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Natural flavonoid pectolinarigenin (PEC) was reported to alleviate tubulointerstitial fibrosis of unilateral ureteral obstruction (UUO) mice in our previous study. To further investigate nephroprotective effects of PEC in hyperuricemic nephropathy (HN), adenine and potassium oxonate induced HN mice and uric acid-treated mouse kidney epithelial (TCMK-1) cells were employed in the study. As a result, PEC significantly lowered serum uric acid level and restored hyperuricemia-related kidney injury in HN mice. Meanwhile, PEC alleviated inflammation, fibrosis, and reduced adipokine FABP4 content in the kidneys of HN mice and uric acid-treated TCMK-1 cells. Mechanistically, PEC inhibited the TGF-β1 expression as well as the phosphorylation of transcription factor SMAD3 and STAT3 to regulate the corresponding inflammatory and fibrotic gene expression in kidney tissues. In conclusion, our results suggested that PEC could inhibit the activation of SMAD3 and STAT3 signaling to suppress inflammation and fibrosis, and thereby alleviate HN in mice. [ABSTRACT FROM AUTHOR]

Abstract: Tumor necrosis factor-alpha (TNF-α) promotes in vitro retinal pigment epithelial (RPE) cell migration to initiate proliferative vitreoretinopathy (PVR). Here we report that TNF-α promotes human RPE cell migration by inducing matrix metallopeptidase 9 (MMP-9) expression. Inhibition of MMP-9 by its inhibitor or its neutralizing antibody inhibited TNF-α-induced in vitro RPE cell migration. Reversely, exogenously-added active MMP-9 promoted RPE cell migration. Suppression Akt/mTOR complex 1(mTORC1) activation by LY 294002 and rapamycin inhibited TNF-α-mediated MMP-9 expression. To introduce a constitutively active Akt (CA-Akt) in cultured RPE cells increased MMP-9 expression, and to block mTORC1 activation by rapamycin inhibited its effect. RNA interference (RNAi)-mediated silencing of SIN1, a key component of mTOR complex 2 (mTORC2), had no effect on MMP-9 expression or secretion. In conclusion, this study suggest that TNF-α promotes RPE cell migration by inducing MMP-9 expression through activation of Akt/ mTORC1, but not mTORC2 signaling. [Copyright &y& Elsevier]

Kidney fibrosis is a histological hallmark of chronic kidney disease (CKD), where hyperuricemia is a key independent risk factor. Considerable evidence indicated that STAT3 is one of the crucial signaling pathways in the progression of kidney fibrosis. Here, we investigated that pharmacological blockade of STAT3 delayed the progression of renal fibrosis in hyperuricemia-induced CKD. In the study, we used the mixture of adenine and potassium oxonate to perform kidney injury and fibrosis in hyperuricemic mice, accompanied by STAT3 activation in tubular and interstitial cells. Treatment with STAT3 inhibitor S3I-201 improved renal dysfunction, reduced serum uric acid level, and delayed the progression of kidney fibrosis. Furthermore, S3I-201 could suppress fibrotic signaling pathway of TGF-β/Smads, JAK/STAT and NF-κB, as well as inhibit the expression of multiple profibrogenic cytokines/chemokines in the kidneys of hyperuricemic mice. These data suggested that STAT3 inhibition was a potent anti-fibrotic strategy in hyperuricemia-related CKD. [Display omitted] [ABSTRACT FROM AUTHOR]

The human N-Myc downstream-regulated gene 2 (NDRG2) is expressed in astrocytes, and may be involved in the modulation of gliacyte function in the central nervous system. Our previous study found suppression of NDRG2 up-regulation in reactive astrocytes in cerebral ischemic tolerance. 2-Arachidonylglycerol (2-AG) can induce cerebral ischemic tolerance. However, the underlying mechanism of NDRG2 in cytoprotection induced by 2-AG in primary astrocytesis still unknown. In this study, we investigated the role of NDRG2 in cerebral ischemic tolerance induced by 2-AG after oxygen-glucose deprivation (OGD) in primary astrocytes. The results showed that primary astrocytes exposed to OGD resulted in marked increase of lactate dehydrogenase (LDH) release and decrease of methyl thiazolyl tetrazolium (MTT) reduction activity in comparison to control cultures. The levels of NDRG2 and phospho-signal transducer and activator of transcription 3 (pSTAT3) in the OGD group were comparably higher than those in the control group, and the up-regulation of NDRG2 and pSTAT3 was suppressed in NDRG2 siRNA group. The cell viability in the 2-AG group was higher than that in the OGD group, and transfecting the NDRG2 pSRL-CDH1-GFP vector reversed the protective effects of 2-AG. The levels of NDRG2 and pSTAT3 in the 2-AG group were lower than those in the OGD group. 2-AG suppressed STAT3 phosphorylation by decreased expression of NDRG2. In conclusion, 2-AG protects primary astrocytes exposed to oxygen-glucose deprivation through a blockade of NDRG2 signaling and STAT3 phosphorylation. These findings bring insight to the roles of NDRG2 in ischemic-hypoxic injury and provide novel potential targets for future potent clinical therapies on cerebral ischemia injury. [ABSTRACT FROM AUTHOR]

Liriodendron chinense (Hemsl.) Sarg , known as the Chinese tulip tree, has a long history of cultivation and utilization in many Asia countries, especially in China to use in traditional Chinese medicine for expelling "wind and dampness", a term corresponding to rheumatic fever and rheumatoid arthritis. Interestingly, the barks of Liriodendron chinense (Hemsl.) Sarg was also found in folk to treat gout. However, further experimental studies remained to confirm its uric acid-lowering effects. The aim of the study was to evaluate the protective effect of ethanol extract of the barks of Liriodendron chinense (Hemsl.) Sarg (EELC) in a mouse model of hyperuricemic nephropathy (HN) and the involved mechanisms. EELC at a respective dose of 250 mg/kg/d or 500 mg/kg/d were orally administered to HN mice induced by a mixture of adenine (160 mg/kg/d)/potassium oxonate (2.4 g/kg/d) for 21 days. At the end of the treatment, serum uric acid, kidney functions (serum creatinine, blood urea nitrogen and urine microalbumin), 24-h urine uric acid excretion, as well as kidney pathological changes were investigated by biochemical assay, histopathological score, immunofluorescence and histochemistry, RT-qPCR, and western blotting analysis. Oral administration of EELC significantly lowered serum uric acid level at 500 mg/kg (185.75 ± 15.49 μmol/L of EELC vs. 238.28 ± 20.97 μmol/L of HN model, p < 0.01) in HN mice. EELC at 500 mg/kg also remarkably reduced the levels of serum creatinine (82.92 ± 7.86 μmol/L of EELC vs. 92.08 ± 6.13 μmol/L of HN model, p < 0.0001), blood urea nitrogen (21.50 ± 1.87 mmol/L of EELC vs. 29.40 ± 3.95 mmol/L of HN model, p < 0.001) and urine microalbumin (4.25 ± 0.40 mg/L of EELC vs. 5.95 ± 0.33 mg/L of HN model, p < 0.001) to improve renal function. It also attenuated renal fibrosis, especially the high-dose of EELC. Furthermore, EELC could inhibit the activation of NF-κB, ASK1/JNK/c-Jun, JAK2/STAT3 signaling pathways and reduce the release of pro-inflammatory cytokine TNF-α in the kidneys of HN mice. Additionally, EELC remarkably increased urine uric acid excretion of HN mice, which may be achieved by the upregulation of organic anion transporter 1 (OAT1), OAT3 and ATP-binding cassette subfamily G member 2 (ABCG2) proteins. EELC alleviated the progression of HN by suppressing the activation of NF-κB, ASK1/JNK/c-Jun and JAK2/STAT3 signaling pathway, reducing the infiltration of inflammatory factors and uric acid accumulation in the kidney. Image 1 [ABSTRACT FROM AUTHOR]