Oral cancer is one of the most frequent malignant diseases worldwide, and areca nut is a primary carcinogen causing this cancer in Southeast Asia. It has been widely reported that areca nut induced several cytotoxic effects in oral cells, including ROS generation, inflammation, tissue hypoxia, DNA damage, and cell invasion. Recently, through chronic exposure model, more extensive pathological effects due to areca nut have been found. These include the induction of autophagy, promotion of epithelial- mesenchymal transition, and facilitation of cancer stemness conversion. Clinical findings support these adverse effects. Oral submucosal fibrosis, a premalignant condition, is prevalent in the area with habitual chewing of areca nuts. Consistently, oral cancer patients with habitual chewing areca nut exhibit more aggressive phenotypes, including resistance to chemo-radiotherapy. In this review, we comprehensively discuss and concisely summarize the up-to-date molecular and cellular mechanisms by which areca nuts contribute to malignant transformation. This review may provide critical information regarding clinical applications in risk assessment, disease prevention, diagnosis, and personalized therapeutics for areca nut-induced oral malignancy.

Objectives: To investigate the safety, feasibility, and possible adverse events of single-dose human umbilical cord-derived mesenchymal stem cells in patients with moderate-to-severe acute respiratory distress syndrome. Design: Prospective phase I clinical trial. Setting: Medical center in Kaohsiung, Taiwan. Patients: Moderate-to-severe acute respiratory distress syndrome with a Pao ₂/Fio ₂ ratio less than 200. Interventions: Scaling for doses was required by Taiwan Food and Drug Administration as follows: the first three patients received low-dose human umbilical cord-derived mesenchymal stem cells (1.0 × 10⁶ cells/kg), the next three patients with intermediate dose (5.0 × 10⁶ cells/kg), and the final three patients with high dose (1.0 × 10⁷ cells/kg) between December 2017 and August 2019. Measurements and Main Results: Nine consecutive patients were enrolled into the study. In-hospital mortality was 33.3% (3/9), including two with recurrent septic shock and one with ventilator-induced severe pneumomediastinum and subcutaneous emphysema. No serious prespecified cell infusion-associated or treatment-related adverse events was identified in any patient. Serial flow-cytometric analyses of circulating inflammatory biomarkers (CD14⁺CD33⁺/CD11b+CD16+/CD16+MPO+/CD11b+MPO+/CD14^dimCD33+) and mesenchymal stem cell markers (CD26+CD45–/CD29+CD45–/CD34+CD45–/CD44+CD45–/CD73+CD45–/CD90+CD45–/CD105+CD45–/CD26+CD45–) were notably progressively reduced (p for trend < 0.001), whereas the immune cell markers (Helper-T-cell^CD3+CD4+/Cytotoxity-T-cell^CD3+CD8+/Regulatory-T-cell^{CD4+CD25+FOXp3+}) were notably increased (p for trend < 0.001) after cell infusion. Conclusions: The result of this phase I clinical trial showed that a single-dose IV infusion of human umbilical cord-derived mesenchymal stem cells was safe with favorable outcome in nine acute respiratory distress syndrome patients.

This study tested the hypothesis that early administration of empagliflozin (Empa), an inhibitor of glucose recycling in renal tubules, could preserve heart function in cardiorenal syndrome (CRS) in rat. Chronic kidney disease (CKD) was caused by 5/6 subtotal nephrectomy and dilated cardiomyopathy (DCM) by doxorubicin (DOX) treatment. In vitro results showed that protein expressions of cleaved-caspase3 and autophagy activity at 24 h/48 h in NRK-52P cells were significantly upregulated by para-Creso treatment; these were significantly downregulated by Empa treatment. Flow cytometric analysis showed that annexin-V (i.e., early/late apoptosis) in NRK-52P cells expressed an identical pattern to cleaved-caspase3 between the two groups (all p < 0.001). Adult-male-SD rats (n = 18) were equally categorized into group 1 (sham-control), group 2 (CRS) and group 3 [CRS + Empa; 20 mg/kg/day]. By day-42 after CRS induction, left-ventricular ejection fraction (LVEF) level exhibited an opposite pattern, whereas LV end-diastolic dimension and creatinine level displayed the same pattern, to cleaved-caspase3 among the three groups (all p < 0.0001). In LV tissues, protein expressions of inflammatory (tumor-necrosis factor-α/nuclear-factor-κB/interleukin-1ß/matrix-metalloprotianse-9), oxidative stress (NOX-1/NOX-2/oxidized protein), apoptotic (mitochondrial-Bax/cleaved-caspase-3/cleaved-PARP), fibrotic (transforming-growth factor-ß/Smad3), DNA/mitochondrial-damage (γ-H2AX/cytosolic-cytochrome-C) and heart failure (brain natriuretic peptide (BNP) levels displayed an opposite pattern to LVEF among the three groups (all p < 0.0001). Additionally, cellular expressions of DNA-damage/heart-failure (γ-H2AX+//XRCC1+CD90+//BNP+) biomarkers and histopathological findings of fibrotic/condensed collagen-deposition areas and apoptotic nuclei showed an identical pattern, whereas connexin43 and small-vessel number exhibited an opposite pattern, to inflammation among the three groups (all p < 0.0001). In conclusion, Empa therapy protected heart and kidney against CRS injury.

Desmoglein 3 (DSG3) is a component of the desmosome, which confers strong cell-cell adhesion. Previously, an oncogenic function of DSG3 has been found in head neck cancer (HNC). Here, we investigated how this molecule contributes to the malignant phenotype. Because DSG3 is associated with plakoglobin, we examined whether these phenotypic alterations were mediated through the plakoglobin molecule. Immunoprecipitation and immunofluorescence staining revealed that DSG3 silencing disrupted its interaction with plakoglobin and induced plakoglobin translocation from the cytoplasm to the nucleus. Knockdown of DSG3 significantly increased the interaction of plakoglobin with the transcriptional factor TCF and suppressed the TCF/LEF transcriptional activity. These effects further conferred to reduced expression of the TCF/LEF downstream target genes, including c-myc, cyclin D1, and MMP-7. Functional analyses showed that DSG3 silencing reduced cell growth and arrested cells at G0/G1 phase. Besides, cell migration and invasion abilities were also decreased. These cellular results were confirmed using tumor xenografts in mice, as DSG3 silencing led to the suppressed tumor growth, plakoglobin translocation and reduced expression of TCF/LEF target genes in tumors. Therefore, our study shows that the desmosomal protein DSG3 additionally functions to regulate malignant phenotypes via nuclear signaling. In conclusion, we found that DSG3 functions as an oncogene and facilitates cancer growth and invasion in HNC cells through the DSG3-plakoglobin-TCF/LEF pathway.

GDF15 contributes to radioresistance and cancer stemness of head and neck cancer by regulating cellular reactive oxygen species via a SMAD-associated signaling pathway