Matrix metalloproteinase 9 (MMP-9) plays a key role in the pathogenesis of inflammatory diseases and is upregulated by TNF-α. ITE (2-[1'H-indole-3'-carbonyl]-thiazole-4-carboxylic acid methyl ester) functions as an endogenous ligand for the aryl hydrocarbon receptor and is involved in inflammation. It is still uncertain whether ITE could affect TNF-α-induced MMP-9 expression in monocytic cells. In this study, we explored the effect of ITE on TNF-α-induced MMP-9 expression and the underlying mechanisms involved. Our results show that pretreatment of THP-1 monocytic cells with ITE significantly blocked TNF-α-induced MMP-9 expression at both the mRNA and protein secretion levels. Similar results were seen in primary human monocytes. The inhibition of MMP-9 by ITE occurs independently of TNFR1/2 modulation and apoptotic processes. RNA transcription data revealed that ITE suppresses the genes associated with inflammatory pathways. Mechanistically, histone modification profiling identified H3K9 acetylation as an epigenetic regulatory mark of TNF-α-induced MMP-9 expression. ChIP-qPCR data revealed that ITE pretreatment decreased TNF-α-triggered transcriptionally permissive acetylation marks at H3K9 in the MMP-9 promoter. Pharmacological inhibition of histone acetylation mimics the action of ITE in suppressing TNF-α-induced MMP-9 gene expression. Conversely, the acetylation induced by trichostatin A effectively reverses the inhibitory action of ITE. Moreover, increased TNF-α-induced binding of NF-κB or AP-1 at the MMP-9 promoter region was inhibited by ITE, resulting in suppression of MMP-9 gene expression. In conclusion, our study demonstrates that ITE reduces the TNF-α-induced MMP-9 expression via the H3K9 acetylation/NF-κB/AP-1 axis, highlighting a potential mechanism for mitigating MMP-9-related inflammatory disorders.
The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that is essential for glucose homeostasis, energy balance and appetite. GLP-1R is a key therapeutic target for the treatment of type 2 diabetes and obesity, owing to its central role in insulin secretion, glucagon suppression, and body weight regulation. Increasing evidence suggests that genetic polymorphisms in GLP-1R can influence the expression of the receptor, ligand binding, and downstream signalling processes, thereby affecting individual responses to GLP-1R agonists. Understanding these variants is essential for advancing precision medicine, as inter-individual genetic differences can influence both therapeutic efficacy and susceptibility to adverse events. This review highlights the current knowledge on GLP-1R polymorphisms, with particular focus on their structural and functional consequences and their potential clinical implications.
Overweight and obesity have emerged as global health crises and are increasingly recognized as drivers of central nervous system (CNS) dysfunction. Beyond excess energy storage, white adipose tissue (WAT) functions as an active endocrine and immune organ that, during obesity, undergoes inflammatory remodeling and releases cytokines, lipid mediators, adipokines, and extracellular vesicles that influence brain physiology. These peripheral signals disrupt key brain interfaces, including the blood-brain barrier (BBB), perivascular and glymphatic clearance pathways, promoting endothelial dysfunction, altered astrocyte-pericyte support, impaired amyloid-β clearance, and region-specific glial activation. Obesity-associated neuroinflammation is characterized by microglial priming and astrocyte reactivity across the hypothalamus, hippocampus, and other circuits governing metabolism, cognition, and reward, with growing evidence for sex-dependent vulnerability. We further highlight adipokines as key mediators of adipose-brain communication. In obesity, leptin resistance impairs central energy regulation, reduced adiponectin contributes to neuroinflammation and synaptic dysfunction, and elevated resistin enhances TLR4-dependent inflammatory signaling and BBB permeability, collectively linking metabolic stress to neurodegenerative processes. Finally, we review therapeutic strategies targeting the adipose-brain axis, including exercise and dietary interventions that improve neuroplasticity and barrier integrity, and pharmacological approaches such as orlistat and incretin-based therapies. Emerging multi-incretin agonists, including tirzepatide and retatrutide, raise important questions regarding direct CNS actions beyond metabolic benefits, underscoring the need to integrate barrier biology and neuroimmune mechanisms in future studies.
This study assessed how individuals’ perceived safety and mental health are associated with novel indicators of micro-neighborhood level exposure to crime- and safety-related stressors. Using data from the Canadian Community Health Survey, respondents’ (n = 1281) perceived safety and self-reported mental health were predicted based on novel indicators of crime and safety produced for the city of Montreal using data from the General Social Survey and the Canadian Census. These micro-neighborhood level indicators, derived using a regression kriging approach, were validated based on indicators of robustness and convergent validity. Nearly all micro-neighborhood crime-related stressors predicted individual-level perceived safety. Only the probability of exposure to perceived social disorder was associated with individual-level self-reported mental health. The estimates of neighborhood exposure were most robust for perceived social disorder, perceived community hospitability, and experiences of violent victimization. Estimated experiences of household victimization, experiences of discrimination, perceived insecurity, and contact with the police were less robust. Micro-neighborhood level exposures to a host of crime- and safety-related stressors are associated with individuals’ perceived safety and mental health, suggesting that a refined scale of analysis and broader scope of the conceptualization of crime and safety stressors is necessary when measuring mental health outcomes.
Introduction Obesity is a global public health issue, with its effects a particular issue in Kuwait. Advances in pharmaceutical treatment (eg, glucagon-like peptide-1s) offer an effective solution, with the magnitude of weight lost something to celebrate. However, this level of weight loss also results in dramatic reductions in lean mass, reflecting loss of muscle mass and muscle strength which can predispose people to sarcopenia. This is a particular issue in people with type 2 diabetes in Kuwait, where the prevalence of muscle weakness is extremely high. Solutions to mitigate this loss of muscle mass and strength are needed, with a pragmatic resistance exercise intervention and increasing dietary protein intake having potential. This trial aims to determine whether resistance exercise and/or protein intake can preserve muscle mass and improve physical function in people with obesity initiating semaglutide/tirzepatide therapy.Methods and analysis This single-centre, 6-month, randomised controlled trial at Dasman Diabetes Institute will enrol 232 adults with obesity, randomised (1:1:1:1) to control, resistance exercise, protein supplementation or combined resistance exercise and protein in conjunction with semaglutide or tirzepatide therapy. Resistance exercise will be home-based and involve three sessions per week, progressing from one to three sets targeting major muscle groups. Protein supplementation will target 1.6 g/kg/day via dietary adjustment and protein products. Assessments at baseline and 6 months will include MRI measured quadriceps cross-sectional area (primary outcome), plus measures of secondary outcomes of MRI measured liver fat content and stiffness and intramuscular fat, body composition (dual energy X-ray absorptiometry), strength, physical function, dietary assessment, physical activity levels, sleep patterns, quality of life, glycaemic control and metabolic biomarkers.Ethics and dissemination The study has received ethical approval from the Dasman Diabetes Institute Ethical Review Committee (HR-RA-2025-01, 19 February 2025) and is registered at ClinicalTrials.gov (NCT06885736, 26 June 2025). Written informed consent will be obtained from all participants, with no financial compensation provided. Data will be reported in accordance with Consolidated Standards of Reporting Trials (CONSORT) guidelines, ensuring participant anonymity. Findings will be disseminated through peer-reviewed publications and presentations at national and international conferences.Trial registration number NCT06885736.
