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peptide science.

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.

Neuroendocrine signature of ME/CFS: Meta-analytic evidence for bioactive cortisol deficit and exaggerated feedback sensitivity.

Mol Psychiatry

Tae-Wook Woo, Yu-Jin Choi, Jun-Yeol Kim +2 more

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a major clinical challenge as a complex multisystemic disorder with no well-established pathophysiological mechanism, characterized by persistent fatigue and post-exertional malaise, along with unrefreshing sleep, cognitive impairment, and impaired stress recovery. Despite decades of investigation into the hypothalamic-pituitary-adrenal (HPA) axis, a definitive neuroendocrine hallmark has remained elusive due to inconsistent findings across various cortisol matrices. Therefore, this systematic review and meta-analysis aimed to provide an integrated understanding of HPA-axis regulation in ME/CFS. We identified 46 case-control studies (comprising 46 independent datasets, including 12 pharmacological challenge studies), involving 1388 ME/CFS patients (71.9% female; mean age 37.3 ± 6.2 years) and 1349 matched healthy controls. Meta-analyses showed lower salivary cortisol at awakening and in the morning. Reductions were also observed in 24-h urinary cortisol and hair cortisol. In pharmacological challenge tests, patients exhibited impaired cortisol release in response to adrenocorticotropic hormone (ACTH) stimulation and exaggerated suppression following glucocorticoid administration. Collectively, these alterations indicate reduced free cortisol availability and enhanced HPA-axis negative feedback sensitivity, consistent with a hyporeactive endocrine state in ME/CFS. This neuroendocrine hypo-reactivity may underlie hallmark clinical features such as unrefreshing sleep, post-exertional malaise, and severe fatigue, as well as cognitive slowing, emotional blunting, and diminished stress resilience frequently observed in ME/CFS and related functional disorders. Integrating neuroendocrine and psychological perspectives may help clarify mechanisms of chronic stress maladaptation and inform psychobiological interventions for fatigue syndromes.

Early GH therapy and neurodevelopmental outcome in a child with compound heterozygous IGF1R variants.

JCEM Case Rep

Mariana Sá Pinto, Mariana Oliveira, Tomás Ferrão +3 more

Causal variants in the IGF 1 receptor (IGF1R) gene are associated with variable degrees of growth and neurodevelopmental impairment. While heterozygous variants often manifest as less severe phenotypes, homozygous loss-of-function mutations are widely regarded as incompatible with life. Biallelic hypomorphic variants are exceptionally rare and their clinical spectrum remains poorly defined. We report the case of a girl born at term after severe symmetric fetal growth restriction (FGR), identified prenatally through trio whole-exome sequencing as carrying compound heterozygous IGF1R variants-c.155G>C (p.Cys52Ser) and c.3476A>G (p.Asp1159Gly). Postnatally, she exhibited microcephaly, dysmorphic features, and marked growth failure. Growth hormone therapy was initiated at 13 months of age, leading to gradual and sustained improvement in head circumference, linear growth, and psychomotor development. We report a rare case of a prenatal diagnosis of compound heterozygous IGF1R variants with early GH treatment. The case broadens current knowledge on IGF1R-related disorders, shows that survival is possible in compound heterozygous states, and suggests a potential benefit of early GH therapy.

Single cell analysis of muscle contracture in cerebral palsy reveals pro-fibrotic and anti-myogenic stem cell populations with altered cell-cell interactions.

Am J Physiol Cell Physiol

Madison Stewart, Lin-Ya Hu, Taryn Loomis +8 more

Development of muscle contractures are common in cerebral palsy (CP) and characterized by high muscle stiffness that limits function and mobility. However, the state of stem cells within contracture, particularly muscle stem cells and fibro-adipogenic progenitors, are largely unknown. This study leverages single cell RNA sequencing technology to determine how specific cell types are altered in the contracture environment. Skeletal muscle biopsies were collected from children with CP or typically developing (TD) children undergoing surgery. The 10X Genomics platform was used on tissue from n=3 patients per condition. Significant changes in CP compared to TD were investigated within individual cell types for differentially expressed genes, gene ontologies, cell subpopulations and predicted interactions. CP muscle stem cells demonstrated significant upregulation of fibrotic genes and down regulation of myogenic genes compared to typically developing. Fibro-adipogenic progenitors in CP showed the emergence of a significant proportion of a highly profibrotic subpopulation, leading to the most dramatically up-regulated genes in CP also being extracellular matrix constituents. Interacting signals between fibro-adipogenic progenitors, muscle stem cells, and immune cells were identified that support contracture progression. Contracture reduces myogenic muscle stem cells and enhances fibrotic signals in muscle stem cells and fibro-adipogenic progenitors that perpetuate contracture. The study reveals specific genes and signaling pathways as therapeutic targets to reduce muscle contracture in children with CP.

Differential effects of human fibromyalgia sera on murine satellite glial cells: comment on the article by Mercado et al.

Clin Exp Rheumatol

Suhail Aamar, Emil Aamar

Liver benefits of early initiation of low-dose GLP-1 receptor agonists in newly diagnosed type 2 diabetes - A case report.

J Family Med Prim Care

Joyce Y Lee, Huy Nguyen, Tan Nguyen

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to exert favorable effects on hepatic biomarkers and liver-related conditions, including nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. However, the optimal dosage and duration of GLP-1RA therapy necessary to achieve these extrapancreatic hepatic benefits remain unclear. In this case report, we presented a 28-year-old White Hispanic female with Class I obesity and newly diagnosed type 2 diabetes who demonstrated a marked and rapid normalization of persistently elevated alanine aminotransferase levels following the initiation of subcutaneous semaglutide therapy. This case report highlighted the potential for immediate hepatic improvement with GLP-1RA treatment, exceeding commonly anticipated clinical outcomes in primary care.

Efficacy, Safety and PK of Once-Daily Oral Semaglutide 25 mg for Obesity With and Without Type 2 Diabetes in Comparison With Subcutaneous Semaglutide 2.4 mg: A Model-Informed Drug Development Approach.

Diabetes Obes Metab

Rune Viig Overgaard, Oscar Birkhan, Naveen Rathor +4 more

Semaglutide has previously been approved for weight management and cardiovascular disease as a subcutaneous formulation, and more recently also as an oral formulation. However, there is limited information across oral dose levels, and there are no studies for the 25 mg dose in people with obesity and type 2 diabetes (T2D). To fulfil health authority approval requirements, population pharmacokinetic and exposure-response analyses were used to extrapolate efficacy and safety data from subcutaneous to oral semaglutide.

Enhancing economic modelling in obesity: integrating novel type 2 diabetes progression & obstructive sleep apnea remission - a UK case study.

J Med Econ

Lieven Annemans, Erin Johansson, Erik Spaepen +4 more

This study presents an updated health economic model for evaluating the long-term cost-effectiveness of interventions in overweight and obesity, integrating new clinical evidence from the SURMOUNT clinical trial programme and methodological advancements in type-2 diabetes and obstructive sleep apnea (OSA) modelling.

Therapeutic peptides in gerontology: mechanisms and applications for healthy aging.

Front Aging

Volodymyr Mavrych, Inna Shypilova, Olena Bolgova

Peptide therapeutics represent an emerging frontier in gerontological medicine, targeting fundamental hallmarks of aging including metabolic dysfunction, telomere attrition, tissue repair impairment, and hormonal decline.

Glymphatic System Dysfunction in Epilepsy: Clinical and Translational Perspectives.

Epilepsy Curr

Dong Ah Lee, Ho-Joon Lee, Kang Min Park

Epilepsy has traditionally been viewed as a disorder involving neuronal hyperexcitability and brain network dysfunction. However, growing evidence indicates that recurrent seizures are associated with widespread disturbances in brain homeostasis, including metabolic stress, neuroinflammation, vascular dysregulation, and sleep disruption. These processes extend beyond neurons and involve brain-wide clearance mechanisms that have received limited attention in epilepsy research. The glymphatic system is a specialized pathway that facilitates cerebrospinal fluid-interstitial fluid exchange and promotes the clearance of metabolic waste and neurotoxic solutes from the brain. Glymphatic transport depends on astrocytic aquaporin-4 channels and is strongly modulated by sleep-wake state, which is highly relevant to epilepsy given the close bidirectional relationship between seizures and sleep disturbances. Impaired glymphatic clearance has been linked to protein accumulation, neuroinflammation, and cognitive decline during aging and in neurodegenerative diseases, suggesting that similar mechanisms may contribute to epilepsy-related disease progression. In this review, we summarize current knowledge of glymphatic anatomy and physiology, focusing on advances in neuroimaging. We then synthesize emerging evidence demonstrating glymphatic dysfunction across multiple epilepsy syndromes. We discuss the clinical implications of impaired cerebral waste clearance for disease burden, treatment outcomes, and cognitive dysfunction and highlight potential therapeutic strategies aimed at modulating glymphatic function. Finally, we address the ongoing debates regarding glymphatic mechanisms, imaging biomarkers, and causal relationships in epilepsy. Collectively, the available data suggest that glymphatic system dysfunction represents a system-level abnormality in epilepsy, offering a complementary framework that integrates the metabolic, vascular, and sleep-related aspects of epileptic brain dysfunction.

Targeting the FOXO4-p53 axis by retro-inverso peptide senolytic agents: a pharmacological strategy to mitigate brain aging and cognitive decline.

Naunyn Schmiedebergs Arch Pharmacol

Ayman Ali Mohammed Alameen, Hayder M Al-Kuraishy, Mohamed N Fawzy +1 more

Cellular senescence, driven by the interaction between FOXO4 and p53, is increasingly recognized as a crucial mechanism in brain aging and the development of neurodegenerative disorders. The senolytic peptide FOXO4-DRI, which has been thoughtfully designed, selectively disrupts the FOXO4-p53 complex, inducing apoptosis in senescent cells while preserving healthy tissue. In aged mammalian models, administering FOXO4-DRI decreases the accumulation of senescent cells, restores cerebral blood flow and the integrity of the blood-brain barrier (BBB), reverses hippocampal atrophy, and enhances cognitive function. Furthermore, in models of Alzheimer's disease (AD) and tauopathy, this intervention eliminates amyloid-β and pathological tau, leading to improved memory performance. Preliminary human studies involving FOXO4-axis modulators, such as high-dose fisetin, show a reduction in the senescence-associated secretory phenotype (SASP) and enhancements in cognitive and physical measures among older adults. These findings collectively identify the FOXO4-p53 axis as a potential pharmacological target in brain aging and highlight senolytic therapy as a promising strategy for altering diseases to postpone or reverse age-related cognitive decline. This review consolidates recent findings indicating that FOXO4-dependent senescence significantly contributes to neuroinflammation, synaptic dysfunction, and impaired neurogenesis in the aging brain.