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PubMed | Key Laboratory of Medical Cell Biology, Troops of 95935 Unit and Liaoning Medical University
Type: Journal Article | Journal: Molecular medicine reports | Year: 2016

There is emerging evidence that tubulointerstitial fibrosis is the final common pathway of the majority of chronic progressive renal diseases, including diabetic nephropathy (DN). Zinc, an essential dietary element, has been suggested to be important for a number of protein functions during fibrosis invivo and invitro. However, the effect of zinc deficiency (ZnD) on renal interstitial fibrosis in DN remains unclear. The present study investigated the effect and the underlying mechanisms of ZnD on renal interstitial fibrosis during DN using an streptozotocininduced model of diabetes with immunofluorescence staining and western blot analysis. The present study identified that dietary zinc restriction significantly decreased zinc concentrations in the plasma and mouse kidney. ZnD enhanced albuminuria and extracellular matrix protein expression, associated with diabetic renal interstitial fibrosis by activation of renal interstitial fibroblasts and regulation of the expression of fibrosisassociated factors, which may be mediated by the activation of fibroblasts via the TGF/Smad signaling pathway. The data indicates that ZnD serves an important role in the pathogenic mechanisms of renal interstitial fibrosis during the development of DN.


PubMed | Heilongjiang University, Key Laboratory of Medical Cell Biology, Shuangcheng District Peoples Hospital, Troops of 95935 Unit and Liaoning Medical University
Type: Journal Article | Journal: Biological trace element research | Year: 2016

Evidence has demonstrated that hypoxia may have a central pathogenic mechanism in the development of diabetic nephropathy (DN). Epithelial-to-mesenchymal transition (EMT) of mature tubular epithelial cells in kidney is a contributor to the renal accumulation of matrix protein in DN and is highly associated with the progression of tubulointerstitial fibrosis. Zinc (Zn) has anti-fibrosis effects in liver and lungs. In the present study, we aimed to investigate the effect of Zn on renal tubulointerstitial fibrosis especially under hypoxic conditions and its association with DN. We found that Zn treatment blockaded tubular EMT and attenuated renal tubulointerstitial fibrosis by downregulation of hypoxia-inducible factor alpha (HIF-1) in the kidneys of diabetic streptozotocin-treated mice. High glucose (HG)/hypoxic conditions stimulated EMT in renal tubular cells as indicated by the significant decrease in epithelial marker E-cadherin and ZO-1 while the increase in mesenchymal markers -smooth muscle actin (-SMA). Zn supplement mainly prevented HG/hypoxic-induced HIF-1 accumulation and EMT marker changes. In co-treatment Zn with PI3K/Akt/GSK-3 signaling pathway, inhibitor LY294002 prevented HG/hypoxic-induced HIF-1 increase and EMT changes, suggesting that Zn may mediate HG/hypoxic-induced EMT through PI3K/Akt/GSK-3 pathway. Therefore, we concluded that Zn had an important anti-fibrosis role under HG/hypoxic conditions, and a novel mechanism contributing to Zn protection on renal tubular epithelial cells from HG/hypoxia-induced EMT through activation of PI3K/Akt/GSK-3 signaling pathway, which subsequently leads to the downregulation of the expression of HIF-1.


PubMed | Key Laboratory of Medical Cell Biology, Liaoning Medical University, Heilongjiang University, Troops of 95935 Unit and Liaoning Province Benxi Center Hospital
Type: Journal Article | Journal: Apoptosis : an international journal on programmed cell death | Year: 2016

Apoptosis of tubular epithelial cells is a major feature of diabetic kidney disease, and hyperglycemia triggers the generation of free radicals and oxidant stress in tubular cells. Berberine (BBR) is identified as a potential anti-diabetic herbal medicine due to its beneficial effects on insulin sensitivity, glucose metabolism and glycolysis. In this study, the underlying mechanisms involved in the protective effects of BBR on high glucose-induced apoptosis were explored using cultured renal tubular epithelial cells (NRK-52E cells) and human kidney proximal tubular cell line (HK-2 cells). We identified the pivotal role of phosphatidylinositol 3-kinase (PI3K)/Akt in BBR cellular defense mechanisms and revealed the novel effect of BBR on nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2) and heme oxygenase (HO)-1 in NRK-52E and HK-2 cells. BBR attenuated reactive oxygen species production, antioxidant defense (GSH and SOD) and oxidant-sensitive proteins (Nrf2 and HO-1), which also were blocked by LY294002 (an inhibitor of PI3K) in HG-treated NRK-52E and HK-2 cells. Furthermore, BBR improved mitochondrial function by increasing mitochondrial membrane potential. BBR-induced anti-apoptotic function was demonstrated by decreasing apoptotic proteins (cytochrome c, Bax, caspase3 and caspase9). All these findings suggest that BBR exerts the anti-apoptosis effects through activation of PI3K/Akt signal pathways and leads to activation of Nrf2 and induction of Nrf2 target genes, and consequently protecting the renal tubular epithelial cells from HG-induced apoptosis.


PubMed | Liaoning Medical University, Troops of 93253 Unit and Troops of 95935 Unit
Type: Journal Article | Journal: Molecular medicine reports | Year: 2015

Curcumin has been observed to exhibit an anti-fibrotic effect in the liver, lung and gallbladder. However, the mechanisms underlying the cytoprotective effects of curcumin remain to be elucidated. The epithelial-to-mesenchymal transition (EMT) of mature tubular epithelial cells in the kidney is considered to contribute to the renal accumulation of matrix proteins associated with diabetic nephropathy. The EMT is also closely associated with the progression of renal interstitial fibrosis and oxidative stress. This process may occur through abrogation of high glucose (HG)-induced oxidative stress via activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1) in kidney tubular epithelial cells. In the present study, the effect of curcumin on HG-induced EMT in the NRK-52E normal rat kidney tubular epithelial cell line was investigated, and whether the effect of curcumin was mediated by the induction of Nrf2 and HO-1 expression was examined. The present study revealed that curcumin was able to prevent events associated with EMT, including the downregulation of E-cadherin and the increased expression of -smooth muscle actin. Further analysis revealed that the expression levels of Nrf2 and HO-1 protein were elevated to a greater extent in the curcumin pretreated NRK-52E cells compared with those of the control. Notably, knockdown of Nrf2 with small interfering RNA prevented the curcumin-induced elevation in expression of HO-1 and the associated anti-fibrotic effects. In conclusion, the present findings suggested that curcumin may be significant in cellular antioxidant defense, through the activation of Nrf2 and HO-1, thereby protecting the NRK-52E cells from HG-induced EMT.


Liang D.,Liaoning Medical University | Liang D.,Troops of 95935 Unit | Yang M.,Liaoning Medical University | Guo B.,Liaoning Medical University | And 3 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2012

Background β-Elemene, isolated from more than 50 Chinese herbs and plants, has shown promising anticancer effects against a broad spectrum of tumors, such as lung, breast, prostate, cervical, colon and ovarian carcinomas (Wang et al. in Cell Mol Life Sci 62: 881-893, 2005; Li et al. in Cell Mol Life Sci 62: 894-904, 2005; J Pharm Pharmacol 62(8): 1018-1027, 2010). But it has not reported in osteosarcoma cells. The aim of the present study is to investigate the antitumor effect of β-elemene on human osteosarcoma cancer cells and the molecular mechanism involved. Results β-Elemene inhibited the viability of human osteosarcoma cells in a dose-time-dependent manner. The suppression of cell viability was due to the induction of apoptosis. Our study also found that β-elemene treatment upregulated HIF-1α protein, which partially inhibits apoptosis. Knockdown of HIF-1α with small interfering RNA or co-treatment with the HIF-1α inhibitor YC-1 significantly enhanced the antitumor effects of β-elemene. Conclusions Our study first found that β-elemene could increase the expression of HIF-1α through ROS and PI3K/Akt/mTor signaling pathway. And HIF-1α partially prevents human osteosarcoma cells from undergoing apoptosis. The anticancer effects of β-elemene was weakened by HIF-1α. So, we recognize that a combination of β-elemene with HIF-1α inhibitor might be a useful therapeutic option for osteosarcoma. © Springer-Verlag 2012.


Liang D.,Liaoning Medical University | Liang D.,Troops of 95935 Unit | Yang M.,Liaoning Medical University | Guo B.,Liaoning Medical University | And 5 more authors.
Biological Trace Element Research | Year: 2012

Zinc has been shown to increase bone mass and promote bone cell proliferation and differentiation. We, therefore, hypothesized that zinc might be cytoprotective for bone cells during oxidative stress. The cells were divided into H2O2, zinc and zinc+H2O2 groups. In the present study, zinc was found to inhibit H2O 2-induced apoptosis in MC3T3-E1 cells, as shown by analysis of Annexin V/PI double staining. Western blot data showed that in zinc+H 2O2-treated cells, zinc decreased the levels of AIF, Bax and active caspase-9 and -3, which are pro-apoptotic factors. And zinc inhibited release of cytochrome c from mitochondria to cytosol in zinc+H 2O2-treated cells. Further investigation shows that protection is via activation of PI3K/Akt/mTor and MAPK /ERK pathways and inhibition of MAPK/P38 and MAPK/JNK pathways. Protecting osteoblast cells from oxidative damage presents a potential application in the treatment of osteoporosis. © 2011 Springer Science+Business Media, LLC.


Zhang X.,Liaoning Medical University | Zhang X.,Benxi Center Hospital | Zhao Y.,Liaoning Medical University | Chu Q.,Liaoning Medical University | And 3 more authors.
Biological Trace Element Research | Year: 2014

Hyperglycemia is a characteristic of diabetic nephropathy, inducing renal tubular cell apoptosis by eliciting oxidative stress and inflammation. Zinc (Zn) is known as an essential trace element in many enzymes and proteins involved in antioxidant defenses, electron transport, and exerting antiapoptotic or cytoprotective effects. In this study, the underlying mechanisms involved in the protective effects of Zn on high glucose-induced cytotoxicity were explored using cultured renal tubular epithelial cells (NRK-52E). The authors discovered that Zn supplementation inhibited high glucose (HG)-induced NRK-52E cell apoptosis by attenuating reactive oxygen species production, inhibiting HG-induced caspase-3 and caspase-9 activation, and inhibiting the release of cytochrome c from mitochondria to the cytosol. Further analysis revealed that Zn supplementation facilitated cell survival through increasing nuclear translocation of NF-E2-related factor 2 (Nrf2), leading to increased regulation of levels of two antioxidant enzymes, hemeoxygenase-1 and glutamate cysteine ligase, which provided an adaptive survival response against the HG-induced oxidative cytotoxicity. Moreover, the Zn-mediated increases in Nrf2 activity were suppressed by the pharmacological inhibition of Akt or extracellular signal-regulated kinase 1/2. Taken together, these findings suggest that Zn antiapoptosis capacity through the activation of Akt and ERK signal pathways leads to Nrf2 activation and, subsequently, Nrf2 target gene induction, thereby protecting the NRK-52E cells from HG-induced apoptosis. © 2014 Springer Science+Business Media.


Zhang X.,Liaoning Medical University | Zhang X.,Benxi Railway Hospital | Liang D.,Liaoning Medical University | Liang D.,Troops of 95935 Unit | And 4 more authors.
Biological Trace Element Research | Year: 2012

Zinc (Zn) plays an important role in influencing many types of apoptosis. However, its function in apoptosis in peritoneal mesothelial cells (PMCs) remains unknown. Here, we studied the effects of Zn on high glucose (HG)-induced apoptosis in rat PMCs (RPMCs) and examined the underlying molecular mechanisms. We found that Zn supplementation inhibited HG-induced RPMC apoptosis significantly, by attenuating reactive oxygen species (ROS) production, inhibiting HG-induced sFasR and sFasL over-expression, caspase-8 and caspase-3 activation, and inhibiting release of cytochrome c from mitochondria to the cytosol. Further analysis revealed that Zn supplementation facilitated cell survival through activation of the phosphatidylinositol 3-kinase/Akt signaling pathway and MAPK/ERK pathways. These results indicate that Zn can inhibit apoptosis in HG-induced RPMCs by several independent mechanisms, including an indirect antioxidative effect and probably by inhibition of caspase-8 and caspase-3 activation. © 2012 Springer Science+Business Media, LLC.


PubMed | Benxi Center Hospital, Troops of 95935 Unit and Liaoning Medical University
Type: Journal Article | Journal: International journal of molecular sciences | Year: 2016

Diabetic nephropathy (DN) is a serious diabetic complication with renal hypertrophy and expansion of extracellular matrices in renal fibrosis. Epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells may be involved in the main mechanism. Berberine (BBR) has been shown to have antifibrotic effects in liver, kidney and lung. However, the mechanism of cytoprotective effects of BBR in DN is still unclear. In this study, we investigated the curative effects of BBR on tubulointerstitial fibrosis in streptozotocin (STZ)-induced diabetic mice and the high glucose (HG)-induced EMT in NRK 52E cells. We found that BBR treatment attenuated renal fibrosis by activating the nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway in the diabetic kidneys. Further revealed that BBR abrogated HG-induced EMT and oxidative stress in relation not only with the activation of Nrf2 and two Nrf2-targeted antioxidative genes (NQO-1 and HO-1), but also with the suppressing the activation of TGF-/Smad signaling pathway. Importantly, knockdown Nrf2 with siRNA not only abolished the BBR-induced expression of HO-1 and NQO-1 but also removed the inhibitory effect of BBR on HG-induced activation of TGF-/Smad signaling as well as the anti-fibrosis effects. The data from present study suggest that BBR can ameliorate tubulointerstitial fibrosis in DN by activating Nrf2 pathway and inhibiting TGF-/Smad/EMT signaling activity.


PubMed | P.A. College, Liaoning Medical University and Troops of 95935 Unit
Type: Journal Article | Journal: International journal of molecular medicine | Year: 2016

Previous studies have demonstrated that zinc (Zn) is an essential trace element which is involved in male reproduction. The zinc transporter(ZnT) family, SLC30a, is involved in the maintenance of Zn homeostasis and in mediating intracellular signaling events; however, relatively little is known regarding the effect of ZnTs on testosterone synthesis. Thus, in the present study, we aimed to determine the effect of Zn transporter7(ZnT7) on testosterone synthesis in male CD-1 mice and mouse Leydig cells. The findings of the present study revealed that the concentrations of Zn in the testes and Leydig cells were significantly lower in mice fed a Zn-deficient diet compared with the control mice fed a Zn-adequate diet. In addition, ZnT7 was principally expressed and colocalized with steroidogenic acute regulatory protein(StAR) in the Leydig cells of male CD-1 mice. ZnT7 expression was downregulated in the mice fed a Zn-deficient diet, which led to decreases in the expression of the enzymes involved in testosterone synthesis namely cholesterol sidechain cleavage enzyme(P450scc) and 3-hydroxysteroid dehydrogenase/D5-D4 isomerase(3-HSD) as well as decreased serum testosterone levels. These results suggested that Znt7 may be involved in testosterone synthesis in the mouse testes. To examine this hypothesis, we used the mouse Leydig tumor cell line(MLTC-1 cell line) in which the ZnT7 gene had been silenced, in order to gauge the impact of changes in ZnT7 expression on testosterone secretion and the enzymes involved in testosterone synthesis. The results demonstrated that ZnT7 gene silencing downregulated the expression of StAR, P450scc and 3-HSD as well as progesterone concentrations in the human chorionic gonadotrophin(hCG)-stimulated MLTC-1 cells. Taken together, these findings reveal that ZnT7 may play an important role in the regulation of testosterone synthesis by modulating steroidogenic enzymes, and may represent a therapeutic target in testosterone deficiency.

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