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.
AIM:The purpose of this paper is to examine the acute and nocturnal glycaemic response to morning fasted, fed or afternoon fed resistance exercise in people with type 1 diabetes. METHODS:In a crossover RCT, people with type 1 diabetes performed three acute bouts of resistance exercise in (1) morning (8 AM-10:30 AM) in a fed state, (2) morning (8 AM-10:30 AM) in a fasted state and (3) afternoon (3-8 PM) in a fed state, with interstitial glucose levels measured 6-h post-exercise and in the nocturnal period (11 PM-6 AM). RESULTS:In all participants (n = 66), mean glucose levels were lower in the 6-h period after afternoon fed versus morning fasted resistance exercise (9.46 ± 2.56 vs. 8.65 ± 2.04 mmol/L, P = 0.04), with no other differences noted. In multiple daily injections (MDI), users (n = 47), but not insulin pump users (n = 19), in the 6-h period post-exercise mean glucose levels were higher (9.63 ± 2.58 vs. 8.44 ± 1.93 mmol/L, P = 0.007), time-in-range (3.9-10.0 mmol/L) lower (50.9 ± 29.5% vs. 67.0 ± 27.6%, P = 0.007) and time above range (> 10.0 mmol/L) higher (44.4 ± 32.1% vs. 26.3 ± 25.3%, P = 0.003) in morning fasted versus afternoon fed state; no other differences were noted. CONCLUSION:Resistance exercise timing and feeding status (fed vs. fasted) independently influence post-exercise glycaemic responses in people with type 1 diabetes. Performing resistance exercise in the afternoon under fed conditions was associated with a more favourable glucose profile, particularly among MDI users. These findings indicate that consideration of both time of day and feeding status is important when optimising resistance exercise prescription in this population. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT05884814 (Registered on 10 May 2023).
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.
This study aimed to evaluate the preparedness of diabetes educators (DEs) to support the use of MiniMed™ 780G in clinical practice, identifying knowledge gaps, onboarding barriers, success factors, and regional variations to inform a standardized training pathway for type 1 diabetes mellitus (T1DM) care. A cross-sectional, multiregional survey was conducted among 82 DEs from Africa, the Arabian Peninsula (Gulf States), Central and Eastern Europe, Türkiye, and Central Asia (June–July 2025). The questionnaire, adapted from a validated Delphi-derived tool, assessed knowledge and confidence, training challenges, success factors, educational needs, and professional development. Responses were collected using Likert scales, multiple-choice, and free-text fields. Quantitative data were analyzed descriptively, with graphics generated in Excel. Item-level missing data were handled by listwise deletion; all 82 participants completed the survey (100
The rapid evolution of generative and diffusion-based method in artificial intelligence (AI) has transformed de novo peptide and protein design, enabling the creation of sequence–structure–function relationships beyond conventional heuristic exploration. In this work, we developed an AI-guided molecular design pipeline that integrates diffusion-based generative modeling, inverse folding algorithms, and atomistic simulation to design and evaluate novel peptide inhibitors of the LasR quorum-sensing receptor of Pseudomonas aeruginosa. Peptides were generated using multiple complementary AI frameworks, including DiffPepBuilder (a diffusion-based denoising generator), ProteinMPNN (an inverse folding network), RFdiffusion2, Evobind2, and BindCraft (a hybrid sequence–structure generative model). These peptides were then subjected to physicochemical profiling and molecular docking to estimate binding affinities (Kd) and interface complementarity. The top candidates were subjected to 400 ns all-atom molecular dynamics (MD) simulations, performed in triplicate, to assess stability, flexibility, and interaction persistence, and were compared against the experimentally validated peptides benchmark. Post-simulation metrics, including RMSD, RMSF, and radius of gyration (Rg), revealed reproducible but architecture-specific dynamic behaviors, with BindCraft 4 maintaining the most compact and stable configuration, exhibiting minimal fluctuations and consistent binding-site retention. MMGBSA, performed at different time intervals, revealed strong van der Waals and electrostatic stabilization, correlating with sub-micromolar dissociation constants predicted computationally. In contrast, DiffPepBuilder 1–2 exhibited balanced flexibility and moderate stabilization, while ProteinMPNN 2 and the control (Aqs1C) displayed comparatively weaker energetic convergence. Principal Component Analysis (PCA) and Free Energy Landscape (FEL) projections confirmed that BindCraft 4 sampled a single deep energy basin, signifying a thermodynamically optimized conformational state. Collectively, this integrative AI-simulation hybrid computational framework demonstrates the capability of generative diffusion and inverse folding models to design peptides with superior structural stability and binding thermodynamics, offering a rational framework for AI-driven peptide therapeutics targeting Pseudomonas aeruginosa communication networks.
