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Determination of the relationship between thymoquinone and apelin in isoproterenol-induced myocardial infarction.
Tissue Cell
Rifat Özmen, Derya Karabulut, Aysun Çetin +5 more
Experimental MI models induced by isoproterenol (ISO) are frequently used because they show many similarities to the human heart attack model. Thymoquinone (THQ) is a biologically active compound known for its antioxidant and anti-inflammatory properties. This study aimed to induce experimental MI using ISO and to investigate the effects of THQ through its relationship with apelin.
Plasma proteomics enhances heart failure risk prediction among individuals with type 2 diabetes: a prospective cohort study.
Am J Clin Nutr
Hancheng Yu, Jijuan Zhang, Frank Qian +17 more
Heart failure (HF) is a severe complication of type 2 diabetes (T2D), yet the association between plasma proteins and HF in individuals with T2D remains underexplored.
Risk factors for adrenal insufficiency after adrenalectomy for mild autonomous cortisol secretion.
Surgery
Akanksha Aggarwal, Ali Osman Balkan, Divya Sistla +9 more
Although unilateral adrenalectomy can improve metabolic outcomes associated with mild autonomous cortisol secretion, it can also be associated with postoperative adrenal insufficiency. We aimed to look at the incidence and risk factors of suspected adrenal insufficiency in these patients.
Psychiatric Symptoms in Women with Mild Autonomous Cortisol Secretion Versus Non-Functioning Adrenal Adenomas: A Cross-Sectional Study.
Horm Metab Res
Ilkay Cakir, Fuat Mısıroğlu, Zeynep Elustu Belten +7 more
The potential association between mild autonomous cortisol secretion and psychopathological symptoms remains inadequately studied. This study aimed to investigate whether women with mild autonomous cortisol secretion exhibit greater psychological symptom severity and distress compared with patients with nonfunctional adrenal adenomas, as assessed by multidimensional self-report scales including the Beck Depression Inventory-II, Beck Anxiety Inventory, and Symptom Checklist‑90. A cross-sectional study was conducted at the endocrinology department of a tertiary-care hospital in Turkey between June 2022 and 2025. The study cohort included 91 women with adrenal adenomas, comprising 50 patients with mild autonomous cortisol secretion and 41 patients with nonfunctional adrenal adenoma. Questionnaire-derived scores from the 10 subscales and Global Severity Index of the Symptom Checklist-90, as well as the Beck Anxiety Inventory and Beck Depression Inventory-II, along with hormonal parameters, including morning cortisol, adrenocorticotropic hormone, dehydroepiandrosterone sulfate, 1-mg dexamethasone-suppressed cortisol, 24-hour urinary free cortisol, the dehydroepiandrosterone sulfate ratio, and the cortisol/dehydroepiandrosterone sulfate ratio, were compared between the groups. Women with mild autonomous cortisol secretion exhibited higher overall psychological distress, as measured by the Global Severity Index of the Symptom Checklist-90. Depressive (Beck Depression Inventory-II) and anxiety (Beck Anxiety Inventory) symptoms did not differ significantly between groups, although a non-significant pattern suggested that depressive symptom severity may increase with higher basal cortisol levels. No significant associations were found between hormonal parameters and psychological scores. These findings indicate that patients with mild autonomous cortisol secretion may experience increased general psychological distress, highlighting the importance of considering mental health in their clinical evaluation and warranting further research into the relationship between mild cortisol excess and specific psychiatric symptoms.
Quadruple Non-Insulin Therapy for Advanced Type 2 Diabetes Mellitus With Cognitive Impairment: A Case Report.
Cureus
Stjepan Skudar
Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder that often requires treatment intensification over time. In complex patients with multiple comorbidities and cognitive impairment, therapeutic decisions must balance glycemic control with safety and feasibility. We present a 59-year-old male with long-standing T2DM, marked body weight fluctuations, and emerging neurocognitive decline. Baseline glycated hemoglobin (HbA1c) was 9.4%, with progressive improvement to 7.1% under quadruple non-insulin therapy consisting of metformin, sitagliptin, glimepiride, and semaglutide. Insulin therapy was avoided due to cognitive impairment and a high risk of dosing errors. Sustained glycemic control was achieved without severe hypoglycemia. This case highlights the importance of individualized, multidisciplinary management in advanced T2DM and demonstrates that non-insulin strategies may be a viable and safe alternative in selected high-risk patients.
Renal or Hepatic Impairment Does Not Affect Pharmacokinetics, Safety, or Tolerability of Subcutaneous Cagrilintide.
Clin Pharmacokinet
Mette J F Nielsen, Niels-Peter Becker, Helene H Hansen Duus +6 more
Cagrilintide is a long-acting amylin agonist under development as monotherapy for weight management and as a fixed-dose combination with the glucagon-like peptide-1 receptor agonist semaglutide (CagriSema) for weight management and treatment of type 2 diabetes. Two studies were conducted to assess the effects of renal or hepatic impairment on pharmacokinetics, safety and tolerability following single doses of cagrilintide.
15-PGDH inhibition promotes muscle repair and strength recovery during GLP-1 receptor agonist-induced weight loss.
Proc Natl Acad Sci U S A
Minas Nalbandian, Jameel Lone, Emmeran Le Moal +9 more
Glucagon-like peptide-1 receptor agonists, including long-acting semaglutide, are transformative anti-obesity therapies. However, emerging evidence indicates that weight loss may come at the expense of skeletal muscle mass, a tissue essential for mobility, metabolic regulation, and overall health. Here, we show that inhibition of the gerozyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme that increases with injury and aging, improves muscle repair and strength recovery in the presence of semaglutide. In a high fat diet-induced mouse model of obesity, semaglutide alone caused significant loss of muscle mass, while preserving contractile function. Following injury, obese mice exhibited pathological calcifications previously reported for the heritable myopathy, Duchenne Muscular Dystrophy. Semaglutide had both beneficial and deleterious effects, reducing calcific remodeling, but causing reduced regenerated myofiber sizes. This impaired regenerative myofiber growth in semaglutide-treated mice was surmounted by cotreatment with a 15-PGDH inhibitor (PGDHi), which stimulated muscle stem cell function and myofiber growth, leading to enhanced strength. Importantly, PGDHi synergizes with semaglutide to boost postinjury muscle quality and muscle force without compromising weight loss.
Myocardial deformation links combined liraglutide-empagliflozin therapy with improved cardiovascular and economic outcomes in type 2 diabetes: a 6-year study.
Eur Heart J Imaging Methods Pract
John Thymis, Grigoris Oikonomidis, Georgios Georgiopoulos +7 more
We investigated whether the early favourable effects of combined GLP-1 receptor agonist (GLP-1RA) and SGLT2 inhibitor (SGLT2i) therapy in left ventricular deformation is associated with long-term cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM). We also addressed the healthcare costs.
Pharmacovigilance Assessment of Thrombotic Adverse Events Linked to GLP-1 Receptor Agonists: Analysis of FAERS Reports from 2020-2025.
Curr Drug Saf
Eman M Mansory, Osman O Radhwi
Glucagon-like peptide-1 receptor agonists are widely prescribed for diabetes and obesity. The association between GLP-1 RAs and thrombotic events remains unclear, with conflicting evidence from clinical and experimental studies. This study aims to assess the reporting of thrombotic adverse events with GLP-1 RAs in the FDA Adverse Event Reporting System (FAERS).
Exendin-4 averts all-trans-retinal-driven damage to photoreceptors and the retina via the GLP-1R/PKA/CREB1 signaling axis.
Cell Mol Biol Lett
Beiting He, Yuling Chen, Peixin Cai +6 more
Atrophic macular degeneration comprises dry age-related macular degeneration (AMD) and autosomal recessive Stargardt disease (STGD1). These disorders lead to irreversible blindness and still lack effective therapies. The rise of all-trans-retinal (atRAL) brought on by visual cycle disruption closely links to retinal atrophy in both conditions, yet the key downstream targets remain obscure. Exendin-4 (EX-4) is a natural glucagon-like peptide-1 receptor (GLP-1R) agonist. Recent clinical retrospective studies indicate that GLP-1R agonists such as exenatide (synthetic EX-4) can markedly lower the 5-year risk of developing dry AMD. Here, we sought to clarify the protective effect of natural EX-4 against retinal degeneration in atrophic macular degeneration linked to impaired clearance of atRAL.
The GLP-1 agonist exenatide is associated with improved adherence to health behavior and lifestyle treatment in adolescents with obesity, a randomized controlled trial.
Obes Facts
Rasmus Stenlid, Sara Y Cerenius, Gabriel Torbahn +13 more
We aimed to study the effects of the glucagon-like peptide-1 receptor agonist exenatide on behavioral outcomes in children and adolescents with obesity.
Acute glucagon-like peptide-1 receptor agonist, semaglutide, attenuates cue-, drug-, and stress-induced fentanyl seeking in male Sprague-Dawley rats.
Behav Pharmacol
Brianna Evans, Nikhil Acharya, Christopher G Brandl +5 more
Opioid overdose deaths continue to be a significant public health problem worldwide, with fentanyl, the primary driver of these losses of life. Indeed, in the USA, overdose deaths continue despite the availability of three food and drug administration-approved medications for the treatment of opioid use disorder (OUD) due to minimal access to these medications and to stigma. Fortunately, a growing preclinical and clinical literature suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists may serve as new treatments for OUD. Exendin-4/exenatide and liraglutide have been found to reduce opioid intake, cravings, and cue-, drug-, and stress-induced opioid seeking. While these are important findings, exenatide has a higher risk of gastrointestinal distress and, due to its short half-life, requires multiple daily injections for treatment. Liraglutide has a longer half-life, is less likely than exenatide to cause gastrointestinal distress, but still requires daily injections, which many patients find objectionable. Semaglutide, on the other hand, is a GLP-1R agonist with a longer half-life that requires once weekly injections in humans. Some evidence suggests that semaglutide can reduce responding for alcohol, but it is not known whether it can reduce responding for opioids. Here we test whether acute treatment with semaglutide at 0.026, 0.056, and 0.078 mg/kg administered subcutaneously can reduce cue-, drug-, and stress-induced fentanyl seeking in rats. Results show that all doses of semaglutide fully prevented drug- and stress-induced reinstatement of fentanyl seeking elicited by an i.v. infusion of 1.85 µg/kg fentanyl or the i.p. administration of 0.5 mg/kg yohimbine, respectively, while the mid (0.056 mg/kg) and higher doses (0.078 mg/kg) most effectively reduced cue-induced fentanyl seeking. These findings suggest that semaglutide may serve as an additional nonopioid GLP-1R agonist for the treatment of OUD.
The autophagy-inhibitory tissue hormone DBI/ACBP contributes to the pathogenesis of multiple organ dysfunction syndrome in septic shock.
Autophagy
Flavia Lambertucci, Maria Chiara Maiuri, Isabelle Martins +1 more
Systemic microbial infection leading to septic shock with multiple organ dysfunction syndrome (MODS) is a major cause of mortality and represents a substantial unmet medical need. We recently observed that, compared with uninfected controls, patients with septic shock exhibit significantly elevated circulating concentrations of the tissue hormone acyl-CoA binding protein (ACBP), encoded by the diazepam binding inhibitor (DBI) gene, a potent inhibitor of autophagy. Increased plasma DBI/ACBP levels correlated with disease severity and poor clinical outcome. Similarly, DBI/ACBP concentrations were elevated in three distinct mouse models of septic shock induced by (i) bacterial lipopolysaccharide injection, (ii) inoculation with monomicrobial Escherichia coli or (iii) polymicrobial sepsis following cecal ligation and puncture. In all three models, neutralization of DBI/ACBP using specific monoclonal antibodies significantly reduced mortality. Comprehensive behavioral, cardiac, pulmonary, hepatic, renal and splenic phenotyping further demonstrated that DBI/ACBP neutralization alleviated all hallmarks of MODS, including impaired thermoregulation, lethargy and organ failure affecting the heart, lungs, liver and kidneys. Multi-omics analyses, including bulk transcriptomics, metabolomics and high-dimensional immunophenotyping, revealed that DBI/ACBP neutralization attenuated sepsis-associated alterations in gene expression, metabolism and myeloid cell infiltration across major organs. Mechanistically, DBI/ACBP inhibition enhanced organ resistance to lipopolysaccharide-induced sterile inflammation while simultaneously promoting bacterial clearance by macrophages and granulocytes both in vivo and in vitro in models of monomicrobial and polymicrobial sepsis. Collectively, these findings identify DBI/ACBP as a pathogenic mediator of sepsis, consistent with its previously described anti-autophagic, immunosuppressive, pro-inflammatory and pro-senescent properties.
Lipid Droplet-Accumulating Microglia as a Therapeutic Node in Neurodegenerative Disease.
ACS Chem Neurosci
Siqi Guo, Qingyu Zhang, Rui Guo +3 more
Neurodegenerative disorders increasingly reflect failures of cellular state control rather than the linear accumulation of a single toxic lesion. Microglia become trapped in maladaptive states in which inflammatory activation is decoupled from effective cargo processing. Lipid droplet-accumulating microglia (LDAM) represent a recurrent convergence state across aging and neurodegeneration, characterized by persistent neutral lipid sequestration, reduced phagocytosis-to-degradation capacity, oxidative amplification, and chronic but functionally inefficient inflammation. LDAM emerges when lipid substrate influx exceeds the capacity of cholesterol efflux, lysosomal lipophagy, and mitochondrial β-oxidation, converting lipid droplets from transient buffers into stable metabolic anchors. This entrenchment is reinforced by mitochondrial exhaustion, vacuolar H+-ATPase-linked lysosomal deacidification, and inflammasome/interferon locking, often further amplified by cGAS-STING signaling. Together, these constraints converge on a state of metabolic-epigenetic locking that sustains permissive chromatin landscapes at pro-inflammatory loci. On this basis, state-resetting strategies are considered that rebalance lipid flux, restore organelle clearance capacity, and transiently restrain inflammatory amplification, while spatial multiomics and fluid biomarkers are discussed as candidate tools for stage- and niche-resolved stratification of combination interventions.
Avoiding false-positive adrenal insufficiency diagnoses in children: insights from cortisol kinetics during pediatric low-dose ACTH stimulation test.
Eur J Pediatr
Derya Tepe, Sirmen Kızılcan Çetin, İrem Gökdemir +3 more
The low-dose ACTH stimulation test (LDST) is widely used to evaluate hypothalamic-pituitary-adrenal (HPA) axis function in children; however, optimal cortisol sampling times and interpretation strategies remain controversial. Reliance on early or single time-point measurements may lead to false-positive diagnoses of adrenal insufficiency (AI). The aim of the study is. to characterize the timing of peak cortisol responses during LDST in children without AI and to assess the incremental diagnostic contribution of extended sampling and time-specific cortisol thresholds. We retrospectively analyzed 177 pediatric patients who underwent LDST for suspected central adrenal insufficiency at a single tertiary center. Serum cortisol was measured at baseline and at 15, 30, 45, and 60 min following intravenous administration of 1 µg ACTH. Adrenal sufficiency was defined as a peak cortisol ≥ 18 µg/dL(497 nmol/L). Peak timing distribution, basal predictors, incremental diagnostic contribution of additional time points, number needed to test (NNT), and false-positive rates using fixed versus time-specific cutoffs were evaluated. Peak cortisol occurred most frequently at 15 min (48.6%), followed by 30 min (28.8%), baseline (10.7%), 45 min (9.0%), and 60 min (2.8%). Termination of testing at 30 min would have misclassified 11.9% of patients as insufficient despite normal later responses. Extension to 45 min provided meaningful diagnostic improvement, whereas routine extension to 60 min presented only marginal additional benefit (NNT = 30). Higher basal cortisol levels were independently associated with earlier peak responses (p = 0.021), while demographic and auxological factors showed no association. Application of time-specific, percentile-based cortisol thresholds reduced false-positive classifications nearly fivefold at 30 min compared with a uniform 18 µg/dL cut-off.
Impact of gelatin supplementation on indices of skeletal muscle recovery: a pilot study.
Eur J Appl Physiol
Rebecca R Graham, Brian E Salgado, Emedel Guerrero +2 more
This pilot study examined whether collagen supplementation, via gelatin, influences indices of skeletal muscle recovery following strenuous exercise.
Semaglutide 25 mg Oral Versus Semaglutide 2.4 mg Injectable: An Indirect Treatment Comparison of Weight Loss Outcomes.
Diabetes Obes Metab
Molly Plotkin, Milana Ivkovic, Inger Smith +4 more
Semaglutide, a GLP-1 receptor agonist, has demonstrated significant weight loss benefits for patients with overweight or obesity in both oral and subcutaneous (s.c.) formulations. Given comparable systemic exposure between formulations, an indirect treatment comparison (ITC) was conducted to confirm comparable efficacy.
Oral Semaglutide 25 mg Versus Orforglipron 36 mg in Obesity: A Population-Adjusted Indirect Treatment Comparison.
Diabetes Obes Metab
Wojciech Michalak, Martin Bøg, Theiss Bendixen +5 more
This study aimed to indirectly compare the effects of oral semaglutide 25 mg versus orforglipron 36 mg on body weight loss, other cardiometabolic biomarkers, and tolerability in adults with overweight (body mass index [BMI] ≥ 27 kg/m2 and at least one obesity-related complication) or obesity (BMI ≥ 30 kg/m2), without diabetes, using data from OASIS 4 and ATTAIN-1.
IL-4/IL-13 signaling suppresses ABT-263-induced apoptosis in senescent human fibroblasts.
Int Immunopharmacol
Takashi Nishinaka, Hidenori Wake, Masahiro Watanabe +4 more
Senescent cells, which have irreversibly arrested cell proliferation and a senescence-associated secretory phenotype, are characterized by the production of proinflammatory cytokines and growth factors. The selective clearance of senescent cells might have beneficial effects on physiological functions or aging-related diseases. Senolytic drugs, such as ABT-263, an inhibitor of BCL-2 family proteins, selectively kill senescent cells. In the present study, we investigated the effect of IL-4 and IL-13, which contribute to type 2 immunity and fibrosis, on ABT-263-induced apoptosis in senescent cells. Doxorubicin was used to induce senescence in TIG-1 cells, a normal diploid fibroblast line commonly used to study cellular senescence. Although ABT-263 selectively induced apoptosis in senescent TIG-1 cells at lower concentrations than were required to induce apoptosis in non-senescent cells, IL-4 and IL-13 suppressed ABT-263-induced apoptosis in senescent TIG-1 cells. Pharmacological experiments using inhibitors revealed that the suppressive effects of IL-4 and IL-13 involved the IL-4Rα/JAK/STAT6 signaling pathway. We found that IL-4 and IL-13 altered the expressions of molecules involved in extracellular matrix and cell adhesion, and induced phosphorylation of the downstream FAK/Akt/GSK3β signaling pathway. In addition, senescent TIG-1 cells treated with IL-4 and IL-13 showed increased glucose consumption, and the suppressive effect of IL-4 and IL-13 was partially abolished by inhibitors of the glucose metabolic pathway. Taken together, IL-4/IL-13 signaling had a suppressive effect on ABT-263-induced apoptosis in senescent human fibroblasts. These results suggest that a combination of senolytic drugs and inhibitors targeting IL-4/IL-13 signaling might be effective for aging-related diseases.
Acute GIP and GLP-1 Administration Exerts Differential Metabolic Effects in Totally Pancreatectomised Individuals.
Diabetes Obes Metab
Liva S L Krogh, Maja B Hansen, Natasha C Bergmann +6 more
While being recognised for stimulating pancreatic insulin secretion, GIP and GLP-1 exert various extrapancreatic effects relevant in the context of incretin-based therapies. Here, we evaluated the extrapancreatic effects of GIP and GLP-1, separately and combined, on postprandial physiology in totally pancreatectomised individuals.