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Mechanistic Integration of Beta-Alanine-Carnosine Buffering and Glutamine Metabolism in Exercise-Induced Muscle-Brain Crosstalk: Implications for Aging, Neurodegeneration, and Cognitive Decline.
Mol Neurobiol
Rui Wang, Yan Guo, Juan Li +2 more
Aging is marked by a gradual deterioration in muscular performance, cognitive abilities, and metabolic flexibility, phenomena that are intricately linked through the muscle-brain axis. Recent research indicates that particular amino acids, notably beta-alanine (BA) and glutamine, may not function in isolation but instead converge mechanistically to modulate this axis through synergistic influences on intracellular pH regulation, nitrogen metabolism, and redox equilibrium. BA, through its involvement in the biosynthesis of carnosine, augments intracellular buffering capacity and maintains pH stability during metabolic stress scenarios such as exercise and age-related mitochondrial dysfunction. This buffering capability holds particular significance for pH-sensitive enzymes implicated in glutamine metabolism, such as glutamine synthetase and glutaminase, thereby potentially safeguarding glutamine turnover and nitrogen flux in acidic environments. Simultaneously, glutamine operates as a pivotal metabolic substrate that connects skeletal muscle and the brain by facilitating energy homeostasis, immune modulation, antioxidant protection, and neurotransmitter recycling through the glutamate-glutamine axis. Within this cohesive framework, the regulation of pH mediated by carnosine and the metabolic pathways reliant on glutamine collectively enhance mitochondrial functionality, neuroplasticity, and the mitigation of neuroinflammation. Physical exercise further intensifies these interactions by influencing both the availability of carnosine and the dynamics of glutamine, thereby strengthening their significance in the communication between muscle and brain. This review consolidates the prevailing evidence regarding BA and glutamine within a unified mechanistic paradigm, emphasizing their synergistic contributions to the regulation of metabolic resilience and neuroprotection in the context of aging and neurodegenerative disorders. In aggregate, this integrative viewpoint offers a more robust biological justification for the targeted modulation of these amino acids as complementary agents within the muscle-brain axis. Future investigations should prioritize personalized interventions that integrate amino acid supplementation and exercise regimens within the paradigm of predictive, preventive, and personalized medicine to enhance the trajectories of healthy aging.
PIEZO1 regulates smooth muscle cell plasticity by integrating mechanical stretch with glycolytic metabolism.
Cardiovasc Res
Yapeng Cao, Liran Xu, Min Zhang +23 more
Pulmonary artery smooth muscle cells (PASMCs) sense and respond to constant mechanical strain, which is vital for lung homeostasis and disease. Mechanical stimuli and altered glycolytic metabolism are intrinsically intertwined in proliferative PASMCs undergoing a phenotypic switching, however, it remains unclear how biophysical forces and glycolysis are coupled in PASMCs. We report that PIEZO1 plays a critical role in PASMC metabolism and distinguishable mechanical cues differently rewire PIEZO1-mediated signalling into pro- and anti-glycolytic metabolism.
Sotatercept in Congenital Heart Disease-Associated Pulmonary Arterial Hypertension and Eisenmenger Syndrome: First Case Series.
JACC Case Rep
Gillian P Leung, Elaine C Major, Sydney C Cason +3 more
Eisenmenger syndrome (ES) is a form of World Health Organization Group 1 pulmonary arterial hypertension (PAH). Initial therapy typically involves monotherapy with an endothelin-receptor antagonist or a phosphodiesterase-5 inhibitor, whereas evidence for advanced therapies remains limited. Sotatercept, a first-in-class therapy, modulates vascular cell proliferation. Phase 3 results were promising; however, they excluded patients with ES. Concerns exist that sotatercept could exacerbate pre-existing erythrocytosis and bleeding risk. This case series describes the authors' experience with the use of sotatercept in patients with ES and illustrates its feasibility.
Effect of GLP-1 receptor agonists at doses for obesity management on muscle health: systematic review and meta-analysis of randomized controlled trials (RCTs).
Int J Obes (Lond)
Ligia Patricia Laverde, Oscar Mauricio Muñoz-Velandia, Diana Alfonso +1 more
The impact of GLP-1 receptor agonists (GLP1-RA) treatment on lean mass and body composition in patients with obesity is not fully understood.
Integrating condensates into protein lifespan - from birth to death.
J Biol Chem
Chloe A Langridge, Emily M Sontag
Proper protein production is an essential biological process for all known living organisms. The cell depends on a functional protein homeostasis, or proteostasis, network to facilitate proper gene expression, transcription, translation, polypeptide folding, and degradation. Several condensates are involved in the "birth" and maturation of newly synthesized proteins. In conditions of cellular stress, gene expression and protein production are altered, and protein degradation often increases. Under various types of cellular stress, new condensates often form. This review will highlight the condensates that are involved in the protein lifespan. This includes condensates that regulate gene expression, protein translation, sequester misfolded proteins, and those associated with protein degradation. We will summarize what is known about these condensates under unstressed conditions, and how their regulation changes under stressed conditions. Understanding the functions and regulation of condensates during the protein life cycle will be critical to determining how things go awry in disease.
Apoptotic bodies in bone homeostasis and skeletal disease: biology and therapeutic implications.
Apoptosis
Yuhang Xi, Ying Qu, Ziyang Zhang +3 more
Bone is among the most apoptotically active tissues in the body. During remodeling, repair, and disease, dying osteoclasts, osteoblast-lineage cells, osteocytes, mesenchymal stem/stromal cells, and injury-associated cells release apoptotic bodies (ABs) that retain parent-cell-derived cargo and surface ligands. These vesicles are increasingly viewed not only as debris for efferocytic clearance but also as source-specific signalling units that shape skeletal cell fate, immune activity, mineralization, and repair. This review integrates current evidence for ABs across skeletal homeostasis and disease. We first define ABs within the broader extracellular vesicle landscape, emphasizing vesicle heterogeneity, isolation and characterization challenges, and terminology boundaries. We then examine AB sources and recipient interfaces, including osteoclasts, osteoblast-lineage cells, osteocytes, mesenchymal stem/stromal cells, platelet-derived ABs in injury repair, macrophages, osteoclast phagocytes, chondrocytes, and bone lining cells. We further discuss how dysregulated AB signalling contributes to osteoporosis, osteoarthritis, and bone metastasis, as well as alveolar bone destruction, aging-related bone loss, osteochondral mineralization, and bone injury repair. We highlight therapeutic implications, including AB-based or AB-inspired strategies, the cathepsin K (CTSK)-responsive self-assembling peptide nanoparticle OsteoSAVE for in vivo generation of osteoclast-derived ABs, and the hypothesis that antiresorptive therapies may reshape osteoclast-derived AB (OC-AB) production. We also identify unresolved translational questions, including AB lifespan, circulation, source attribution, and direct human validation.
Development and Validation of Prescribing Appropriateness Criteria (PAC) for Sri Lankan Older Adults.
Drugs Aging
Maneesha P Godakanda Arachchige, Rebekah J Moles, Sarath Lekamwasam +4 more
Inappropriate prescribing in Sri Lankan older adults, contributes to adverse drug events, hospital admissions and increased healthcare expenditure. Although international tools exist to assess prescribing appropriateness in older adults, their direct application in Sri Lanka is limited by differences in clinical practices, resource constraints and variability in medicine availability.
Distinctive patterns of glucagon and incretin responses to oral and isoglycaemic intravenous glucose load in fibrocalculous pancreatic diabetes.
Sci Rep
Shivendra Verma, Riddhi Dasgupta, Shajith Anoop +9 more
Fibrocalculous pancreatic diabetes mellitus (FCPD) is characterised by pancreatic calcification, intraductal calculi and severe insulin deficiency, yet abnormalities in glucagon regulation and incretin hormone responses remain incompletely understood. We evaluated the glucagon, incretins and oxyntomodulin secretory responses to oral and intravenous glucose administration in participants with FCPD. Participants with FCPD (cases; n = 9; mean age 34 ± 7.2 years) and healthy individuals (controls; n = 6; mean age 29.8 ± 7.7 years) underwent an extended oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion (IIGI). Serial measurements of plasma glucose, insulin, C-peptide, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), oxyntomodulin (OXM), and pancreatic polypeptide (PP) were done. Serial hormone responses were analysed using linear mixed-effects models, with area-under-the-curve analyses using trapezoidal rule, performed as secondary summaries. On primary mixed-model analysis, the participants with FCPD exhibited significantly higher fasting and post-OGTT glucagon concentrations with glucagon exposure being greater following OGTT than IIGI in the group with FCPD, whereas no route-dependent difference was observed in control participants. GLP-1 and OXM responses were similarly increased in participants with FCPD, particularly following, oral glucose tolerance test, while GIP responses were attenuated. In contrast, C-peptide and pancreatic polypeptide responses were profoundly suppressed during both OGTT and IIGI in FCPD, consistent with severe pancreatic endocrine failure. Despite matched glycaemic exposure, the incretin effect and gastrointestinal glucose disposal were reduced in the FCPD group. These findings demonstrate persistent hyperglucagonemia accompanied by a distinctive pattern of incretin secretion in FCPD, characterised by exaggerated L-cell-derived hormone secretion with attenuated K-cell (GIP) response and impaired pancreatic peptide responses, highlighting altered entero-pancreatic hormonal regulation in this condition.
Hierarchical regulation and mechanism of "open-hollow-fibrous network" structures: Osteogenic-angiogenic coupling responses of poly(γ-benzyl-L-glutamate) microspheres.
Biomater Adv
Jieyu Su, Yuxin Zhang, Yongqiang Cao +4 more
Biomimetic fibrous microspheres with a high specific surface area hold substantial promise for bone tissue engineering. In this study, asymmetric open-hollow nanofibrous microspheres (HNMs) were fabricated from polypeptide poly(γ-benzyl-L-glutamate) (PBLG) via a combination of emulsion and thermally induced phase separation, yielding PBLG HNMs. To further impart biofunctionality, the copper peptide (GHK-Cu) was covalently grafted onto the microspheres to obtain osteoinductive and pro-angiogenic PBLG-GCu HNMs. The optimized microspheres exhibited an average diameter of 372 ± 102 μm, which is suitable for injectability, and an opening size of 219 ± 53 μm, enabling efficient cellular infiltration. The internal surface featured an interconnected nanofibrous network with a fiber diameter of 417 ± 78 nm, mimicking the extracellular matrix (ECM) microenvironment and providing abundant cell-interactive sites. Live/Dead staining and CCK-8 assays confirmed the cytocompatibility of the PBLG-GCu HNMs. Compared with non-functionalized PBLG HNMs, PBLG-GCu HNMs enhanced bone marrow mesenchymal stem cell (BMSC) mineralization and upregulated osteogenic gene expression, with Runx2, OPN, and OCN expression increased by 1.61-, 3.53-, and 2.29-fold, respectively. In addition, the tube formation assay verified robust angiogenic stimulation. Overall, the PBLG-GCu HNMs integrated hierarchical structural biomimicry with dual osteogenic-angiogenic bioactivity, exhibiting great potential as injectable scaffolds for repairing irregular bone defects.
Modulation of satellite cell function to alleviate age-related sarcopenia: Electrical stimulation & Ca²⁺ signaling combined approach.
iScience
Canyu Chen, Yersen Mulat, Dongsheng Jiang +1 more
Age-related sarcopenia is a degenerative condition characterized by loss of muscle mass and strength. Satellite cells (SCs), the stem cells of skeletal muscle, decline in number and function with age, contributing to sarcopenia. Enhancing SC function represents a promising therapeutic strategy. Neuromuscular electrical stimulation (NMES) induces passive muscle contraction and improves SC activity, partly through calcium-dependent mechanisms. Calcium signaling is essential not only for excitation-contraction coupling but also for SC proliferation and differentiation. This review summarizes age-related changes in SCs, current sarcopenia treatments, and the therapeutic potential of NMES. We propose a novel combined strategy integrating NMES with calcium signaling modulation to synergistically enhance SC function. This approach offers a promising avenue for treating age-related sarcopenia and warrants further investigation.
Vitamin D and antimicrobial peptides in skin health and disease: Mechanisms and therapeutic potential.
Biochem Biophys Rep
Hanlin Gao, Jianwei Zhu, Zhi Chen +1 more
As the body's frontline barrier against the external environment, the skin maintains homeostasis through a complex network of innate defense factors, among which antimicrobial peptides (AMPs) play pivotal roles in pathogen defense, inflammation regulation, and tissue repair. Apart from its classical role in bone metabolism, Vitamin D has been shown, mainly in experimental and translational studies, to modulate the expression and processing of selected AMPs through VDR-dependent and non-classical pathways. These findings suggest a possible link between Vitamin D signaling and cutaneous innate immunity. However, the functional consequences of Vitamin D-mediated AMP regulation appear to be highly context-dependent. Evidence from cell-based studies, animal models, human skin samples, and limited clinical studies suggests that this axis may participate in antimicrobial defense, inflammatory regulation, angiogenesis, and tissue repair, but direct clinical evidence demonstrating therapeutic benefit through AMP modulation remains limited and sometimes inconsistent. Finally, building on current evidence, we analyze the limitations of research on the Vitamin D-AMP axis and highlight future directions, including the context-dependent functions of AMPs in diverse skin environments, their interactions with the skin microbiota, and the design and evaluation of translational studies. We argue that this review not only advances our understanding of skin immune mechanisms but also provides valuable insights and references for future research.
Cardiovascular outcomes of semaglutide and tirzepatide in type 2 diabetes mellitus and obesity: a systematic review and meta-analysis.
Diabetol Metab Syndr
Xiao-Yu Zhou, Qi Wu, Hao-Lan Lu +5 more
To systematically evaluate cardiovascular outcomes associated with semaglutide and tirzepatide in adults with type 2 diabetes mellitus (T2DM), overweight or obesity.
Tirzepatide and the Cardiovascular Continuum: Metabolic, Cardiorenal and Heart Failure Evidence.
Clin Med Insights Cardiol
Antonio Lm Parlati, Luca Martini, Ermanno Nardi +4 more
Tirzepatide is a first-in-class, once-weekly dual GIP and GLP-1 receptor agonist approved for type 2 diabetes and obesity. Given the tight link between hyperglycemia, adiposity, and cardiovascular disease, tirzepatide has rapidly gained interest as a broader cardiometabolic intervention. This narrative review summarizes mechanistic rationale and clinical evidence on cardiovascular risk-factor modification, cardiorenal signals, and outcome data. Across the SURPASS program in type 2 diabetes, tirzepatide produces large, dose-dependent reductions in HbA1c and substantial weight loss, with consistent benefits versus active comparators. In obesity, the SURMOUNT trials showed marked and durable weight reduction over long follow-up, with clinically relevant improvements in waist circumference, blood pressure, triglycerides, and inflammatory biomarkers. Beyond weight and glycaemia, available data suggest favorable effects on lipids, ambulatory blood pressure, inflammatory markers, and kidney-related endpoints in exploratory analyses. Tirzepatide also improves obstructive sleep apnea severity in adults with obesity. Regarding cardiovascular outcomes, SURPASS-CVOT supports cardiovascular safety by demonstrating noninferiority versus dulaglutide for 3-point major adverse cardiovascular events in patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD). In obesity-related HFpEF, SUMMIT shows reductions in worsening heart failure (HF) events and improvements in health status, supporting a phenotype-specific role in HF. Overall, tirzepatide is emerging as a key therapeutic option for integrated cardiometabolic risk reduction, with ongoing research needed to define its incremental benefit versus established GLP-1 receptor agonists, long-term effectiveness in routine care, and optimal positioning across HF phenotypes.
Long-term effects of weight-reducing drugs in people with hypertension.
Cochrane Database Syst Rev
Ulrike Spary-Kainz, Nicole Posch, Christina Radl-Karimi +7 more
Long-term weight management drugs have the potential to reduce body weight and blood pressure in obese or overweight individuals. Being overweight or obese is often associated with hypertension, which is linked to an increased risk of cardiovascular mortality and morbidity. The effects of weight-reducing drugs on patient-relevant outcomes, especially in people with hypertension, are currently unclear. This review is the fourth update of one first published in July 2009.
Pulmonary adverse events associated with GLP-1 receptor agonists: a systematic review of respiratory safety signals.
Cardiovasc Diabetol Endocrinol Rep
Aarushi Ahuja, Sai Prasad, Sahana Manoharan +11 more
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are among the most rapidly growing drug classes in contemporary medicine, approved for type 2 diabetes mellitus (T2DM) and obesity management. Although gastrointestinal adverse effects are well characterised, the pulmonary safety profile of GLP-1 RAs remains incompletely defined, representing an important evidence gap given the scale of global prescribing.
Potential of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Mitigating Metabolic Side Effects Associated With Clozapine or Olanzapine Therapy: A Literature Review.
Cureus
Amir Meftah, Bolaji Yoade, Cade Cowart +8 more
Clozapine and Olanzapine can cause severe metabolic side effects, increasing cardiovascular risk. Glucagon-like peptide-1 (GLP-1) receptor agonists, primarily approved for use in patients with type 2 diabetes, may counter these effects by promoting weight loss, improving glucose metabolism, and enhancing cardiovascular health, offering a promising approach for managing antipsychotic-related metabolic complications. We conducted a literature review using the search terms "clozapine OR olanzapine AND GLP-1 agonist," "schizophrenia AND GLP-1 agonist," "antipsychotic AND GLP-1 agonist," and "psychosis AND GLP-1 agonist" on PubMed and Google Scholar. This search initially yielded 172 articles. We focused on clinical trials or case reports investigating the use of GLP-1 agonists in conjunction with Olanzapine or Clozapine. Our final selection included two clinical trial studies, one case report, and a retrospective study. In a case report, a schizophrenic patient on Clozapine treated with liraglutide experienced a reduction in glycated hemoglobin (HbA1c ), from 10% to 6.5% over 14 months, along with a total weight loss of 7.7 kg (8.7% body weight reduction) after two years, and decreased insulin requirements. In a retrospective study reviewing 16 obese patients with schizophrenia treated with liraglutide, of whom 14 were on Clozapine, significant reductions in body weight, waist circumference, body mass index (BMI), and plasma glucose levels were observed over 16 weeks (P < 0.001). A randomized clinical trial with 103 patients, with diagnoses within the schizophrenia spectrum disorders, who have been treated with Olanzapine or Clozapine, and liraglutide, showed significant improvement in glucose tolerance when compared to placebo (P < 0.001), with 63.8% of liraglutide-treated patients achieving normal glucose tolerance versus 16.0% in the placebo group. Additional benefits included significant reductions in body weight, waist circumference, blood pressure, visceral fat, and low-density lipoprotein (LDL) cholesterol levels. In another outpatient study with 28 participants randomized to receive subcutaneous, extended-release exenatide in one arm, or standard of care in the other arm for 24 weeks, six participants in the exenatide group achieved more than 5% weight loss, compared to just one in the usual care group (P = 0.029). The exenatide group experienced significantly greater mean weight loss compared to the usual care group (P = 0.015). Additionally, the exenatide group showed a more substantial reduction in BMI (P = 0.019) and improved glycemic control, with significant reductions in fasting glucose (P = 0.036) and glycated hemoglobin (P = 0.004) compared to the usual care group. This review underscores the need for future studies that involve the use of GLP-1 agonists in conjunction with Clozapine or Olanzapine. Although results from preliminary studies are promising, there is a need for more randomized controlled clinical trials to validate these findings, assess long-term efficacy, and develop clinical guidelines.
Glucagon-Like Peptide-1 Agonist vs. Placebo and Pulmonary Decline After Open-Heart Surgery: A Substudy of the GLORIOUS Randomised Clinical Trial.
Acta Anaesthesiol Scand
Astrid Duus Mikkelsen, Sebastian Wiberg, Hans Henrik Lawaetz Schultz +7 more
Postoperative pulmonary decline is an established complication of open-heart surgery extending beyond the immediate postoperative phase. Inflammation-mediated lung damage and ischaemia-reperfusion injury secondary to extracorporeal circulation is a proposed pathophysiological driver. GLP-1 receptor agonists (GLP-1RA) have emerged as promising protective agents in this setting.
GLP-1 Agonists in Adolescent Obesity: A Narrative Review of Single, Dual, and Triple Agonists.
Diabetes Metab Syndr Obes
Mahroz Abid, Khizer Sohail Sheikh, Muhammad Shahbaz Ahmad +1 more
Adolescent obesity is an escalating global health concern associated with increased risks of cardiovascular disease, type 2 diabetes mellitus, and long-term metabolic complications. Although lifestyle interventions remain first-line therapy, their limited long-term effectiveness has led to increasing interest in pharmacological approaches. This narrative review evaluates the mechanisms, clinical efficacy, and safety of glucagon-like peptie-1 (GLP-1) receptor agonists, as well as emerging dual and triple incretin-based therapies, in the management of adolescent obesity. A literature search was conducted using PubMed and Scopus, focusing on clinical trials, systematic reviews, and real-world studies published between 2010 and 2024. Evidence from pediatric and adolescent populations was prioritized, while adult data were included where adolescent-specific evidence remains unavailable and are interpreted cautiously. Among single-agent therapies, GLP-1 receptor agonists have demonstrated clinically meaningful weight reduction and metabolic benefits in adolescents. In the STEP TEENS trial, once-weekly semaglutide resulted in approximately 16% mean body weight reduction over 68 weeks, while liraglutide produced more modest reductions. Dual agonists such as tirzepatide and emerging triple agonists, including retatrutide, have shown superior weight-loss efficacy in adult populations; however, pediatric data for these agents remain limited or unavailable. Across all incretin-based therapies, gastrointestinal adverse effects are the most commonly reported side effects. In conclusion, GLP-1 receptor agonists represent an effective pharmacological option for adolescents with obesity, while dual and triple incretin agonists offer promising future therapeutic potential. Nevertheless, the clinical application of multi-receptor agonists in adolescents requires caution, as long-term safety, developmental outcomes, and real-world adherence data in pediatric populations are still lacking. Further well-designed pediatric trials are essential before broader adoption can be recommended.
Post-translational modifications as a regulatory code for tau function in health and disease.
Front Dement
Abigail J Nordbeck, Bhirisha Sharma, Charles A Garcia +1 more
Tau is an intrinsically disordered microtubule-associated protein that performs diverse roles in neuronal physiology, including regulation of microtubule stability, intracellular transport, and synaptic signaling. These functions are dynamically regulated by an extensive array of post-translational modifications (PTMs) that collectively shape tau conformation, interactions, localization, and turnover. Under physiological conditions, PTMs act as a regulatory system that enables tau to transition between functional states in response to cellular cues. In neurodegenerative diseases collectively known as tauopathies, however, this finely balanced modification landscape becomes disrupted, leading to tau mislocalization, impaired clearance, and assembly into toxic oligomers and fibrillar aggregates. Although phosphorylation has historically dominated the tau field, growing evidence indicates that multiple PTMs, including acetylation, ubiquitination, truncation, oxidation, nitration, methylation, and glycosylation, cooperatively influence tau structure and pathogenic potential. Recent proteomic studies reveal that tau can harbor dozens of modifications simultaneously, highlighting the importance of understanding PTMs as an integrated regulatory network rather than independent events. Crosstalk between modifications can generate synergistic or antagonistic effects that influence tau aggregation, proteostasis, and propagation. In this review, we synthesize current knowledge of major tau PTMs and highlight emerging principles governing their interactions. We discuss how dysregulation of PTM networks contributes to tau state transitions during aging and neurodegeneration and consider how targeting PTM-regulating enzymes may provide therapeutic strategies for Alzheimer's disease and related tauopathies.
Ovarian-derived signals reprogram hepatic lipid metabolism in aging: Implications for therapeutic targeting of metabolic dysfunction.
Adv Transl Res
Nathan D McCoy, Michael T Kinter, Augusto Schneider +3 more
Aging in mammals is a complex, multifaceted process involving the progressive decline of physiological functions, in which energy metabolism plays a pivotal role. β-oxidation-the primary pathway for converting fatty acids into energy-is tightly linked to aging and to female reproductive senescence. In the present study, we investigated how ovarian tissue remodels hepatic proteins central to the β-oxidation pathway.