of chemokine monocyte chemoattractant protein-1 (MCP-1) by pathogenic variant in IL-31RA reduces monocyte-mediated clearance of amyloid fibrils, thereby promoting their pathological retention. The mechanisms of IL-31-mediated pruritus remain to be elucidated, given the conflicting observations that while some studies report wider cutaneous innervation in FPLCA patients, others demonstrate opposing results in general lichen amyloidosis patients. This review aims to synthesize recent advances in understanding PLCA pathogenesis with a focus on IL-31 and OSM cytokines network dysregulation especially driven by pathogenic variants, and provide critical insights for identifying therapeutic targets and put forward challenges in the future.
Correlates and Prognostic Value of Serial N-Terminal Pro-B-Type Natriuretic Peptide Assay in Congenitally Corrected Transposition of the Great Arteries.
J Am Heart Assoc
Ahmed Bahnasy, Meena Bai, Sara Aboelmaaty +5 more
Cardiovascular biomarkers such as NT-proBNP (N-terminal pro-B-type natriuretic peptide) are used for heart failure risk stratification in patients with acquired heart disease, but there are limited data about its role in patients with congenitally corrected transposition of the great arteries. The current study aims to assess the role of serial NT-proBNP measurements for risk stratification in adults with congenitally corrected transposition of the great arteries.
Prognostic value of cardiopulmonary exercise testing parameters in young heart failure patients with moderately reduced exercise capacity.
JHLT Open
Shotaro Komeyama, Osamu Seguchi, Makoto Murata +10 more
Exercise capacity, evaluated using cardiopulmonary exercise testing (CPET), is an important prognostic factor in ambulatory heart failure (HF) patients. However, interpreting the results of CPET in young, ambulatory HF patients who tend to be optimistic about their prognosis is complicated. This study aimed to assess the clinical impact of CPET parameters in predicting the prognosis of young, ambulatory HF patients.
Evaluating the Use of GLP-1 Receptor Agonists in Wolfram syndrome Patients.
medRxiv
Laura Lee, Abby F Tang, Anna Asako +8 more
Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene, characterized by early-onset diabetes mellitus, optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and progressive neurodegeneration. The condition selectively affects pancreatic β cells and neurons via chronic endoplasmic reticulum (ER) stress, and no proven disease-modifying therapy currently exists. Diabetes mellitus is typically the first manifestation, presenting at a mean age of 6 years as an insulin-dependent phenotype with preserved C-peptide and negative diabetes-related autoantibodies. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well-established agents in the management of type 2 diabetes, augmenting glucose-dependent insulin secretion, suppressing glucagon, slowing gastric emptying, and promoting satiety. Preclinical evidence further suggests that GLP-1 RAs preserve β-cell mass, attenuate ER stress, and confer neuroprotective effects, properties of particular therapeutic relevance to Wolfram syndrome. We conducted a retrospective cohort study of 84 participants with genetically confirmed Wolfram syndrome and insulin-dependent diabetes mellitus enrolled in the Washington University Wolfram Syndrome International Registry and Clinical Study. Clinical data were extracted from medical records; for participants concurrently enrolled in the Tracking Neurodegeneration in Early Wolfram Syndrome study, longitudinal data were obtained from that source as well. Thirty-five percent of eligible participants had received a GLP-1 RA at some point during follow-up. We characterize the prevalence of GLP-1 RA use, documented rationale for initiation, observed effects on glycemic control and visual outcomes, adverse effects, and reasons for discontinuation. No statistically significant changes in hemoglobin A1c (HbA1c) or body mass index (BMI) were observed. Visual acuity declined significantly at two years, consistent with expected disease progression. Gastrointestinal adverse effects were common and contributed to frequent discontinuation. These observational data provide important clinical context and a foundation for future prospective trials evaluating GLP-1 RAs as a potential disease-modifying strategy in Wolfram syndrome.
Modest Contribution of Bradykinin to Blood Pressure Reduction by Sacubitril/Valsartan in Chronic Heart Failure.
Circ Heart Fail
Deepak K Gupta, Lynne W Stevenson, Erica M Garner +6 more
Symptomatic hypotension can limit sacubitril/valsartan therapy. Neprilysin inhibition may augment vasodilators, such as bradykinin. We hypothesized that bradykinin contributes to blood pressure (BP) lowering with sacubitril/valsartan in stable ambulatory patients with heart failure and reduced ejection fraction <50%.
Cav3.1 is a neuronal leucine sensor that mediates satiety and weight loss in response to dietary protein.
Cell Metab
Anthony H Tsang, Nicholas Heeley, Constanza Alcaino +18 more
Dietary protein promotes satiety and weight loss, yet how appetite-regulating neurons sense dietary protein remains poorly understood. Here, we show that Cacna1g, which encodes the T-type voltage-gated calcium channel Cav3.1, is enriched in hypothalamic leucine-sensing neurons and mediates neuronal leucine sensing. Pharmacological inhibition of Cav3.1 blunts leucine-induced activation of pro-opiomelanocortin (POMC) neurons in cultured neurons and brain slices, thereby suppressing the anorectic response to hypothalamic leucine in vivo. Genetic deletion of Cacna1g in POMC neurons abolishes the appetite- and weight-suppressive effects of high-protein feeding. Mechanistically, leucine binds a hydrophobic pocket of Cav3.1 and lowers its threshold for voltage-dependent activation. Finally, pharmacological activation of mediobasal hypothalamic Cav3.1 promotes weight loss in diet-induced obese mice and potentiates responses to anorectic agents, including liraglutide. Together, these findings establish hypothalamic Cav3.1 as a neuronal leucine sensor and nominate it as a tractable target for anti-obesity therapy.
Glucagon-Like Peptide-1 Receptor Agonists and Risk of Systemic and Ocular Vascular Complications in Patients with Type 2 Diabetes and Diabetic Retinopathy.
Am J Ophthalmol
Jui Shah, Bhargav Makwana, Krisha Panchal +11 more
To evaluate the association of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) use on macrovascular and microvascular outcomes in patients with type 2 diabetes (T2D) and diabetic retinopathy (DR)-a high-risk group often excluded from clinical trials.