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Adrenergic nerve fibers in the tumor microenvironment promote tumor growth and represent a potential target for cancer therapy. However, the effectiveness of targeting adrenergic nerve fibers for oral squamous cell carcinoma (OSCC) therapy needs to be evaluated by preclinical data. Herein, the 4NQO-induced and orthotopic xenograft OSCC mice models were established. We demonstrated that using 6OHDA chemical denervation as well as using nebivolol adrenergic blockade could halt the oral mucosa carcinogenesis. Our preclinical studies suggested that nebivolol, which is widely used to treat cardiovascular diseases, can be repositioned as a potential candidate to treat OSCC. Remarkably, we revealed the precise effect and mechanism of nebivolol on OSCC cells proliferation, cell cycle, and cell death. Administration of nebivolol could activate the endoplasmic reticulum (ER) stress signaling pathway through increasing the expression of inducible nitric oxide synthase, which subsequently triggers the integrated stress response and cell growth arrest. Simultaneously, ER stress also induced mitochondrial dysfunction in OSCC cells. We found that the accumulation of dysfunctional mitochondria with the impaired electron transport chain caused increasing reactive oxygen species production, which ultimately resulted in OSCC cell death. Altogether, our finding suggested a novel therapeutic opportunity for OSCC by targeting adrenergic nerve fibers, and repurposing nebivolol to treat OSCC can be represented as an effective strategy., 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., (Copyright © 2021 Chen, Jiang, Wang, Cai, Jiang, Xie, Zhou, Zeng, Ji, Shen and Chen.)

It is widely accepted that genetic polymorphisms impact atorvastatin (ATV) metabolism, clinical efficacy, and adverse events. The objectives of this study were to identify novel genetic variants influencing ATV metabolism and outcomes in Chinese patients with coronary artery disease (CAD). A total of 1079 CAD patients were enrolled and followed for 5 years. DNA from the blood and human liver tissue samples were genotyped using either Global Screening Array-24 v1.0 BeadChip or HumanOmniZhongHua-8 BeadChip. Concentrations of ATV and its metabolites in plasma and liver samples were determined using a verified ultra-performance liquid chromatography mass spectrometry (UPLC-MS/MS) method. The patients carrying A allele for the rs4148323 polymorphism ( UGT1A1 ) showed an increase in 2-hydroxy ATV/ATV ratio ( p = 1.69E-07, false discovery rate [FDR] = 8.66E-03) relative to the value in individuals without the variant allele. The result was further validated by an independent cohort comprising an additional 222 CAD patients ( p = 1.08E-07). Moreover, the rs4148323 A allele was associated with an increased risk of death (hazard ratio [HR] 1.774; 95% confidence interval [CI], 1.031-3.052; p = 0.0198). In conclusion, our results suggested that the UGT1A1 rs4148323 A allele was associated with increased 2-hydroxy ATV formation and was a significant death risk factor in Chinese patients with CAD., 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., (Copyright © 2021 Lei, Qin, Cai, Wu, Tang, Liu, Deng, Liu, Zhu, Li, Hu, Yang, Zhu and Zhong.)

Background and Aims: It's reported that bone morphogenetic protein 9 (BMP9) played an important role in lipid and glucose metabolism, but the role of BMP9 in nonalcoholic fatty liver disease (NAFLD) is unclear. Here, we evaluated the therapeutic efficacy of recombined BMP9 in NAFLD mice and investigated the potential mechanism. Methods: The effects of recombinant BMP9 on NAFLD were assessed in HFD-induced NAFLD mice. C57BL/6 mice were administrated with high-fat diet (HFD) for 12 weeks. In the last 4 weeks, mice were treated with PBS or recombined BMP9 once daily. Insulin sensitivity was evaluated by glucose tolerance test (GTT) and insulin tolerance test (ITT) at the end of the 12th week. Then NAFLD related indicators were assessed by a variety of biological methods, including histology, western blotting, real-time PCR, RNA-seq and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analyses. Results: BMP9 reduced obesity, improved glucose metabolism, alleviated hepatic steatosis and decreased liver macrophages infiltration in HFD mice. RNA-seq showed that Cers6, Cidea, Fabp4 involved in lipid and glucose metabolism and Fos, Ccl2, Tlr1 involved in inflammatory response downregulated significantly after BMP9 treatment in HFD mouse liver. ATAC-seq showed that chromatin accessibility on promoters of Cers6, Fabp4, Ccl2 and Fos decreased after BMP9 treatment in HFD mouse liver. KEGG pathway analysis of dysregulated genes in RNA-seq and integration of RNA-seq and ATAC-seq showed that TNF signaling pathway and Toll-like receptor signaling pathway decreased in BMP9 treated HFD mouse liver. Conclusion: Our data revealed that BMP9 might alleviate NAFLD via improving glucose and lipid metabolism, decreasing inflammatory response and reshaping chromatin accessibility in HFD mouse liver. BMP9 downregulate genes related to lipid metabolism, glucose metabolism and inflammation expression, at least partially via decreasing promoter chromatin accessibility of Cers6, Fabp4, Fos and Tlr1. BMP9 may also reduce the expression of liver Ccl2, thereby changing the number or composition of liver macrophages, and ultimately reducing liver inflammation. The effect of BMP9 on NAFLD might be all-round, and not limit to lipid and glucose metabolism. Therefore, the underlying mechanism needs to be studied in detail further., 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., (Copyright © 2021 Sun, Cai, Jian, Cui, Huang, Liu, Lu, Wang, Zeng and Zhong.)

The selection of optimum statin intensity is inconclusive, and the association of plasma exposure of statins and metabolites with major adverse cardiovascular events (MACEs) is unclear. This study sought to compare the effect of low (quartile 1), intermediate (quartiles 2 and 3), and high (quartile 4) plasma exposure of statins and metabolites on MACE, re-ischemia events and death in patients with coronary artery disease (CAD) at 5 years. A total of 1,644 patients in atorvastatin (AT) cohort and 804 patients in rosuvastatin (RST) cohort were included, and their plasma concentration of statins and metabolites was categorized as low-, mid-, or high-group. The association between the plasma levels of statins and metabolites and the incidence of primary endpoint in patients was assessed by Cox proportional hazard models. Intensive AT exposure (Q4 > 5.32 ng/ml) was significantly associated with increased risk of death compared with low (hazard ratio [HR]: 1.522; 95% confidence interval [CI]: 1.035-1.061; P = 0.0022) or moderate exposure (HR: 2.054; 95% CI: 1.348-3.130; P = 0.0008). This association was also found in AT's five metabolites (all P < 0.01). In patients with RST treatment, moderate RST concentration (0.53-4.29 ng/ml) versus low concentration had a significantly lower risk of MACE and re-ischemia events. (HR: 0.532, 95% CI: 0.347-0.815, P = 0.0061 and HR: 0.505, 95% CI: 0.310-0.823, P = 0.0061, respectively). A higher plasma exposure of AT and metabolites has a significantly higher risk of death, and moderate RST exposure has a significantly lower risk of MACE and re-ischemia events in Chinese patients with CAD. The harms of high plasma exposure should be considered when prescribing statins to patients because it may be a risk factor for having poor prognosis in patients with CAD., (Copyright © 2020 Zhou, Cai, Lai, Bai, Liu, Zhu, He, Chen, Huang, Zhou and Zhong.)