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Efficacy of Glucagon-Like Peptide-1 Receptor Agonists for Psychological Well-Being and Depressive Symptoms: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Hum Psychopharmacol
Tsung-Hsuan Hung, Chyi-Rong Chen, Chih-Wei Hsu +5 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for metabolic disorders. Howeve, their effects on depressive symptoms and psychological well-being remain uncertain.
Impact of GLP-1 and dual agonists on the incidence of new cases of physician-reported sleep apnea: a real-world study.
Ann Am Thorac Soc
Beatriz S Prado, Diego R Mazzotti, André Franci +5 more
Previous studies have shown that glucagon-like peptide-1 (GLP-1) agonists and dual GLP-1/glucose-dependent insulinotropic peptide (GIP) agonists (tirzepatide) reduced severity of sleep apnea. However, whether these medications impact incidence of new cases of physician-reported sleep apnea (PRSA) is unknown.
Insights into the renin-angiotensin-aldosterone system in transthyretin amyloid cardiomyopathy.
Eur J Heart Fail
Christina Kronberger, Oliver Domenig, Noemi Pavo +14 more
This study aimed to characterize circulating renin-angiotensin-aldosterone system (RAAS) patterns in transthyretin amyloid cardiomyopathy (ATTR-CM), examine their relationship with clinical and echocardiographic parameters and determine their prognostic value.
Effects of intravenous furosemide plus small-volume hypertonic saline solutions on inflammatory, remodelling markers and epigenetics signatures of patients with congestive acute decompensated heart failure (ADHF).
Aging (Albany NY)
Mario Daidone, Alessandra Casuccio, John Sebastian Soldano +14 more
In a randomised controlled trial (RCT), we compared the effects of treatment with furosemide + small volumes of hypertonic saline solution (HSS) with those of furosemide alone in patients with decompensated heart failure (HF), and their effects on inflammatory and remodelling markers and epigenetic signatures.
Primary cilia regulate GLP-1 signaling in pancreatic β cells.
bioRxiv
Isabella Melena, Jeong Hun Jo, Shannon E Townsend +5 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are mainstay therapies for diabetes and obesity, acting in part by enhancing glucose-dependent insulin secretion. While the primary cilium is a known signaling compartment for certain G-protein coupled receptors (GPCRs), its role in the β-cell response to incretins remains undefined. Here, we show that primary cilia are essential for GLP-1R signaling. Loss of β-cell cilia in mouse and human islets severely impaired GLP-1-potentiated insulin secretion, an effect preceded by blunted whole-cell cAMP and Ca²⁺ responses. Immunofluorescence and immunogold scanning electron microscopy revealed endogenous GLP-1R localized to the primary cilium. Critically, disrupting ciliary GPCR trafficking via Tulp3 knockdown - while preserving cilia structure - recapitulated the signaling and secretory deficits, demonstrating a specific requirement for the ciliary receptor pool. These findings establish the primary cilium as a non-redundant signaling compartment for GLP-1R and uncover a new layer of subcellular organization in incretin action in β cells.
The acid-sensing ion channel 1a modulates anxiety- and depression-related behaviors via its influencing on the activity of corticotropin-releasing hormone-expressing neurons in the hypothalamic paraventricular nucleus in male mice.
Transl Psychiatry
Jiayin Yue, Qilun Zhang, Mengyuan Wang +9 more
A variety of studies show the involvement of acid-sensing ion channel 1a (ASIC1a) in the modulation of stress, however, the precise underlying mechanisms remain unclear. In this study, we provided evidence that ASIC1a, the Ca2+-permeable cationic ion channel, was co-expressed with corticotropin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN). Downregulation of ASIC1a in the PVN CRH neuron decreased the hypothalamic-pituitary-adrenal (HPA) axis activity, which further ameliorated anxiety- and depression-related behaviors by reducing CRH neuron activity. In vitro, activation of ASIC1a elevated the intracellular Ca2+ concentration and promoted the expression of CRH by activating Ca2+/CaMKII/c-Fos signaling pathways. This study reveals a novel mechanism of the modulation of negative mood by ASIC1a and suggests a potential novel therapeutic target for stress-related diseases.
TRH can stimulate the release of two POMC-derived pituitary hormones, ACTH and MSH, in medaka.
Endocrinology
Mana Yamakawa, Deodatta Shyam Gajbhiye, Matan Golan +1 more
Anterior pituitary hormone secretion is generally considered to be under the strong regulation of hypothalamic neuropeptides. In mammals, adrenocorticotropic hormone (ACTH), which plays a crucial role in the stress response, is secreted from corticotropes and is regulated primarily by corticotropin-releasing hormone (CRH). In teleosts, although the pharmacological effects of hypothalamic factors have been demonstrated, their relative importance in regulating ACTH release remains controversial. One reason for this is the lack of methods for evaluating ACTH release at cellular resolution. Using medaka as a model organism, we systematically examined the direct effects of hypothalamic peptides on ACTH cells by combining cell type-specific transcriptomics with Ca²⁺ imaging. We show that thyrotropin-releasing hormone (TRH) robustly elevates intracellular Ca²⁺ ([Ca²⁺]ᵢ) levels in ACTH cells, surpassing the responses elicited by CRH or arginine vasotocin (AVT). TRH also strongly activates MSH cells, the other POMC-derived pituitary cell population, while CRH induces only a modest response. Furthermore, in situ hybridization chain reaction analyses revealed that TRH receptor (trhra) is expressed in MSH cells, supporting their direct responsiveness to TRH signaling, whereas TRH receptor expression in ACTH cells was below thsse detection limit, leaving open the possibility that their activation is mediated by indirect or low-abundance receptor pathways. These findings suggest the existence of a novel TRH-driven regulatory pathway orchestrating both the teleost stress axis and pigmentation axis.
Cellular Senescence in Gastric Cancer: Molecular Mechanisms, Microenvironment Remodeling and Therapeutic Implications.
Aging Dis
Zhiyuan Shi, Zhao Sun, Yuan Liu +6 more
Gastric cancer (GC) remains a leading cause of cancer-related morbidity and mortality worldwide, with poor prognosis for advanced-stage patients. Therefore, in-depth exploration of the mechanisms underlying GC initiation and progression, as well as the development of novel therapeutic strategies, is of crucial importance. Cellular senescence is a stable cell cycle arrest program that plays a dual role in GC. It exerts tumor-suppressive effects via growth arrest but also promotes tumor progression and immune evasion by remodeling the tumor microenvironment (TME) through senescence-associated secretory phenotype (SASP). This review comprehensively elucidates the molecular mechanisms of cellular senescence in GC and the core regulatory networks involving gene regulation, epigenetic modifications, metabolic reprogramming, and cell cycle arrest. Additionally, the review highlights how senescent cells foster an immunosuppressive microenvironment via SASP, forming a self-reinforcing feed-forward loop. Regarding therapeutic strategies, we summarize potential approaches targeting cellular senescence, including senescence induction, senescent cell clearance, SASP modulation, and multi-target synergistic therapy by integrating epigenetic regulation, metabolic intervention, and immune microenvironment modulation. Despite progress, numerous challenges remain. Future studies should leverage multi-omics technologies, novel models' development, and large-scale clinical trials to advance the clinical translation of GC cellular senescence research, providing new insights for improving prognosis.
Large-scale bidirectional arrayed genetic screens identify OXR1 and EMC4 as modifiers of αSynuclein aggregation.
FEBS Open Bio
Sandesh Neupane, Lea Nikolić, Lorenzo Maraio +9 more
In Parkinson's disease and other synucleinopathies, αSynuclein (αSyn) misfolds and forms Ser129-phosphorylated aggregates (pSyn129) with the factors controlling this process largely unknown. Here, we used arrayed CRISPR-mediated gene activation and ablation to discover new pSyn129 modulators. Using quadruple-guide RNAs (qgRNAs) and Cas9, or an inactive Cas9 fused to a synthetic transactivator, we ablated 2304 and activated 2428 human genes related to mitochondria, trafficking, and motility functions in HEK293 cells. After exposure of cells to αSyn fibrils, pSyn129 signals were recorded by high-throughput fluorescence microscopy and aggregates were identified by image analysis. We found that pSyn129 was increased by activating the mitochondrial protein OXR1, which decreased ATP levels and altered the mitochondrial membrane potential. Instead, pSyn129 was reduced by ablation of the endoplasmic reticulum (ER)-associated protein EMC4, which enhanced ER-driven autophagic flux and lysosomal clearance. OXR1 activation preferentially modulated cellular reactions to fibrils derived from multiple system atrophy (MSA) patients, whereas EMC4 ablation broadly reduced pSyn129 across diverse αSyn polymorphs. These findings were confirmed in human iPSC-derived cortical and dopaminergic neurons, where OXR1 preferentially promoted somatic aggregation and EMC4 reduced both somatic and neuritic aggregates. These results uncover previously unrecognized roles for OXR1 and EMC4 in αSyn aggregation, thereby broadening our mechanistic understanding of synucleinopathies.
Intercompartmental communication in senescence.
FEBS Open Bio
Krystyna Mazan-Mamczarz, Eleanor J Wind, Jixiang Leng +1 more
Cellular senescence represents a response to sublethal damage, characterized by persistent growth arrest and a robust pro-inflammatory trait, the senescence-associated secretory phenotype (SASP). Senescent cells accumulate in the body with age, promoting tissue dysfunction and age-related disease. In addition to profound reprogramming of gene expression patterns, senescent cells undergo broad remodeling of cellular compartments, including the plasma membrane, nucleus, endoplasmic reticulum (ER), Golgi apparatus, endolysosomal system, mitochondria, biomolecular condensates, and cytoskeleton. These changes alter the intracellular communication networks required for homeostasis. Here, we review how senescence alters (i) vesicular trafficking along secretory, endocytic, and autophagic routes, (ii) interorganelle contact sites such as those among mitochondria, ER, and lysosomes to modulate lipid and calcium exchange, and (iii) diffusion and transport of regulatory signals across the cytosol and membranes. We discuss how the impaired crosstalk among compartments increases ROS, exacerbates proteostatic stress, impairs clearance of damaged components, and activates p53/p21, p16/Rb, cGAS-STING, NF-κB, and mTOR pathways, enhancing apoptosis resistance and the SASP. Finally, we highlight emerging technologies to study the senescent organelle 'interactome' and identify therapeutic vulnerabilities in age-associated declines and diseases linked to senescence. Impact statement We synthesize evidence that cellular senescence arises not only from gene expression changes but also from disrupted interorganelle communication. We discuss defects in vesicle trafficking and organelle contact sites that redefine senescence as failure of the organellar interactome, highlighting future mechanistic work and therapeutic opportunities in age-related disease.
Extracellular Protein Quality Control in Tau Pathology.
Mol Neurobiol
Prasun Kumar Bhunia, Deepanshu Verma, Priyanka Vimal +1 more
Aging is the primary risk factor for neurodegenerative diseases that are marked by the accumulation of misfolded and aggregated proteins, commonly known as proteinopathies. Among these, tauopathies are the disorders characterized by abnormal tau protein aggregation that are particularly significant in Alzheimer's Disease. Tau protein undergoes pathological post-translational modifications that promote its aggregation into neurofibrillary tangles, which disrupt neuronal function and cognitive decline. Tau can also spread between neurons via extracellular pathways in a prion-like manner, accelerating disease progression. Extracellular protein quality control (PQC) mechanisms modulate this process by balancing tau stability and clearance. However, age-related decline in these PQC systems enhances toxic tau assemblies, their extracellular accumulation and widespread dissemination. This review explores tau secretion, propagation, and extracellular protein quality control (PQC) in maintaining tau homeostasis, aiming to identify therapeutic strategies for tauopathies.
Identification of a small-molecule targeting PLAGL2 DNA-binding domain inhibits extracellular matrix formation and enhances lenvatinib sensitivity in hepatocellular carcinoma.
Acta Pharm Sin B
Weiwei Hu, Jiaping Ni, Shufang Zheng +15 more
The increased stiffness of the extracellular matrix (ECM) is known to promote the progression of hepatocellular carcinoma (HCC). Currently, there are no approved therapies for targeting ECM sensors and remodelers. The objective of this study was to identify the molecular mechanisms underlying the role of Pleomorphic adenoma gene-like 2 (PLAGL2) in HCC ECM remodeling and to formulate compounds that effectively inhibit PLAGL2 transcriptional regulation. Our work revealed that PLAGL2 remodeled the ECM produced by HCC cells via an autocrine mechanism and activated HSCs via a paracrine pathway. Mechanistically, PLAGL2 functioned as a transcriptional regulator of insulin-like growth factor 2 (IGF2) and insulin-like growth factor 1 receptor (IGF1R). IGF2 enhanced ECM remodeling by HCC cells and activated HSCs through the IGF1R-PI3K-Akt signaling pathway. Furthermore, using a computer-aided drug design strategy, a novel compound, DC218, derived from the chemical evolution of cytisine, has been developed for the first time to exhibit specificity as an inhibitor of the PLAGL2 DNA binding domain. DC218 significantly degraded ECM, overcame lenvatinib resistance, and synergistically inhibited HCC. These findings provide mechanistic insight into the role of PLAGL2 in HCC ECM remodeling, as well as suggest a novel strategy for inhibiting ECM and treating HCC.
Global, regional and national burden of ischemic heart disease attributable to suboptimal diet, 1990-2023: a Global Burden of Disease study.
Nat Med
Sooji Lee, Hayeon Lee, Yejun Son +1036 more
Ischemic heart disease (IHD) remains a leading cause of death worldwide, with dietary risks being its most significant modifiable factor. Here, using the Global Burden of Diseases, Injuries and Risk Factors Study 2023, we estimated the mortality and disability-adjusted life years from diet-related IHD across 204 countries. In 2023, a suboptimal diet was responsible for 4.06 million (95% uncertainty interval (UI) 0.74-6.22) IHD deaths and 96.84 million (18.82-142.52) IHD disability-adjusted life years. The global age-standardized death rate of IHD attributable to suboptimal diet decreased by 43.92% (95% UI 34.44-53.23) per 100,000 population from 1990 to 2023. Among dietary factors, low intake of nuts and seeds (9.87, 95% UI 2.84-17.12 deaths per 100,000 population), low whole grains (9.22, 4.73-13.67), low fruits (7.25, 1.54-13.34) and high sodium (7.15, 0.92-17.97) were primary contributors to IHD deaths. The burden was particularly pronounced in low- and middle-sociodemographic index countries. By disentangling dietary risk factors, we identified the portion of IHD burden directly modifiable through food interventions.
A Rare Case of Tirzepatide-Associated Immune Thrombocytopenia.
Cureus
Kelvin Rojas, Arshia Ahmed, Salman J Khan +1 more
Tirzepatide, a novel dual glucagon inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, is used in the management of type 2 diabetes mellitus (T2DM) and chronic weight management. There are no current case reports on tirzepatide causing drug-induced thrombocytopenia (DIT) despite its metabolic benefits and common gastrointestinal side effects being well documented. This case report details a 47-year-old male with a history of obesity and T2DM who presented with an ecchymotic, petechial rash within a week of increasing the dose of tirzepatide to 12.5 mg. Pertinent labs showed isolated thrombocytopenia (6000/µL), and other secondary causes of thrombocytopenia were ruled out. The patient was started on intravenous immunoglobulin (IVIG) and steroids. Platelet counts ultimately increased to baseline in response to the treatment with tirzepatide cessation, IVIG, and corticosteroids. Overall, these findings suggest an immune-mediated, drug-induced mechanism of severe thrombocytopenia. Our case intends to raise clinical awareness regarding this potential rare side effect of tirzepatide-induced thrombocytopenia. Prompt discontinuation of the drug and early initiation of steroids/IVIG can prevent life-threatening bleeding and promote recovery.
Safety and efficacy of switching from dulaglutide to tirzepatide across clinically relevant baseline characteristics in participants with T2D: subgroup analysis of SURPASS-SWITCH.
BMJ Open Diabetes Res Care
Rafael Violante-Ortiz, Ludger Rose, Palash Sharma +3 more
In SURPASS-SWITCH, switching from dulaglutide to tirzepatide resulted in greater improvements in glycemic control and body weight in adults with type 2 diabetes (T2D). This study aimed to investigate the efficacy and safety of switching from weekly dulaglutide to weekly tirzepatide in adults with T2D in prespecified baseline subgroups from SURPASS-SWITCH.
Cardiovascular Outcomes and Safety of GLP-1 Receptor Agonists in Elderly Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis.
Diabetes Metab Syndr Obes
Weifei Gao, Xiaoming Cai, Xiaolu Wang +1 more
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes. However, evidence specific to elderly patients remains limited. Elderly patients with diabetes are associated with high cardiovascular (CV) risk and increased susceptibility to adverse events. Therefore, this study systematically evaluated the CV outcomes and safety of GLP-1 RAs in elderly patients with T2DM.
Emulating the LEADER trial in China: a regulatory science case study on non-interventional research.
Front Endocrinol (Lausanne)
Jun Zhao, Xiaona Xin, Yuanyuan Song +4 more
Integrating real-world evidence (RWE) into regulatory decision-making requires validation against pivotal randomized controlled trials for the same estimand. We emulated the LEADER trial using Chinese claims data to evaluate liraglutide's cardiovascular safety, assessing RWE-RCT concordance and examining the methodological adaptations and operational challenges encountered when emulating RCTs with claims data.
Potential Antiarrhythmic Mechanisms of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs).
Drug Des Devel Ther
Jianhong Li, Kun Fu, Jiaqian Zhao +9 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a novel class of glucose-lowering agents that offer benefits beyond glycemic control and weight loss and are increasingly recognized for their cardioprotective benefits, including protective effects against hypertension, heart failure, myocardial infarction, and arrhythmias. Notably, GLP-1RAs have demonstrated a significant capacity to reduce arrhythmia risk not only in animal models but also in large-scale clinical trials. However, the antiarrhythmic mechanisms of GLP-1RAs remain incompletely understood. This mechanistic review synthesizes current preclinical and clinical evidence to delineate the key pathways through which GLP-1RAs may exert their antiarrhythmic effects. The primary mechanisms discussed include the attenuation of cardiomyocyte death, improvement of myocardial metabolism, and inhibition of the inflammatory response. Additional mechanisms, such as the promotion of autophagy, maintenance of ion homeostasis in cardiomyocytes, and modulation of the autonomic nervous system, are also examined. By clarifying these mechanisms, this review aims to offer novel therapeutic strategies for arrhythmia prevention, especially in the high-risk population with cardiometabolic diseases.
GLP-1 Receptor Agonist Therapy in Older Adults with Diabetes: A Qualitative Analysis of Phase 4 ClinicalTrials.gov Studies.
Diabetes Metab Syndr Obes
Nouf M Alourfi, Nasser M Alorfi
Type 2 diabetes mellitus is highly prevalent among older adults and often requires multidrug therapy to optimize glycemic control while minimizing adverse effects. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are among the most effective antihyperglycemic drugs with demonstrated cardiometabolic benefits. However, their real-world safety, tolerability, and long-term outcomes in geriatric populations remain under-explored.
Heart Failure Therapy Improves Outcomes in Adults With Congenital Heart Disease and Left Ventricular Dysfunction.
JACC Adv
Zeyad M Kholeif, Mohamed Ellabbad, William R Miranda +5 more
There are limited data about the role of guideline-directed medical therapy (GDMT) in adults with congenital heart disease presenting with heart failure with reduced ejection fraction.