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peptide science.

[Tirzepatide in real-world clinical practice: changes in body composition and muscle function in patients with obesity].

Nutr Hosp

Jorge Blanco Anesto, Keyla María Dotres Fallat, Joana Nicolau

obesity is a chronic and relapsing disease. Tirzepatide, a dual GLP-1 and GIP receptor agonist, has demonstrated weight loss exceeding 20 % at higher doses. However, real-world data remain limited, particularly regarding body composition and muscle function.

The 40th Minute Cortisol Measurement is the Key Time-Point in the Low-Dose Synacthen Stimulation Test: A Large, Assay-Specific Pediatric Validation Study.

J Clin Res Pediatr Endocrinol

Busra Gurpinar Tosun, Hazal Arikan Gacemer, Didem Helvacioglu +3 more

Low-dose synacthen stimulation test (LDSST) is widely used to assess central adrenal insufficiency (CAI). With the adoption of monoclonal antibody (mAb) cortisol immunoassays, lower basal and peak cortisol concentration thresholds require external validation under real-world clinical conditions.

Molecular and Cellular Mechanisms of Anti-Obesity Agents: An Integrative Review.

FASEB J

Harmandeep Kaur, Deepika Kaushik, Prasad Rasane +3 more

Genes play a pivotal role in appetite regulation and energy homeostasis during a person's obesity. LEP (Leptin) and POMC (Proopiomelanocortin) are vital for appetite suppression and promoting satiety, while AgRP (Agouti-related peptide) and NPY (Neuropeptide Y) serve to stimulate appetite, creating a balanced interplay between hunger and satiety signals. GHRL (Ghrelin) further promotes hunger, emphasizing the complexity of these regulatory mechanisms. BDNF (Brain-derived neurotrophic factor) shows a dual role, impacting energy homeostasis not only in the brain but also in adipose tissue, thereby influencing lipid metabolism. PCSK1 (Proprotein Convertase Subtilisin/Kexin Type 1) is critical for the processing of neuropeptides that modulate energy balance. IGF2BP2 (Insulin-like Growth Factor 2 mRNA-Binding Protein 2) and MAP2K5 (Mitogen-Activated Protein Kinase 5) contribute to metabolic processes involved in fat accumulation and glucose regulation. Thus, emphasizing the significance of these mechanisms offers valuable insights that could lead to effective interventions for obesity prevention and management.

Obesity and Heart Failure: Introducing the Theme.

J Cardiovasc Dev Dis

Francesco Monitillo, Paolo Basile, Giuseppe Lisco

Obesity is a chronic, highly prevalent disease affecting nearly one-third of the global population and represents a major independent risk factor for heart failure (HF), particularly heart failure with preserved ejection fraction (HFpEF). Excess adiposity-especially visceral and epicardial adipose tissue (EAT)-acts as an active endocrine and immune organ, promoting chronic low-grade inflammation, oxidative stress, endothelial dysfunction, and adverse myocardial remodeling. Expanded EAT exerts both paracrine inflammatory effects and mechanical constraint on the myocardium, contributing to diastolic dysfunction, microvascular impairment, atrial arrhythmogenesis, and elevated filling pressures despite preserved systolic function. Evidence demonstrates a dose-response relationship between increasing body mass index and incident HF. Clinically, obesity-related HFpEF is characterized by concentric left ventricular hypertrophy, impaired relaxation, increased plasma volume, reduced exercise tolerance, and relatively low natriuretic peptide levels, complicating diagnosis. HF management includes traditional treatment with diuretics, renin-angiotensin system inhibitors, β-blockers, mineralocorticoid receptor antagonists, and angiotensin receptor-neprilysin inhibitors. These agents widely remain foundational as they primarily target hemodynamic and neurohormonal pathways in HF. In contrast, sodium-glucose cotransporter 2 inhibitors consistently reduce HF hospitalizations across the ejection fraction spectrum, while glucagon-like peptide-1 receptor agonists and dual incretin therapies (e.g., tirzepatide) promote substantial weight loss, improve symptoms, and demonstrate promising anti-remodeling effects in obesity-related HFpEF. Recognizing obesity-driven HF as a distinct cardiometabolic entity supports an integrated therapeutic strategy combining structured weight reduction with guideline-directed HF polypharmacotherapy to address both hemodynamic burden and upstream adiposity-related mechanisms.

Medical Nutrition in the Glucagon-Like Peptide-1 (GLP-1) Era: Protein Strategies, Micronutrient Monitoring, and Lean Mass Preservation.

Clin Nutr ESPEN

Sedat Arslan

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 agents produce substantial, sustained weight loss primarily by suppressing appetite and lowering ad libitum energy intake. While fat mass loss predominates, randomized trials with body-composition substudies indicate a clinically relevant reduction in absolute lean mass. Concurrently, baseline micronutrient inadequacies are common in people with obesity and may be exacerbated by reduced intake, nausea, or vomiting during therapy. This narrative review synthesizes evidence on energy/macronutrient dynamics, body-composition outcomes, and guideline-informed protein targets to present a practical, dietitian-led framework for care. We propose pragmatic energy floors to preserve micronutrient adequacy; daily protein intakes of ≥1.2 g/kg (up to 1.6 g/kg in appropriate adults without chronic kidney disease (CKD)) with meal-wise targets of ∼0.3-0.4 g/kg and ∼2.5-3 g leucine; a structured laboratory panel (vitamin D, B12, iron studies, folate, zinc, and thiamine in high-risk patients); and integration of progressive resistance training. We also outline monitoring schedules using dual-energy X-ray absorptiometry (DXA)/bioelectrical impedance analysis (BIA) and adaptations for special populations (older adults, type 2 diabetes, CKD, vegetarian/vegan, sarcopenic obesity). The goal is to preserve lean mass, prevent deficiencies, and optimize outcomes of GLP-1-based obesity pharmacotherapy.

[Wheat bran reduces oxidative stress and promotes glucagon-like peptide-1 secretion in high-fat-fed rats].

Wei Sheng Yan Jiu

Aisikaier Rukeye, Ting Shang, Kuerbanjiang Maierheba +5 more

This study aimed to investigate the effects of wheat bran intervention on oxidative stress status and glucagon-like peptide-1(GLP-1) secretion in rats fed a high-fat diet(HFD).

The novel PDE5 inhibitor CPD1 attenuates pulmonary arterial hypertension through dual modulation of cGMP and TRPM8-mediated pathways.

Bioorg Chem

Yunping Mu, Jinlin Sun, Xindan Zhang +7 more

Pulmonary arterial hypertension (PAH) remains a fatal condition with limited treatment options. While phosphodiesterase-5 (PDE5) inhibitors such as sildenafil and tadalafil are standard treatments, their therapeutic efficacy is limited by poor aqueous solubility and an incomplete understanding of the mechanisms underlying their long-term benefits on vascular remodeling. To overcome these critical limitations, we developed a novel, highly water-soluble potassium salt polymorph of a PDE5 inhibitor, designated CPD1. In a monocrotaline-induced rat model of PAH, CPD1 demonstrated superior in vivo efficacy. It dose-dependently alleviated key pathological hallmarks by significantly reducing pulmonary arterial pressure, reversing right ventricular hypertrophy, and inhibiting the remodeling of small muscular pulmonary arteries. At the vascular level, CPD1 significantly attenuated the enhanced contractile responses to endothelin-1, cyclopiazonic acid, and 1-oleoyl-2-acetyl-sn-glycerol in endothelium-denuded arteries. Mechanistically, we reveal a novel dual-pathway mechanism: in addition to elevating cyclic guanosine monophosphate (cGMP) through PDE5 inhibition, CPD1 uniquely and dose-dependently upregulates the expression of the transient receptor potential melastatin-8 (TRPM8) channel. This upregulation sensitizes the pulmonary vasculature, markedly enhancing vasodilation induced by TRPM8 activation. Our findings position CPD1 not merely as a more soluble PDE5 inhibitor but as a first-in-class agent that simultaneously modulates the cGMP pathway and the TRPM8 channel, offering a promising new therapeutic strategy to correct dysregulated calcium homeostasis and reverse vascular remodeling in PAH.

Using biomarkers to detect intramammary infections in dairy cows at dry-off.

Res Vet Sci

Lorenzo Viora, P Theo Pepler, Emily L O'Reilly +3 more

Prevention and treatment of intramammary infections (IMI) associated with subclinical mastitis (SCM) are among the leading reasons for antimicrobial usage (AMU) in dairy cows, especially at dry-off. By adopting a selective dry cow therapy ((S)DCT), only cows or quarters with a demonstrable risk of IMI would be treated and AMU would be decreased. Several tools have been proposed to identify cows for SDCT, including algorithms based on clinical mastitis and somatic cell count (SCC). The potential of milk proteins as biomarkers for IMI at dry-off has not been fully evaluated. In this study, biomarkers in 185 milk samples collected aseptically at drying off were quantified and their value in detecting IMI was evaluated (individually and in combination) in comparison to SCC and California Mastitis test using a case-control design with culture-based detection of IMI as gold standard comparator. Biomarkers quantified were lactoferrin, α-lactalbumin, haptoglobin, mammary amyloid A, C-reactive protein and cathelicidin. Of the six biomarkers examined, three had accuracies greater than 61% based on univariate biomarker trees (62%, 65% and 65% for haptoglobin, cathelicidin and milk amyloid A, respectively). A two-biomarker decision tree combining cathelicidin and milk amyloid A improved overall accuracy to 70% (sensitivity 72%, specificity 67%), comparable in performance to SCC, maintaining an acceptable level of sensitivity, but with greater specificity - an attribute desirable for SDCT. This performance highlights its potential use as a practical tool to reduce unnecessary antimicrobial treatments at dry-off, supporting selective dry cow therapy without compromising detection of infected quarters.

Preserving brain health in aging: structural and biochemical benefits of water based resistance training, a randomized controlled trial.

BMC Geriatr

Mahdiyeh Haj Hosseini, Masoumeh Baghalishahi, Mandana Moshrefi +7 more

Brain aging leads to structural changes, especially atrophy, which can result in dysfunction. Mitochondrial dysfunction is thought to explain the structural changes in brain aging.

The joint association of intrinsic capacity and physical activity with cardiovascular risk in older adults: evidence from four longitudinal cohorts.

BMC Geriatr

Zhengqiu Zhang, Ziyin Liu, Feng Ye +8 more

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.