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Role of Bruton's Tyrosine Kinase in mast cell driven urothelial barrier injury in an LL-37 induced model of interstitial cystitis.
Sci Rep
Guang Wang, Bin-Sen Li, Jin-Yi Chu +4 more
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic urinary disorder with unclear pathogenesis. Previous studies identified BTK as a hub gene potentially involved in IC/BPS. This study investigates BTK's role in mast cell (MC) activation and bladder inflammation. An LL-37-induced IC/BPS rat model and an in vitro MCs Co-culture system were established. BTK expression was modulated via adenoviral vectors and cell transfection. Bladder inflammation, MC degranulation, and urothelial barrier function were assessed using histology, ELISA, RT-qPCR, Western blot, IHC, TEM, and IF. MC function was evaluated via CCK-8, flow cytometry, Transwell, and TEM. LL-37 upregulated BTK in IC/BPS rats, promoting inflammation, cytokine release, collagen deposition, MC degranulation, and urothelial damage. BTK overexpression exacerbated, while knockdown alleviated these effects. In vitro, LL-37 stimulated MC proliferation, invasion, and degranulation, and reduced apoptosis. Co-culture with activated MCs decreased glycosaminoglycan (GAG) and tight junction (TJ) proteins in SV-HUC-1 cells, enhanced by BTK overexpression and reversed by knockdown. BTK promotes LL-37-induced MC activation and urothelial barrier disruption by suppressing GAGs and TJ proteins, contributing to IC/BPS pathophysiology.
Septal GLP-1 receptors control alcohol taking and seeking.
Neuron
Ginevra D'Ottavio, Kenichiro Negishi, Yavin Shaham
In this issue of Neuron, Tian et al.1 describe a lateral septum GABAergic microcircuit through which systemic administration of the GLP-1 receptor agonist liraglutide, acting via GLP-1 receptor-expressing neurons, inhibits alcohol intake in rodent models.
Effects of Retatrutide on Learning and Memory in Streptozotocin-Induced Male Diabetic Rats.
Behav Brain Res
Ulya Keskin, Eslem Altin, Melkan Kagan Kara +6 more
Diabetes mellitus is associated with cognitive impairment and neurodegenerative changes, partly through hyperglycaemia-driven neuroinflammation and disrupted neuronal signalling. Retatrutide, a triple GIP/GLP-1/glucagon receptor agonist, has shown strong metabolic efficacy, but its effects on diabetes-associated cognitive dysfunction remain unclear. The present study investigated whether Retatrutide attenuates learning- and memory-related impairments in a streptozotocin-induced, insulin-deficient diabetic rat model. Male Sprague-Dawley rats were allocated to four groups: control (C), streptozotocin-induced diabetic (STZ), streptozotocin-induced diabetic treated with Retatrutide (STZR), and Retatrutide alone (R). Diabetes was induced with streptozotocin, and spatial learning and memory were assessed using the Morris Water Maze and Passive Avoidance tests. Metabolic parameters were monitored, while hippocampal cytokine levels (IL-1β, TNF-α), BDNF, CREB, and AKT mRNA expression, Tau protein levels, and cortical and hippocampal histopathology were evaluated using biochemical, molecular, and histological methods. Streptozotocin-induced diabetes produced persistent hyperglycaemia, marked body weight loss, and impaired behavioural performance, particularly prolonged escape latencies in the Morris Water Maze and a selective short-term Passive Avoidance deficit. Retatrutide reduced blood glucose levels but did not prevent diabetes-associated weight loss. In behavioural testing, Retatrutide-treated diabetic rats showed preserved overall Morris Water Maze performance relative to untreated diabetic rats and a limited, task-dependent attenuation of short-term avoidance deficits rather than complete normalisation across all memory measures. These effects were accompanied by a significant reduction in hippocampal TNF-α, a non-significant trend toward lower IL-1β, and partial preservation of cortical and hippocampal cytoarchitecture. Retatrutide alone did not improve behavioural performance beyond control levels, although BDNF and CREB mRNA expression were increased in the non-diabetic Retatrutide group. These findings indicate that Retatrutide is associated with a partial attenuation of streptozotocin-induced behavioural and neuroinflammatory alterations in male rats. The observed effects are consistent with actions extending beyond glycaemic control alone, although direct central exposure of Retatrutide was not established in the present study. Further studies in insulin-resistant and type 2 diabetes-like models are needed to clarify the underlying mechanisms and translational relevance.
Caffeine suppresses inflammation and subretinal fibrosis through modulation of the thrombospondin-1-Bim axis.
Exp Eye Res
Nader Sheibani, Shoujian Wang, Soesiawati R Darjatmoko +1 more
Age-related macular degeneration (AMD) in the aging population frequently leads to vision impairment. Treatment for neovascular AMD (nAMD) focuses on the tortuous leaky vessels that typify choroidal neovascularization (CNV). Subretinal fibrosis in nAMD patients is more challenging to treat, as few effective options exist. This fibrosis notably impairs vision and typically develops in patients who do not fully respond to current treatments. To gain a better understanding of pathways that could be utilized to subvert subretinal fibrosis, we examined the role Bim, a pro-apoptotic mediator in the intrinsic cell death pathway, and thrombospondin-1 (TSP1), a key regulator of ocular angioinflammatory processes, have in moderating fibrosis. Here we show caffeine treatment significantly reduced subretinal fibrosis in the mouse laser photocoagulation model consistent with its known ability to enhance mononuclear phagocyte (MP) clearance and reduce CNV. Since the TSP1-Bim axis facilitates MP clearance, suppresses inflammation, prevents subretinal fibrosis and CNV, we assessed its necessity for the mitigation of fibrosis by caffeine. We show that caffeine did not prevent subretinal fibrosis or CNV in mice lacking Bim or TSP1. Thus, caffeine utilizes the intrinsic death pathway though TSP1-Bim axis to subvert subretinal fibrosis, likely by suppressing inflammation during CNV.
Multi-omics profiling reveals systemic rejuvenation of the aged kidney through senolytic therapy.
NPJ Regen Med
Shilin Chen, Chenglin Zhang, Pengxu Cang +14 more
Cellular senescence is a key driver of kidney aging, leading to functional decline and increased susceptibility to chronic kidney disease. While the senolytic combination of dasatinib and quercetin (D + Q) has shown promise in mitigating age-related pathologies, its long-term effects and underlying multi-level systemic mechanisms in the aging kidney remain poorly defined. Here, we systematically evaluated the long-term effects of D + Q in naturally aged mice using multi-omics approaches. We show that D + Q treatment reduces senescence markers (p16, p21, SA-β-gal), restores the anti-aging protein Klotho, and attenuates renal fibrosis and inflammation. Proteomic profiling reveals that D + Q enhances apoptotic clearance of senescent cells and promotes proliferative and regenerative pathways. Moreover, D + Q reactivates PPARα signaling, improves fatty acid oxidation, and reduces lipid accumulation in aged kidneys. Single-cell transcriptomics further demonstrates that D + Q reverses transcriptional aging signatures across multiple renal cell types and remodels cell-type-specific pathways associated with metabolism, inflammation, and fibrosis. Cell-cell communication analysis reveals that D + Q normalizes the hyperconnected intercellular network in aged kidneys, particularly by modulating inflammation-related signaling. Our findings offer a comprehensive, systems-level understanding of how senolytic therapy restores renal homeostasis, emphasizing its potential as a multifaceted intervention to combat kidney aging.
CSF turnover dysfunction: a hidden early biomarker in iRBD?
NPJ Parkinsons Dis
Stephan Grimaldi, Kavita Singh, María Guadalupe García-Gomar +6 more
Evidence in Alzheimer's disease and other dementias shows that changes in cerebrospinal fluid (CSF) turnover and perivascular spaces (PVS) volume are associated with disease progression through impairment of waste-clearance glymphatic pathways. Volume of CSF, PVS, and drainage structures such as venous sinus are mostly excluded in current MRI studies of premanifest synucleinopathy. Here, we used 7 Tesla MRI to investigate whether modifications in CSF, PVS, and venous sinus volumes occur in 18 prodromal synucleinopathy patients (namely isolated rapid-eye-movement sleep behavior disorder, iRBD) compared to 20 healthy young and 18 elderly controls. Our results demonstrated increased CSF and PVS volumes in iRBD without a matching increase in drainage venous structures, as observed in elderly controls. This suggests increased CSF and PVS fluid stasis, possibly due to impaired CSF filtration, a mechanism that could reduce glymphatic function and exacerbate the neurodegenerative process in iRBD.
Clinical characterization of Japanese children with Cushing's disease.
Endocr J
Mari Yamamoto, Yuri Mukoyama, Kentaro Kishi +12 more
Cushing's disease (CD) is very rare in children. Nineteen children (≤18 years) with CD (median age at diagnosis: 13 [6-17] years; 12 females) were retrospectively analyzed using medical records (1994-2025) from Toranomon Hospital, Tokyo, Japan. Facial changes (88.9%), weight gain with decreased growth rate (88.9%), central obesity (88.9%) and hirsutism (94.4%) were frequently observed at diagnosis. Median time to diagnosis was 2.7 (0.25-5.8) years. Screening for endogenous hypercortisolism was assessed by 24-hour urinary free cortisol levels, serum cortisol levels at 23:00, and serum cortisol levels at 8:00 after a low-dose dexamethasone suppression test (DST), each with 100% sensitivity. Etiological diagnosis was evaluated by serum cortisol levels at 8:00 after a high-dose DST, plasma adrenocorticotropic hormone (ACTH) levels after a corticotropin-releasing hormone test, and plasma ACTH levels at 8:00, with sensitivities of 85.7%, 93.8%, and 83.3%, respectively. The actual tumor detection rate on magnetic resonance imaging (MRI) was 72.2%. Micro-pituitary neuroendocrine tumors were identified in 77.8% of patients. The total remission rate was 94.4% (median follow-up: 3.8 [0-10.4] years). The mean standard deviation scores (SDS) (SD) of height and body mass index (BMI) at onset and diagnosis were -0.45 (0.63) and -2.0 (1.1), and 0.61 (0.95) and 1.6 (0.75), respectively. Height and BMI SDS (SD) improved to -1.0 (0.80) and 0.091 (1.2) at the last visit (age: 11.4-17.5 years; follow-up: 1-8.6 years), respectively. This study revealed clinical characteristics of Japanese children with CD, including distinctive BMI SDS and a high tumor detection rate by MRI.
Sprayable bioadhesive microcarriers loaded with Tβ4-Engineered ADSC exosomes for diabetic wound healing.
Bioact Mater
Youjun Ding, Danqing Huang, Zhiwei Zhao +6 more
Stem cell-derived therapeutics show strong potential to recalibrate diabetic wound immunity, yet their stability, retention, and practical usability remain major barriers to effective application. Here, we report a novel microcarrier platform loaded with thymosin β4 (Tβ4)-overexpressing stem cell-derived exosomes for a sprayable diabetic wound dressing. Adipose-derived stem cells (ADSCs) were genetically engineered to overexpress Tβ4, generating potent immunoregulatory exosomes that were efficiently encapsulated into uniform, micron-scale hydrogel microcarriers via microfluidic fabrication and further functionalized with a mesoporous polydopamine (mPDA) coating to enhance wet adhesion and tissue retention. The resulting EXOsTβ4/mPDA@MS system stabilizes the exosome payload and enables convenient spray-based wound administration. These microcarriers provide sustained, localized exosome release, significantly enhance macrophage efferocytosis, suppress inflammatory signaling, and accelerate wound repair in diabetic models. Thus, our engineered, sprayable, and adhesive microcarrier platform offers a stable, minimally invasive, and clinically adaptable strategy for advancing stem cell-derived exosome therapies in chronic diabetic wound repair.
Effects of Supplementation in Masters Athletes and Older Adults: A Narrative Review.
Curr Sports Med Rep
Chantal Nguyen, Matthew R Allen, Kalvis Hornburg +1 more
Supplementation use in athletes is common and increasing in popularity, especially for adults seeking improvements in athletic performance. However, the effects of supplementation for older adults or Masters athletes in improving athletic performance or musculoskeletal health are less well explored. The aim of this narrative review is to explore common supplements, namely protein, caffeine, creatine, beta-alanine, nitrates, and peptides, including collagen, body protection compound-157, and thymosin-beta 4 and 500, in improving performance or musculoskeletal health in Masters athletes and adults over 55 years of age.
Starvation-Type Euglycemic Ketoacidosis After Unsupervised Tirzepatide Use in a Non-Obese, Non-Diabetic Woman.
Am J Case Rep
Eslam Elsayed Abdelshafey, Khaled Sewify, Atheer Almutairi +5 more
BACKGROUND Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for type 2 diabetes and chronic weight management in adults meeting clinical criteria. Appetite suppression and gastrointestinal intolerance can markedly reduce intake. This report describes a 30-year-old woman with tirzepatide-associated euglycemic ketoacidosis after unsupervised use of tirzepatide obtained without a prescription for weight loss, despite having no history of obesity or diabetes. CASE REPORT A 30-year-old woman with a body mass index of 24.8 kg/m² and no known diabetes presented with 4 days of severe nausea, approximately 10 vomiting episodes daily, poor intake, and periumbilical abdominal pain. She had self-administered tirzepatide 2.5 mg once weekly and increased the dose to 5 mg 1 week before presentation. Initial testing showed high anion gap metabolic acidosis with a pH of 7.15, bicarbonate level of 10.5 mEq/L, and an anion gap of 24. Lactate was in the normal range. Urine ketones were positive, serum ketones measured 4.5 mmol/L, and glucose level was 4.2 mmol/L. Acidosis persisted after administration of 1.5 L crystalloid, prompting intensive care unit admission. Tirzepatide was stopped. She received 10% dextrose, lactated Ringer's solution, thiamine, antiemetics, electrolyte monitoring and replacement, and gradual refeeding. The anion gap closed and ketones normalized within 36 hours, without bicarbonate therapy or insulin infusion. CONCLUSIONS Tirzepatide-related nausea, vomiting, and caloric deprivation can be associated with significant euglycemic ketoacidosis even without diabetes or obesity. Clinicians should consider starvation ketoacidosis in tirzepatide users with vomiting, poor intake, abdominal pain, and high anion gap metabolic acidosis.
Weight loss and cardiovascular outcomes with incretin-based therapies after metabolic and bariatric surgery: a nationwide US cohort study.
EClinicalMedicine
Andrew Gillikin, Yung Lee, Catherine Varney +4 more
Long-term weight management after metabolic and bariatric surgery (MBS) remains a prevalent clinical challenge. Given the efficacy of glucagon-like peptide-1 receptor (GLP-1RA) and dual GIP/GLP-1 receptor agonists (GIP/GLP-1RA), there is increasing interest in their role as adjunctive therapy after MBS. We examined weight loss and major adverse cardiovascular events (MACE) in people who underwent MBS and subsequently received incretin-based therapy.
Micronutrient risk with GLP-1 receptor and dual incretin agonists in obesity: Mechanistic pathways, clinical signals, and a monitoring framework.
Obes Pillars
Daniel Simancas-Racines, Martín Campuzano-Donoso, Gianluca Rossetti +7 more
Incretin-based pharmacotherapies, including GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists, have transformed obesity management by producing substantial weight loss through appetite suppression, reduced energy intake, and gastrointestinal effects. These mechanisms may also modify dietary intake, gastrointestinal physiology, and weight-loss-related metabolic adaptations, raising concern about micronutrient disturbances during long-term treatment.
Orforglipron for the treatment of moderate-to-severe obstructive sleep apnea in adults with obesity or overweight: Study design and baseline characteristics of ATTAIN-OSA, a phase 3 trial.
Contemp Clin Trials Commun
Atul Malhotra, Daniel J Gottlieb, Vaishnavi Kundel +4 more
Obstructive sleep apnea (OSA) is highly prevalent, yet current treatment remains limited. Poor adherence to positive airway pressure (PAP) and barriers associated with injectable therapies can limit potential therapeutic options for moderate-to-severe OSA. The SURMOUNT-OSA trials demonstrated that tirzepatide contributes to OSA severity improvements; however, the injectable mode of administration introduces barriers that may limit accessibility and long-term adherence. Orforglipron, a once daily oral glucagon-like-peptide-1 receptor agonist, may offer a more feasible and accepted therapeutic option. ATTAIN-OSA was developed to evaluate the efficacy and safety of oral orforglipron in adults with moderate-to-severe OSA.
Evaluation of the Clinical Effectiveness and Cost-Effectiveness of Tirzepatide for Type 2 Diabetes in Canada Using Bayesian Transportability Analysis.
Value Health Reg Issues
Rebecca K Metcalfe, Yichen Yan, Shomoita Alam +4 more
To estimate the clinical and cost-effectiveness of tirzepatide in Canada using transportability analysis.
Assessing the risk of diabetic retinopathy progression with GLP-1 receptor agonists: a systematic review and meta-analysis.
BMC Ophthalmol
Qian Yang, Waseem Hassan, Hammad Ahmed +1 more
Diabetic retinopathy (DR) is a significant cause of vision impairment in patients with diabetes. The impact of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on the progression of DR remains unclear. This systematic review and meta-analysis aimed to evaluate the association between GLP-1RA therapy and DR progression.
Change in circulating irisin level and its association with lipid metabolism after exenatide treatment in patients with type 2 diabetes mellitus.
J Clin Transl Endocrinol
Yuting Gao, Xiaoyu Hong, Kun Yang +5 more
Irisin is a metabolism-related myokine associated with lipid metabolism and insulin resistance. However, its changes during glucagon-like peptide-1 (GLP-1) receptor agonist therapy remain unclear.
Brain protein burden is related to intravoxel incoherent motion: PET-MR imaging study.
Front Neurosci
Dimuthu Hemachandra, Kevin Zheng, Sara A Lorkiewicz +7 more
Dysfunction in brain protein clearance mechanisms is thought to contribute to many neurodegenerative diseases, yet non-invasive assessment of these mechanisms in humans remains challenging. This study is the first to examine whether intravoxel incoherent motion (IVIM) diffusion MRI metrics, measures of water diffusion and fluid dynamics, are associated with pathological protein accumulation and cognition in aging individuals, and hence whether they serve as a proxy for brain waste clearance function.
Neutrophils From Aged Individuals Release NETs to Impair Oral Wound Healing Through NLRP3 Activation.
Oral Dis
Dongyang Wang, Fuwei Bai, Zhanqi Wang +7 more
This study aimed to investigate the mechanisms underlying impaired oral wound healing in aged individuals, with a focus on the roles of neutrophil extracellular traps (NETs) and NLRP3 inflammasome activation.
Cardiac characteristics of Chinese patients with Danon disease associated with LAMP2 p.Leu325fs variants.
Int J Cardiol Heart Vasc
Kunlun Yin, Yuanming Li, Huazheng Zhao +6 more
This study characterized the clinical and genetic features of Danon disease (DD), focusing on participants harboring LAMP2 frameshift variants at the 325th amino acid position (p.Leu325fs), and explored their cardiac implications. These frameshift variants result in loss of functional LAMP2 protein through premature termination, thereby impairing lysosomal function. Although the association between LAMP2 variants and DD is established, the cardiac phenotype specifically associated with p.Leu325fs variants remains incompletely characterized.
Admission NT-proBNP provides stronger prognostic discrimination than the AHEAD score for 1-year mortality in hospitalized acute heart failure: A retrospective cohort study.
PLoS One
Duc Khanh Nguyen, Thanh Tuan Tran, Van Sy Hoang
Both admission N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the AHEAD score predict prognosis in acute heart failure, but their comparative and complementary value for admission risk stratification remains uncertain.