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摘要： GLP-1 receptor agonists have emerged as key pharmacological tools in the treatment of type 2 diabetes and obesity. While their anorexigenic effects are well characterized, the mechanisms by which GLP-1 modulates pancreatic beta-cell function remain only partially understood. In this article, we argue that GLP-1 receptor agonists should be viewed as integrative regulators of beta-cell function and explore the multifaceted actions of GLP-1 analogs on beta-cell signaling. GLP-1 influences key secretagogues and intracellular mediators (calcium, glutamate, gamma-aminobutyric acid, serotonin, and urocortin-3), with complex roles in insulin exocytosis. Additionally, we discuss the interplay between calcium and cAMP, and how GLP-1 modulates both pathways to coordinate insulin secretion. Emerging evidence suggests that GLP-1 analogs affect mitochondrial morphology and redox homeostasis. Considering the relatively low expression of classical antioxidant enzymes in beta-cells, and their reliance on both glycolytic and mitochondrial metabolism to sustain insulin secretion, the influence of GLP-1 on mitochondrial dynamics and reactive oxygen species may play a central role in sustaining cell function and viability. Despite recent advances, critical gaps persist in the literature, particularly regarding organelle cross talk, intracellular calcium stores, and the modulation of vesicular content. Drawing on current evidence, we propose that three mechanistic dimensions (intracellular neurotransmitters, mitochondrial remodeling, and redox control) represent key areas where clarifying GLP-1 actions could most effectively advance the field. Further investigation into these mechanisms is essential for a comprehensive understanding of GLP-1 actions in beta-cells. This knowledge may help refine current incretin-based therapies and identify novel molecular targets for the treatment of metabolic *** Highlights GLP-1 and its analogs enhance insulin secretion, but the specific

摘要： Aggressive B-cell lymphomas, driven by MYC overexpression, exhibit rapid progression, resistance to therapies, and poor survival. While chimeric antigen receptor (CAR)-engineered T cells have demonstrated remarkable clinical efficacy in B-cell lymphomas, nearly half of patients who initially respond to CAR-T therapy eventually develop resistance and disease progression. In this study, we report the presence of residual drug-tolerant persister (DTP) and resistant lymphoma cells remaining within a highly immunogenic tumor microenvironment (TME) induced by the MCL-1 inhibitor (MCL-1i) S63845. MCL-1 inhibition downregulates MYC and activates the STAT1-interferon inflammatory pathway, promoting cytotoxic T-cell infiltration with reduced tumor-associated myeloid cells both in vitro and in vivo. Sublethal dose of the MCL-1i enhances TME immunogenicity and reawakens anti-tumor immune responses in murine models. We show that MCL-1i and CD19-targeted CAR-T cells reciprocally overcome resistance to each single-agent therapy, and combining MCL-1i with CD19 CAR-T cells significantly improves treatment efficacy, resulting in near-complete eradication of MYC-driven lymphoma in vivo. Together, these findings highlight a synergistic, dual-pronged therapeutic strategy targeting both tumor-intrinsic survival pathways and the immunosuppressive TME. This combinatorial one-two-punch approach offers a promising path to eliminate DTP and residual disease, prevent relapse and pave the way for deep clinical remissions in aggressive B-cell lymphomas.

关键词： colon cancer   noncoding RNA   nuclear factor-kappa B   rectal cancer   transforming growth factor-beta 1  

摘要： This study aimed to explore the clinical significance and potential mechanisms of the transforming growth factor- beta 1 (TGF-beta 1)/small mother against decapentaplegic (SMAD) and nuclear factor kappa B (NF-kappa B) pathways in colorectal cancer (CRC). Transcriptomic and clinical data of CRC patients were retrieved from TCGA and GEO databases, analyzed via TCGAbiolinks, GEPIA 2, KEGG, and GO. A total of 275 colon cancer and 92 rectal cancer samples were included. Results showed T beta R2 and SMAD2 expression was significantly associated with CRC pathological stage (P < 0.05), while low TGF-beta 1, T beta R1, and T beta R2 expression correlated with longer disease-free survival (DFS, P < 0.05). Pathway component correlations differed between normal and cancerous tissues;high co-expression of NF-kappa B1 and SMAD2 linked to longer DFS in rectal cancer (P < 0.05). Signal transducer and activator of transcription 3 (STAT3) strongly correlated with NF-kappa B1, SMAD2/4 (R = 0.7, 0.63, 0.65;P < 0.001), and combinations of NF-kappa B1 with SMAD2/SMAD4 showed strong correlations with STAT3 (R = 0.73;P < 0.001). NF-kappa B1 combined with SMAD2 has prognostic value for rectal cancer, and STAT3 may be a common upstream transcription factor regulating both pathways.

关键词： Anti-apoptotic   Anti-oxidant   Heme oxygenase-1   Ischemia reperfusion injury   reperfusion injury Kelch-Like ECH-associated protein 1   Metformin   NF-E2-Related factor 2  

摘要： Objective(s): This study aimed to investigate the effect of metformin on testicular ischemia-reperfusion (I/R) injury in rats. Materials and Methods: Eighteen male SD rats were randomly divided into three groups: Sham group, I/R group, and Metformin (Met) group (n=6 per group). The I/R model was established by rotating the left testis 720 degrees clockwise and fixing it for 1 hr, followed by reperfusion for 4 hr. Rats in the Met group were intraperitoneally injected with 300 mg/kg metformin for 30 min before reperfusion. In contrast, the Sham group underwent a similar surgical procedure without testicular rotation. Histopathological examination, biochemical assays (MDA and SOD), TUNEL assay for germ cell apoptosis, and Western blot analysis for Nrf2, HO-1, and Keap1 protein expressions were performed. Results: Compared with the Sham group, the I/R group exhibited severe testicular tissue damage, including seminiferous tubule atrophy, disordered spermatogenic epithelium, increased MDA levels, decreased SOD activity, elevated germ cell apoptosis index, up-regulated Nrf2 and HO-1 expressions, and down-regulated Keap1 expression. In contrast, pretreatment with metformin in the Met group significantly ameliorated these pathological changes, as evidenced by improved testicular histology, reduced MDA concentration, increased SOD activity, decreased apoptosis, and reversal of the expression of Nrf2, HO-1, and Keap1 compared with the I/R group. Conclusion: These results indicate that metformin exerts a protective effect against testicular I/R injury, which may be associated with its anti-oxidant, anti-apoptotic properties, and regulation of the Nrf2/ HO-1pathway.

关键词： transition to adult care   transitional care   type I diabetes mellitus   young adult  

摘要： Aims Globally, the incidence of Type 1 Diabetes Mellitus (T1DM) is increasing, with a growing number of adolescents with T1DM transitioning from paediatric to adult healthcare. Whilst this transition is known to be a high-risk period, few studies incorporate the patient perspective into service design. The aim of this study is to determine what is currently known about the experiences of T1DM healthcare transition for young people and synthesise these perspectives to better facilitate the inclusion of the patient perspective into future service design and *** A systematic review of qualitative studies was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Studies were included if (1) participants were between the ages of 18-30 with T1DM, who had begun or completed the transition to adult care;and (2) they reported qualitative data from the patient perspective. Quality assessment was undertaken using the Critical Appraisal Skills Program (CASP) checklist for qualitative research. Reflexive thematic analysis, according to Braun and Clarke, was used to integrate and synthesise the *** A total of 690 citations were obtained through database searching, and 45 studies met the eligibility criteria. Three themes were identified: (i) Shifting the gears of responsibility, (ii) Coordinated care to bridge the limbo, and (iii) Owning diabetes self-management as a young *** For young adults, successful transition involves continuous care with trusted providers who support a holistic approach to management. To ensure young adults with T1DM stay connected within healthcare, their experiences and perspectives should be incorporated into the design of transitional care models.

关键词： Medial prefrontal cortex   CaMKII alpha   Cannabinoid receptor 1   Sex differences   Pain  

摘要： Patients suffer greatly from neuropathic pain, and pharmacological therapies usually prove insufficient. Although the causes are yet unknown, sex differences in reaction to analgesics help to explain poor outcomes. Cannabinoid-based treatments are more effective in female patients, although the reasons are not well understood. The ventrolateral periaqueductal gray (vlPAG) is a crucial node in the descending pain inhibitory system. Our previous research shows that the GABA-vGlut2 inhibitory circuitry in the vlPAG regulates vGlut2 neuron activity in a sex-specific manner to modulate cannabinoid analgesia. However, it remains unknown whether this circuitry is regulated by upstream neurons. This study identified CaMKII alpha neurons in the upstream medial prefrontal cortex (mPFC) that control vlPAGGABA. Deleting cannabinoid receptor 1 (CB1R) in this pathway causes severe pain in female mice and diminishes vlPAGvGlut2 inhibition, leading to overall output. These results clarify CB1R's function in the mPFCCaMKII alpha-vlPAGGABA-vlPAGvGlut2 circuit, shedding light on sex-specific cannabinoid analgesia and providing a basis for developing more potent analgesics for both sexes.

关键词： Fundus image   Image enhancement   Wavelet transform   Attention mechanism  

摘要： High-quality fundus images provide essential anatomical information for clinical screening and ophthalmic disease diagnosis. Yet, due to hardware limitations, operational variability, and patient compliance, fundus images often suffer from low resolution and signal-to-noise ratio. Recent years have witnessed promising progress in fundus image enhancement. However, existing works usually focus on restoring structural details or global characteristics of fundus images, lacking a unified image enhancement framework to recover comprehensive multi-scale information. Moreover, few methods pinpoint the target of image enhancement, e.g., lesions, which is crucial for medical image-based diagnosis. To address these challenges, we propose a multi-scale target-aware representation learning framework (MTRL-FIE) for efficient fundus image enhancement. Specifically, we propose a multi-scale feature encoder (MFE) that employs wavelet decomposition to embed both low-frequency structural information and high-frequency details. Next, we design a structure-preserving hierarchical decoder (SHD) to fuse multi-scale feature embeddings for real fundus image restoration. SHD integrates hierarchical fusion and group attention mechanisms to achieve adaptive feature fusion while retaining local structural smoothness. Meanwhile, a target-aware feature aggregation (TFA) module is used to enhance pathological regions and reduce artifacts. Experimental results on multiple fundus image datasets demonstrate the effectiveness and generalizability of MTRL-FIE for fundus image enhancement. Compared to state-of-the-art methods, MTRL-FIE achieves superior enhancement performance with a more lightweight architecture. Furthermore, our approach generalizes to other ophthalmic image processing tasks without supervised fine-tuning, highlighting its potential for clinical applications. The code and models will be made publicly available at https://***/RyanWu31/MTRL-FIE.