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The Physical Senotype in Cellular Senescence: Mechanical and Physical Strategies for Senotherapy.
Ageing Res Rev
Bingjie Wang, Xiangqing Qi, Johnny Huard +1 more
Cellular senescence is traditionally described through durable cell-cycle arrest, DNA-damage signaling, metabolic remodeling, mitochondrial and lysosomal dysfunction, and acquisition of a senescence-associated secretory phenotype (SASP). However, senescent cells also undergo prominent structural and biomechanical changes, including enlarged and flattened cell shape, altered stiffness and force transmission, cytoskeletal reorganization, defective nucleo-cytoskeletal coupling, impaired organelle positioning, and extracellular matrix (ECM) remodeling. In this review, we use the term Physical Senotype as a working framework to describe this recurrent but heterogeneous mechanical state. Rather than proposing a separate hallmark of senescence, this framework emphasizes loss of mechanical plasticity: the reduced capacity of senescent cells and tissues to sense, buffer, dissipate, and adapt to mechanical stress. We discuss how cytoskeletal maladaptation may amplify nuclear damage, impair mitochondrial and lysosomal quality control, reinforce inflammatory signaling, and interact with a mechanically altered extracellular niche. We also critically evaluate emerging physical and mechanical approaches to senotherapy, including pressure-based senolysis, remotely activated nanomaterials, ultrasound, exercise-associated immune surveillance, mechanical stimulation, cytoskeletal re-dynamization, and mechanically tuned biomaterials. Current evidence suggests that these interventions may produce distinct outcomes, including direct senescent-cell killing, immune-assisted clearance, or functional reprogramming of mechanically recoverable cells. However, most approaches remain early-stage, and major questions remain regarding specificity, tissue dependence, dosing thresholds, durability, and safety. We argue that integrating mechanical phenotyping with canonical senescence markers will be essential for distinguishing mechanically recoverable senescent states from irreversible states requiring clearance, and for predicting how the aged tissue niche shapes senotherapeutic response.
Stable pentadecapeptide therapy counteracts gentamicin-induced nephrotoxicity via nitric oxide-system modulation: evidence from a triple nitric oxide-agent approach in rats.
J Physiol Pharmacol
I Vukoja, J Vlainic, M Francina +22 more
In rats, stable gastric pentadecapeptide (BPC 157) therapy may resolve severe gentamicin nephrotoxicity (100 mg/kg ip/daily through 8 days) and the nitric oxide (NO)-system relation. We applied BPC 157 (10 µg/kg, 10 ng/kg, in drinking water or daily intraperitoneally) along with a triple NO-agent approach. Triple NO-agent approach captures NO-system, as a whole, simultaneously the inhibition (N(G)-nitro-L-arginine methylester (L-NAME) 5 mg/kg ip/daily), the overstimulation (L-arginine, 100 mg/kg ip/daily), and the immobilization (L-NAME + L-arginine/daily). BPC 157 therapy counteracted gentamicin nephrotoxicity clinical presentation (i.e., close to normal), serum urea, and creatinine (i.e., values close to normal preserved), maintained diuresis (polyuria/oliguria completely avoided), and no renal mass increase. Finally, fully preserved normal tubular epithelium cells and nephron presentation were present in the microscopy. Counteracted were in kidney gentamicin-increased malondialdehyde (MDA)-levels, and gentamicin-decreased NO-, and superoxide dismutase (SOD)-levels. NO-agents exhibited the opposite (worsening/attenuation) relations: L-arginine (a further increase of urea and creatinine serum values, polyuria, oliguria) vs. L-NAME relations (decrease of the increased urea and creatinine serum values, delayed polyuria, avoided oliguria, less tubular necrosis). These opposite points, combined (L-NAME + L-arginine), resulted in even stronger lesions, and more pronounced oliguria occurred, indicating the annihilation of the beneficial effect of L-NAME when it was combined with L-arginine. BPC 157 regimens (peroral or intraperitoneal) overwhelmed these NO-agents' effects. Thereby, in general, a triple NO-agent approach can reveal all essential gentamicin points of the NO-system (attenuation (L-NAME)/worsening (L-arginine)), revealing the full spectrum of the NO-system functions. Combined with the BPC 157 application, the triple NO-agent approach shows BPC 157's full efficacy in maintaining and/or reestablishing NO-system effects and functions, and kidney integrity in the gentamicin-rats.
A non-bactericidal antimicrobial peptide provides protective effect against bacterial sepsis via regulation of antimicrobial immunity and vascular endothelial functions.
Zool Res
Yan-Mei He, Ting Lin, Li-Xian Mu +8 more
The anti-infective properties of bactericidal antimicrobial peptides (AMPs) have been extensively studied, yet the functions and mechanisms of non-bactericidal AMPs in sepsis remain poorly understood. In this study, a novel β-sheet cathelicidin peptide, named Og-CATH, was identified from the skin of Odorrana grahami. Although Og-CATH showed no detectable direct antimicrobial activity in vitro, it provided both prophylactic and therapeutic protection in mouse models of sepsis induced by Staphylococcus aureus, Escherichia coli, or cecal ligation and puncture. This protection depended on neutrophils and monocytes/macrophages, but not T or B lymphocytes. Og-CATH did not directly chemoattract phagocytes. Instead, it stimulated P2X7 receptor-dependent chemokine release from macrophages, thereby promoting macrophage and neutrophil trafficking to sites of infection. Og-CATH also enhanced oxygen-independent bacterial clearance by increasing phagocytosis and neutrophil degranulation. In parallel, Og-CATH suppressed tissue factor production, a major trigger of the extrinsic coagulation cascade, and increased activated protein C expression in endothelial cells and mice, thereby reducing pulmonary fibrin deposition and thrombosis. Mechanistically, Og-CATH targeted myeloid differentiation protein 2 (MD2) and inhibited lipopolysaccharide (LPS)-induced recruitment of MyD88 to TLR4 in endothelial cells, thus preserving endothelial barrier integrity during sepsis. These findings identify Og-CATH as a non-bactericidal AMP that protects against sepsis by coordinating phagocyte recruitment, antibacterial effector activity, coagulation control, and endothelial stabilization. Og-CATH therefore represents a promising immunomodulatory candidate for further therapeutic development against sepsis.
Effectiveness & safety of semaglutide in weight reduction in obese nondiabetic patients: A systematic review and meta-analysis.
Medicine (Baltimore)
Faryal Naz, Fawad Qaiser, Arif Mumtaz +5 more
Obesity is a chronic multifactorial disease characterized by excess adiposity and persistent low-grade systemic inflammation, contributing substantially to cardiometabolic morbidity and mortality. Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist approved for chronic weight management, promotes weight loss by reducing appetite, delaying gastric emptying, and decreasing energy intake while also demonstrating potential anti-inflammatory effects. Although semaglutide has shown promising efficacy for weight reduction, an updated evaluation of its efficacy and safety in nondiabetic individuals with overweight or obesity is warranted.
Tirzepatide and SGLT2 Inhibitors for Heart Failure With Preserved Ejection Fraction and Obesity: Entering a New Cardiometabolic Therapeutic Era.
Endocrinol Diabetes Metab
Zakariye Isak Mohamed, Abdinasir Adam Shidane, Abdullahi Mohamud Abdiasis +6 more
Heart failure with preserved ejection fraction (HFpEF) accounts for over half of all heart failure hospitalizations, with obesity increasingly recognized as a central driver through expansion of epicardial adipose tissue, chronic low-grade inflammation and obesity-related haemodynamic overload culminating in ventricular hypertrophy.
Outpatient Dispensing Patterns and Changes in Tirzepatide Strength Mix in Japan: A Study Using the National Open Claims Data.
Cureus
Takuya Omura, Takahiro Kamihara
Tirzepatide is a once-weekly injectable dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors; in Japan, it is approved for the treatment of type 2 diabetes and marketed under the brand name Mounjaro, which is available in six strengths. Japanese studies of tirzepatide have primarily evaluated efficacy, real-world effectiveness, safety, persistence, and patient-level maintenance doses. National patterns in dispensing settings and longitudinal changes in the product-strength mix have not been described. We examined whether increases in claim-recorded quantities were accompanied by structural changes in outpatient dispensing and strength mix.
Post-cessation Weight Regain After Weight Management Medications: A Systematic Review and Meta-Analysis.
Cureus
Henna Patel, Shimul A Babli, Shivani Shah +10 more
Approved weight management medications achieve clinically meaningful weight loss, yet post-cessation weight regain is the central barrier to sustained benefit. No prior synthesis has pooled regain estimates exclusively from longitudinal studies published since January 2020, the period in which incretin-based pharmacotherapy became the standard of care. PubMed, Embase, Scopus, Web of Science, and the Cochrane Library were searched from January 2020 to May 2026. Eligible designs included randomised controlled trials (RCTs) with a withdrawal phase, prospective cohort studies, and retrospective database analyses. Risk of bias was assessed with Cochrane RoB 2 for RCTs and the Newcastle-Ottawa Scale (NOS) for observational studies. A DerSimonian-Laird random-effects model was applied in R 4.3.3 (metafor 4.4.0). The primary outcome was mean percentage body weight regain from end-of-treatment to follow-up. Seventeen studies met all eligibility criteria: three RCTs, three prospective cohort studies, and 11 retrospective database analyses (N = 3,793 participants in cessation arms). Fifteen of 17 studies (88.2%) were rated high quality. Pooled mean weight regain was 7.20% (95% CI: 5.93-8.48; I² = 97.6%; Q[df = 16] = 676.74; p < 0.001). Subgroup analysis by drug class yielded: semaglutide 2.4 mg, 7.19% (k = 6; 95% CI: 6.42-7.96); liraglutide 3.0 mg, 4.83% (k = 4; 95% CI: 3.87-5.79); and tirzepatide, 13.04% (k = 3; 95% CI: 11.87-14.21). In three comparative RCTs, cessation arms gained a mean 14.26 percentage points more than continuation arms (95% CI: 8.86-19.65). Egger's test was not statistically significant (z = 1.91, p = 0.056), consistent with no systematic reporting bias. Stopping approved weight management medications consistently produces clinically significant weight regain across drug classes, study designs, and geographic regions. The magnitude of regain tracks initial efficacy and supports a long-term pharmacotherapy model analogous to chronic disease management. Future trials should pre-specify post-cessation follow-up as a mandatory outcome.
Prescription Sequence Symmetry Analysis of Glucagon-Like Peptide-1 Receptor Agonists and Neuropsychiatric Conditions.
Clin Pharmacol Ther
Maria J Alfonso Arvez, Sam Wade, Darshna Goordeen +4 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly prescribed for type 2 diabetes and weight management. However, conflicting evidence from preclinical, clinical, and pharmacovigilance studies suggests potential neuropsychiatric effects. This study examined associations between GLP-1RA use and initiation of a range of neuropsychiatric medications using real-world prescription data. A Prescription Sequence Symmetry Analysis was conducted using Australia's Pharmaceutical Benefits Scheme 10% random sample between July 1, 2013 and December 31, 2024. Individuals with an incident dispensing of both a GLP-1RA and a neuropsychiatric medication were included. Outcomes comprised antidepressants, medication for substance use disorder (SUD), antipsychotics, psychostimulants, antidementia medications, antiparkinsonian medications, antiepileptics, and antimigraine agents. Adjusted sequence ratios (aSRs) with 95% confidence intervals (CIs) were calculated using a one-year exposure window, with sensitivity analyses varying various time windows. Among 2,033 individuals, semaglutide was the most common GLP-1RA (50.6%), followed by exenatide (27.5%) and dulaglutide (21.9%). GLP-1RA initiation was inversely associated with initiation of antidepressants (aSR: 0.85; 95% CI: 0.76-0.94) and medications for SUD (aSR: 0.70; 95% CI: 0.51-0.88). No significant associations were observed for other neuropsychiatric outcomes. GLP-1RA use was inversely associated with subsequent initiation of antidepressants and medications for SUD, while no associations were identified for other neuropsychiatric marker medications. These findings highlight the need for further studies to clarify the nature and magnitude of these potential neuropsychiatric associations with GLP-1RAs.
Hypertensive disorders of pregnancy and GLP-1 receptor agonist timing: a systematic review and meta-analysis.
Endocrine
Davide Pisani, Driul Lorenza, Mario Fordellone +7 more
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), used to treat type 2 diabetes and obesity, may improve metabolic health before conception. However, their association to hypertensive disorders of pregnancy (HDP) after periconceptional or early pregnancy exposure remains unknown.
Association Between Heart Failure Medications and Outcomes in Patients With Cardiac Sarcoidosis and Left Ventricular Systolic Dysfunction: Insights From ILLUMINATE-CS.
J Am Heart Assoc
Yu Yamada, Kimi Sato, Masayoshi Yamamoto +11 more
Heart failure associated with cardiac sarcoidosis (CS) is typically managed using conventional heart failure medications (HFMs). However, their effectiveness in this specific population remains unclear. We aimed to evaluate the association between HFMs and clinical outcomes in patients with CS and left ventricular systolic dysfunction.
Sex-specific changes in appetite and energy intake in response to chronic resistance training in rats.
Physiol Rep
Josh C Kuzminski, Jared R Rollingson, Connor Bunnage +2 more
Resistance training (RT) is widely prescribed for health, yet its effects on energy compensation and appetite regulation remain poorly defined, particularly across sexes. This study examined the effects of chronic RT on energy intake and appetite-regulating hormones in rats. Animals (n = 40) were assigned to female control, female RT, male control, or male RT and completed a 12-week ladder-based RT protocol. Energy intake was assessed longitudinally, and hormonal responses were measured during a resistance training exercise test (RTET). RT reduced total energy intake (p = 0.022) without altering energy intake relative to body weight. Males exhibited reduced body weight and energy intake, whereas females did not, despite greater relative training volume. Postexercise energy intake was elevated in RT groups (p = 0.029), indicating delayed compensatory feeding. Acyl-ghrelin increased following RTET (p < 0.001) and was higher in RT and females (p < 0.001). Leptin, insulin, GLP-1, and PYY were unchanged. These findings demonstrate sexually dimorphic energy compensation during RT, associated with ghrelin secretion rather than tonic appetite hormones. RT appears to shift compensation toward episodic, ghrelin-mediated pathways, with females exhibiting greater sensitivity. This identifies an endocrine framework for RT-induced energy compensation and emphasizes the need for sex-specific approaches to exercise prescription and energy balance regulation.
Beyond glycemic control: clinical cardiovascular effects of tirzepatide-a narrative review.
Ther Adv Endocrinol Metab
Azza O Alawad, Tarig H Merghani, Tarig E Fadelelmoula +11 more
The risk of cardiovascular disease is significantly increased by both type 2 diabetes mellitus (T2DM) and obesity through overlapping pathways involving insulin resistance, dyslipidemia, systemic inflammation, and endothelial dysfunction. Tirzepatide, the first dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, has shown significant glycemic and weight-reducing effects and is increasingly recognized as a cardiometabolic therapy that extends beyond glucose control. This narrative review summarizes clinical and translational evidence about the cardiovascular and metabolic benefits of tirzepatide and the biologic mechanisms that may underpin its effects. Tirzepatide has consistently shown high improvements in key indicators of glycemic control and body weight across the SURPASS program in patients with T2DM and the SURMOUNT program in patients with obesity. Benefits include marked reduction in glycated hemoglobin and cardiovascular risk factors, such as systolic and diastolic blood pressure, atherogenic lipid parameters, visceral adiposity, and several inflammatory biomarkers. Dual incretin signaling seems to increase endothelial function by enhancing the bioavailability of nitric oxide, reducing oxidative stress, inhibiting pro-inflammatory pathways such as nuclear factor kappa B, and favorably modulating adipokine profiles, collectively supporting cardiovascular protection. Promising data suggest symptomatic and functional improvements in obesity-related heart failure with preserved ejection fraction. Reductions in major adverse cardiovascular events are currently under investigation in dedicated outcome trials, including the SURPASS Cardiovascular Outcomes Trial. Overall, tirzepatide provides broad cardiometabolic benefits, making it a promising treatment in the changing landscape of cardiometabolic disease management.
[An historical overview of GLP-1/GIP incretins. From hormone to "swiss-army knife" medications].
Biol Aujourdhui
Bernard Portha
Incretins are hormones released from the gut that play a vital role in regulating postprandial metabolism. It has been 30 years since the first demonstration of the glucose-lowering effects of GLP-1 in people with type 2 diabetes. Here, we review the foundational science that led to an unparalleled development in the pharmacological treatment of diabetes. A first step was achieved with the discovery of inhibitors of the dipeptidyl peptidase-4 (DPP-4), which prevent the inactivation of GLP-1 and GIP, thereby prolonging their raised levels after meal ingestion. At the same time, several GLP-1 receptor agonists (GLP1-RAs) were engineered. The GLP1-RAs used clinically are based on exendin-4 and native GLP-1 and are now available as formulations for daily or weekly s.c. (exenatide, liraglutide, semaglutide) or oral administration (oral semaglutide). They mimic (better effectiveness) the action of native GLP-1 to reduce glucose levels through stimulation of insulin secretion and inhibition of glucagon secretion. They also demonstrated remarkable cardiovascular and weight-regulating benefits, including safety, leading to their prominent inclusion in current treatment recommendations for type 2 diabetes. Exciting advancements continue to emerge as the fundamental research efforts led to the development of monomeric multi-incretin receptor agonists: GLP-1/GIP (tirzepatide) dual receptor agonists and GLP-1/GIP/glucagon (retatrutide) triple receptor agonists which can achieve more than 20% weight loss in obesity as well as offering superior benefits in diabetes. This review also presents the promise of GLP1-RAs for more extensive application of this new class of drugs, in treating other metabolic disorders such as obesity, MASLD/NAFLD, cardio-vascular diseases and neurodegeneration.
Sepsis reporting signals associated with endothelin receptor antagonists and IFITM3-Centered interferon-responsive monocyte features: a pharmacovigilance and transcriptomic study.
Front Pharmacol
Zekun Cheng, Jiahang Li, Feng Liu
Whether pulmonary arterial hypertension (PAH)-targeted therapies, particularly endothelin receptor antagonists (ERAs), are associated with disproportionate sepsis reporting in real-world pharmacovigilance data remains insufficiently explored. The monocyte transcriptional states that characterize sepsis-related immune dysregulation and may provide biological context for such reporting signals are also incompletely defined.
Comparative clinical evaluation of endothelin receptor antagonists in pulmonary arterial hypertension using a multi-criteria decision analysis framework.
Int J Clin Pharm
Zihan Cao, Long Meng, Yunlong Li +5 more
Endothelin receptor antagonists are important therapies for pulmonary arterial hypertension, but differences in efficacy, safety, monitoring requirements, drug interactions, costs, and accessibility complicate treatment selection.
Cardiac function in zebrafish embryos is linked to an androgen receptor-adrenomedullin-proepicardium axis.
Cell Commun Signal
Max Duong Phu, Alessandra Guerrero Samanidis, Sabrina Laibacher +7 more
Congenital heart defects (CHDs) comprise the most common congenital malformation affecting nearly 1% of all newborns. In individuals with sex chromosome aneuploidy syndromes, however, the prevalence reaches up to 50% of all livebirths. One commonality to these syndromes is a marked reduction in sex hormones, particularly androgens. Androgen receptor (Ar) insufficiency represents a culprit in the pathophysiology of adult onset cardiovascular disease and arrhythmia, but there are no reports regarding Ar function during heart development. This is surprising as androgens along with its nuclear receptor exist already during early development, even before gonads develop and become functional.
Impurities and Potential Immunogenicity Associated With Follow-on and Compounded Glucagon-like Peptide-1 Receptor Agonists.
Pharm Res
Katharina L Kopp, Kasper Lamberth, Ole Schelde +7 more
To assess impurity profiles/potential immunogenicity of multiple samples of follow-on or compounded products for two glucagon-like peptide-1 receptor agonists (GLP-1 RAs): semaglutide and liraglutide.
Beyond the Barrier: Physiological Determinants of Nanoformulation Availability in the Aging Brain.
Ageing Res Rev
Ruei-Dun Teng, Jui-Ming Sun, Ting-Lin Yen +3 more
Nanomedicine has revolutionized brain-targeted therapeutics; however, most design paradigms remain centered on overcoming the blood-brain barrier while overlooking the dynamic physiological milieu that governs nanoparticle fate after entry. Emerging evidence reveals that barrier penetration alone is insufficient to ensure efficacy, particularly in the aging brain, where vascular stiffness, impaired interstitial flow, reduced glymphatic clearance, and chronic immune activation reshape nanoparticle distribution, retention, and metabolism. Aging introduces structural and functional heterogeneity that can invert design principles validated in young systems, leading to reduced therapeutic performance and unpredictable outcomes. This review integrates current insights into how age-related vascular remodeling, altered cerebrospinal fluid dynamics, and disrupted circadian-metabolic coupling influence nanoformulation performance. We highlight the need for adaptive design strategies, including stimuli-responsive carriers, redox- or enzyme-triggered release systems, and chronopharmacological dosing, that exploit residual rhythmicity and local biochemical cues to optimize delivery. Beyond design, we discuss translational and regulatory implications, emphasizing age-specific protein corona profiling, biomarker-guided patient stratification, and physiologically relevant safety evaluation. Integrating these insights establishes aging not as a confounder but as a biological framework enables the creation of adaptive, context-aware nanomedicines aligned with the evolving physiology of the aging brain which advancing the field toward durable efficacy, enhanced safety, and genuine precision neurotherapeutics.
GnRH pulse frequency is decoded by distinct Gαs- and Gαq/11-mediated signaling pathways in gonadotropes in vitro.
Hormones (Athens)
George A Stamatiades, Iain R Thompson, Han Kyeol Kim +2 more
Pulsatile gonadotropin-releasing hormone (GnRH) secretion differentially regulates follicle-stimulating hormone β-subunit (Fshb) expression according to pulse frequency; however, the mechanisms by which pituitary gonadotropes decode GnRH pulsatility remain incompletely understood. GnRH activates both Gαs- and Gαq/11-mediated signaling pathways, and the transcriptional regulators cAMP response element-binding protein (Creb) and inducible cAMP early repressor (Icer) have been implicated in Fshb regulation. This study examined whether distinct G protein-dependent pathways regulate Creb and Icer in a GnRH pulse frequency-dependent manner.
Loss of Slc39a5 in α-cells impairs glucose metabolism by chronically increasing glucagon.
J Adv Res
Wenli Chen, Weiyi Cui, Yan Xu +7 more
Glucagon is a critical regulator of glucose homeostasis by regulating liver glycogenolysis and gluconeogenesis. Hyperglucagonemia has been observed in patients with type 2 diabetes mellitus (T2DM). However, whether elevated glucagon is cause or consequence in the pathogenesis of T2DM is poorly investigated.