Effects of uric acid-lowering therapy on the progression of chronic kidney disease: a systematic review and meta-analysis

<p><b>Objectives:</b> Whether uric acid levels were associated with the progression of chronic kidney disease (CKD) remained controversial. This meta-analysis was aimed to assess the effect of lowering serum uric acid therapy on the progression of CKD to clarify the role of uric acid in the progression of CKD indirectly.</p> <p><b>Methods:</b> Pubmed, Embase, the Cochrane library, CBM were searched for randomized controlled trials (RCTs) that assessed the efficiency of lowering serum uric acid therapy on the progression of CKD without language restriction. Summary estimates of weighted mean differences (WMDs) and relative risk (RR) were obtained by using random-effect or fixed-effect models. Sensitivity analyses were performed to identify the source of heterogeneity.</p> <p><b>Results:</b> A total of 12 randomized controlled trials with 832 CKD participants were included in the analysis. Pooled estimate for eGFR was in favor of lowering serum uric acid therapy with a mean difference (MD) of 3.88 ml/min/1.73 m², 95% CI 1.26–6.49 ml/min/1.73 m², <i>p</i> = .004 and this was consistent with results for serum creatinine. The risk of worsening of kidney function or ESRD or death was significantly decreased in the treatment group compared to the control group (RR 0.39, 95% CI 0.28–0.52, <i>p</i>< .01).</p> <p><b>Conclusions:</b> Uric acid-lowering therapy may be effective in retarding the progression of CKD. Further randomized controlled trials should be performed to confirm the effect of lowering serum uric acid therapy on the progression of CKD.</p

Effect of IL-17A on the Migration and Invasion of NPC Cells and Related Mechanisms

<div><p>In carcinogenesis, inflammasomes may play contradictory roles through facilitating anti-tumor immunity or inducing oncogenic factors. Their function in cancer remains poorly characterized. In this study, we explored the effect of interleukin-17A (IL-17A) on the migration and invasion activity of nasopharyngeal carcinoma (NPC) cell lines and account for related mechanisms. Our results revealed that exogenous IL-17A promoted cell migration and invasion significantly in both NPC-039 and CNE-2Z cell lines. In addition, the expression of matrix metalloproteinase-2 (MMP-2)/-9 and Vimentin could be elevated by IL-17A stimulation; meanwhile the expression of E-cadherin was decreased. The results also show that IL-17A could activate the p38 signaling pathway in IL-17A-stimulated NPC-039 and CNE-2Z cell lines. Combining treatment with a p38 inhibitor (SB203580) resulted in decreased invasion capabilities of NPC-039 and CNE-2Z cell lines. SB203580 also inhibited the expression of MMP-2/-9 and increased the expression of E-cadherin in IL-17A-stimulated NPC-039 and CNE-2Z cell lines. IL-17A also could activate NF-κB in NPC-039 and CNE-2Z cell lines. In summary, our data show that IL-17A promote the cell migration and invasion of NPC cells. The effect of IL-17A on cell migration and invasion may be mediated via regulation of the expression of MMP-2/-9 and epithelial-mesenchymal transition (EMT) via p38-NF-κB signaling pathway. Thus, IL-17A or its related signaling pathways may be a promising target for preventing and inhibiting NPC metastasis.</p></div

IL-17A promotes the expressions of MMP-/-9 and Vimentin suppresses the expressions of E-cadherin in NPC-039 and CNE-2Z cells.

<p>(A) Expressions of MMP-2/-9, Vimentin and E-cadherin in NPC-039 cells were compared by western blotting between cells treated with different concentrations of IL-17A (0, 1, 10 and 50 ng/ml) for 24 hours. (B) Quantification of the protein levels of MMP-2/-9, Vimentin and E-cadherin in NPC-039 cells. (C) Expressions of MMP-2/-9, Vimentin and E-cadherin in CNE-2Z cells were compared by western blotting between cells treated with different concentrations of IL-17A (0, 1, 10 and 50 ng/ml) for 24 hours. (D) Quantification of the protein levels of MMP-2/-9, Vimentin and E-cadherin in CNE-2Z cells. Values represent the means ± SD of three independent experiments performed in triplicate. *<i>p</i><0.05 and **<i>p</i><0.01 compared with the control group.</p

IL-17A activated p38 signaling pathway in NPC cells.

<p>(A) Western blotting analysis was used to detect p38 and p-p38 expression in NPC-039 cells treated with IL-17A (0, 1, 10 and 50 ng/ml) at indicated time points. (B) Quantification of the protein levels of p38 and p-p38 in NPC-039 cells. (C) Western blotting analysis was used to detect p38 and p-p38 expression in NPC-039 cells treated with IL-17A (0, 1, 10 and 50 ng/ml) at indicated time points in CNE-2Z cells. (D) Quantification of the protein levels of p38 and p-p38 in CNE-2Z cells. Values represent the means ± SD of three independent experiments performed in triplicate. *<i>p</i><0.05 and **<i>p</i><0.01 compared with the control group.</p

IL-17A activated NF-κB NPC in NPC cells.

<p>(A) Western blotting analysis was used to detect nuclear p52, p50, p65, c-Rel and RelB expression in NPC-039 cells treated with IL-17A. (B) Quantification of the protein levels of nuclear p52, p50, p65, c-Rel and RelB in NPC-039 cells. (C) The DNA-binding capacity of NF-κB in NPC-039 cells was measured using TransAM NF-κB ELISA. (D) Western blotting analysis was used to detect nuclear p52, p50, p65, c-Rel and RelB expression in CNE-2Z cells treated with IL-17A. (E) Quantification of the protein levels of nuclear p52, p50, p65, c-Rel and RelB in CNE-2Z cells. (F) The DNA-binding capacity of NF-κB in CNE-2Z cells was measured using TransAM NF-κB ELISA. Values represent the means ± SD of three independent experiments performed in triplicate. *<i>p</i><0.05 compared with the control group.</p

IL-17A promotes NPC cell migration and invasion.

<p>(A) IL-17A treated NPC-039 cells showed higher motility in a wound-healing assay, compared with cells without IL-17A treatment. (B) Effect of IL-17A on NPC-039 cells invasion was detected by transwell assay. Representatives of cells migrated through Matrigel-coated transwell were shown. (C) Total invasive cell number in each chamber was summarized as a percentage of control. (D) Effect of IL-17A on CNE-2Z cells invasion was detected by transwell assay. Representatives of cells migrated through Matrigel-coated transwell were shown. (E) Total invasive cell number in each chamber was summarized as a percentage of control. Values represent the means ± SD of three independent experiments performed in triplicate. *<i>p</i><0.05 and **<i>p</i><0.01 compared with the control group.</p

Effects of the p38 inhibitor and IL-17A on cell invasion and MMP-2, MMP-9, Vimentin and E-cadherin expressions in NPC-039 and CNE-2Z cells.

<p>(A) NPC-039 cells were pretreated with SB203580 (20 µM) for 30 min and then incubated in the presence or absence of IL-17A (50 ng/ml) for 24 h. Cellular invasiveness was measured using the transwell invasion assay. (B) The percent invasion rate in NPC-039 cells was expressed as a percentage of control. (C, D) NPC-039 cells were treated and then subjected to western blotting to analyze the protein levels of MMP-2/-9, Vimentin and E-cadherin. (E) CNE-2Z cells were pretreated with SB203580 (20 µM) for 30 min and then incubated in the presence or absence of IL-17A (50 ng/ml) for 24 h. Cellular invasiveness was measured using the transwell invasion assay. (F) The percent invasion rate in CNE-2Z cells was expressed as a percentage of control. (G, H) CNE-2Z cells were treated and then subjected to western blotting to analyze the protein levels of MMP-2/-9, Vimentin and E-cadherin. Values represent the means ± SD of three independent experiments performed in triplicate. *<i>p</i><0.05 and **<i>p</i><0.01 compared with the control group.</p