Decoding and reconstructing disease relations between dry eye and depression: a multimodal investigation comprising meta-analysis, genetic pathways and Mendelian randomization.

INTRODUCTION: The clinical presentations of dry eye disease (DED) and depression (DEP) often comanifest. However, the robustness and the mechanisms underlying this association were undetermined. OBJECTIVES: To this end, we set up a three-segment study that employed multimodality results (meta-analysis, genome-wide association study [GWAS] and Mendelian randomization [MR]) to elucidate the association, common pathways and causality between DED and DEP. METHODS: A meta-analysis comprising 26 case-control studies was first conducted to confirm the DED-DEP association. Next, we performed a linkage disequilibrium (LD)-adjusted GWAS and targeted phenotype association study (PheWAS) in East Asian TW Biobank (TWB) and European UK Biobank (UKB) populations. Single-nucleotide polymorphisms (SNPs) were further screened for molecular interactions and common pathways at the functional gene level. To further elucidate the activated pathways in DED and DEP, a systemic transcriptome review was conducted on RNA sequencing samples from the Gene Expression Omnibus. Finally, 48 MR experiments were implemented to examine the bidirectional causation between DED and DEP. RESULTS: Our meta-analysis showed that DED patients are associated with an increased DEP prevalence (OR = 1.83), while DEP patients have a concurrent higher risk of DED (OR = 2.34). Notably, cross-disease GWAS analysis revealed that similar genetic architecture (rG = 0.19) and pleiotropic functional genes contributed to phenotypes in both diseases. Through protein-protein interaction and ontology convergence, we summarized the pleiotropic functional genes under the ontology of immune activation, which was further validated by a transcriptome systemic review. Importantly, the inverse variance-weighted (IVW)-MR experiments in both TWB and UKB populations (p value <0.001) supported the bidirectional exposure-outcome causation for DED-to-DEP and DEP-to-DED. Despite stringent LD-corrected instrumental variable re-selection, the bidirectional causation between DED and DEP remained. CONCLUSION: With the multi-modal evidence combined, we consolidated the association and causation between DED and DEP.

Antipsychotic drug trifluoperazine as a potential therapeutic agent against nasopharyngeal carcinoma.

BACKGROUND: Trifluoperazine (TFP) is a typical antipsychotic primarily used to treat schizophrenia. In this study, we aimed to evaluate whether TFP can be used as a therapeutic agent against nasopharyngeal carcinoma (NPC) and identify its underlying molecular mechanisms. METHODS: We used NPC-TW01, TW03, TW04, and BM to assess the anticancer effects of TFP by using cytotoxicity, wound healing, colony formation, and cell invasion assays. An in vivo animal study was conducted. RNA sequencing combined with Ingenuity Pathways Analysis was performed to identify the mechanism by which TFP influences NPC cells. RESULTS: Our data revealed that TFP decreased NPC cell viability in a dose-dependent manner. The invasion and migration of NPC tumor cells were inhibited by TFP. An in vivo study also demonstrated the anticancer effects of TFP. RNA sequencing revealed several anticancer molecular mechanisms following TFP administration. CONCLUSIONS: The antipsychotic drug TFP could be a potential therapeutic regimen for NPC treatment.