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Introduction: It has been found that programmed cell death protein-1 (PD-1) or its ligand PD-L1 may play an important role in the onset and progression of coronary heart disease (CHD). Thus, we conducted this mendelian randomization analysis (MR) to estimate the causal relationship between PD-1/PD-L1 and 5 specific CHDs (chronic ischemic heart disease, acute myocardial infarction, angina pectoris, coronary atherosclerosis, and unstable angina pectoris), complemented by gene set enrichment analysis (GSEA) for further validation., Methods: Publicly available summary-level data were attained from the UK Biobank with genetic instruments obtained from the largest available, nonoverlapping genome-wide association studies (GWAS). Our analysis involved various approaches including inverse variance-weighted meta-analysis, alternative techniques like weighted median, MR-Egger, MR-multipotency residuals and outliers detection (PRESSO), along with multiple sensitivity assessments such as MR-Egger intercept test, Cochran's Q test, and leave-one-out sensitivity analysis to evaluate and exclude any anomalies., Results: Gene expression profile (GSE71226) was obtained from Gene Expression Omnibus (GEO) database for GSEA. IVW analysis showed a causal association between PD-1 and chronic ischemic heart disease (OR, 0.997; 95%CI, 0.995-0.999; P , 0.009), chronic ischemic heart disease and PD-1 (beta, -3.1; 95%CI, -6.017 to -0.183; P , 0.037), chronic ischemic heart disease and PD-L1 (beta, -3.269; 95%CI, -6.197 to -0.341; P , 0.029). No significant causal relationship was found between PD-1/PD-L1 and other 4 CHDs. The accuracy and robustness of these findings were confirmed by sensitivity tests. GSEA found that the KEGG pathway and related core genes of "PD-L1 expression and PD-1 checkpoint pathway in cancer" pathway were downregulated in CHD., Discussion: This study provided evidence of a bidirectional causal relationship between PD-1 and chronic ischemic heart disease and a protective association between chronic ischemic heart disease and PD-L1., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Zeng, Liang, Zhou, Yang, Chen, He, Qiu, Liu, Zhou, Xiao, Liang, Zhang, Li, Yu, Yi and Lin.)

Green tea catechins have been reported to have antitumor activity. The objective of this study was to examine the effect of catechins on the antitumor efficacy of doxorubicin (DOX) in a murine model for chemoresistant hepatocellular carcinoma (HCC). Epicatechin gallate (ECG) and epigallocatechin gallate (EGCG) are the most abundant polyphenolic compounds in green tea. Here, we show that ECG or EGCG at higher doses had a slight inhibitory effect on cell proliferation in the resistant human HCC cell line BEL-7404/DOX in vitro and in vivo, whereas the administration of DOX with these compounds at lower doses significantly inhibited HCC cell proliferation in vitro and hepatoma growth in a xenograft mouse model, compared with treatment with either agent alone at the same dose. Furthermore, the administration of DOX in combination with ECG or EGCG markedly enhanced intracellular DOX accumulation, which implies that the catechins inhibited P-glycoprotein (P-gp) efflux pump activity. Consistent with these results, the intracellular retention of rhodamine 123, a P-gp substrate, was increased and the level of P-gp was decreased in cells concurrently treated with DOX and ECG or EGCG. EGCG increased topo II expression, but did not alter GST protein levels in tumor xenografts. The expression of MDR1 and HIF-1alpha mRNA was obviously reduced, whereas MRP1 and LRP expression was not changed significantly. These data suggest that tea catechins at non-toxic doses can augment DOX-induced cell killing and sensitize chemoresistant HCC cells to DOX. The chemosensitizing effect of catechins may occur directly or indirectly by reversal of multidrug resistance, involving the suppression of MDR1 expression, or by enhancement of intracellular DOX accumulation, involving inhibition of P-gp function.