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peptide science.
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Changes in patient-reported outcomes and objective assessments based on baseline symptom severity in SURMOUNT-OSA: Post-hoc analyses.
Sleep
Chisom Kanu, Shraddha Shinde, Beverly Falcon +4 more
These post-hoc analyses of SURMOUNT-OSA evaluated patient-reported outcome measures (PROMs) and objective assessments, considering participants' baseline characterization of fatigue, sleepiness, snoring, and sleep quality.
Greater choroid plexus volume is linked to poor sleep, neurodegeneration, and cognitive deficits in older adults: Evidence from the IGNITE Study.
Alzheimers Dement
Miranda G Chappel-Farley, Kelsey R Sewell, Audrey M Collins +18 more
Poor sleep is associated with neurodegenerative disease, but mechanisms are unclear. Greater volume of the choroid plexus (ChP), a brain structure supporting neurotoxic waste clearance, is linked to neurodegeneration and cognitive decline. We tested whether poor sleep promotes neurodegeneration and cognitive deficits via ChP dysfunction.
Identification of the Mitochondrial Gene NME6 as an Immune Modulator in Heart Failure.
Front Biosci (Landmark Ed)
Pan Liu, Fan Yang, Yang Zhang +7 more
Heart failure (HF) is characterized by mitochondrial dysfunction and immune dysregulation. However, the underlying molecular mechanisms remain unclear. Functional enrichment analyses study aimed to identify key mitochondrial genes involved in HF pathogenesis and to explore their association with immune cell infiltration.
Refining free fatty acid receptor agonism for metabolic control: Pharmacological and functional features of novel dual GPR40/GPR120 ligands.
Biomed Pharmacother
Kashi Brunetti, Bruno Fassari, Elisabetta Catalani +11 more
Metabolic disorders require therapeutic strategies targeting complementary pathways beyond current incretin-based therapies. Free fatty acid receptors GPR40 (FFAR1) and GPR120 (FFAR4) regulate insulin and incretin secretion as well as lipid metabolism, supporting the development of dual agonists. Here, we characterized three novel compounds (DFL23914, DFL23915 and DFL24102) derived from a previously validated scaffold, combining in vitro pharmacology with in vivo functional analyses. All compounds exhibited low-micromolar agonist activity at human GPR40 and GPR120, activating both Ca²⁺-dependent and β-arrestin signaling pathways, with DFL24102 showing the most balanced dual-agonist profile. In Drosophila models of diet-induced metabolic dysfunction, chronic administration significantly improved locomotor performance, reduced body weight gain, and normalized hyperglycemia and triglyceride accumulation in both adult and larval stages, without affecting survival. In vitro assays demonstrated the significant stimulation of glucagon-like peptide-1 secretion by DFL23914, DFL23915, and DFL24102 as well as the absence of hepatotoxicity, while cells permeability and mouse pharmacokinetics revealed minimal systemic exposure, supporting a gut-restricted mechanism of action. Consistently, oral administration in mice improved glucose tolerance in an oral glucose tolerance test, with significant reductions in glycemic excursions, particularly for DFL23915 and DFL24102. Overall, these findings indicate that dual GPR40/GPR120 agonists of this chemical series exert robust metabolic benefits through coordinated receptor activation and local intestinal activity. This study further supports dual FFAR targeting as a promising pharmacological approach and identifies leading candidates for the development of innovative therapies for metabolic disorders.
Safety of swallowed corticosteroids and their influence on the hypothalamic-pituitary-adrenal gland axis and on markers of bone resorption and formation in patients with eosinophilic esophagitis.
Br J Clin Pharmacol
Jesús Sánchez César, Valentín Roales Gómez, Martín Cuesta Hernández +3 more
Corticosteroids have side effects like adrenal insufficiency (AI) and bone decalcification, amongst others. Swallowed formulations appear to be les harmful. Our aim is to study the effects of orodispersable budesonide used in patients with eosinophilic esophagitis (EoE) on the hypothalamic-pituitary-adrenal axis, by using a test with higher sensitivity than measuring basal cortisol levels, and on bone resorption and formation.
Cardiovascular Outcomes With Tirzepatide Versus GLP-1 Receptor Agonists in Overweight or Obesity: A Systematic Review and Meta-Analysis.
Diabetes Obes Metab
João Pedro Machado Ribeiro Jacintho Silva, Bruno Viruez Nogueira, Deborah Lomelino Sartori +4 more
To compare cardiovascular outcomes associated with tirzepatide versus glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in adults with overweight or obesity.
GLP-1 Receptor Agonists for Weight Loss and Risk of Major Safety Outcomes: A Multicentre Cohort Study.
Diabetes Obes Metab
Jisu Park, Ju Hwan Kim, Yoon Seob Kim +17 more
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly prescribed for weight loss, yet their safety in clinical practice remains uncertain. We evaluated associations between weight-management semaglutide or liraglutide initiation and safety outcomes in a multicentre cohort.
Computationally guided cross-linking overcomes interfacial mismatch in protein dimerization: Creating a long-acting cocaine esterase.
Int J Biol Macromol
Xingyu Deng, Zhiguo Wang, Yuxin Hou +9 more
Engineering intermolecular disulfide bonds to stabilize protein dimers is a conventional strategy, yet its efficacy is frequently constrained by the topological mismatch between rigid disulfide linkages (~2.0 Å) and the dynamic fluctuations of protein interfaces. This structural rigidity often leads to incomplete dimerization, conformational strain, and suboptimal in vivo persistence, as exemplified by the engineered cocaine esterase (CocE) mutant E196-301. In response to this challenge, we propose a computationally guided, topologically adaptive cross-linking strategy that harnesses the dynamic conformational ensemble of protein interfaces. Firstly, utilizing molecular dynamics simulation, we mapped the interfacial plasticity of the CocE subunit, identifying a converged C196-C301 distance of ~9.10 Å. Rather than relying on static structural approximations, we rationally matched this spatial requirement with a specific bifunctional cross-linker, bis-maleimidoethane (BMOE, 8.06 Å), achieving a robust interfacial bridge that accommodates natural structural fluctuations was achieved. Next, the off-target surface cysteines (C107S and C551S) were strategically ablated, yielding a precisely controlled, site-specific homodimer of CocE (CocE-HD). CocE-HD exhibited significant improvements in thermal, chemical, and serum stability relative to the monomer. In a rat model, CocE-HD (10 mg/kg) demonstrated a plasma half-life of 103.94 ± 43.62 min, representing a 3.6-fold extension compared to the monomer. Functional assays confirmed that CocE-HD maintains rapid cocaine clearance even 2 h post-administration, completely abolishing cocaine-induced hyperlocomotion. This work establishes CocE-HD as a promising therapeutic candidate and provides a rational approach for protein stabilization by aligning cross-linker chemistry with interfacial topology.
Mapping the Heart-Brain Continuum beyond Heart Failure: Why Neurology Matters.
J Neurosci
Xia Zhang, Khosrov A Grigoryan, Nico Scherf +4 more
To investigate whether cardiac dysfunction predicts further gray matter microstructural integrity and whether this integrity mediates the association with cognitive performance, we conducted a prospective observational cohort study of 73 patients (20 females and 53 males; mean age 54.8 years) from the Leipzig Heart Study. We performed baseline cardiac assessments followed by diffusion-weighted magnetic resonance imaging and cognitive testing after a follow-up of 3.5 years. Participants included patients with established heart failure and matched patients without heart failure presenting with suspected coronary artery disease. We assessed baseline cardiac biomarkers including left ventricular ejection fraction and N-terminal pro-B-type natriuretic peptide. The main outcomes were gray matter microstructural integrity (mean diffusivity) and cognitive performance. Mediation analysis evaluated whether regional mean diffusivity mediated the association between cardiac function and cognition. Across all 73 participants, a lower baseline ejection fraction predicted greater future gray matter mean diffusivity even in patients without clinical heart failure, acting as an early-stage indicator. Conversely, higher natriuretic peptide levels predicted extensive microstructural damage exclusively in the established heart failure group. Notably, increased mean diffusivity in Alzheimer's disease-vulnerable regions (specifically the cingulate and lingual gyri) significantly mediated the association between cardiac health and subsequent memory performance. In conclusion, cardiac dysfunction is associated with a predictable continuum of brain microstructural damage where conventional imaging previously failed. Crucially, this microstructural degradation mediates the link to memory decline, identifying brain microstructural integrity as a high-priority targets for upstream intervention aimed at preserving cognitive health.Significance Statement This study establishes a specific link between cardiac dysfunction and cognitive decline based on microstructural brain alterations. We identify a "heart-brain continuum" where routine cardiac biomarkers predict future brain microstructural damage. Crucially, this microstructural degradation targets Alzheimer's disease-vulnerable regions and acts as the mediator driving memory loss. By validating gray matter mean diffusivity as a sensitive tracker of this progression, our findings underscore that preserving brain microstructural integrity is a critical target in patients with cardiac dysfunction, offering a vital opportunity to intervene upstream before the onset of dementia.
Prognostic significance of serum laminin and the Zhejiang University index in patients with acute heart failure.
BMC Cardiovasc Disord
Jiaqi Ye, Xiaoyun Yan, Ying Jiang +1 more
This study was conducted to evaluate the prognostic utility of serum laminin (LN) and the Zhejiang University (ZJU) index in patients diagnosed with acute heart failure (AHF).
A Sequential Dual GLP-1R/GIPR Agonist-To-Antagonist Molecule Achieves Superior Weight Loss in Obese Mice.
Diabetes Obes Metab
Yunxiao Zhang, Bo Zhu, Binhui Peng +8 more
The GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) are key targets for diabetes and obesity therapies. Pharmacological agents including GLP-1R agonists (e.g., Semaglutide), dual GLP-1R/GIPR agonists (e.g., Tirzepatide) and a GLP-1R agonist/GIPR antagonist (AMG133) have demonstrated considerable promise in anti-diabetic and weight management applications. However, a systematic comparison of the specific contributions of GIPR activation versus GIPR inhibition to weight loss within the context of GLP-1/GIP dual-targeting therapies remains unexplored.
Copper peptide activated cascade catalysis for glucose regulation and hypoxia reversing in infected diabetic wound healing.
Mater Today Bio
Zeng-Jin Huang, Rui-Feng Huang, Ping-Ping Jiao +7 more
Starvation therapy has emerged as a promising strategy in diabetic wounds treating by regulating glucose level to deplete microbial nutrients without inducing antimicrobial resistance. However, this process consumes large amounts of oxygen, exacerbating wound hypoxia and compromising therapeutic efficacy. In this study, we designed a GOX-loaded hydrogel incorporated with copper peptide (GHK-Cu) to construct a copper peptide-activated cascade catalysis system for concurrent glucose regulation and hypoxia reversing. GOX initiates the cascade by catalyzing glucose oxidation, which reduces local hyperglycemia levels and generates hydrogen peroxide (H2O2). Subsequently, copper ions in GHK-Cu activate the subsequent step by mediating the decomposition of H2O2 through a catalase(CAT)-like reaction, releasing local oxygen to effectively alleviate the hypoxic state of the wound, and its own biological activity can further promote skin repair. The research results show that the Gel@GHK-Cu/GOX hydrogel can efficiently facilitates the decomposition of glucose into oxygen via the cascade reaction. Moreover, this hydrogel has been confirmed to have multiple therapeutic effects, including antibacterial activity, tissue repair promotion, antioxidant capacity, and angiogenesis stimulation. In conclusion, the Gel@GHK-Cu/GOX hydrogel provides an effective approach for chronic diabetic wound therapy. Its multifunctional synergistic mechanism offers novel insights for addressing clinical challenges in refractory diabetic wound healing.
Semaglutide Injection Once-Weekly for Weight Management in Adults: Results From A Randomized Phase III, Active-Controlled Study.
Diabetes Obes Metab
Unnikrishnan Ambika Gopalakrishnan, Ameya Joshi, Harish Kumar +24 more
To evaluate and compare the efficacy, safety, and immunogenicity of a synthetic semaglutide injection (Test semaglutide) with Wegovy (Reference semaglutide) injection for weight management.
Comparative Positioning of Orforglipron Among Selected GLP-1 Receptor Agonist Benchmarks: A Narrative Review.
Cureus
José Castro-Gamboa, Jeaustin Mora-Jiménez, Sebastián Arguedas-Chacón +1 more
Orforglipron is an oral, nonpeptide, small-molecule glucagon-like peptide-1 receptor agonist developed for type 2 diabetes and obesity. This narrative review evaluates its comparative positioning among marketed GLP-1 receptor agonists by integrating structural, pharmacological, clinical, and practical evidence. A narrative literature review was conducted using PubMed/MEDLINE, Embase, Scopus, Web of Science, ClinicalTrials, official prescribing information, and citation tracking. The synthesis was organized by comparative domains, including molecular structure, receptor pharmacology, early clinical pharmacology, direct comparative evidence, contextual comparator evidence, and practical administration. From 245 screened records, 88 duplicates were removed, 157 unique records were assessed, and 35 orforglipron-focused sources were retained. Seven additional comparator trials were selected through targeted citation verification because they represented clinically relevant benchmarks for oral semaglutide in type 2 diabetes and obesity, danuglipron as another oral small-molecule GLP-1 receptor agonist, and injectable semaglutide as a high-efficacy class comparator. Current evidence identifies several domains relevant to the comparative positioning of orforglipron, including its nonpeptide small-molecule structure, receptor pharmacology, once-daily oral dosing profile, and direct comparator evidence against dulaglutide and oral semaglutide. Food-effect and prescribing-information sources describe fewer food-related administration constraints for orforglipron than for oral semaglutide. However, indirect comparisons remain limited by differences in populations, doses, follow-up duration, comparators, and endpoints. At present, orforglipron should be viewed as an oral small-molecule GLP-1 receptor agonist with emerging comparative evidence, rather than as a broadly superior replacement for existing agents. Further long-term comparative, cardiovascular, renal, safety, adherence, and real-world effectiveness data are needed to define its final place in therapy.
Comparative 24-month cardiovascular outcomes and biomarker trajectories with semaglutide, empagliflozin, and sitagliptin in people with obesity and type 2 diabetes: a multicenter real-world study.
Ther Adv Endocrinol Metab
Jo-Ching Chen, Kai-Wen Liu, Yu-Nan Huang +3 more
Comparative evidence on 24-month clinical outcomes and biomarker trajectories with semaglutide, empagliflozin, and sitagliptin in adults with type 2 diabetes (T2D) and obesity remains limited.
Semaglutide and Musculoskeletal Health: A Mendelian Randomization Study Based on GLP-1 Receptor Expression.
Endocr Metab Immune Disord Drug Targets
Dong Li, Xinyu Liang, Zhijun Li +2 more
Semaglutide, a glucagon-like peptide-1 receptor (GLP1R) agonist, is clinically used for glycemic control and weight loss. However, it is still unclear whether it has any impact on bones and muscles. Does semaglutide have any impact on the musculoskeletal system of patients during its use, or does it have any negative effects on them? This study aims to assess the impact of GLP1R on bone and muscle using Mendelian Randomization.
Exercise-induced anaphylaxis with a cofactor of GIP/GLP-1 receptor agonist: A case report.
J Allergy Clin Immunol Glob
Albert C Chong, Amani Elshaer, Maximiliano Diaz-Menindez +3 more
We report a patient who developed exercise-induced anaphylaxis after starting the dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist tirzepatide, who after discontinuing tirzepatide, experienced resolution of exercise-induced anaphylaxis.
Respiratory Microbiome Remodeling in Aging: Implications for Immunosenescence and Therapeutic Intervention.
Immune Netw
Seong-Mook Jung, Wonkeon Sunwoo, Young Min Son
Aging involves progressive declines in lung structure and immune function, increasing the incidence and severity of respiratory diseases and reducing vaccine responsiveness. Meanwhile, the respiratory tract harbors a dynamic microbial ecosystem that contributes to immune homeostasis and colonization resistance. Growing evidence indicates that aging disrupts this host-microbe balance within the respiratory tract; however, the mechanisms and therapeutic implications remain incompletely integrated. This review summarizes age-related remodeling of the respiratory microbiome. Beyond compositional shifts, aging alters microbial functions, including metabolic output and resilience to perturbation, exhibiting downstream effects on epithelial barriers, mucus clearance, and immune priming. Furthermore, as the microbiome-immune axis is modifiable, microbiome-targeted therapies represent key opportunities to restore respiratory homeostasis during aging. These interventions, combined with senescence- and cytokine-directed immunomodulation and vaccine optimization using adjuvants and mucosal immune-informed designs, may reduce infection burden and chronic lung disease progression in older populations. Together, this review highlights that a deeper understanding of age-related respiratory microbiome remodeling and its interplay with immunosenescence will be essential for the rational design of microbiome-informed therapies.
Analysis of Circulating Long Non-Coding RNA in Prediabetes or Newly Diagnosed Type 2 Diabetes Subjects With or Without Heart Stress.
Diabetes Metab Res Rev
Francesco Di Giacomo Barbagallo, Giosiana Bosco, Lorena Lanzafame +15 more
Early myocardial stress may develop in subjects with prediabetes or newly diagnosed type 2 diabetes (T2D) even in the absence of overt heart failure. We aimed to evaluate circulating lncRNAs in prediabetes or newly diagnosed T2D subjects.
The Effect of Fructose and FTO Gene Polymorphism on the Efficacy of GLP-1 and GIP Combination Therapies: A Narrative Review.
Cureus
Douglas S Larner
This literature review examines how dietary fructose intake and fat mass and obesity-associated (FTO) gene polymorphisms may influence the efficacy of glucagon-like peptide-1 (GLP-1)- and glucose-dependent insulinotropic polypeptide (GIP)-based therapies in obesity and metabolic syndrome. The narrative review synthesizes evidence showing that incretin-based therapies, particularly GLP-1 receptor agonists and dual GLP-1/GIP agonists, produce substantial weight loss and metabolic improvement, but response varies considerably among individuals. A central theme is that high fructose consumption promotes hepatic steatosis, de novo lipogenesis, insulin resistance, oxidative stress, and systemic inflammation, thereby creating a metabolic environment that may contribute to variability in incretin responsiveness. In parallel, FTO risk alleles are associated with increased obesity susceptibility, altered appetite regulation, impaired leptin signaling, and greater vulnerability to metabolic dysfunction. The review proposes an integrated model in which FTO-mediated leptin resistance and fructose-induced hepatic and inflammatory stress converge to reduce the appetite-suppressive and metabolic benefits of GLP-1/GIP therapies. Furthermore, it discusses the clinical implications of this interaction, emphasizing dietary fructose reduction, combination pharmacotherapy, and precision medicine strategies such as FTO genotyping and individualized therapeutic selection. Overall, the evidence suggests that gene-diet interactions may meaningfully shape incretin treatment outcomes and that more personalized, multi-targeted approaches may improve weight-loss efficacy in patients with obesity and metabolic syndrome. However, direct clinical evidence linking FTO genotype and fructose intake to reduced GLP-1/GIP therapeutic efficacy remains limited.