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Purpose The overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC. Experimental design The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to compare their responses to cisplatin. The T24 cancer cells exhibited the lowest sensitivity to cisplatin and was therefore selected to explore the mechanisms of drug resistance. We performed genome-wide CRISPR screening in T24 cancer cells in vitro, and identified that the gene heterogeneous nuclear ribonucleoprotein U (HNRNPU) was the top candidate gene related to cisplatin resistance. Epigenetic and transcriptional profiles of HNRNPU-depleted cells after cisplatin treatment were analyzed to investigate the relationship between HNRNPU and cisplatin resistance. In vivo experiments were also performed to demonstrate the function of HNRNPU depletion in cisplatin sensitivity. Results Significant correlation was found between HNRNPU expression level and sensitivity to cisplatin in bladder cancer cell lines. In the high HNRNPU expressing T24 cancer cells, knockout of HNRNPU inhibited cell proliferation, invasion, and migration. In addition, loss of HNRNPU promoted apoptosis and S-phase arrest in the T24 cells treated with cisplatin. Data from The Cancer Genome Atlas (TCGA) demonstrated that HNRNPU expression was significantly higher in tumor tissues than in normal tissues. High HNRNPU level was negatively correlated with patient survival. Transcriptomic profiling analysis showed that knockout of HNRNPU enhanced cisplatin sensitivity by regulating DNA damage repair genes. Furthermore, it was found that HNRNPU regulates chemosensitivity by affecting the expression of neurofibromin 1 (NF1). Conclusions Our study demonstrated that HNRNPU expression is associated with cisplatin sensitivity in bladder urothelial carcinoma cells. Inhibition of HNRNPU could be a potential therapy for cisplatin-resistant bladder cancer.

Protein phosphorylation is an important post‐transcriptional modification involving an extremely wide range of intracellular signaling transduction pathways, making it an important therapeutic target for disease intervention. At present, numerous drugs targeting protein phosphorylation have been developed for the treatment of various diseases including malignant tumors, neurological diseases, infectious diseases, and immune diseases. In this review article, we analyzed 303 small‐molecule protein phosphorylation kinase inhibitors (PKIs) registered and participated in clinical research obtained in a database named Protein Kinase Inhibitor Database (PKIDB), including 68 drugs approved by the Food and Drug Administration of the United States. Based on previous classifications of kinases, we divided these human protein phosphorylation kinases into eight groups and nearly 50 families, and delineated their main regulatory pathways, upstream and downstream targets. These groups include: protein kinase A, G, and C (AGC) and receptor guanylate cyclase (RGC) group, calmodulin‐dependent protein kinase (CaMK) group, CMGC [Cyclin‐dependent kinases (CDKs), Mitogen‐activated protein kinases (MAPKs), Glycogen synthase kinases (GSKs), and Cdc2‐like kinases (CLKs)] group, sterile (STE)‐MAPKs group, tyrosine kinases (TK) group, tyrosine kinase‐like (TKL) group, atypical group, and other groups. Different groups and families of inhibitors stimulate or inhibit others, forming an intricate molecular signaling regulatory network. This review takes newly developed new PKIs as breakthrough point, aiming to clarify the regulatory network and relationship of each pathway, as well as their roles in disease intervention, and provide a direction for future drug development. Human protein phosphorylation kinases were divided into eight groups and nearly 50 families, and delineated their main regulatory pathways, upstream and downstream targets. We analyzed more than 300 small‐molecule protein phosphorylation inhibitors listed by Food and Drug Administration or in clinical research for classification, generalization, and analysis. This review takes newly developed drugs as entry point, aiming to clarify the regulatory network and relationship of each pathway, as well as their roles in disease intervention, and provide a direction for future drug development.

Despite the success of targeted therapies in cancer treatment, therapy-induced resistance remains a major obstacle to a complete cure. Tumor cells evade treatments and relapse via phenotypic switching driven by intrinsic or induced cell plasticity. Several reversible mechanisms have been proposed to circumvent tumor cell plasticity, including epigenetic modifications, regulation of transcription factors, activation or suppression of key signaling pathways, as well as modification of the tumor environment. Epithelial-to-mesenchymal transition, tumor cell and cancer stem cell formation also serve as roads towards tumor cell plasticity. Corresponding treatment strategies have recently been developed that either target plasticity-related mechanisms or employ combination treatments. In this review, we delineate the formation of tumor cell plasticity and its manipulation of tumor evasion from targeted therapy. We discuss the non-genetic mechanisms of targeted drug-induced tumor cell plasticity in various types of tumors and provide insights into the contribution of tumor cell plasticity to acquired drug resistance. New therapeutic strategies such as inhibition or reversal of tumor cell plasticity are also presented. We also discuss the multitude of clinical trials that are ongoing worldwide with the intention of improving clinical outcomes. These advances provide a direction for developing novel therapeutic strategies and combination therapy regimens that target tumor cell plasticity.

Hypertension is one of the major risk factors for morbidity and mortality worldwide. In this study, Mendelian randomization was utilized to investigate how dietary supplement intake can impact hypertension based on circulating plasma metabolite genome-wide association study (GWAS) datasets, protein quantitative trait loci (pQTLs) of plasma proteins, and multiple public summary-level GWAS data. Pathway enrichment analysis combined with the results of inverse variance weighted Mendelian randomization revealed that a lower risk of hypertension was associated with the dietary intake of glucosamine, an anti-inflammatory supplement: odds ratio (OR) (95% CI): 0.888 (0.824–0.958). Additionally, glucosamine 6-phosphate N-acetyltransferase was identified as a protective factor against hypertension, OR (95% CI): 0.995 (0.992–0.998), shedding light on the potential protective mechanism of glucosamine. Mediation Mendelian randomization indicated that the protective effect of glucosamine metabolism was mediated by glutaminyl-peptide cyclotransferase, with a mediation proportion of 12.1% (5.9–18.2%), p < 0.05. This study offers new insights into preventive strategies for individuals with hypertension risk.

Coal flow in belt conveyors is often mixed with foreign objects, such as anchor rods, angle irons, wooden bars, gangue, and large coal chunks, leading to belt tearing, blockages at transfer points, or even belt breakage. Fast and effective detection of these foreign objects is vital to ensure belt conveyors’ safe and smooth operation. This paper proposes an improved YOLOv5-based method for rapid and low-parameter detection and recognition of non-coal foreign objects. Firstly, a new dataset containing foreign objects on conveyor belts is established for training and testing. Considering the high-speed operation of belt conveyors and the increased demands for inspection robot data collection frequency and real-time algorithm processing, this study employs a dark channel dehazing method to preprocess the raw data collected by the inspection robot in harsh mining environments, thus enhancing image clarity. Subsequently, improvements are made to the backbone and neck of YOLOv5 to achieve a deep lightweight object detection network that ensures detection speed and accuracy. The experimental results demonstrate that the improved model achieves a detection accuracy of 94.9% on the proposed foreign object dataset. Compared to YOLOv5s, the model parameters, inference time, and computational load are reduced by 43.1%, 54.1%, and 43.6%, respectively, while the detection accuracy is improved by 2.5%. These findings are significant for enhancing the detection speed of foreign object recognition and facilitating its application in edge computing devices, thus ensuring belt conveyors’ safe and efficient operation.

Coal gangue identification is the primary step in coal flow initial screening, which mainly faces problems such as low identification efficiency, complex algorithms, and high hardware requirements. In response to the above, this article proposes a new “hardware friendly” coal gangue image recognition algorithm, RRBM-YOLO, which is combined with dark light enhancement. Specifically, coal gangue image samples were customized in two scenarios: normal lighting and simulated underground lighting with poor lighting conditions. The images were preprocessed using the dim light enhancement algorithm Retinexformer, with YOLOv8 as the backbone network. The lightweight module RepGhost, the repeated weighted bi-directional feature extraction module BiFPN, and the multi-dimensional attention mechanism MCA were integrated, and different datasets were replaced to enhance the adaptability of the model and improve its generalization ability. The findings from the experiment indicate that the precision of the proposed model is as high as 0.988, the mAP@0.5(%) value and mAP@0.5:0.95(%) values increased by 10.49% and 36.62% compared to the original YOLOv8 model, and the inference speed reached 8.1GFLOPS. This indicates that RRBM-YOLO can attain an optimal equilibrium between detection precision and inference velocity, with excellent accuracy, robustness, and industrial application potential.

Bioactive peptides isolated from marine organisms have shown to have potential anti-inflammatory effects. This study aimed to investigate the intestinal protection effect of low molecular peptides (Mw < 1 kDa) produced through enzymatic hydrolysis of tuna processing waste (tuna bioactive peptides (TBP)) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in BALB/c mice. Here, we randomly divided twenty-four male BALB/c mice into four groups: (i) normal (untreated), (ii) DSS-induced model colitis, (iii) low dose TBP+DSS-treated (200 mg/kg/d), and (iv) high dose TBP+DSS-treated groups (500 mg/kg/d). The results showed that TBP significantly reduced mice weight loss and improved morphological and pathological characteristics of colon tissues. In addition, it increased the activities of antioxidant enzymes (SOD and GSH-Px) and decreased inflammatory factors (LPS, IL-6, and TNF-α) expression. TBP increased the gene expression levels of some tight junction (TJ) proteins. Moreover, TBP increased the short-chain fatty acids (SCFAs) levels and the diversity and imbalance of intestinal flora. Therefore, TBP plays some protective roles in the intestinal tract by enhancing antioxidant and anti-inflammatory abilities of the body, improving the intestinal barrier and metabolic abnormalities, and adjusting intestinal flora imbalance.

Clear cell renal cell carcinoma (KIRC) is the most aggressive renal carcinoma subtype of renal carcinoma, characterized by high mortality, early metastasis, and resistance to treatment. Ammonia-induced cell death (AICD) has recently been identified as a novel metabolic mechanism influencing tumor progression, yet its prognostic implication and regulatory networks in KIRC remain underexplored. Transcriptomic and clinical information from the TCGA-KIRC cohort and the validation cohort (E-MTAB-1980) were analyzed. Differentially expressed AICD-related genes were identified through differential expression analysis, univariate Cox regression, and machine learning algorithms (LASSO, random forest, and CoxBoost). A prognostic risk model was developed via multivariate Cox regression. Spatial and single-cell transcriptomics were employed to characterize the immune microenvironment heterogeneity. Cell-based experiments were performed to investigate the potential involvement of in KIRC. Molecular docking and pan-cancer analyses were conducted to identify therapeutic candidates and ATP1A1-related mechanisms. Five AICD-related genes ( , , , , and ) were identified and selected to construct a risk score model. The model demonstrated high accuracy and was integrated into a nomogram for clinical application. High-risk (HR) patients exhibited immunosuppressive microenvironments, elevated tumor mutational burden (TMB), and genomic instability. functional assays confirmed that knockdown significantly enhanced the proliferative, migratory, and invasive capabilities of renal carcinoma cells (A498 and 786-O), suggesting a suppressive role for in malignant tumor progression. , a core gene, was associated with metabolic reprogramming and chemotherapy sensitivity across multiple cancers. Molecular docking revealed Emodinanthrone as a high-affinity ligand for (-6.8 kcal/mol). This study identifies an AICD-associated gene signature as a robust prognostic tool for KIRC, revealing its interactions with immune evasion and genomic instability. is proposed as a promising therapeutic target, with Emodinanthrone emerging as a novel drug candidate. These findings contribute to the advancement of personalized treatment strategies for KIRC patients.

To explore the mechanism by which Astragalus membranaceus and Salvia miltiorrhiza (AS) regulates the “metabolic- transcriptional” co-expression network to improve Hypertensive renal damage (HRD). Spontaneously hypertensive rats (SHRs) were used to establish the model of HRD. The structure and function of the kidney were observed following AS intervention. We identified various metabolites in the kidneys using UHPLC-MS/MS and observed renal mRNA expression through RNA sequencing. The “metabolism-transcription” coexpression network was further constructed, and the target metabolites and target genes of AS were ultimately screened and validated. AS significantly reduced blood pressure, improved renal function and alleviated renal pathological damage in SHRs. A total of 596 target mRNAs of AS were identified. Of note, 254 of these mRNAs were expressed in 25 pathways that were closely related to metabolic processes. Additionally, the target metabolites of AS were determined, predominantly enriched in 8 pathways, including linoleic acid metabolism, cholesterol metabolism, choline metabolism in cancer, and the synthesis and degradation of ketone bodies, etc. In addition, the target metabolites and target mRNAs of AS were co-enriched in 3 specific pathways of linoleic acid metabolism, cholesterol metabolism, taurine and hypotaurine metabolism, involving 7 different metabolites and 18 differentially expressed (DE) mRNAs. The 7 metabolites exhibited high AUC prediction values, and the verification and sequencing results of the 4 genes were basically consistent. Conclusion The mechanisms by which AS improves HRD may be closely related to the regulation of linoleic acid metabolism, cholesterol metabolism and taurine and hypotaurine metabolism pathways as well as the relevant target genes.

Despite N6-methyladenosine (m6A) is functionally important in various biological processes, its role and the underlying regulatory mechanism in the liver remain largely unexplored. In the present study, we showed that fat mass and obesity-associated protein (FTO, an m6A demethylase) was involved in mitochondrial function during hepatic ischemia–reperfusion injury (HIRI). We found that the expression of m6A demethylase FTO was decreased during HIRI. In contrast, the level of m6A methylated RNA was enhanced. Adeno-associated virus-mediated liver-specific overexpression of FTO (AAV8-TBG-FTO) ameliorated the HIRI, repressed the elevated level of m6A methylated RNA, and alleviated liver oxidative stress and mitochondrial fragmentation in vivo and in vitro. Moreover, dynamin-related protein 1 (Drp1) was a downstream target of FTO in the progression of HIRI. FTO contributed to the hepatic protective effect via demethylating the mRNA of Drp1 and impairing the Drp1-mediated mitochondrial fragmentation. Collectively, our findings demonstrated the functional importance of FTO-dependent hepatic m6A methylation during HIRI and provided valuable insights into the therapeutic mechanisms of FTO.