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From an optimizer's perspective, achieving the global optimum for a general nonconvex problem is often provably NP-hard using the classical worst-case analysis. In the case of Cox's proportional hazards model, by taking its statistical model structures into account, we identify local strong convexity near the global optimum, motivated by which we propose to use two convex programs to optimize the folded-concave penalized Cox's proportional hazards regression. Theoretically, we investigate the statistical and computational tradeoffs of the proposed algorithm and establish the strong oracle property of the resulting estimators. Numerical studies and real data analysis lend further support to our algorithm and theory., Comment: 42 pages

Wenyan Gong,1,* Jie Li,2,* Wenying Chen,3 Fuzhen Feng,3 Yanhui Deng3 1Department of Cardiology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou 310000, People’s Republic of China; 2Medical Research Center, Guangdong Second Provincial General Hospital, Guangzhou 510317, People’s Republic of China; 3Department of Pharmacy, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yanhui DengDepartment of Pharmacy, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, People’s Republic of ChinaTel +86 20 62784810Email shiningdyh@sina.comPurpose: Chronic inflammation plays a key role in the pathogenesis of various diseases such as diabetic nephropathy (DN). Resveratrol (RSV), a natural polyphenol, has been proven to have renoprotective effects. In this study, we used a lipopolysaccharide (LPS)-induced rat glomerular mesangial cells (RMCs) model, to elucidate the renoprotective effect of RSV on sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate receptor 2 (S1P2)/NF-κB activation and the expression of downstream inflammatory mediators, such as intercellular adhesion molecule-1 (ICAM-1), inducible nitric oxide synthase (iNOS) and fibronectin (FN) protein expression in RMCs.Methods: Cell proliferation was tested by 3-(4, 5-dimethylthiazol-2-yl)-2, 5- diphenyltetrazolium bromide (MTT). The protein levels of FN, ICAM-1, iNOS, SphK1, S1P2 and NF-κB p65 in RMCs were detected by Western blot. The DNA-binding activity of NF-κB was detected by electrophoretic mobility shift assay (EMSA). SphK1 activity and S1P content were measured by using sphingosine kinase activity assay kit and ELISA assay, respectively.Results: We first found that LPS could stimulate SphK1/S1P axis activation, whereas this occurrence was significantly blocked by RSV pretreatment. RSV obviously repressed LPS-induced upregulated expression of fibronectin (FN), intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) in RMCs. Moreover, RSV markedly reduced SphK1 activity and its protein expression, and attenuated S1P content in LPS-induced RMCs. Furthermore, RSV could block LPS-induced upregulation of NF-κB p65 and DNA-binding activity of NF-κB. And this phenomenon was notably attenuated by SphK1 inhibitor and S1P2 inhibitor.Conclusion: RSV inhibited LPS-induced RMCs’ proliferation and inflammation and FN expression by SphK1/S1P2/NF-κB pathway, suggesting that RSV may be independent of its hypoglycemic effect on preventing or delaying the development of mesangial cell fibrosis.Keywords: diabetic nephropathy, resveratrol, lipopolysaccharide, sphingosine kinase 1, sphingosine 1-phosphate, NF-κB