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Tirzepatide attenuates lipopolysaccharide-induced acute lung injury via AMPK/NF-κB signaling pathway.

Tissue Cell

Yan Zhang, Ling Li

Sepsis-associated acute lung injury (ALI) is characterized by unregulated systemic inflammation, disruption of the redox balance, and impaired pulmonary function. Tirzepatide, a synthetic dual GLP-1 and GIP receptor agonist possessing anti-inflammatory and metabolic-regulating properties, was investigated for its protective effects in lipopolysaccharide (LPS)-induced ALI and the underlying mechanisms.

Tirzepatide for maintenance of bodyweight reduction in people with obesity in the USA (SURMOUNT-MAINTAIN): a multicentre, double-blind, randomised, placebo-controlled trial.

Lancet

Deborah B Horn, Louis J Aronne, Sean Wharton +10 more

Obesity treatment improves long-term health and quality of life outcomes. Weight reduction and its maintenance play an important role in achieving these goals. We evaluated the efficacy and safety of continuing tirzepatide at the maximum tolerated dose (MTD) or lowering the dose to 5 mg compared with switching to placebo on the maintenance of bodyweight reduction obtained with tirzepatide MTD in adults with obesity.

Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial.

Nat Med

Louis J Aronne, Deborah B Horn, Carel W le Roux +11 more

Incretins have improved the management of obesity and its related complications, but maintaining these health benefits requires ongoing administration, which can be challenging. Orforglipron, a once-daily oral nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated weight loss efficacy, improvements in cardiometabolic risk factors, and safety generally similar to injectable GLP-1 receptor agonists. Here this double-blind, placebo-controlled trial randomized participants previously treated with tirzepatide (cohort 1: N = 205) or semaglutide (cohort 2: N = 171) during the SURMOUNT-5 study to orforglipron once daily or placebo. Cohort 1 participants who achieved body weight plateau maintained a model-based estimate (MBE) of 74.7% (s.e.m. 4.05) of body weight reduction with orforglipron compared with an MBE of 49.2% (s.e.m. 3.92) with placebo, resulting in an estimated treatment difference of MBE 25.5% (95% confidence interval 14.5 to 36.5); P < 0.001; treatment-regimen estimand) at week 52. Cohort 2 participants who achieved body weight plateau maintained an MBE of 79.3% (s.e.m. 4.42) of body weight reduction with orforglipron compared with an MBE of 37.6% (s.e.m. 7.46) with placebo, resulting in an estimated treatment difference of MBE 41.7 (95% confidence interval 24.4 to 59.0); P < 0.001; treatment-regimen estimand) at week 52. All key secondary endpoints were met. The most common adverse events were gastrointestinal effects, which were mostly mild to moderate in severity. These data demonstrate orforglipron's potential as a globally scalable option for minimizing weight changes after injectable therapy. Trial limitations include the absence of a comparator arm involving continued use of injectable obesity-management medications and the trial's 1-year duration. ClinicalTrials.gov registration: NCT06584916 .

A multi-organ atlas of microcirculatory signatures for systemic profiling of diabetic and therapeutic states.

Sci Data

Yuan Li, Weiqi Liu, Yinguyu Wang +5 more

Microcirculatory deterioration in diabetes mellitus causes severe organ-specific complications, yet a systemic understanding of its cross-organ pathophysiology remains elusive due to a lack of comprehensive data. To address this gap, we present a high-dimensional dataset mapping microhemodynamic and oxygenation profiles across six organs in murine models of health, pre-diabetes, and type 1 and 2 diabetes. Structured as a third-order tensor, the dataset comprises 10-parameter physio-signatures for each condition, documenting responses to insulin and the GLP-1 receptor agonist liraglutide at one- and two-week endpoints. Our resource enables direct deconvolution of disease- and organ-specific signatures and provides a quantitative platform for comparing therapeutic pharmacodynamics. We propose a vectorial and tensorial analytical framework to dissect systemic patterns, quantify disease perturbation, and identify significant drug-organ interactions. Our foundational dataset is intended to catalyze the development of system-level computational models for managing diabetic microvascular disease.

Immunotherapy for Senescent Cell Clearance: Hallmarks, Strategies and Translational Challenges.

Ageing Res Rev

Wenjie Zhang, Shihong Chen, Xianghua Zhuang

Cellular senescence, a complex multifactorial process, is involved in the pathophysiology of various age-related diseases, such as cardiovascular disease and neurodegenerative disorders. Traditional interventions targeting single mechanisms yield limited efficacy. As a core hallmark and driver of aging, immunosenescence provides a critical target for precision interventions. This systematic review examines the hallmarks of aging, including cellular damage, epigenetic abnormalities, and immunosenescence. It highlights immunotherapy strategies targeting senescent cells, including CAR-T/NK cell therapies, vaccines, and immune checkpoint blockade. These approaches have demonstrated significant efficacy in animal models by eliminating senescent cells and improving senescence phenotypes. Simultaneously, it analyzes current challenges such as insufficient target specificity, safety and cost concerns in cell therapies, and species differences. It also explores future directions including multi-target synergistic strategies, AI-assisted target screening, and the integration of precision medicine technologies. Immunotherapy offers a revolutionary paradigm for aging intervention, holding promise to extend healthy lifespan by regulating the immune system. However, further breakthroughs are needed for its clinical translation.

Modulating hepatic stellate cell senescence: A promising therapeutic strategy for liver fibrosis.

Hepatobiliary Pancreat Dis Int

Muthusethupathi Sharmila, Karthik Shree Harini, Devaraj Ezhilarasan

Fibrosis is characterized by the abnormal deposition of extracellular matrix (ECM) components in liver tissue following chronic liver injury, ultimately leading to hepatic cirrhosis. Following liver damage, hepatic stellate cells (HSCs) undergo transition from a quiescent to an activated phenotype which differentiate into proliferative, fibrogenic, and contractile myofibroblasts. The activated HSCs act as the primary source of collagen in the injured liver, promoting scar formation and fibrogenesis while reducing ECM degradation. Therefore, potential therapeutic strategies for liver fibrosis include inhibiting HSC activation, proliferation, and function, as well as promoting their clearance through autophagy, pro-apoptotic agents, and senescence inducers. In recent years, the induction of HSC senescence has emerged as a promising therapeutic approach to halt fibrosis progression. This review provided a comprehensive analysis of the fundamental role of the senescence-associated secretory phenotype and its regulatory pathways, including cyclic GMP-AMP synthase-stimulator of interferon genes, Notch signaling, nuclear factor kappa B, and mechanistic target of rapamycin complexes. This review also discussed each of these pathways in terms of their influence on the senescence behaviour of HSCs and their interactions within the fibrotic hepatic microenvironment. Recent advancements in identifying senescence markers, such as p21, β-galactosidase, interleukin-6, and urokinase plasminogen activator receptor, offer promising opportunities for targeted therapeutic interventions. Consequently, the strategic targeting of HSC senescence emerges as a compelling therapeutic approach for liver fibrosis, with the potential not only to halt disease progression but also to promote essential tissue remodeling processes.

Porcine plasma-derived extracellular vesicles orchestrate multi-target neuroimmune reconfiguration to alleviate Alzheimer's disease pathology in a 5×FAD mouse model.

J Neuroinflammation

Xiaoyang Lu, Yiling Jiang, Xiuqing Lin +3 more

Systemic factors found in young blood possess the capacity to revitalize the aging brain, yet the clinical translation of human-derived therapeutics is severely limited by donor scarcity. We hypothesized that porcine plasma-derived small extracellular vesicles (PpSEVs) could serve as a scalable, cross-species alternative by leveraging evolutionarily conserved bioactive cargoes.

Aspirin (Acetylsalicylic Acid) Exerts Antineoplastic Effects on Bile Duct Carcinoma Cells Through Modulation of COX-2/ EGFR, AMPK, and IGF-1R Signaling Pathways.

Turk J Gastroenterol

Yoonchan Lee, Jin Lee, Eun Mi Hong +3 more

Bile duct carcinoma (BDC) is a highly aggressive malignancy. While epidemiological evidence suggests that acetylsalicylic acid (ASA [aspirin]) reduces BDC risk, the underlying molecular mechanisms have not been fully elucidated. This investigation explored the antineoplastic mechanisms of ASA in BDC cells.

Effectiveness of GLP-1 Receptor Agonists in Patients With Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

Cureus

Sukainnya Buragohain, Indrani Sarma, Dibyajyoti Saikia +4 more

Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder, and while metformin is widely used in its management, its efficacy remains variable. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as potential alternatives due to their metabolic benefits. In this systematic review, we have evaluated the effectiveness of GLP-1 RAs on body mass index (BMI), homeostatic model assessment of insulin resistance (HOMA-IR), and total testosterone (TT) in women with PCOS. Randomised controlled trials (RCTs) comparing the effect of GLP-1 RAs with metformin, standard, or placebo on BMI, HOMA-IR, and TT in women with PCOS were selected following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines. A comprehensive literature search was conducted in various databases, including PubMed, Scopus, Embase, MEDLINE, Web of Science, Cochrane, and CINAHL through May 20, 2025. Eighteen RCTs comparing GLP-1 RAs with placebo, metformin, or standard therapy were included. Quality assessment was done using Cochrane's 'Risk of Bias tool (RoB2)'. Review Manager (RevMan) version 5.4.1 (The Cochrane Collaboration, London, United Kingdom) was used to perform random-effects meta-analysis. Continuous outcomes were pooled as mean differences (MD) when measured on the same scale and as standardised mean differences (SMD) when the scales differed, each with a 95% confidence interval (CI). Inter-study heterogeneity among the trials was assessed using the chi-squared test for heterogeneity, with I² to quantify the level of heterogeneity. The certainty of evidence was determined using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. GLP-1 RAs significantly reduced BMI compared with control interventions (MD: -1.09 kg/m²; 95% CI: -1.80 to -0.38; p = 0.003), with liraglutide showing superiority over both metformin and placebo in subgroup analyses. Insulin resistance improved significantly (SMD: -0.38; 95% CI: -0.61 to -0.16; p = 0.001), particularly with exenatide. However, no significant overall effect on TT levels was observed (SMD: -0.10; 95% CI: -0.38 to 0.18; p = 0.49). Risk of bias was generally low, with minor concerns in select domains. Funnel plots suggested minimal publication bias. The certainty of evidence was moderate for BMI and HOMA-IR and very low for TT. GLP-1 receptor agonists are effective in improving metabolic outcomes in PCOS, particularly in reducing BMI and insulin resistance. However, their effect on androgen levels remains inconclusive. These agents may represent a promising therapeutic option, especially in overweight or obese women with PCOS, though further large-scale studies are needed to confirm long-term benefits.

Comparison of IBD-related outcomes in patients with obesity treated with GLP-1 receptor agonists versus bariatric surgery.

Crohns Colitis 360

M Housam Nanah, Arjun Chatterjee, Hisham Wehbe +1 more

The global prevalence of obesity is rising, paralleled by an increase in IBD (inflammatory bowel disease). While studies examining the impact of obesity on IBD have yielded conflicting results, some suggest that obesity may increase adverse outcomes, whereas BS (bariatric surgery) has been associated with improved IBD outcomes in patients with obesity. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a less invasive alternative to BS for managing obesity, with recent studies indicating potential benefits for IBD outcomes. However, GLP-1 RAs have not been directly compared with BS in patients with obesity and IBD.

Clinical impact of potential drug-drug interactions between midostaurin and posaconazole in FLT3-mutated AML.

Antimicrob Agents Chemother

Carolin S Joisten, Sibylle C Mellinghoff, Danila Seidel +9 more

To determine midostaurin and posaconazole plasma concentrations and investigate adverse events (AEs) resembling drug-drug interactions (DDI) when both drugs were administered concomitantly during induction chemotherapy for acute myeloid leukemia (AML). Patients with FLT3-mutated AML who received midostaurin and posaconazole concomitantly between May 2019 and December 2022 were included and followed up to March 2023. Twice-weekly trough levels for midostaurin and posaconazole were measured with validated liquid chromatography-tandem mass spectrometry methods. Potential DDIs were independently reviewed by two physicians and attributed using the Drug Interaction Probability Scale (DIPS). Population pharmacokinetics analysis was done via nonlinear mixed-effect modeling. In 29 patients, concentrations ranged from 0.6 to 24.5 mg/L for midostaurin and from <30 to 2,572 µg/L for posaconazole. A total of 375 AEs in 66 midostaurin cycles, with 280 AEs classified as grade ≥3, were recorded. Probable DDI with a DIPS score of ≥5 was attributed in 14/375 AEs; no highly probable AEs were registered. Eight AEs led to dose modification or discontinuation of midostaurin in seven patients. Clearance for midostaurin during co-administration with posaconazole was 0.52 L/h (95% CI, 0.42-0.62 L/h). A breakthrough fungal infection was recorded in eight patients (27.5%). DDI of midostaurin and posaconazole is clinically meaningful but infrequent. High inter- and intra-individual variabilities of midostaurin and posaconazole plasma exposure were observed. Midostaurin clearance was delayed during co-administration. Midostaurin therapeutic drug monitoring may serve for decision-making when DDI with CYP3A4 inhibitors is suspected.

A Historical Review of Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide in Sepsis.

Biology (Basel)

Razia Dawlaty, Philomena Entsie, Emmanuel Boadi Amoafo +2 more

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) have emerged as potent modulators of immune responses during sepsis, yet their roles remain complex, alternating between protective and permissive depending on timing, tissue compartment, and inflammatory context. This review presents a historical assessment of VIP and PACAP in sepsis research, highlighting the evolution of conceptual advances across five decades. Starting in the 1980s, early studies revealed that VIP levels rise during endotoxemia and correlated with hypotension and mortality, suggesting a deleterious role. By the 1990s, research pivoted toward understanding gut-derived VIP and its interaction with nitric oxide, culminating in the classification of VIP and PACAP as "macrophage deactivating factors" that downregulate TNFα and IL-6. The 2000s further clarified their cell-specific actions through VPAC1/2 and PAC1 receptors, showing anti-inflammatory effects on both innate and adaptive immune cells, while illuminating delivery challenges overcome by liposomal encapsulation. The 2010s expanded this narrative by dissecting receptor dynamics, gut barrier regulation, and VIP's role in neuroimmune crosstalk and thrombo-inflammation. Most recently, studies in the 2020s provide a nuanced view of how VIP suppresses inflammatory damage but also enables pathogen persistence during live bacterial infection, implicating VIP signaling in trade-offs between tolerance and clearance. Across this chronological framework, VIP and PACAP have oscillated between friend, foe, and frenemy, underscoring the importance of context in leveraging their therapeutic potential in sepsis.

Effects of intracerebroventricular Metrnl administration on the hypothalamic-pituitary-testicular axis in male rats.

Mol Biol Rep

Burak Bircan, Güldeniz Şekerci, Yavuz Erden +3 more

Metrnl (Meteorin-like) is a recently identified adipokine expressed in key components of the hypothalamic-pituitary-testicular (HPT) axis. However, its role in male reproductive function remains unclear. This study aimed to investigate the effects of central Metrnl administration on the HPT axis and spermatogenesis in male rats.

Atrial natriuretic peptide counteracts aldosterone secretion by preventing acute angiotensin II-induced cAMP signalling.

Br J Pharmacol

Sanika Mohagaonkar, Egor B Skryabin, Bettina M Buchholz +4 more

Aldosterone plays a key role in blood pressure and volume regulation. Enhanced aldosterone secretion contributes to cardiovascular and renal diseases. Therefore, inhibitors of aldosterone receptors and synthase are essential drugs for the treatment of hypertension and heart failure. Both adrenocorticotropic hormone (ACTH) and angiotensin II (AngII) acutely increase aldosterone release via cAMP and Ca2+-signalling, respectively. Atrial natriuretic peptide (ANP) prevents excessive aldosterone secretion from adrenal zona glomerulosa (ZG) cells. ANP reduces ACTH-stimulated aldosterone by enhancing cAMP degradation through cGMP-stimulated phosphodiesterase (PDE2A). It is not known whether PDE2A also participates in counteracting AngII-induced aldosterone secretion.

Tirzepatide Versus Semaglutide and Cardiovascular Outcomes in Type 2 Diabetes With Established Cardiovascular Disease: An Indirect Treatment Comparison Meta-Analysis.

Diabetes Obes Metab

Ronald M Goldenberg, Jill Trinacty, Christine Ibrahim

Tirzepatide ameliorates cisplatin-induced acute kidney injury by restoring NAMPT/NAD + homeostasis and enhancing Pink1-Parkin-mediated mitophagy.

Biochem Pharmacol

Chongyang Han, Zhicheng Tan, Yu Wang +8 more

Mitochondrial dysfunction and insufficient mitophagy are central to cisplatin-induced acute kidney injury (AKI). Tirzepatide, a dual GLP‑1/GIP receptor agonist, exhibits reno-protective effects, but its mechanism related to mitochondrial homeostasis remains unclear. Here, we used metabolomics, in vivo mouse AKI model, and in vitro cisplatin-injured HK‑2 cells to explore the protective effects and underlying mechanisms. Tirzepatide pretreatment significantly alleviated renal dysfunction, tubular injury, and mitochondrial damage caused by cisplatin. Metabolomic analysis revealed that tirzepatide strongly regulated energy metabolism and autophagy , particularly NAD + homeostasis. Mechanistically, tirzepatide boosted NAD+ levels by nicotinamide phosphoribosyl transferase (NAMPT), the rate-limiting enzyme for NAD + synthesis , which in turn activating the Pink1-Parkin mitophagy pathway. Inhibition of autophagy or NAMPT abolished the mitochondrial and reno-protective effects of tirzepatide. Taken together, our findings demonstrate that tirzepatide protects against cisplatin‑induced AKI by enhancing NAMPT‑dependent NAD + restoration and promoting mitophagy, highlighting a promising therapeutic strategy for chemotherapy‑related nephrotoxicity.

Efficacy and safety of GLP-1 receptor agonists for adolescents and children with obesity: a meta-analysis of randomized controlled trials.

BMC Endocr Disord

Qirong Chen, Haixia Liu, Jie Xu +2 more

To evaluate the efficacy and safety of glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of obesity among children and adolescents.

The association of longitudinal NT-proBNP levels with echocardiographic measurements in heart failure with preserved ejection fraction: Insights from the PURSUIT-HFpEF registry.

Int J Cardiol

Daisuke Sakamoto, Yuki Matsuoka, Daisaku Nakatani +17 more

In heart failure with preserved ejection fraction (HFpEF), the relationship between N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and echocardiographic parameters and the influence of atrial fibrillation (AF) on the relationship remain poorly understood.

Dual inhibition of intercellular adhesion molecule-1 and nucleolin reduces RSV infection efficiency in human respiratory organoids.

Mol Ther Nucleic Acids

Abeer Keshta, Rina Hashimoto, Yuki Kitai +5 more

Respiratory syncytial virus (RSV) is one of the major causes of lower respiratory tract infections, particularly in infants and older adults. However, the host factors mediating infection remain poorly defined. It has been suggested that four host surface proteins, namely intercellular adhesion molecule-1 (ICAM-1), epidermal growth factor receptor (EGFR), nucleolin (NCL), and insulin-like growth factor 1 receptor (IGF1R), may interact with the RSV fusion (F) protein. To investigate these roles under physiologically relevant conditions, we employed human induced pluripotent stem cell (iPSC)-derived respiratory organoids as a model for RSV infection. In this model, ICAM-1 and EGFR were genetically depleted using the CRISPR-Cas9 genome editing technique, while NCL and IGF1R were inhibited with neutralizing antibodies. Suppression of ICAM-1 or NCL significantly reduced RSV nucleoprotein gene expression, whereas inhibition of EGFR or IGF1R had no observable effect on viral gene expression. Notably, simultaneous suppression of ICAM-1 and NCL resulted in a more substantial reduction in infectious viral titers and RSV F protein expression than inhibition of either protein alone. Our results suggest that both ICAM-1 and NCL may play important roles during RSV infection in human iPSC-derived respiratory organoids.

Sodium tanshinone IIA sulfonate modulates proliferation and differentiation of human skeletal muscle satellite cells via the PI3K/AKT pathway.

Cytotechnology

Zongyu Zhang, Zhijing Zhou, Peng Zhang +2 more

Human skeletal muscle satellite cells (HSkMSCs) are the primary stem cells responsible for skeletal muscle regeneration and repair. The balance between their proliferation and differentiation is essential for maintaining muscle homeostasis. Sodium tanshinone IIA sulfonate (STS) has been reported to possess anti-inflammatory, antioxidant, and antifibrotic effects. However, the regulatory role and underlying mechanisms of STS in governing the fate of HSkMSCs remain largely unexplored. This study aimed to investigate the effects of STS on the proliferation and differentiation of HSkMSCs and to elucidate the potential molecular mechanisms. HSkMSCs were treated with different concentrations of STS. Cell proliferation was assessed using EdU assay. The expression levels of the proliferation marker Pax7 and the myogenic differentiation-related genes MyoD and fast-twitch skeletal myosin heavy chain (MyHC -II) were determined by RT-qPCR and western blotting. To verify the involvement of PI3K/AKT signaling pathway, the inhibitor LY294002 was co-administered with STS to further evaluate the regulatory role of this signaling in mediating the biological effects of STS. EdU staining revealed that STS significantly reduced the proliferation of HSkMSCs in a dose-dependent manner. STS markedly downregulated the expression of Pax7, while upregulating the expression of MyoD and MyHC-II. Furthermore, STS treatment significantly enhanced the phosphorylation levels of PI3K and AKT. Notably, co-treatment with LY294002 effectively attenuated the regulatory effects of STS on Pax7, MyoD, and MyHC-II expression. In conclusion, STS inhibits the proliferation and upregulates myogenic differentiation markers expression in HSkMSCs by activating the PI3K/AKT signaling pathway.