Pharmacogenomics of biological treatment in rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) demonstrates a high heterogeneity in clinical responses to treatment. Although the efficacy of biological therapy has undoubtedly been established, the response differs considerably between individuals. This variability between individuals has aroused the research for biomarkers predictive of treatment response. Pharmacogenomics underlying individual responses to drugs is rapidly developed and has the potential of realizing the personalized therapy in RA. This review will summarize the pharmacogenomics of biological therapies approved for clinical RA treatment. AREAS COVERED: The pharmacogenomics underlies individual responses to biological drugs in RA. Current studies on pharmacogenomics of biological therapy in RA are presented. EXPERT OPINION: The personalized treatment in RA according to pharmacogenomics is promising, but the available pharmacogenomic data on biological treatment in RA are not adequate and consistent and still require further larger sample studies to corroborate.

Norcantharidin inhibits the expression of extracellular matrix and TGF-ß1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway.

Norcantharidin (NCTD) was shown in our previous studies to attenuate renal tubulointerstitial fibrosis in rat models with diabetic nephropathy (DN). The aim of this study was to determine the effects of NCTD on the expression of extracellular matrix (ECM) and TGF-ß1 in HK-2 cells stimulated by high glucose and on calcineurin (CaN)/NFAT pathway. Whether or not the antifibrotic effect of NCTD on renal interstitium was dependent on its inhibition of CaN pathway was also investigated. Experimental concentrations of NCTD were verified by cytotoxic test and MTT assay. HK-2 cells were transfected with CaN small interference RNA (siRNA). The mRNA and protein expressions of FN, ColIV, TGF-ß1, and CaN in HK-2 cells were detected by real-time PCR and western blot. The CaN/NFAT pathway was examined by indirect immunofluorescence and western blot. Our study revealed that NCTD concentrations over 5 mg/l had overt cytotoxicity on HK-2 cells. Meanwhile, both 2.5 and 5 mg/l NCTD inhibited HK-2 cell proliferation (P < 0.05). NCTD inhibited the upregulation of FN, ColIV, and TGF-ß1 of HK-2 cells stimulated by high glucose (P < 0.05), and also significantly downregulated the expression of CaN mRNA and protein in HK-2 cells (P < 0.05). In addition, not only was the nuclear translocation of NFATc inhibited, but its protein level in the nucleus was also reduced. Following CaN siRNA transfection, CaN mRNA and protein expression were significantly decreased. In contrast, the protein levels of FN, ColIV, and TGF-ß1 increased in HK-2 cells stimulated by high glucose (P < 0.05). However, NCTD treatment downregulated their expression. These results indicated that NCTD could decrease the expression of ECM and TGF-ß1 in HK-2 cells stimulated by high glucose, downregulate CaN expression, and block the CaN/NFAT signaling pathway. However, the effect of NCTD on inhibition of the expression of ECM and TGF-ß1 was not associated with its inhibition of the CaN/NFAT pathway.

Norcantharidin attenuates tubulointerstitial fibrosis in rat models with diabetic nephropathy.

OBJECTIVE: To investigate the effects of norcantharidin (NCTD) on tubulointerstitial fibrosis of diabetic nephropathy (DN) in streptozotocin-induced rat model. METHODS: Sprague-Dawley rats were randomly divided into control group, model group, low-dose NCTD (0.05 mg/kg/day) group, and high-dose NCTD (0.1 mg/kg/day) group. The model group was induced by injection intraperitoneally with 30 mg/kg streptozotocin in 0.1 mol/L sodium citrate solution (pH 4.5), after high-calorie foods were given for 2 months. NCTD was administered daily after the DN rat model was built. Rats were sacrificed at the end of the third and the eighth week; renal fibrosis and the expression of FN, collagen IV, TGF-ß1, and calcineurin (CaN) were detected by Masson and immunohistochemistry staining, respectively. RESULTS: Tubulointerstitial fibrosis was observed in DN rats, this kind of pathological changes was ameliorated in NCTD treatment group (p < 0.05). The expressions of FN, collagen IV, and TGF-ß1 protein increased in the tubulointerstitial field of DN rats compared with the rats in control group. NCTD treatment could dose-dependently decrease their expression and reverse the fibrotic degree (p < 0.05). Meanwhile, the expression of CaN was detected in tubular fields of normal kidney and increased in the tubulointerstitial field in DN rats. However, NCTD downregulated its expression in a dose-dependent manner (p < 0.05). CONCLUSIONS: NCTD could downregulate FN, collagen IV, and TGF-ß1 expression in tubulointerstitial fields and attenuate tubulointerstitial fibrosis in the early stage of DN rats. NCTD also alleviated the expression of CaN in tubules in DN. The relationship between the role of NCTD's anti-tubulointerstitial fibrosis and its inhibition to CaN expression remains to be further elucidated.