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The glucagon-like peptide-1 receptor agonist, Ex4, reduces intromission in sexually experienced male mice.
Psychoneuroendocrinology
Olesya Shevchouk, Christian E Edvardsson, Mia Ericson +2 more
The physiological effects of glucagon-like peptide-1 (GLP-1) are vast, including food and glucose homeostasis. As the half-life is short, both short-acting, exendin-4 (Ex4) and long-acting, liraglutide and dulaglutide, GLP-1 receptor (GLP-1R) agonists have been developed and are approved for type 2 diabetes and/or obesity. They have also been found to reduce behaviors linked to addictive drugs through involvement of mesolimbic brain regions such as the medial amygdala. Additionally, Ex4 reduces sexual interactions in sexually naïve male mice and experienced females. However, the effects of GLP-1, short- and long-acting GLP-1R agonists on sexual behaviors in sexually experienced males remain unknown. Therefore, we examined how GLP-1 and Ex4 affect sexual behavior in experienced male mice, influenced associated neurochemical changes in the medial amygdala, and evaluated the potential modulatory factors through social behaviors. Additionally, we assess whether long-acting GLP-1R agonists impacted similar behaviors as well as the levels of corticosterone and insulin. Ex4 reducced the number of intromissions and ejaculations in sexually experienced male mice without GLP-1 having an effect. Moreover, social behaviors were unaffected by short-acting GLP-1R agonists. In the medial amygdala of these male mice treated with Ex4, the levels of glutamate and other amino acids were lower. Conversely, liraglutide and dulaglutide did not modify sexual behaviors but enhanced time in the social zone, with no effect on corticosterone or insulin levels. Together, these studies suggest that GLP-1R activation modulates both sexual and social behaviors, but the outcome depends on which agonists have been used.
Evolution of incretin-based therapies: From GLP-1 monotherapy to dual and triple agonists: A new era in metabolic therapy.
Indian J Med Res
Monika Gupta, Jitendra Shukla
Incretin-based therapies have revolutionised the management of metabolic disorders, transitioning from DPP-4 inhibitors to advanced GLP-1 receptor agonists (GLP-1RAs) and next-generation dual and triple agonists. This review explores the evolving role of incretin pharmacology in type 2 diabetes mellitus (T2DM), obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD). Literature from PubMed, Scopus, and Google Scholar up to July 2025 was reviewed, emphasising pivotal trials and real-world evidence. While DPP-4 inhibitors offer modest glycaemic benefits, GLP1RAs such as liraglutide and semaglutide have demonstrated significant weight loss and cardiometabolic protection. Dual GIP/GLP-1 agonist tirzepatide and triple agonist retatrutide have shown unprecedented efficacy, with up to 24% body weight reduction and improvement in hepatic and inflammatory markers. Agents like cotadutide and efinopegdutide further expand indications to MASLD and metabolic dysfunction associated steatohepatitis (MASH). Despite promising outcomes, challenges persist in terms of cost, accessibility, and the underrepresentation of low- and middle-income countries in major trials. Pharmacogenomic variability may also influence therapeutic response. Incretin-based multi-agonists offer a transformative, multi-system approach to metabolic disease but require tailored implementation. This review provides an updated synthesis of therapeutic developments and outlines priorities for future research, regulatory policy, and equitable global integration as incretin-based therapies have evolved into a versatile class addressing glycaemic control, weight loss, and cardio-metabolic risk.
Native PLGA nanoparticles attenuate disease pathology via multiple pathways in 5xFAD Alzheimer's model.
Alzheimers Dement
Govindarajan Karthivashan, Shuai Wang, Qi Wu +6 more
Elevated amyloid beta (Aβ) levels and aggregation contribute to neurotoxicity and development of Alzheimer's disease (AD), the leading cause of dementia in the elderly. While we reported that native poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, clinically used in drug delivery, suppress Aβ aggregation/toxicity, their effects in adult 5xFAD mice with advanced Aβ pathology remain unknown.
Applications of Mesenchymal Stromal Cells in Hematologic Disease: Advances, Challenges, and Bioengineering Strategies.
Curr Stem Cell Res Ther
Yicheng Zhu, Chao Liu, Jing Yang
Mesenchymal stromal cells (MSCs) are multipotent cells of mesodermal origin capable of self-renewal and multilineage differentiation. Characterized by low immunogenicity and tropism toward injury sites, MSCs exhibit critical properties including hematopoietic support, immunomodulation, and tissue regeneration. These unique attributes position MSCs as promising therapeutic tools for hematologic diseases, where disruption of the bone marrow niche impairs normal hematopoiesis. Co-transplantation of MSCs with hematopoietic stem cells (HSCs) facilitates HSC homing to the bone marrow niche and significantly improves post-transplant hematopoietic reconstitution. Furthermore, MSCs show considerable therapeutic potential in both prophylaxis and management of graftversus- host disease (GVHD), a major complication of allogeneic transplantation. The therapeutic mechanisms of MSCs have evolved from an initial focus on engraftment to a broader understanding of their paracrine actions via the "hit-and-run" mechanism, wherein MSCs exert functions through secreted factors and extracellular vesicles before host clearance. Despite these advances, clinical translation faces significant challenges, including poor homing efficiency, cellular heterogeneity, culture-induced senescence, and vulnerability to inflammatory and oxidative stress. This review summarizes clinical applications of MSCs in aplastic anemia, leukemia, and co-transplantation with HSCs, while critically evaluating the balance between therapeutic efficacy and potential risks. Additionally, we discuss emerging bioengineering strategies designed to overcome current limitations and enhance MSC therapeutic potency for next-generation cell therapies in hematologic diseases.
Symptom-Level Precision Neurology in Amyotrophic Lateral Sclerosis (ALS): Linking Microglial Pruning, Mitochondrial Nicotinamide Adenine Dinucleotide (NAD+) Compensation, and Autophagy Failure Across the Aging Spectrum.
Cureus
Ngo Cheung
Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurological disease with limited disease-modifying treatment options and, for many patients, a short survival window. The clinical course varies widely. Limb weakness, bulbar impairment, respiratory decline, fine-motor dysfunction, cognitive change, mood symptoms, and fatigue may each appear at different times and progress at different rates. This variability suggests that motor neuron loss alone may not fully explain the patient-level pattern of symptoms. This article is a narrative hypothesis framework, not a clinical guideline or a validated stratification tool. Established ALS biology, associative genomic findings, preclinical observations, computational predictions, and author-derived hypotheses are therefore separated throughout the article. This review brings together four interlinked studies by the current author as a primary hypothesis-generating corpus, which proposes that synaptic plasticity fragility may initiate a microglial pruning continuum shared by major depressive disorder and ALS, while ALS-specific progression may depend on mitochondrial stress, oxidized nicotinamide adenine dinucleotide (NAD+) compensation failure, and collapse of autophagy under aging-related limits. The model presented here maps symptom domains to vulnerable circuit compartments and separates three broad biological states: compensated plasticity, fragile plasticity, and network collapse. A compact mechanistic formulation is used to describe the balance between pruning pressure, glutamatergic burden, and aging stress on one side, and oxidative phosphorylation capacity, NAD+ reserve, and autophagic clearance on the other. The framework also incorporates opposing phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) pathway patterns that may distinguish ALS from frontotemporal dementia (FTD) within an aging context. The result is a falsifiable, biomarker-oriented hypothesis model for future studies, not an evidence-based diagnostic or therapeutic algorithm.
Single-subject proteomic signatures in Alzheimer's disease reflect clinical phenotypes and distinguish asymptomatic from symptomatic cases.
Alzheimers Dement (N Y)
Avijit Podder, Yi Juin Liew, Gregory A Cary +2 more
Alzheimer's disease (AD) exhibits considerable inter-individual variability in clinical presentation, neuropathological burden, and underlying molecular processes. Conventional cohort-based analyses of omics molecular data often mask individual-level heterogeneity, limiting insights into precision therapeutic strategies. To address this challenge, we developed INdividual-level DIfferential GenOmics (INDIGO), a computational framework that quantifies molecular deviations for each individual relative to healthy controls, enabling subject-specific profiling of disease-associated alterations in proteomic data, with a framework that is readily applicable to other omics modalities.
The oscillatory biology of sleep: Linkage to dementia.
Science
Maiken Nedergaard
During wakefulness, neuromodulators operate largely independently to support behavior and cognition. By contrast, sleep reorganizes their activity into a coordinated brain rhythm. During sleep, the major neuromodulators-norepinephrine, acetylcholine, serotonin, and dopamine-exhibit synchronized fluctuations with a periodicity of ~50 seconds. These oscillations appear as recurrent bursts of fast (10 to 30 hertz) electroencephalography activity and are phase-coupled to cerebrospinal fluid flow. Neuromodulators are vasoactive agents and drive slow vasomotion, which provide the mechanical force that supports glymphatic clearance of metabolic waste. Disruption of neuromodulator signaling, as seen in psychiatric disorders, cardiovascular disease, aging, or with commonly prescribed drugs, impairs clearance of neurotoxic proteins, including amyloid-β and tau. Failure of this evolutionarily conserved brain rhythm may therefore represent a previously unrecognized mechanistic pathway linking diverse disorders with sleep disturbances to increased dementia risk.
The novel GLP-1/GIP dual receptor agonist DA5-CH is superior to tirzepatide and exendin-4 in the 6-OHDA Parkinson rat model.
Front Endocrinol (Lausanne)
Zhang Lingyu, Feng Peng, Zhong Wanting +5 more
Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no cure. Diabetes is one of the risk factors for developing PD. Tirzepatide is a novel long-acting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist that is on the market as a treatment for diabetes. Importantly, two phase II trials in PD patients showed good effects with the GLP-1 receptor agonists Exendin-4 and Lixisenatide.
Interactions between nutrition, GLP-1 secretion, and composition of the gut microbiome.
Curr Opin Clin Nutr Metab Care
Afroditi Kouraki, Daniel McWilliams, Ana M Valdes
Glucagon-like peptide-1 (GLP-1) is a key incretin hormone regulating insulin secretion, appetite, and energy balance. Recent research highlights complex interactions between dietary composition, gut microbiome metabolism and GLP-1 secretion. Understanding these relationships is increasingly important given the widespread clinical use of GLP-1 receptor agonists for obesity and type 2 diabetes and the growing interest in microbiome-targeted nutritional strategies.
Adrenal axis integrity after IV methylprednisolone therapy for thyroid eye disease: a retrospective cohort study.
Eur J Endocrinol
Grigoris Effraimidis, Athanasios Kasotas, Alexandra Bargiota
Only 5 prior studies, each involving 12 to 32 patients, have evaluated the impact of high-dose intravenous methylprednisolone (IVMP) on hypothalamic-pituitary-adrenal (HPA) axis function in patients with active moderate-to-severe thyroid eye disease (TED). Due to their small sample sizes and methodological limitations, uncertainty remains regarding the risk of adrenal suppression following this regimen.
The collapse of the food matrix: how ultra-processed foods impact satiety and metabolism by altering physical structure beyond nutrient composition.
Front Nutr
Xinna Wang, Hang Chen, Yan Xu +3 more
The global consumption of ultra-processed foods (UPFs) is strongly associated with the prevalence of non-communicable diseases (NCDs). This link has traditionally been attributed to their poor nutritional profiles. However, evidence shows that even when nutrient-matched, UPFs promote excess energy intake and weight gain, suggesting a pathogenic mechanism beyond their chemical composition. This review proposes a central conceptual framework: the core threat of UPFs to health may originate profoundly from the industrial collapse of their physical "food matrix." While evidence-informed, this framework remains a conceptual proposition requiring further causal validation. We hypothesize that this structural disintegration triggers a proposed top-down cascade of dysregulation. In the oral phase, a soft matrix accelerates eating rates by reducing chewing requirements, thereby weakening early satiety signals. In the gastrointestinal tract, the excessively rapid absorption of nutrients suppresses the secretion of distal gut satiety hormones, such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). This supraphysiological nutrient flux imposes a significant challenge on core metabolic organs, driving insulin resistance and hepatic de novo lipogenesis. Ultimately, the impoverished matrix leads to gut microbiota imbalance, compromised intestinal barrier function, and low-grade systemic chronic inflammation. In conclusion, the integrity of the food matrix is an indispensable dimension for evaluating the health value of food. This paper calls for a fundamental shift in perspective within nutritional science and public health policy: from focusing solely on "what is in our food" to equally considering "what has been done to our food."
The NPR1 agonist antibody XXB750 in heart failure: a phase 2 randomized trial.
Nat Med
Scott D Solomon, John J V McMurray, G Michael Felker +9 more
Therapies targeting the natriuretic peptide system have the potential to reduce death or heart failure events in heart failure with reduced ejection fraction. Here we assess XXB750, a human monoclonal antibody activating natriuretic peptide receptor 1, in patients with heart failure. Patients with heart failure and a left ventricular ejection fraction <50% were enrolled. Those patients who were on background angiotensin-converting enzyme inhibitor or angiotensin receptor blocker treatment were randomized to receive 60 mg XXB750, 120 mg XXB750 or placebo in a blinded fashion or sacubitril/valsartan treatment in an open-label fashion. Those patients on background sacubitril/valsartan treatment were randomized to either 60 mg XXB750, 120 mg XXB750 or placebo treatment in a blinded fashion. The primary endpoint was the change in NT-proBNP levels at 16 weeks after treatment initiation, and safety was also assessed. We randomized 136 participants (70% male, 30% female) to 60 mg XXB750 (n = 26), 120 mg XXB750 (n = 55), matching placebo (n = 29) or sacubitril/valsartan (n = 25). At 16 weeks, NT-proBNP levels rose (ratio of change from baseline 1.34, 95% confidence interval (CI) 1.07-1.66) and cyclic guanosine monophosphate (cGMP) levels declined (ratio of change from baseline 0.77, 95% CI 0.65-0.91) in the pooled XXB750 arms, whereas NT-proBNP levels declined from baseline (ratio of change from baseline 0.70, 95% CI 0.45-1.10), and cGMP levels rose (ratio of change from baseline 1.38, 95% CI 1.13-1.69) in the sacubitril/valsartan arm. Death or worsening heart failure events occurred more frequently in those receiving XXB750 (25%) compared with those receiving sacubitril/valsartan (8%), or placebo (0%). Because of the excess heart failure events in participants receiving XXB750, the data monitoring committee recommended stopping the trial prematurely. In contrast to the expected mechanism of drug action, XXB750 treatment led to increased NT-proBNP levels, lowered cGMP levels and more worsening heart failure events, suggesting that XXB750 may paradoxically behave as a functional antagonist of endogenous natriuretic peptides in patients with heart failure. Clinicaltrials.gov registration: NCT06142383 .
[Value and benefit of basic insulin/GLP-1RA weekly preparation in clinical treatment of type 2 diabetes in adults].
Zhonghua Yi Xue Za Zhi
S C Zhang, L Zang, Y Cheng +2 more
The prevalence of type 2 diabetes mellitus has been rising continuously in China. However, glycemic control rates remain suboptimal, posing a significant public health challenge. Although traditional intensive insulin strategies are effective in improving glycemic control, they are often associated with risks such as hypoglycemia and weight gain. Fixed-ratio combinations of basal insulin and glucagon-like peptide-1 receptor agonist (GLP-1RA) offer complementary mechanisms of action, enhancing efficacy and safety while simplifying treatment regimens, making them a key focus of clinical development. Insulin icodec/semaglutide fixed-ratio combination (IcoSema), the first once-weekly dual-component preparation combining a basal insulin and a GLP-1RA, utilizes advanced formulation technology to achieve stable co-formulation of the ultra-long-acting once-weekly basal insulin and the once-weekly GLP-1RA, with the two components acting in a complementary and synergistic manner. The Phase 3 COMBINE clinical trial program demonstrated that, compared with insulin icodec, semaglutide(1.0 mg), or basal-bolus insulin regimens, IcoSema provides superior or equivalent glycemic control, and the risk of clinically significant or severe hypoglycemic events is comparable to that of semaglutide(1.0 mg). Once-weekly administration helps to simplify the treatment regimen and improve treatment adherence. The clinical application of IcoSema is expected to alleviate the dilemma in Chinese type 2 diabetes management of balancing effective glycemic control with safety and simplicity, offering a new therapeutic option for patients requiring insulin intensification that combines efficacy, safety, and convenience.
Effects of Agonists on Skin Quality: A Comprehensive Literature Review.
Aesthetic Plast Surg
Mauro Barone, Beniamino Brunetti, Roberta D'Emilio +3 more
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly semaglutide and liraglutide, have revolutionized the treatment of type 2 diabetes and obesity due to their potent effects on weight loss and glycemic control. However, emerging evidence has highlighted dermatologic side effects associated with the rapid reduction of subcutaneous adipose tissue, particularly in the context of aesthetic skin integrity. This systematic review aims to comprehensively evaluate the current evidence on the effects of GLP-1 RAs on skin quality, including dermal structure alterations, adipose compartment loss, and skin elasticity changes.
Targeting microglia: A new strategy for the treatment of Alzheimer's disease.
J Neuroimmunol
Manyv Zheng, Mingjuan Yang, Wenya Su +2 more
Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation, remains without curative therapies. Emerging evidence underscores microglia, the brain's resident immune cells, as pivotal players in AD pathogenesis, exerting dual roles in neuroprotection and neurotoxicity. This review synthesizes current knowledge on microglial dynamics, including their heterogeneous activation states (e.g., disease-associated microglia), metabolic reprogramming, aging-related dysfunction, and subset heterogeneity, which collectively influence Aβ clearance, tau propagation, and synaptic integrity. We highlight the interplay between microglial receptors-such as TREM2, APOE, and neurotransmitter receptors (e.g., cholinergic, glutamatergic, and cannabinoid receptors)-and AD pathology, emphasizing their roles in modulating neuroinflammation, phagocytosis, and neuronal excitotoxicity. Furthermore, we evaluate therapeutic strategies targeting microglia, including pharmacologic modulation of neuroinflammatory pathways, metabolic interventions, and cell transplantation, which aim to restore homeostatic microglial functions. Challenges in clinical translation, such as temporal specificity of interventions and microglial plasticity, are critically discussed. By integrating recent advances in single-cell genomics and neuroimmunology, this review provides a roadmap for developing microglia-centric therapies to disrupt the vicious cycle of neuroinflammation and neurodegeneration in AD, offering novel insights for future research and therapeutic innovation.
Progressive loss of glycemic control during chronic DPP-4 inhibitor therapy despite preserved β-cell function: a case report suggesting acquired incretin resistance.
Cardiovasc Diabetol Endocrinol Rep
Sai Prasad, Aarushi Ahuja, Shreya Sharma +4 more
Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely prescribed second-line agents for type 2 diabetes mellitus (T2DM). Secondary treatment failure with DPP-4 inhibitors is conventionally attributed to progressive β-cell dysfunction. Acquired resistance to DPP-4 inhibitor therapy, characterised by progressive glycemic deterioration despite preserved endogenous insulin secretion, remains an under-recognised and poorly documented clinical phenomenon. We report a case of secondary DPP-4 inhibitor failure with preserved β-cell function, raising the hypothesis of acquired incretin resistance as an alternative mechanism of treatment failure.
Treatment strategies for pulmonary arterial hypertension associated with adult congenital heart diseases.
Expert Rev Clin Pharmacol
Satoshi Akagi, Shingo Kasahara, Kentaro Ejiri +2 more
The number of patients with adult congenital heart disease (ACHD) is gradually increasing worldwide due to advances in surgical techniques and pharmacological therapies. ACHD can lead to pulmonary arterial hypertension (PAH), and treatment strategies for PAH associated with ACHD have also evolved.
Injectable Peptides in Sports Medicine: A Structured Narrative Review of Evidence, Safety, and Antidoping Implications.
JBJS Rev
Alan D Villegas Meza, Michael Nocek, Brendon C Mitchell +5 more
Injectable peptides are increasingly promoted for musculoskeletal recovery, tissue repair, and performance enhancements; however, clinical adoption has outpaced high-quality evidence and regulatory consensus.
Primary Neuroendocrine Carcinoma of the Breast: A Diagnostic Challenge and Case Report.
Cancer Rep (Hoboken)
Hamid Zeinali Nezhad, Shima Yaghoobi, Nazanin Zeinali Nezhad +3 more
Primary neuroendocrine carcinoma of the breast (NECB) represents an exceedingly rare entity, comprising less than 0.5% of all breast carcinomas and approximately 1% of all neuroendocrine neoplasms. The 2019 WHO classification defines NECB as tumors expressing neuroendocrine markers in > 90% of tumor cells with morphological features resembling neuroendocrine tumors of other anatomical sites.
A phosphorylated variant of the mast/stem cell growth factor receptor KIT is upregulated in dorsal root ganglia of Friedreich ataxia.
Histol Histopathol
Arnulf H Koeppen, Joseph E Mazurkiewicz, Paul J Feustel +4 more
Friedreich ataxia (FA) causes hypoplasia of nerve cells in dorsal root ganglia (DRG). Beyond hypoplasia, however, the lesion in DRG includes disorganization and proliferation of satellite cells, formation of residual nodules, and neuronophagia. Antibody microarray analyses of DRG lysates with 878 validated antibodies that target cell signaling proteins reveal prominent up-regulation of the mast/stem cell growth factor (SCF) receptor-tyrosine kinase KIT. In its bioactive form upon engagement with SCF, KIT undergoes dimerization and autophosphorylation at Tyr-936 amongst other sites, and is hereafter called KIT-pY936. By immunohistochemistry and double-label laser scanning confocal immunofluorescence, KIT-pY936 is located in satellite cell cytoplasm. Electrophoresis and Western blots of DRG lysates show that the strong immunoreactivity of KIT-pY936 is due to a new truncated KIT variant of 50 kDa. KIT is a proto-oncogenic protein with prominent roles in hematopoiesis including mast cell proliferation. In conclusion, proteomic analysis confirms the prominent participation of a new truncated KIT in satellite cells in the pathogenesis of FA in DRG.