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The systems medicine view of semaglutide: from clinical trials to molecular mechanisms.

Expert Rev Clin Pharmacol

Rui Vitorino

Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is a key therapy in managing type 2 diabetes (T2D), offering significant improvements in glycemic control, weight loss, and cardiovascular protection. Beyond these clinical benefits, multi-omics research is clarifying the molecular mechanisms underlying its systemic metabolic effects.

Long-Term Safety and Renal Outcomes of Semaglutide in Non-Diabetic Obesity with Chronic Kidney Disease or Hypertension: A Systematic Review and Meta-Analysis.

Clin Ter

Mohamed Kamal ElSayed Elganyny, Abdelhakim Kamal ElSayed Elganyni, Hib Alla Maskji +12 more

Semaglutide, a GLP-1 receptor agonist, has demonstrated metabolic and renal benefits in diabetic populations. However, its efficacy and safety in non-diabetic individuals with obesity and chronic kidney disease (CKD) remain largely unstudied. Given the high cardiometabolic risk in this group and limited therapeutic options, evaluating semaglutide's role is crucial.

Repurposed Drugs and Cardiovascular Morbidity: A Cost-Effectiveness Analysis.

Am J Ther

Oana-Monica Leah, Florin G Leaşu, Mihaela Badea +3 more

Cardiovascular disease remains the leading cause of global mortality (19.8 million deaths in 2022; 32% of all deaths worldwide). Drug repurposing-extending approved agents beyond their original indications-has emerged as a high-impact strategy in cardiovascular prevention, offering reduced development timelines, established safety profiles, and faster implementation than de novo molecular development.

Liraglutide-mediated protection against ethanol-induced gastric ulcer in male and female rats: enhancement of mucosal defense, anti-inflammatory and antioxidant mechanism.

J Pharm Pharmacol

Aslınur Doğan, Elif Merve Betül Yanılmaz, Sibel Ateşoğlu Karabaş +1 more

Gastric ulcer is a pathological condition marked by mucosal lesions resulting from a decrease in protective factors and increased Pro-inflammatory cytokines and ROS. Elevated levels of GLP-1, an incretin hormone released from gastrointestinal cells, have been shown to attenuate gastric ulcer area.

Disruption of the ubiquitin-mediated proteolysis pathway: a study of seed aging in Saposhnikovia divaricata caused by UBC1 gene family suppression.

BMC Plant Biol

Chongyang Yang, Jiayuan Xing, Weixu Han +4 more

Saposhnikovia divaricata (Turcz.) Schischk. is a perennial herb whose seed aging during storage significantly reduces germination rates, limiting industrial-scale production. Reactive oxygen species (ROS)-induced oxidative damage is a key driver of seed aging, but the underlying mechanisms in Saposhnikovia divaricata remain unclear.

[Progress on mechanism of mitochondrial autophagy in pathogenesis of intervertebral disc degeneration based on PINK1/Parkin signaling pathway].

Zhongguo Gu Shang

Jie Guo, Ling Lei, Hongjing Tian +3 more

Intervertebral disc degeneration (IVDD) is one of the main causes of lower back pain. The chronic accumulation of aging and apoptosis of nucleus pulposus cells (NPCs) is believed to be related to IVDD. In recent years, mitochondrial autophagy which as an important clearance mechanism within cells, has gradually attracted attention. The PINK1/Parkin signaling pathway is regarded as the key pathway regulating mitochondrial autophagy, and it plays a significant role in physiological and pathological processes of NPCs. The mechanism by which PINK1/Parkin signaling pathway mediates mitochondrial autophagy could be understood as follows, PINK1, as the sensor for mitochondrial quality regulation, is activated. It recruits and activates Parkin to the mitochondrial membrane through phosphorylation of ubiquitin, and then undergoes Parkin-dependent substrate ubiquitination, recruitment of autophagy receptors, formation of autophagosomes, and fusion with lysosomes, ultimately completing the extremely important autophagy process. Current research indicates that abnormality of PINK1/Parkin signaling pathway may be closely related to IVDD, but the specific mechanism still requires further exploration. The paper explores research progress of mechanism by which mitochondrial autophagy affects IVDD based on PINK1/Parkin signaling pathway, with the aim of providing new strategies and targets for the treatment of IVDD.

Identification of patients receiving amyloid-targeting therapies in observational studies using amyloid PET trajectories: Insights from LEADS.

Alzheimers Dement (Amst)

Renaud La Joie, Ganna Blazhenets, Piyush Maiti +12 more

As amyloid-targeting therapies (ATTs) enter clinical care, observational cohorts must accurately ascertain ATT exposure. We developed an approach to flag mis/undocumented ATT in the Longitudinal Early-Onset Alzheimer's Disease Study using longitudinal amyloid positron emission tomography (PET).

Neutrophil extracellular traps in osteoporosis: mechanistic links to bone remodeling imbalance and therapeutic perspectives.

Mol Biol Rep

Jun Yuan, Fengjiang Li, Jingwen Chen +5 more

Osteoporosis (OP) is increasingly recognized as a disorder driven not only by endocrine and metabolic abnormalities but also by chronic low-grade inflammation and aging-related immune dysregulation. Neutrophil extracellular traps (NETs), web-like extracellular DNA-protein structures released by activated neutrophils, can act as structural inflammatory scaffolds that sustain sterile inflammation, oxidative injury, and microenvironmental imbalance. However, the mechanistic contribution and translational significance of NETs in osteoporosis remain incompletely integrated.

Immune metabolic remodeling during exercise rehabilitation: Linking skeletal muscle regeneration, bone homeostasis, and systemic immune adaptation.

Tissue Cell

Fei Wang, Wenjie Qin

Exercise rehabilitation harnesses immune metabolic remodeling to drive coordinated skeletal muscle regeneration, bone homeostasis, and systemic immune adaptation. Physical activity functions as a controlled metabolic stressor that reprograms immune cell metabolism-shifting macrophages from glycolytic M1 to oxidative M2 phenotypes, expanding regulatory T cells through fatty acid oxidation and ketone body signaling, and modulating neutrophils, NK cells, and B cells via lactate, succinate, itaconate, ROS, NAD⁺, and gut-derived SCFAs. These metabolic shifts regulate immune cell polarization, efferocytosis, cytokine profiles, and growth factor release (IGF-1, amphiregulin, GDF-15), creating an optimal regenerative niche for satellite cell activation, proliferation, and differentiation in muscle while supporting bone remodeling through mechanosensory osteocyte signaling and osteokine secretion (osteocalcin, sclerostin, RANKL/OPG). Distinct exercise modalities generate characteristic immune-metabolic signatures: aerobic training promotes sustained oxidative phosphorylation and anti-inflammatory tolerance beneficial for both muscle and bone; resistance training induces controlled glycolytic bursts followed by anabolic M2 polarization, muscle hypertrophy, and improved bone microarchitecture; HIIT generates oscillatory stress that trains innate immune memory and enhances muscle-bone resilience. Energy-sensing pathways (AMPK, mTOR, HIF-1α, SIRT1/3, PGC-1α) and metabolite checkpoints integrate mechanical loading with immune and endocrine signals to balance pro-regenerative inflammation with timely resolution across the musculoskeletal system. Clinically, this framework enables precision rehabilitation protocols based on immune metabolic phenotyping, lactate kinetics, and skeletal imaging (BMD, microarchitecture) to optimize outcomes in sarcopenia, osteosarcopenia, postoperative recovery, chronic inflammatory diseases, cancer cachexia, and post-viral syndromes. Exercise-induced immune metabolic remodeling thus serves as a master regulator of muscle-bone-immune coupling, offering a mechanism-driven foundation for next-generation rehabilitation medicine that enhances tissue repair, bone quality, and systemic homeostasis.

Combined nonoxynol-9 and antimicrobial peptide LL-37 for barrier contraception.

Reprod Fertil

Murong Xu, Carol Pui Shan Chan, Luping Cong +3 more

Birth control and sexually transmitted infections are global concerns. Nonoxynol-9 (N-9) is the most commonly used component in spermicides, with controversial safety and efficacy. LL-37 has been considered the most promising antimicrobial peptide for developing spermicides. Thus, we aimed to refine the regime of N-9 through the adjunction of LL-37 with higher spermicidal efficacy, safety, and antimicrobial activity. Processed sperm from density gradient centrifugation were treated with nonoxynol-9, LL-37, or the combination for the spermicidal activity. Acrosome reaction, DNA fragmentation, and hemizona binding were evaluated. Minimal inhibitory concentrations were measured using E. coli. Mouse experiments were conducted to investigate skin and vagina irritations. The spermicidal activities of nonoxynol-9 and LL-37 were dose-dependent. Premature acrosome reactions were shown in both groups by increasing acrosome-reacted sperm at around 9 and 21% significantly, and interestingly, the combined group showed a synergistic effect by raising over 60%. In the DNA fragmentation, although there were no significant changes in the nonoxynol-9 or LL-37 groups, the combined group showed a 3% increase at a significant level. Both nonoxynol-9 and LL-37 showed reduced binding capacity with the hemizona-binding indexes at 43.2 and 8.0, and the combined group showed the lowest capacity at 5.6. In animal experiments, the addition of LL-37 to the nonoxynol-9 could alleviate the disruptions caused by nonoxynol-9 in reducing skin epidermal hyperplasia and vaginal irritation. However, the presence of nonoxynol-9 would reduce the antibacterial activity of LL-37. This refined regime showed enhanced spermicidal effects and reduced irritations, but only limited antimicrobial activity.

Type IIB PKA serves as the primary effector of Gs-coupled receptor-potentiated insulin secretion in mice by orchestrating ion channels and granule phenotype.

Diabetologia

Ying Liu, Yunzhi Ni, Chuantong Xie +11 more

G-protein-coupled receptors (GPCRs) play an important role in maintaining systemic glucose homeostasis by regulating insulin secretion, with protein kinase A (PKA) signalling serving as a key downstream effector. Our previous work identified specific expression of type IIB PKA in pancreatic beta cells. Based on these findings, we propose that type IIB PKA is involved in mediating the GPCR signalling in pancreatic beta cells.

Hydrogel-based senomorphic approaches to modulate cellular senescence and promote tissue rejuvenation.

J Control Release

Siwei Chen, Efrosini Kokkoli

Cellular senescence is a major driver of age-related tissue dysfunction, characterized by chronic inflammation, oxidative stress, mitochondrial impairment, and disrupted extracellular matrix homeostasis. While senolytic strategies that eliminate senescent cells have shown therapeutic promise, irreversible cell loss may be detrimental in tissues with limited regenerative capacity. As a result, increasing attention has shifted toward senomorphic and microenvironment-modulating approaches that attenuate senescent phenotypes while preserving resident cells. However, many senescence-modulating agents are limited by poor solubility, spatial localization and rapid tissue clearance. Hydrogels have emerged as powerful platforms to address these challenges by enabling localized and sustained delivery of senescence-modulating cargos. Beyond serving as passive carriers, hydrogels can be engineered with intrinsic bioactivity and tunable biochemical and physical properties that regulate oxidative stress, inflammatory signaling, and cell-matrix interactions within aged or degenerative tissues. This review summarizes recent advances that demonstrate how hydrogel design can synergistically integrate material-driven rejuvenation with controlled delivery of senomorphic cargos, support multimodal therapeutic strategies, and create defined cellular niches that modulate senescence. Collectively, these developments position hydrogel-based systems as an integrative and versatile framework for spatially precise, mechanism-driven modulation of senescence and age-associated tissue dysfunction.

Metabolomic signatures of brain aging: A multimodal and genetic study.

Mol Psychiatry

Zhirong Li, Yating Miao, Xinyao Zhang +2 more

Accelerated brain aging is increasingly recognized as a transdiagnostic risk factor for neuropsychiatric and neurodegenerative disorders, yet its metabolic underpinnings remain poorly understood. Here we integrated multimodal neuroimaging (MRI), plasma metabolomics, and genomic data from the UK Biobank to identify metabolic markers of brain aging and evaluate their causal relevance. Using 1079 imaging-derived phenotypes (IDPs) from 4333 healthy participants, we trained and validated machine learning models for brain age prediction, with a least absolute shrinkage and selection operator (LASSO) regression model achieving the best performance (mean absolute error = 3.26 years, R² = 0.68). Brain age gap (BAG) was then estimated in 37,458 participants. Association analyses in 21,780 individuals identified nine plasma metabolites significantly linked to BAG after Bonferroni correction, with glucose showing the strongest effect (β = 0.32, P = 9.90 × 10⁻¹²). Genome-wide association studies (GWAS) identified 392 BAG-associated single-nucleotide polymorphisms (SNPs) (P < 5 × 10⁻⁸), and two-sample Mendelian randomization (MR) provided evidence supporting a potential causal role of glucose in accelerating brain aging. Clinically, elevated plasma glucose was positively associated with seven brain disorders, including all-cause dementia, Alzheimer's disease, vascular dementia, Parkinson's disease, stroke, depression, and anxiety, and negatively associated with cognitive performance, movement function, and mental health outcomes. Higher glucose concentrations were also associated with reduced regional brain volumes across 80 cortical, subcortical, and cerebellar regions. These findings implicate glucose metabolism as a modifiable pathway in brain aging, with implications for early intervention strategies aimed at preserving brain health across the lifespan.

Potential role of intelectin-1 in the regulation of feeding of goldfish (Carassius auratus).

Peptides

Heidi C Perry, Helene Volkoff

Appetite regulation in vertebrates involves central neuropeptides and peripheral metabolic and endocrine signals that act together to maintain energy homeostasis. These include orexigenic (e.g., neuropeptide Y, orexin, ghrelin) and anorexigenic (e.g., cocaine- and amphetamine-regulated transcript, corticotropin-releasing factor, cholecystokinin, leptin) factors coordinate feeding behavior. Intelectin-1 (ITLN1), a protein implicated in innate immunity and metabolic signaling in mammals, has not yet been investigated in the context of fish feeding physiology. This study examined the potential role of ITLN1 in appetite regulation and energy metabolism in goldfish (Carassius auratus). We first determined tissue distribution of itln1, which showed highest mRNA levels in spleen and liver and lower expression in brain, intestine, kidney, and gonads. Short-term fasting reduced itln1 expression in the hypothalamus and intestine, but not in liver. Peripheral administration of recombinant human ITLN1 (250-500ng/g) significantly reduced food intake without altering blood glucose. At the highest dose (500ng/g), ITLN1 increased brain expression of anorexigenic neuropeptides cart1, crf, trh, cck and lep2, intestinal expression of cck and inflammatory markers (tnfa, il1b) and hepatic lep2 and glycogen synthase (gs) expressions, with no effect on orexigenic peptides or glucose transporters. These findings suggest that ITLN1 might act as a peripheral satiety signal in goldfish, modulating the expression of anorexigenic neuropeptides, gut hormones, and hepatic metabolic genes. This study provides initial evidence that ITLN1 may contribute to appetite regulation in a teleost, suggesting a potential role in coordinating immunity, nutrient metabolism, and central pathways involved in feeding.

Biomarkers in heart failure.

Adv Clin Chem

Manuel Garofalo, Giorgia Panichella, Alberto Aimo

Heart failure (HF) is a leading cause of morbidity and mortality worldwide, characterized by a complex pathophysiology and heterogeneous clinical trajectories. Circulating biomarkers have progressively moved from ancillary diagnostic tools to indispensable instruments that inform diagnosis, prognostication, and therapeutic guidance. B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) remain the cornerstones of biomarker-guided management, yet their interpretation is influenced by age, renal function, obesity, and atrial fibrillation. Cardiac troponins, originally validated for myocardial infarction, provide robust prognostic information in both acute and chronic HF by reflecting ongoing myocardial injury, while high-sensitivity C-reactive protein (hsCRP) captures systemic inflammation and its impact on outcomes. The scope of biomarker research has rapidly expanded to novel pathways. Galectin-3 (Gal-3) and soluble suppression of tumorigenicity-2 (sST2) are established mediators of fibrosis and remodeling, offering incremental prognostic value beyond natriuretic peptides. Growth differentiation factor-15 (GDF-15), myeloperoxidase (MPO), and mid-regional pro-adrenomedullin (MR-proADM) integrate systemic stress, congestion, and oxidative injury into risk assessment. More recently, non-coding RNAs-including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs)-have emerged as minimally invasive, pathophysiologically grounded biomarkers with diagnostic, prognostic, and even therapeutic implications. Looking ahead, multimarker strategies that combine complementary pathways provide a multidimensional perspective on HF progression and therapeutic response. Advances in high-throughput omics platforms and artificial intelligence (AI) promise to refine biomarker integration into precision medicine, enabling individualized risk stratification and therapy optimization. Altogether, biomarkers now represent essential pillars of modern HF care and hold the potential to transform management from population-based to personalized strategies.

Exosomal miRNA-714 derived from adipose tissue macrophages regulates adipocyte glucose and lipid metabolism via IGF1R targeting.

Nutr Metab (Lond)

Rui Ma, Lei Li, Jing Yang +1 more

This study aims to elucidate the regulatory role and underlying molecular mechanisms of exosomal microRNA (miR)-714, derived from adipose tissue macrophages (ATMs), in modulating glucose and lipid metabolism in adipocytes. The findings may contribute to the identification of novel therapeutic targets for obesity-related metabolic disorders.

Semaglutide for Primary Prevention of Major Adverse Cardiac and Cerebrovascular Events in Patients with Type 2 Diabetes and Comorbid Rheumatoid Arthritis: A Target-Trial Emulation.

Eur Heart J Cardiovasc Pharmacother

Farheen Malik, Mandar Shah, Yu Chang +10 more

Rheumatoid arthritis (RA)-related physical limitations often hinder sustained physical activity and weight management, thereby amplifying cardiovascular risk through adverse metabolic profiles and chronic inflammation. We aimed to assess the effectiveness of semaglutide on the risk of incident major adverse cardiovascular and cerebrovascular events (MACCE) in obese adults with type 2 diabetes mellitus (T2DM) and RA in a primary-prevention setting.

Erratum.

Obes Facts

In the Abstract entitled "GLP-1 Receptor Agonist Use in Children and Young People with Severe and Complicated Obesity in 35 Specialist Weight Management Clinics in England" [Obes Facts. 2026;19(suppl 1):295. https://doi.org/10.1159/000551826] by Madeley et al., the following is being corrected.The submitted Abstract was an earlier draft based on data that was still subject to updates at that time. The revised results presented at the conference draw on a more recent version of the dataset.Therefore, the Results section of this Abstract has been updated by the authors as follows:"Results: 406 CYP (53.2% female, mean age 15.3 ± 1.7 years, range 11.3-19.5) receiving semaglutide were matched to 787 comparator patients. Mean baseline %BMIp95 was 172.9 (±29.5; BMI-SDS 3.77 ± 0.47), indicating a cohort with very severe obesity. Across all participants (n = 1,193), there was a high burden of obesity-related complications; 43.0% had metabolic dysfunction-associated steatotic liver disease, 23.2% had dysglycaemia (type 2 diabetes mellitus 4.7%, impaired glucose tolerance 18.5%), 18.9% had obstructive sleep apnoea, and 12.0% had hypertension. 19.6% of females had polycystic ovary syndrome. 56.7% had documented depression, anxiety, or self-harm. At 6, 12, and 18 months, %BMIp95 was 13.8, 19.0, and 22.9 percentage points lower in the semaglutide group than in matched comparators (95% CI: -15.4 to -12.3; -21.3 to -16.9; -27.8 to -18.1), representing relative reductions of 8.8%, 12.5%, and 14.4%. Corresponding between-group differences in BMI were -2.7, -4.0, and -5.2 kg/m2 (95% CI: -3.1 to -2.3; -4.6 to -3.5; -6.5 to -3.9), representing relative reductions of 7.4%, 10.2%, and 11.2%."

Real-world weight loss with injectable semaglutide vs dulaglutide for diabetes.

Am J Manag Care

Allison Spitery, Alison Lobkovich, Emily Thomas

To compare the real-world effects of weekly injectable semaglutide (Ozempic) vs dulaglutide (Trulicity) on weight loss in an urban, predominantly African American patient sample with type 2 diabetes (T2D).

Experience with Tirzepatide and Weight Management During and After a Clinical Trial in Japanese Patients with Obesity Disease: A Qualitative Study.

Adv Ther

Arihiro Kiyosue, Manaka Sato, Zhihong Cai +8 more

The phase 3 SURMOUNT-J clinical trial showed that Japanese adults with obesity disease achieved clinically meaningful body weight loss with once-weekly tirzepatide for 72 weeks. The primary objective of the present study was to explore participants' experiences with tirzepatide during SURMOUNT-J and body weight changes after the trial. Secondary objectives were to explore participant experiences with other weight loss treatments and body weight management after the trial, and to understand the healthcare provider support needs related to obesity disease treatment.