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Long-Term Prognosis and Outcomes in Patients Undergoing His Bundle Pacing Implantation　- A Multicenter, Prospective Observational Study in Japan.
Circ J
Satoshi Yanagisawa, Hiroyuki Kato, Yasunori Kanzaki +15 more
His bundle (HB) pacing (HBP) can achieve an ideal pattern of ventricular activation. The long-term efficacy and clinical outcomes of HBP in Japan remain unclear.
Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial.
Lancet
Harpreet S Bajaj, Michelle Welch, Parag Shah +7 more
Retatrutide is a GIP, GLP-1, and glucagon triple hormone receptor agonist, under clinical development for type 2 diabetes, obesity, and related complications. We aimed to assess the efficacy and safety of retatrutide as a monotherapy in people with type 2 diabetes that is inadequately controlled by diet and exercise alone.
The orexinergic crossroads: Bidirectional links between sleep-wake disturbances and the pathogenesis of Alzheimer's disease in the aging brain.
Sleep Med
Xinxin Tian, Yuqing Shi, Huazhong Xiong +5 more
This review examines the bidirectional relationship between sleep instability and the pathogenesis of Alzheimer's disease, with particular emphasis on the hypothalamic orexinergic system as a key mechanistic link between these processes. Emerging evidence suggests that excessive orexin signaling contributes to insomnia and sleep fragmentation and may accelerate amyloid-β and tau accumulation by impairing glymphatic clearance and activating neurotoxic pathways. Conversely, progressive neurodegeneration can impair sleep-regulatory centers in the brainstem and hypothalamus, thereby creating a vicious cycle that may hasten cognitive decline. We further discuss therapeutic strategies targeting this pathway, with a focus on dual orexin receptor antagonists and complementary medical approaches. Notably, recent preclinical findings suggest that Panax ginseng extracts may inhibit orexin signaling and reactivate autophagy through the mammalian target of rapamycin pathway, thereby attenuating neuronal damage. By synthesizing current mechanistic insights and clinical evidence, this review proposes that modulation of the orexinergic system, through pharmacological and integrative approaches, may represent a promising strategy for delaying disease progression and improving quality of life in older adults.
Pituitary Developmental Gene Defects and Their Contribution to Growth Hormone Deficiency.
Ann Endocrinol (Paris)
Karine Aouchiche, Rachel Reynaud, Theo Charnay +4 more
Growth hormone deficiency (GHD) is a rare endocrine disorder responsible for growth failure. In the absence of an identified secondary cause, a genetic etiology can be identified, affecting genes involved in hypothalamo-pituitary growth hormone (GH) regulation or in pituitary development itself. The anterior pituitary gland arises from the oral ectoderm and is regulated by neuroectodermal signaling and transcription factors that ensure proper differentiation of hormone-producing cells. GH secretion is stimulated by growth-hormone-releasing hormone (GHRH) and ghrelin, with mutations in their respective receptors (GHRHR, GHSR) contributing to isolated GHD (IGHD). Mutations in GH1, encoding GH itself, are the main genetic cause of IGHD. GHD can also arise from mutations in transcription factor genes such as POU1F1, PROP1, IGSF1 or TBX19 or in genes involved in early brain development such as GLI2, LHX3 or HESX1, potentially leading to syndromic presentations with multi-organ involvement. Understanding the genetic basis of GHD is essential to improving diagnostic strategies, genetic counseling and the development of targeted therapies. Although animal models have been fundamental for understanding pituitary ontogenesis, emerging tools such as human pituitary organoids now offer the promise of dissecting human-specific regulatory mechanisms that cannot be fully captured in traditional animal models. This review aims to provide a comprehensive overview of all known genetic causes of GHD, with a particular focus on the underlying molecular mechanisms and their associated phenotypes.
Once-Weekly Subcutaneous Semaglutide 2.4 mg Injection is Cost-Effective for Weight Management in Spain.
Adv Ther
Andreu Altés, Óscar Moreno-Pérez, Miquel Sastre-Belío +6 more
A current major challenge for national health systems (NHS) is the increase of obesity and overweight among populations. Subcutaneous semaglutide 2.4 mg, a glucagon-like peptide 1 analogue, has been approved by the European Medicines Agency as an adjunct to a reduced-calorie diet and increased physical activity (diet and exercise [D&E]) for the treatment of obesity. The aim of this study was to evaluate the cost-effectiveness of semaglutide 2.4 mg in combination with D&E compared with D&E alone in the treatment of patients with obesity in Spain.
Synergistic Intervention for Obesity: Integrating Central Appetite Regulation and Peripheral Energy Expenditure.
Curr Obes Rep
Jiayan Xie, Yujing Yang, Wanting Chen +4 more
Obesity stems from a chronic imbalance between energy intake and expenditure. Current therapeutic strategies primarily focus on reducing caloric intake, yet their long-term efficacy is often limited by compensatory metabolic adaptations that lead to weight regain. This review outlines the neural mechanisms through which the central nervous system regulates appetite and the peripheral metabolic pathways that drive adipose thermogenesis. Furthermore, it examines how integrated approaches-spanning from approved to preclinical and clinical-stage investigational agents (e.g., dual- or multi-target agonists), microbiome-targeted interventions (e.g., probiotics), and exercise therapy-can synergistically overcome the limitations of single-pathway strategies. Ultimately, this review provides a theoretical foundation for designing next-generation, personalized, multimodal obesity management regimens.
Combined Prognostic Value of Follow-Up Ejection Fraction and Natriuretic Peptide Measurements in Heart Failure With Reduced Ejection Fraction Following Initiation of Pharmacotherapy.
J Am Heart Assoc
Nandan Kodur, Paul R Gunsalus, Alex Milinovich +2 more
Few studies have directly compared the prognostic value of left ventricular ejection fraction (LVEF) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) in patients with heart failure (HF) with reduced EF who have initiated guideline-directed medical therapy. This study sought to assess the combined prognostic value of follow-up LVEF and NT-proBNP measurements taken following initiation of guideline-directed medical therapy in patients with HF with reduced EF.
Incretins for Type 2 Diabetes.
Can J Physiol Pharmacol
Esther Min, Andrew Goyette, Elaine Young +3 more
Type 2 diabetes (T2D) is a growing global health challenge. With prevalence projected to rise significantly in the coming decades, T2D is expected to contribute to increased healthcare costs due to associated morbidity and mortality. Characterized by insulin resistance and impaired pancreatic insulin secretion, T2D could be mediated by the effects of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Incretin-based therapies have, therefore, emerged as effective treatments for improving glycemic management and weight reduction in people with T2D. Since the approval of the first twice daily GLP-1 RA in 2005, advancements have led to the development of once-daily and once-weekly injectable formulations and an oral formulation. Furthermore, the approval of a dual GLP-1/GIP RA marked a significant milestone in incretin-based therapies. These agents have demonstrated glycemic-lowering benefits, weight loss, and reduced cardiovascular risk in high-risk populations. The most common adverse effects are gastrointestinal and can be partially mitigated with slow dose titration and patient education. Ongoing research into alternative dosing regimens, combination therapies, and strategies to improve access will be important for optimizing the long-term impact of incretin-based therapies in T2D management.
Angiotensin II Receptor Signaling in the Hypothalamic-Pituitary-Adrenal Axis and Spleen After Spinal Cord Injury Depends on the Sympathetic Innervation Integrity.
Cell Mol Neurobiol
Erika Kellerova, Jana Snopkova, Erika Hvozdikova +1 more
Spinal cord injury (SCI) disrupts the integrated neuroendocrine network linking the hypothalamic-pituitary-adrenal (HPA) axis, renin-angiotensin-aldosterone system, and sympathetic nervous system, resulting in endocrine and immune dysfunction. However, the effects of SCI on angiotensin II receptor signaling remain unclear. This study investigated temporal and lesion-dependent changes in angiotensin II type 1 (AT1) and type 2 (AT2) receptor expression following SCI in rats. Low-thoracic SCI (Th9 compression, 40 g/15 min) was evaluated over 28 days, while acute responses to partial (Th9) versus near-complete (Th1) sympathoadrenal denervation were compared. Receptor expression was assessed in the hypothalamic paraventricular nucleus, pituitary, adrenal gland, and spleen, and correlated with hormonal and morphological alterations. Surgical stress alone activated systemic angiotensin II signaling. Low-thoracic SCI induced time- and tissue-specific changes in angiotensin receptor expression independent of circulating angiotensin II levels, indicating adaptive remodeling of HPA axis sensitivity. SCI caused transient adrenal enlargement, zona fasciculata hypertrophy, dysregulated HPA axis activity, angiotensin II-independent aldosterone production, and altered catecholamine secretion. Splenic AT1 receptor expression showed early upregulation followed by compensatory downregulation, consistent with dynamic neuroimmune modulation. In contrast, high-thoracic SCI markedly reduced receptor expression across central and peripheral HPA axis components and the spleen, accompanied by decreased corticotropin-releasing hormone, aldosterone, and norepinephrine, stable adrenocorticotropic hormone, and elevated corticosterone and epinephrine. These findings demonstrate that the extent of sympathetic disruption critically determines neuroendocrine-immune responses after SCI and identify sympathetic innervation as a key regulator of angiotensin receptor balance and stress-axis homeostasis following spinal cord trauma.
SMAP29: an antibacterial peptide that possesses anti-inflammatory and fast bactericidal actions against colistin-resistant gram-negative bacteria.
Microbiol Spectr
Ziyue Zeng, Mengjie Wei, Deyi Zhao +6 more
Multidrug-resistant (MDR) gram-negative bacteria (GNB) are threatening global public health. Since colistin (COL) is the last resort antibiotic for MDR gram-negative infections, the rise in colistin-resistant ‌(COL-R) bacteria could pose risks to people. The current research investigation explored the antimicrobial, anti-biofilm, and anti-inflammatory capacities of SMAP29, a naturally generated cationic antibacterial peptide, against clinical COL-R Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, and explored its antibacterial mechanisms. The results demonstrated that SMAP29 exhibited a very low minimum inhibitory concentration against COL-R GNB and rapidly killed bacteria within 30 min. In addition, SMAP29 inhibited biofilm growth and eliminated it. According to another study's findings, SMAP29 could lead to the membrane's integrity being wiped out, which could result in the formation of intracellular reactive oxygen species. Moreover, SMAP29 could effectively prevent RAW 264.7 macrophages in mice from generating the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. Assays for cytotoxicity and hemolysis in vitro revealed that SMAP29 proved safe at the tested concentrations. In vivo experiments further demonstrated that the amount of bacteria in the infected mice's thighs was significantly reduced through SMAP29 treatment. Collectively, our findings demonstrate that SMAP-29's efficacy stems from its dual action: rapid bactericidal activity via lipopolysaccharide-mediated membrane disruption and concurrent anti-inflammatory effects. This multifaceted potency, validated both in vitro and in vivo, positions SMAP-29 as a promising therapeutic candidate against multidrug-resistant bacterial infections.
Diabetic Status, Advanced Age, and Hispanic Ethnicity Predict Poorer Weight Loss in Patients with Obesity on Semaglutide.
Endocr Pract
Nicole C Cornet, Adam P Buckholz, Michele Yeung +7 more
Define demographic and clinical predictors of weight loss outcomes in patients with obesity prescribed semaglutide in real-world practice.
Disproportionality Analysis of Tirzepatide-Associated Ketoacidosis.
Endocr Pract
Connor Frey
Tirzepatide, a dual GIP/GLP-1 receptor agonist approved for type 2 diabetes and obesity, has generated post-marketing reports of ketoacidosis-spectrum events. Systematic pharmacovigilance characterization is lacking.
Hair Loss in Patients on Glucagon-Like Peptide 1 Receptor Agonists: Understanding Risks and Managing Outcomes.
Dermatol Ther (Heidelb)
Bianca Maria Piraccini, Sergio Vañó-Galván, Ulrike Blume-Peytavi +2 more
Glucagon-like peptide 1 receptor agonists (GLP-1RAs) and dual gastric inhibitory polypeptide (GIP)/GLP-1RAs are used to improve glycaemic control in patients with type 2 diabetes mellitus; some of these drugs are also used to help with weight loss. In recent years, safety signals concerning a possible link between GLP-1RA therapies and hair loss have been emerging in the USA. The volume of prescriptions for these drugs in Europe is now increasing, and it can be expected that the number of cases of GLP-1RA-associated hair loss will therefore also increase in Europe over the coming years. In this commentary, we consider the pharmacological context and market expansion for GLP-1RAs, examine the evidence for an association between GLP-1RAs and hair loss, explore potential pathophysiological mechanisms, and propose clinical recommendations. Most evidence suggesting a potential association between GLP-1RAs and hair loss comes from pharmacovigilance database analyses and retrospective cohort studies. No prospective, controlled studies have specifically evaluated this issue. The evidence suggesting an increased risk of hair loss is strongest for semaglutide and tirzepatide. However, although cases of hair loss have been noted across diverse settings and multiple analyses, causality has not been established. One potential underlying mechanism is the rapid weight loss seen with these drugs, which could induce telogen effluvium. Further research is needed to evaluate causality, underlying mechanisms, the role of dosing and route of administration, and patient factors that may increase the risk. Clinicians need to be aware of the possibility of hair loss occurring with GLP-1RAs and patients should be informed about the potential risk and monitored for hair loss.
Dual GIP/GLP-1 receptor agonist tirzepatide ameliorates hepatic steatosis and inflammatory responses in a MASLD mouse model associated with the CCL2/CCR2 axis.
BMC Gastroenterol
Yongning Pan, Fanfan Song, Xuehua Liu +4 more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common multisystem chronic progressive liver disease with a rising burden. Tirzepatide (TZP), a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has shown beneficial hepatic effects, but the related molecular mechanisms remain unclear. The aim of this study was to investigate the hepatic molecular signatures associated with TZP in MASLD.
Immunological consequences of senescence in physiology and pathology.
J Transl Med
Anastasija Zubova, Federico Pietrocola, Samir Morsli
Cellular senescence is a sublethal stress response characterized by a durable cell-cycle arrest and the acquisition of a complex secretory program known as the senescence-associated secretory phenotype (SASP), which can profoundly influence local and systemic immunity. In physiological contexts-including embryonic development, tissue repair, and acute tumour suppression-senescent cells coordinate the recruitment and activation of immune cells, enabling their timely immune-mediated clearance and facilitating tissue remodelling and restoration of homeostasis. However, during aging and chronic disease, immune surveillance mechanisms frequently become compromised, allowing senescent cells to accumulate and persist within tissues.
The gut-brain axis in avian appetite regulation: Integrating peripheral signals with central neurocircuitry.
Poult Sci
Kimia Mahdavi, Morteza Zendehdel, Elham Ghashghaei +1 more
The precise regulation of energy homeostasis is essential for sustainable poultry production. Dysregulation of the avian gut-brain axis (GBA) contributes to metabolic disorders such as ascites and sudden death syndrome, impaired feed efficiency, and welfare problems in high-yield broilers. The avian GBA is a specialized bidirectional network that integrates hormonal, neural, and microbial signals to match feeding behavior with acute nutrient availability and long-term metabolic demands. Unique avian traits include a simplified gustatory system, lack of a functional T1R2 sweet receptor, a divergent leptin system, and distinct microbiota composition; these traits necessitate a species-specific framework for appetite control. This narrative review synthesizes current knowledge on how peripheral signals from the gastrointestinal tract, pancreas, liver, adipose tissue, and microbiota are encoded and conveyed to central command centers to regulate feed intake in poultry. We first outline nutrient sensing and gut-derived hormones with complex or divergent actions in birds (ghrelin, peptide YY, somatostatin), then summarize canonical satiety peptides (cholecystokinin, proglucagon-derived peptides, amylin, bombesin-like peptides, and neuromedin U) and long-term metabolic cues (leptin, insulin, insulin-like growth factors, liver-expressed antimicrobial peptide-2). At the central level, we describe how arcuate neuropeptide Y/agouti-related peptide (NPY/AgRP) and pro-opiomelanocortin/cocaine- and amphetamine-regulated transcript (POMC/CART) neurons, downstream hypothalamic nuclei, and brainstem relays integrate these inputs into a dynamic balance between opposing orexigenic and anorexigenic neurochemical effector pathways. Finally, we link these mechanistic insights to potential practical strategies for improving feed conversion, reducing metabolic disease, and enhancing resilience to environmental stressors. These strategies include dietary and microbiota-targeted interventions, receptor-level modulation, and the use of divergent genetic lines.
Structural insights into single-pass transmembrane receptor GC-A activation by distinct antihypertensive antibodies.
Nat Commun
Shian Liu, Onorina Manzo, Jinan Wang +8 more
The single-pass transmembrane receptor guanylyl cyclase A (GC-A), also known as natriuretic peptide receptor A (NPR-A) or NPR1, regulates blood pressure through vasodilation and natriuresis, making it a promising therapeutic target for hypertension and heart failure. We describe two monoclonal antibodies, XX16 and REGN5308, that differentially activate GC-A. Using cryo-electron microscopy and molecular dynamics simulations, we reveal that XX16 stabilizes GC-A in an active conformation even without its ligand ANP, whereas REGN5308 requires ANP to fully promote receptor activation. Both antibodies increase ANP binding affinity to GC-A and enhance GC-A-mediated cGMP signaling, although XX16 exerts a stronger stabilizing influence on ATP and GTP binding. In a mouse model of obesity-induced hypertension, XX16 treatment significantly reduces blood pressure, underscoring its therapeutic potential. These findings outline the structural and functional basis of GC-A activation by antibody positive allosteric modulators, offering strategies for durable antihypertensive therapies and improved management of cardiovascular diseases.
Middle-aged mice treated with GHK-Cu peptide administered intraperitoneally or intranasally show behavioral rescue but divergent hippocampal aging programs.
Res Sq
Jordan Mazzola, Manuela Rosenfeld, Matthew Tucker +3 more
Age-related cognitive decline (ARCD) is driven by conserved biological mechanisms of aging, yet no gerotherapeutic directly targets these processes in the brain. Glycyl-L-histidyl-L-lysine complexed with copper (GHK-Cu) is an endogenous peptide with regenerative and anti-inflammatory properties that declines with age. Whether its effects on cognitive aging depend on delivery route or exposure duration remains unclear. Aged C57BL/6J mice (20-21 months) received GHK-Cu (15 mg/kg) via short-term intraperitoneal (IP; 5 days) or longer-term intranasal (IN; 8 weeks) administration. Hippocampal-dependent escape learning was assessed using a spatial navigation task. Molecular effects were evaluated using hippocampal immunohistochemistry and bulk RNA sequencing. Differential gene expression was analyzed using DESeq2 with false discovery rate (FDR) correction, and pathway-level changes were assessed via gene set enrichment analysis (GSEA). IN GHK-Cu improved escape latency across Trials 2-4 in both sexes ( P  < 0.05), whereas IP dosing produced a transient improvement in males during Trial 2 ( P  < 0.05) without sustained effects or improvement in females. IN treatment increased synaptophysin in females ( P  < 0.001) and decreased GFAP in both sexes ( P  < 0.01), while IP treatment reduced TGF-β, GFAP, and MCP-1 in males ( P  < 0.05) and decreased p21 in females ( P  < 0.0001). Transcriptomic analysis revealed distinct molecular programs. IN GHK-Cu induced coordinated suppression of oxidative phosphorylation (male NES - 5.44, female NES - 4.20; FDR < 0.0001) and MYC target pathways (female NES - 4.31, FDR < 0.0001), with additional attenuation of PI3K-AKT-mTOR signaling in females (NES - 3.15, FDR = 0.062). In contrast, IP treatment activated oxidative phosphorylation (female NES 4.97, FDR < 0.001), DNA repair (NES 5.58, FDR < 0.001), and MYC targets (NES 4.34, FDR = 0.002), indicating engagement of acute stress-response and repair pathways. GHK-Cu improves hippocampal-dependent learning in aged mice through distinct biological modes: IP exposure activates repair and stress-response pathways, whereas IN delivery induces sustained suppression of growth and mitochondrial metabolic signaling associated with aging biology. These findings demonstrate that functional cognitive improvement can arise from divergent molecular states and identify administrative route and exposure duration as key determinants of gerotherapeutic response.
Insulin-like growth factor 1 receptor regulates breast cancer cell adhesion through beta-1 integrin.
Front Endocrinol (Lausanne)
Christopher A Galifi, Elvan Dogan, Luis Fernandez Almansa +7 more
The insulin-like growth factor (IGF-1/IGF1R) pathway has been implicated in breast cancer aggressiveness; however, inhibition of this pathway has not been successful in clinical trials, indicating a lack of understanding about its role in TNBC metastasis. Recent studies have explored IGF1R involvement in integrin function and cancer cell adhesion dynamics. The goal of this study was to test the hypothesis that IGF1R itself regulates cancer cell adhesion.
Glial fibrillary acidic protein in fibromyalgia: its serum levels and antibodies.
Adv Rheumatol
Felipe Massó, Laura-Aline Martínez-Martínez, Luis M Amezcua-Guerra +3 more
Fibromyalgia is a stress-related disorder in which dorsal root ganglia (DRG) may play an important pathogenic role. DRG exhibit unique stress-induced, pro-algesic physio-anatomy, where each pain-sensing nerve fiber soma is encased and interacts with immune-competent satellite glial cells (SGCs). Patients suffering from fibromyalgia harbor anti-SGCs antibodies; however, the specific SGCs antigen(s) remain unidentified. Glial fibrillary acidic protein (GFAP) is an intermediate filament protein serving as early SGCs activation marker. Different environmental stressors induce GFAP upregulation and structural modifications, including citrullination, potentially rendering it immunogenic. GFAP antibodies are implicated in autoimmune encephalomyelitis. We determine whether the serum of patients with fibromyalgia, collected before the COVID-19 pandemic, overexpresses GFAP and/or harbors antibodies against GFAP.