Biochimica et biophysica acta. Molecular basis of disease最新文献

Bladder cancer remains a major cause of global mortality with limited therapies. Here, we reported that epigenetic regulator EP300 acts as oncogenic role in bladder cancer. Public data show EP300 mutations correlated with better prognosis, while high EP300 expression predicted poor outcomes. Our clinical cohort demonstrated that EP300 expressed higher in tumors rather than adjacent tissues. Functionally, impairing of EP300 decreased both cell viability and organoids growth in bladder cancer cells. The selective EP300 inhibitor A485 similarly reduced bladder cancer cell growth in vitro and in vivo. Long-term treatment of A485 alleviated tumor invasion in a BBN-induced spontaneous bladder cancer mouse model. Bioinformatic analysis evaluated both basal/squamous-like markers and papillary-like markers were decreased in A485 treatment. Furthermore, downregulated genes by A485 are mainly related to cell cycle regulation. Mechanistically, A485 decreased the levels of EP300 and H3K27ac upon MYC enhancer, consequently inhibited MYC expression. Additionally, the MYC inhibitor demonstrated similar effects as A485 to decrease cell viability and organoid growth. Critically, in patient-derived organoids (PDOs), A485 selectively attenuated tumor organoid growth and reduced MKI67⁺ and CD44⁺ cell populations, sparing adjacent normal tissue organoids. Collectively, EP300 promotes bladder cancer progression by sustaining proliferation through MYC regulation, and its inhibitor A485 represents a promising targeted therapeutic candidate.

Delayed healing of diabetic wounds (DW) represents a significant complication among diabetic patients, for which current therapeutic approaches remain suboptimal. Accumulating evidence indicates that fibroblast senescence plays a critical role in the impaired healing of diabetic wounds. Abnormal mitochondrial morphology has long been associated with cellular senescence and age-related pathologies, suggesting that mitochondrial dynamics are compromised during senescence. In this study, we explored the potential mechanisms through which adipose-derived mesenchymal stem cell-derived exosomes (ADSC-Exos) facilitate diabetic wound repair. We initially confirmed the presence of a substantial number of senescent fibroblasts in diabetic wound tissues. Subsequent investigations demonstrated that exosomes derived from adipose-derived stem cells can effectively alleviate fibroblast senescence. In-depth mechanistic analyses revealed that these exosomes suppress the expression of SMARCAL1, a chromatin remodeling protein, thereby enhancing the transcription of mitochondrial dynamin-related protein 1 (Drp1), and ultimately restoring mitochondrial dynamics and alleviating senescence in human dermal fibroblasts (HDFs). In vivo experiments further demonstrated that exosome administration significantly reduced HDFs senescence and accelerated wound healing in a diabetic mouse model. Collectively, our findings suggest that ADSC-Exos promote diabetic wound healing by mitigating HDFs senescence via the SMARCAL1-Drp1-mitochondrial dynamics pathway. This study elucidated the molecular mechanisms underlying exosome-mediated fibroblast senescence rescue and proposed a novel therapeutic strategy for diabetes-related wound management through targeted clearance of senescent cells.

Obesity-driven metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic lipid accumulation and impaired lipid metabolism. Enhancing lipophagy, the autophagic degradation of lipid droplets, represents a promising therapeutic strategy. Sestrin2, a stress-responsive protein, promotes lipophagy via the AMPK/ULK1 pathway. Here, we investigated the role of 12,13-diHOME, a brown adipose tissue-derived lipid, in modulating MASLD via Sestrin2. Male Sesn2 knockout and wild-type mice were fed a high-fat diet (HFD) and treated with 12,13-diHOME. Metabolic parameters, liver histology, and lipophagy-related protein expression were analyzed. 12,13-diHOME improved insulin sensitivity, reduced plasma triglycerides and free fatty acids, and alleviated hepatic steatosis and fibrosis by enhancing lipophagy in wild-type mice. Mechanistically, 12,13-diHOME increased Sestrin2 expression, activated AMPK/ULK1 signaling, inhibited mTOR phosphorylation, and enhanced lipophagic degradation of lipid droplets. These effects were abolished in Sesn2-deficient mice and cells, demonstrating that Sestrin2 is essential for 12,13-diHOME's protective actions. Our findings identify 12,13-diHOME as a potential therapeutic agent for MASLD via Sestrin2-mediated lipophagy.

Hepatocellular carcinoma (HCC) is a prevalent and aggressive liver cancer with limited treatment options and poor prognosis. Glucosamine (GlcN), a widely used dietary supplement, demonstrates anti-inflammatory properties but its antitumor potential in HCC remains unknown. Here, we report that GlcN inhibits HCC cell proliferation and migration in a dose-dependent manner in vitro and suppresses orthotopic tumor growth in vivo. Mechanistically, integrated transcriptomics and functional validation revealed that GlcN induces cell cycle arrest in G0/G1 phase by inhibition of E2F1 transcriptional activity. Untargeted metabolomics identified profound nucleotide metabolism disruption, characterized by adenosine triphosphate (ATP) depletion, and partial reversal via nucleoside rescue. Notably, GlcN potentiates the inhibitory efficacy of lenvatinib both in vitro and in vivo. This synergistic effect was further validated in murine models, with the combined GlcN and lenvatinib treatment showing markedly enhanced HCC suppression than monotherapies. Collectively, our findings suggest GlcN as a potential therapeutic agent for HCC and underscore its chemosensitizing potential when combined with lenvatinib. Given GlcN's established clinical safety, this combination offers a translatable strategy for HCC therapy.

Although liver fibrosis presents a substantial global health challenge, therapeutic options that directly target liver fibrosis remain limited. Hepatic stellate cells (HSCs) are key contributors to fibrosis through extracellular matrix production. This study uncovers a previously unrecognized function of HSCs: ATP secretion. We found that HSCs express the vesicular nucleotide transporter (VNUT) on secretory vesicles and actively release ATP. In mouse HSCs, VNUT is localized to the cytosol and around lipid droplets. In a thioacetamide-induced liver fibrosis model, VNUT inhibition with clodronate suppressed HSC proliferation and fibrosis progression, while restoring AMPK phosphorylation. In human hepatic stellate LX-2 cells, VNUT colocalized with v-SNARE proteins VAMP3 and VAMP7 and the vesicular proton pump V-ATPase. ATP secretion from LX-2 cells was observed upon stimulation with the Ca²⁺ ionophore ionomycin and was inhibited by Ca²⁺ chelation or low temperature, supporting an exocytotic mechanism. Clodronate and VNUT-targeting siRNA significantly reduced ATP release. Thapsigargin, an inducer of endoplasmic reticulum Ca²⁺ release, upregulated VNUT expression, suggesting a transcriptional regulation of VNUT-dependent ATP release by Ca²⁺ signaling. TGF-β1 stimulation also upregulated VNUT expression, suggesting its involvement in TGF-β1-induced fibrogenesis pathway. Additionally, serotonin was identified as an ATP secretion stimulator in LX-2 cells, and this effect was blocked by clodronate. Platelets-a major peripheral serotonin source-were increased in TAA-treated liver and found adjacent to serotonin receptor 5-HT2B-positive HSCs. Clodronate treatment reduced CD41-positive platelets in liver tissue. These findings highlight VNUT-mediated ATP secretion as a key regulator of HSC function and a potential therapeutic target for liver fibrosis.

Dapagliflozin (DAPA) is the first sodium-glucose cotransporter 2 (SGLT2) inhibitor to receive approval for clinical use in China. However, the mechanism behind the cardioprotective effects of DAPA remains unclear, as cardiac tissue does not express SGLT2. This study investigated the efficacy of DAPA in alleviating myocardial ischemia-reperfusion (MIR) injury, independent of its glucose-lowering properties. The findings revealed that DAPA significantly improved cardiac function and decreased ventricular remodeling in a murine model of MIR injury-induced heart failure (HF). Furthermore, bioinformatics and cellular thermal shift assays (CETSAs) revealed that retinoid-related orphan receptor gamma t (RORγt) acts as a specific molecular target. Moreover, DAPA alleviated MIR injury-induced increased cardiac CD4⁺ T cells as well as RORγt, interleukin-17 A (IL-17 A), and CD4 levels in cardiac tissue. This immunomodulatory effect was clinically significant, as proportions of peripheral blood T helper 17 (Th17) cells were significantly decreased in post-acute myocardial infarction (post-AMI) HF patients undergoing DAPA therapy. In conclusion, the study investigated the cardioprotective effects of DAPA, demonstrating that it can modulate the cardiac immune micro-environment via RORγt, which regulates the CD4⁺ T cell/Th17 cell axis within cardiac tissue. These findings offer mechanistic validation for the tissue-specific therapeutic effects of DAPA in the heart, establishing pharmacological regulation of immune metabolic pathways as an innovative precision medicine strategy for HF, and highlighting its translational potential.

HER2 (human epidermal growth factor receptor 2) is a well-established oncogenic driver and therapeutic target in breast cancer. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has demonstrated anticancer potential, yet its mechanisms of action in HER2-positive breast cancer remain insufficiently characterized. In this study, we examined the effects of CBD on HER2-positive (SK-BR-3, BT-474) and HER2-negative (MCF-7, MDA-MB-231) breast cancer cell lines, with a focus on its interaction with HER2. CBD selectively reduced the viability of HER2-positive cells, an effect associated with increased intracellular reactive oxygen species (ROS) and a marked reduction in HER2 protein levels. Mechanistically, CBD triggered non-apoptotic cell death pathways, including paraptosis and ferroptosis, as indicated by the modulation of specific molecular markers such as reduced Alix and elevated ATF4 and CHOP for paraptosis, and downregulated GPX4 and SLC7A11 with upregulated TFRC for ferroptosis. HER2 knockdown attenuated CBD-induced cytotoxicity, while HER2 overexpression sensitized cells to CBD, underscoring the HER2-dependence of these effects. Molecular docking predicts the binding conformation and key interactions of ligand with target proteins providing initial insights into potential molecular recognition. Subsequently, molecular dynamics simulations extend this analysis by assessing the stability, flexibility, and energetic characteristics of the ligand-protein complex within a dynamic biological environment. These findings support a model in which CBD downregulates HER2 and, in a HER2-dependent context, promotes paraptosis and ferroptosis. In addition, docking and molecular dynamics analyses suggested a potential interaction between CBD and HER2, providing mechanistic insights into possible molecular recognition relevant to HER2-positive breast cancer.

While immunotherapy has demonstrated remarkable therapeutic potential in certain malignancies, its overall clinical efficacy remains suboptimal. Emerging evidence indicates that the tumor microenvironment (TME) plays a pivotal role in determining immunotherapy responsiveness, with tumor-associated macrophages (TAMs) - the predominant immune cell population within TME - being closely associated with poor prognosis, metastatic progression, and therapeutic resistance. Traditionally, macrophages are classified into two primary activation states: the pro-inflammatory M1 (classically activated) phenotype and the anti-inflammatory M2 (alternatively activated) phenotype. However, this binary classification system fails to fully capture the functional complexity and phenotypic plasticity of TAMs. This comprehensive review critically examines TAM heterogeneity and explores emerging subtyping paradigms beyond conventional M1/M2 dichotomization. Furthermore, we systematically examine three principal therapeutic strategies: recruitment inhibition, TAM depletion, and phenotypic reprogramming, emphasizing their synergistic potential with existing immunotherapies. These multifaceted approaches provide novel insights for developing combination therapies to overcome current limitations in cancer treatment.

Patients with diabetic nephropathy (DN) often experience negative emotions and a decline in quality of life, conditions in which the neuro-endocrine-immune axis plays a crucial role. In this study, we explored the effects of an eight-week multimodal psychological intervention, incorporating cognitive behavioral therapy, mindfulness meditation, and relaxation training, on DN patients. Ninety participants were randomly assigned to an intervention group, a sham intervention group, or a control group. The sham intervention group received nonspecific contact of equivalent duration, while the control group received routine care only. Psychological outcomes were evaluated using HADS and SF-36 scales, and serum levels of cortisol, CRH, ACTH, IL-6, IL-1β, and TNF-α were measured by enzyme-linked immunosorbent assay. Bioinformatic analyses, including Gene Ontology/Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis and protein-protein interaction network mapping, were employed to identify key molecular mechanisms. Results demonstrated that the intervention group exhibited significant improvements in emotional well-being and quality of life, accompanied by reductions in neuroendocrine hormones and inflammatory cytokines. Bioinformatic data further revealed the central role of IL-6 within the inflammatory regulatory network in DN. These findings suggest that multimodal psychological intervention can effectively improve psychological outcomes and inflammatory profiles in DN patients by targeting the neuro-endocrine-immune axis, with IL-6 acting as a pivotal mediator. This work provides novel evidence supporting the integration of psychological interventions into the management of DN and highlights IL-6 as a potential therapeutic target.

Elderly groups usually have an inflammatory response in their bodies, and neuroinflammation is the main pathogenic mechanism of neurological diseases. Pharmacological and pharmacodynamic experiments showed that aspirin eugenol ester (AEE) had good anti-inflammatory, anti-oxidant and anti-hyperlipidemic effects. However, whether AEE can prevent neurological diseases in the old companion animal has not been explored. In this study, we selected adolescent rats (6 weeks old) and old rats (18 months old) as the experimental animals for two weeks. The transcriptomics and metabolomics methods were used to explore the effects of AEE on the hippocampal region in the brains of old rats. The related indexes were detected. AEE significantly reduced the levels of pro-inflammatory cytokines and oxidative stress in lipopolysaccharide (LPS) induced microglia of rats. AEE significantly increased the duration of swimming observed in the forced swimming test for older rats, but did not have a significant effect between adolescent rats. Hematoxylin and eosin staining (HE) showed that AEE had no significant effects on the kidney and gastrointestinal tract and could improve liver function in old rats. AEE improved genes and metabolites in the hippocampal region of the old rat brain. Comprehensive analysis of transcriptomics and metabolomics showed that the gene Chacna3 was correlated positively with metabolic phosphatidylethanolamine (PE) and phosphatidylcholine (PC), and the genes Tnfsf10 and Cacna1f were correlated positively with metabolic PE and PC and negatively with eicosapentaenoic acid (Epa). AEE could play positive effects on preventing neurological diseases in old companion animal.