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Comparative distribution of the hypothalamic neurons activated during wakefulness and paradoxical (REM) sleep using male TRAP2-red mice: contribution of orexin, MCH, Lhx6, and a new marker Meis2.

Sleep

Amarine Chancel, Patrice Fort, Renato M Maciel +5 more

Paradoxical sleep (PS) is a state involving numerous hypothalamic neuronal subpopulations, many remaining neurochemically uncharacterized. Our goal was to compare hypothalamic neurons active during wakefulness or PS rebound (PSR) and explore their potential overlap, with a focus on melanin-concentrating hormone (MCH), Orexin (Orx), Lhx6, and a new contingent of Meis2-expressing neurons.

The weight-loss-independent hepatoprotective benefits of semaglutide are orchestrated by intrahepatic sinusoidal endothelial GLP-1 receptors.

Cell Metab

Maria J Gonzalez-Rellan, Cristina Riobello, Susanna Fang +7 more

Glucagon-like peptide-1 (GLP-1) medicines improve metabolic liver disease through weight-loss-dependent and -independent actions. Here, we interrogated semaglutide's action in mice with metabolic dysfunction-associated steatohepatitis (MASH). In Glp1rWnt1-/- mice resistant to GLP-1RA-induced weight loss, semaglutide improved steatosis, fibrosis, and immune remodeling. GEM-X Flex-seq localized Glp1r expression to pericentral liver sinusoidal endothelial cells (ECs) (LSECs) and CD8+ T cells. EC Glp1r deletion in Glp1rTie2-/- mice or AAV8-Cre-mediated hepatic EC Glp1r knockdown substantially abrogated semaglutide's hepatic benefits despite preserved weight loss. Transcriptomic profiling revealed that Glp1r+ LSECs adopt a stress-responsive phenotype in MASH that is reversed by semaglutide. Glp1r+ LSECs function as dominant contributors to semaglutide-regulated circuits linked to injury and repair involving VWF, SELE, CEACAM, and BMP. Molecular profiling revealed semaglutide-coordinated transcriptional and protein-level reversal of disease signatures. Together, the data using mouse models of MASH reveal an EC-specific, weight-loss-independent, semaglutide-regulated, GLP-1R-dependent intrahepatic network for improving liver health.

Widespread exposure to GLP-1RAs and weight loss-related discourse: Considering potential public health implications.

Can J Public Health

Marilou Côté, Ximena Ramos Salas, Kimberly Carrière +1 more

Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), are approved for the treatment of type 2 diabetes, obesity, and related conditions, and have demonstrated significant benefits for individuals with these conditions. However, in recent years, public interest and demand for GLP-1RAs-often driven by media, social media influencers, advertising, and public discourse-have increased beyond the populations for whom these medications are medically indicated. The ripple effects of widespread public exposure to GLP-1RAs and weight-loss-related discourse on public health have received very little research attention and remain poorly understood. This widespread exposure may contribute to a perception that GLP-1RAs are intended as weight loss solutions for non-medical use, rather than an effective treatment for specific chronic conditions like obesity. Such perceptions could influence demand and affect equitable access for people with medical indications for these medications. Widespread exposure to discourse that highlights GLP-1RAs as weight loss solutions may inadvertently reinforce social desirability for thinness and body image concerns. Despite the established clinical efficacy of GLP-1RAs for medically indicated conditions, this commentary highlights the potential public health risks associated with their growing portrayal as weight loss solutions for non-medical use in the public sphere and calls for research to better understand these broader implications to inform balanced public health communication strategies.

The role of mast cells in simvastatin-induced myopathy and the possible protective role of omega-3 fatty acids in adult male albino rats: light and electron microscopic study.

Ultrastruct Pathol

Dalia Ahmed Baha Eldein, Shereen Hamed, Shireen Mazroa +1 more

Simvastatin is antihyperlipidemic drugs that inhibit hydroxy methylglutaryl CoA reductase to decrease cholesterol synthesis; however, it causes skeletal myopathy. Omega-3 are polyunsaturated fatty acids with anti-inflammatory and anti-oxidant effects. Mast cells have an important role in the response to tissue injury by secreting different mediators and cytokines. The current study was performed to assess the role of mast cells in simvastatin-induced myopathy and the possible protective role of omega-3 fatty acids. Forty adult male albino rats were divided into four main groups received the drugs orally for of 21 days. Group 1: 1 ml distilled water, group 2: 300 mg/kg/day omega-3, group 3: 88 mg/kg/day simvastatin, and group 4: 88 mg/kg/day simvastatin plus 300 mg/kg/day omega-3. Light and electron microscopic studies were done along with morphometric and statistical studies. Group 1 and 2 showed regular histological structure. By light microscope, group 3 revealed muscle fiber disorganization, splitting, loss of striations, and cytoplasmic fragmentation. Some nuclei were centrally displaced. Toluidine blue sections showed a large number of mast cells. By transmission electron microscope, there was loss of the regular banding pattern with irregular mitochondria, nuclei, and sarcolemma. The concurrent administration of simvastatin with omega-3 showed less myopathic changes, decrease in mast cell numbers and more activation of the satellite stem cells to accomplish the process of muscle regeneration. In conclusion, the administration of omega-3 can decrease the myopathic changes of simvastatin. Further studies are recommended to explore the mast cells' role in the progression and repair of statin-induced myopathy.

Isolation, Culture, and Differentiation of Bovine Muscle Resident Stem Cells.

Bio Protoc

Perri Gish, Madison W Stewart, Maykal Tsonov +4 more

Bovine muscle satellite cells (MuSC) and fibro-adipogenic progenitor cells (FAP) are muscle resident stem cells that are responsible for postnatal muscle growth, intramuscular fat deposition, and extracellular matrix generation. These cells are of increasing interest for the cultivated meat community due to their ability to generate all the major components of meat; additionally, these cells are of interest to conventional animal science research to elucidate mechanisms to improve meat quality. To use these cells for these goals, efficient and accurate cell isolation, culture, and differentiation are essential to evaluate their cell fate decisions and behaviors. In this protocol, we detail a simultaneous isolation of both MuSCs and FAPs with multiple intermediate stopping points, allowing for flexibility for day-of time constraints. We also detail improved growth conditions to maximize cell expansion and procedures to assess cell differentiation. This protocol provides a flexible isolation procedure that is compatible with sampling in modern slaughterhouses or from biopsies. Additionally, the differentiation procedures provide improved differentiation but still allow in vitro treatment and assessment. Key features • This protocol offers a flexible in-lab procedure to isolate bovine FAPs and MuSCs from tissue collected post-slaughter with multiple pause points. • The protocol demonstrates successful conditions to grow, expand, and differentiate bovine FAPs with an optimized adipogenic differentiation medium. • Strategies for planning your primary cell isolation, choosing the sampling location, and characterizing differentiation of bovine FAPs and MuSCs are included.

Glucagon-Like Peptide-1 Receptor Agonists: Their Potential Role in Prediabetes.

Diabetes Ther

Theodoros Panou, Evanthia Gouveri, Djordje S Popovic +2 more

Prediabetes is a frequently occurring condition with increased risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are established antidiabetic agents, also used to treat obesity. There is limited, yet promising evidence on their use in prediabetes. T2DM was less frequent among subjects on liraglutide, semaglutide and tirzepatide compared with the control arm. Delayed progression to T2DM has also been observed. Furthermore, normoglycaemia was achieved for subjects on liraglutide (up to 66%), semaglutide (up to 81%) and tirzepatide (up to 93.3%). However, this effect was only partially sustained following drug withdrawal. GLP-1RAs have led to modest decreases in glycated haemoglobin (HbA1c), fasting glucose, weight and fat mass loss, as well as increased insulin sensitivity and improved β-cell glucose-insulin dynamics. Decreased risk for atherosclerotic cardiovascular disease and heart failure was also demonstrated, mostly for subjects on tirzepatide. There is experimental evidence on improvements in liver dysfunction, pointing to potential benefits for metabolic dysfunction-associated steatotic liver disease (MASLD) in prediabetes. The safety profile was acceptable with mild-to-moderate gastrointestinal adverse effects being mostly reported. Future large randomised controlled trials are needed to ascertain the exact role of GLP-1RAs in prediabetes.

Comparative Cardiovascular Effectiveness of Glucagon-Like Peptide 1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors in Diabetes Mellitus.

J Am Coll Cardiol

Fan Bu, Ruopeng Wu, Anna Ostropolets +18 more

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2Is) have established cardiovascular benefits for patients with type 2 diabetes mellitus (T2DM), with similar class-level effectiveness found in previous studies. However, real-world comparative effectiveness assessments of individual agents remain limited.

The Role of the Glymphatic System in Alzheimer's Disease: Mechanisms, Evidence, and Therapeutic Implications.

Rejuvenation Res

Yaran Li, Juan Li, Xinhong Liu +4 more

Alzheimer's disease (AD) is an aging-associated neurodegenerative disorder characterized by amyloid-β (Aβ) and tau accumulation and progressive cognitive decline. Increasing evidence implicates the glymphatic system, a brain-wide perivascular pathway involved in cerebrospinal fluid-interstitial fluid exchange and metabolic waste clearance, in the removal of Aβ, tau, and other solutes relevant to AD pathogenesis. Aging-related alterations in aquaporin-4 polarization, arterial pulsatility, sleep architecture, and cerebrovascular integrity may impair glymphatic transport and thereby promote protein retention and neurodegeneration. In this review, we summarize current knowledge of glymphatic anatomy and function and discuss its implications for AD, with particular emphasis on modifiable factors such as sleep, exercise, vascular health, and aging-associated decline. We further highlight emerging therapeutic and potential intervention strategies aimed at restoring glymphatic function, and critically evaluate current methods for assessing this system in humans together with the evidence obtained to date. Although human studies increasingly support the relevance of perivascular fluid transport to AD-related pathology and cognitive outcomes, mechanistic insights remain largely derived from animal models, and human assessment is still constrained by methodological and imaging limitations. Overall, the glymphatic system provides a useful framework for linking brain aging to impaired clearance in AD. Further refinement of human biomarkers and longitudinal translational studies will be essential for clarifying their clinical relevance and therapeutic potential.

Sleep-Dependent Clearance of Brain Metabolites via the Glymphatic System: Implications for Alzheimer's Pathophysiology.

Brain Behav

Farshad Zare, Gulnora Shakhmurova, Jasur Rizaev +4 more

This review aims to examine how sleep-dependent glymphatic function contributes to the clearance of brain metabolites involved in Alzheimer's disease (AD), with particular emphasis on amyloid-beta (Aβ), tau, astrocytic aquaporin-4 (AQP4), and emerging biomarkers of clearance-related dysfunction.

B cell-driven refractory hemocytopenia in immune checkpoint inhibitor therapy: a report of two cases.

Transl Lung Cancer Res

Feng Li, Chunyan Wang, Guohua Yao +4 more

The integration of immune checkpoint inhibitors (ICIs) with chemotherapy has revolutionized lung cancer treatment, yet it amplifies the risk of severe hematologic toxicities.

Immune signaling and function in neurodegeneration.

J Clin Invest

Yvonne L Latour, Dorian B McGavern

Neurodegenerative diseases arise from interactions among pathogenic proteins, immune responses, and diverse environmental or age-related stressors that disrupt CNS homeostasis. CNS resident microglia detect self-derived danger signals through pattern recognition receptors, and their activation can promote clearance of aberrant proteins, including amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. However, microglial activation may also drive maladaptive states that amplify neuroinflammation. Microglial transitions are further shaped by receptor-mediated signaling and antigen presentation pathways that integrate environmental cues with functional responses. Adaptive immune cells contribute additional layers of regulation, with CD8+ and CD4+ T cells exerting neuroprotective or neurotoxic effects depending on disease context, activation state, and antigen specificity. The identification of granzyme K-expressing CD8+ T cells in several neurodegenerative conditions highlights the growing recognition that distinct T cell subsets may have specialized roles in disease. Aging, repetitive head injury, and viral infection further alter microglial phenotypes, weaken barrier integrity, promote T cell recruitment, and prime the CNS for chronic inflammation. In this review, we synthesize current knowledge of innate and adaptive immune mechanisms in neurodegeneration, examine how external factors influence these responses, and consider how these insights may guide future therapeutic strategies.

Impact of endogenous LH and LH supplementation on clinical outcome following a long GnRH agonist protocol in younger and older patients.

Front Endocrinol (Lausanne)

Jing Chen, Huiliu Fan, Qiuyue Wen +5 more

The optimal luteinizing hormone (LH) concentration on the day of hCG trigger during long-protocol IVF/ICSI remains uncertain. Although some studies associate profound LH suppression with impaired reproductive outcomes, others report no adverse effects. Importantly, most existing evidence does not consider maternal age as a potential effect modifier, despite its well established role in ovarian response and oocyte competence.

Nuclear Translocation of IGF1R Induces Cell Cycle Re-entry via Cyclin D1 Regulation in an Aβ-Driven Alzheimer's Disease Model.

Mol Neurobiol

Priyanka Sengupta, Debashis Mukhopadhyay

Alzheimer's disease (AD) involves progressive neurodegeneration, with abnormal receptor signaling and disrupted cell-cycle activity leading to neuronal loss. Here, we identify a previously unknown mechanism linking β-amyloid (Aβ) exposure to the nuclear translocation of the Insulin-like Growth Factor 1 Receptor (IGF1R) in differentiated SH-SY5Y neuronal cells. The differentiated cholinergic model induced by retinoic acid and BDNF expresses acetylcholinesterase (AChE) and indicates that under amyloidogenic stress, IGF1R may transition from homeostatic membrane and vesicular signaling to a nuclear-centric function. We show that prolonged Aβ treatment causes phosphorylation-dependent nuclear import of IGF1R, confirmed by confocal imaging and biochemical fractionation. IGF1R is conventionally located in the membrane and vesicular membranes; however, under amyloidogenic stress, we show here that it is imported to the nucleus and exerts transcriptional control. The buildup of nuclear IGF1R coincided with increased Cyclin D1 levels and redistribution of neurons into S and G₂ phases, indicating abnormal cell-cycle re-entry. Chromatin immunoprecipitation demonstrated increased IGF1R binding at the CCND1 and JUN promoters after Aβ exposure, suggesting a direct role in gene transcription. Pharmacological blockade of IGF1R phosphorylation by PPP or SUMOylation by Ginkgolic acid significantly reduced Cyclin D1 elevation, implying that both post-translational modifications are involved in receptor nuclear trafficking. Co-immunoprecipitation and confocal imaging identified Nucleophosmin (NPM1) as a putative IGF1R interacting partner, potentially contributing to its nuclear transport and stabilizing receptor-chromatin complexes. These results establish IGF1R as a signaling-transcription connector linking extracellular amyloid stress to nuclear gene regulation, providing a mechanistic explanation for faulty neuronal cell-cycle re-entry in AD. We suggest that abnormal IGF1R-NPM1 interactions contribute to receptor mislocalization and cell-cycle failure, highlighting new targets for therapeutic intervention aimed at receptor trafficking and neuroprotection in Alzheimer's disease.

Novel evidence for tirzepatide, a dual GLP-1/GIP receptor agonist, to reduce the motivation for cocaine in rodents.

EBioMedicine

Lori A Knackstedt

[Protective effect and mechanism of TSPAN9-mediated mitocytosis in interleukin-1β-induced rat chondrocyte senescence].

Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi

Quan Chen, Wacili Da, Naijia Luo +1 more

To investigate the regulatory role and molecular mechanisms of TSPAN9-mediated mitocytosis in an interleukin-1β (IL-1β)-induced rat chondrocyte senescence model, and to identify novel therapeutic targets for osteoarthritis (OA).

Delayed-onset central adrenal insufficiency following adjuvant pembrolizumab therapy for renal cell carcinoma.

BMJ Case Rep

Naseem Eisa

This report describes a woman in her early 70s who developed severe central adrenal insufficiency 11 months after completing 1 year of adjuvant pembrolizumab for resected clear cell renal cell carcinoma. She presented with debilitating fatigue, profound weakness, unintentional weight loss and hypotension. Because these symptoms were non-specific and emerged long after immunotherapy discontinuation, the diagnosis was delayed for several months. Laboratory testing showed a markedly suppressed morning cortisol with an inappropriately low adrenocorticotropic hormone (ACTH) level and no response to cosyntropin, confirming central adrenal insufficiency. Other pituitary hormone axes remained intact, consistent with isolated ACTH deficiency. Imaging demonstrated adrenal atrophy, supporting chronic central adrenal insufficiency. The patient improved rapidly after starting hydrocortisone replacement. This case highlights a prolonged interval between checkpoint inhibitor cessation and endocrine toxicity, emphasising the importance of continued surveillance for late-onset immune-related endocrinopathies even after therapy completion.

Extracellular Matrix-Derived Matrikines: Circulating Peptides as Candidate Mediators of Lung-to-Brain Signaling.

Int J Mol Sci

Andis Klegeris

Recent studies support the concept of a bidirectional lung-brain axis. While neural, immune, and microbial pathways are increasingly recognized in lung-to-brain communication, the role of matrikines-bioactive peptides generated by extracellular matrix (ECM) proteolysis during remodeling-in this inter-organ communication remains underexplored. This review highlights matrikines originating from the lung, particularly the collagen-derived tripeptide Pro-Gly-Pro (PGP) and the elastin-derived hexapeptide Val-Gly-Val-Ala-Pro-Gly (VGVAPG), as potential mediators linking pulmonary pathology with neurological outcomes. The lung is rich in ECM proteins, and inflammatory conditions such as chronic obstructive pulmonary disease (COPD) and emphysema trigger proteolytic activity by matrix metalloproteinases (MMPs) and neutrophil elastase, releasing matrikines into circulation. Under conditions of blood-brain barrier (BBB) dysfunction, they may access the central nervous system (CNS), where they influence neurons, microglia, and astrocytes, modulating neuroinflammation, autophagy, and synaptic integrity. While PGP can exhibit context-dependent neuroprotective effects, its acetylated form and VGVAPG are associated with neurotoxicity, Tau hyperphosphorylation, and microglial activation. Additional matrikines, including Gly-His-Lys (GHK) and endorepellin, may further modulate CNS homeostasis. Collectively, these findings support lung-derived matrikines as circulating mediators of lung-to-brain signaling, providing a novel mechanistic framework linking chronic pulmonary inflammation to neuropathologies, such as stroke and neurodegenerative disorders, and highlighting potential targets for therapeutic intervention.

GLP-1 Receptor Agonist Semaglutide and SGLT2 Inhibitors after Acute Coronary Syndrome in Patients with Diabetes: Real-World Comparative Outcomes from an Observational Registry.

Cardiology

Ivana Jurin, Karlo Gjuras, Dijana Bešić +9 more

Patients with type 2 diabetes (T2D) remain at high cardiovascular risk after acute coronary syndrome (ACS), particularly after myocardial infarction (MI). Evidence on the early post-ACS use of glucagon-like peptide-1 receptor agonists (GLP-1RA), particularly semaglutide, and sodium-glucose cotransporter-2 inhibitors (SGLT2i) is limited.

Comparative Efficacy and Safety of Tirzepatide Versus Dulaglutide in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

Healthcare (Basel)

Sadia Qazi, Mohammad Dawar Zahid, Eshal Atif +8 more

Background: Tirzepatide, a dual GIP/GLP-1 receptor agonist, demonstrates substantial glycemic and weight benefits versus GLP-1 receptor agonists in indirect comparisons, but direct comparative safety evidence versus dulaglutide remains limited. We evaluated comparative safety (primary outcome: overall adverse events) and efficacy. Methods: Following PRISMA 2020 (prospectively registered: PROSPERO CRD420251276594), we searched MEDLINE, Embase, Scopus, and CENTRAL (inception-31 December 2025) for randomized controlled trials (≥26 weeks) comparing once-weekly tirzepatide with dulaglutide in adults with type 2 diabetes. Three trials (N = 13,590 participants) were included. Dichotomous outcomes were pooled using random-effects models (risk ratios [RRs], 95% confidence intervals [CIs]). GRADE assessed certainty of evidence. Results: Overall adverse event incidence did not differ significantly (RR 1.04 [0.98-1.10]; I2 = 36%; moderate-certainty evidence). Discontinuation due to adverse events was consistently higher with tirzepatide (RR 1.32 [1.20-1.45]; I2 = 0%; high-certainty evidence), representing a 32% increased risk across all populations. Categorical HbA1c target achievement was analyzed in two trials; the third trial reported HbA1c as a continuous outcome only. At the primary threshold (HbA1c < 7.0%), tirzepatide was consistently superior with no heterogeneity (RR 1.48 [1.33-1.64]; I2 = 0%; p < 0.00001). Across all thresholds combined, heterogeneity was extreme (I2 = 92%), limiting confidence in any pooled summary estimate; the greatest instability occurred at the strictest threshold (HbA1c < 5.7%; I2 = 98%; p = 0.40). Tirzepatide showed greater HbA1c target attainment in treatment-naive patients receiving dulaglutide 0.75 mg, whereas the glycemic advantage was smaller in patients with established cardiovascular disease receiving dulaglutide 1.5 mg. Categorical weight-loss outcomes were analyzed in two trials; tirzepatide was associated with greater weight-loss threshold achievement (RR 8.80 [4.04-19.17]; very low-certainty evidence), although interpretation is limited by substantial heterogeneity and restricted generalizability. Serious adverse events were not significantly different (RR 0.82 [0.47-1.43]; I2 = 42%). Conclusions: Overall adverse events were similar between treatments, but tirzepatide consistently increased discontinuation risk, indicating a clinically important tolerability-persistence trade-off. Glycemic efficacy was highly population-dependent: benefits were consistent at the primary HbA1c target (<7.0%; I2 = 0%) in early-stage disease, whereas the advantage was smaller in long-standing disease with established cardiovascular disease. Tirzepatide may be favored when glycemic or weight efficacy is prioritized in earlier-stage disease, provided tolerability is proactively managed. Dulaglutide remains appropriate when persistence is threatened by tolerability concerns or cardiovascular risk reduction is the primary goal.

Disproportionality Analysis of Tirzepatide vs. Semaglutide and Liraglutide: System Organ Class-Level Post-Marketing Reporting Patterns in EudraVigilance.

Int J Mol Sci

Ruxandra Cristina Marin, Cosmin Mihai Vesa, Delia Mirela Tit +2 more

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, introduces a mechanistically distinct approach within incretin-based therapies. While its efficacy is established, real-world data comparing post-marketing safety with established GLP-1 receptor agonists remain limited. This study assessed System Organ Class (SOC)-level reporting patterns for tirzepatide versus semaglutide and liraglutide using EudraVigilance data. Aggregated individual case safety reports (ICSRs) were analyzed using pairwise disproportionality analyses based on a case/non-case approach. Reporting odds ratios (RORs) with 95% confidence intervals were calculated. False discovery rate (FDR) correction using the Benjamini-Hochberg procedure and sensitivity analyses restricted to serious and healthcare professional-reported cases were performed to assess robustness. After FDR adjustment, 20 SOCs were significant in tirzepatide-semaglutide and 23 in tirzepatide-liraglutide comparisons; eight SOCs remained significant across all analytical conditions. Compared with semaglutide, tirzepatide showed higher reporting for immune (ROR 1.97, 95% CI 1.75-2.21) and hepatobiliary disorders (ROR 1.71, 95% CI 1.61-1.82). Versus liraglutide, higher odds occurred for musculoskeletal (ROR 2.02, 95% CI 1.85-2.21) and psychiatric disorders (ROR 2.14, 95% CI 1.99-2.30), and lower odds for neoplasms (ROR 0.28, 95% CI 0.26-0.31). Tirzepatide shows heterogeneous reporting patterns compared with GLP-1 receptor agonists, with consistent excess reporting for hepatobiliary, immune, and musculoskeletal disorders. These findings are hypothesis-generating and warrant confirmation in exposure-adjusted studies.