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Chen L.,Nanjing Medical University | Li C.,Nanjing Medical University | Zhang R.,Nanjing Medical University | Gao X.,Nanjing Medical University | And 5 more authors.
Cancer Letters | Year: 2011

miRNAs play important roles in the regulation of cell proliferation, differentiation and apoptosis. The deregulation of miRNAs expression contributes to tumorigenesis by modulating oncogenic and tumor suppressor signaling pathways. Oncogenic transcription factor Myc can control expression of a large set of microRNAs (miRNAs). Previous studies have shown that the expression of miR-17-92 cluster, a polycistron encoding six microRNAs (miRNA), has close relationship with the expression of Myc. In current study, silencing Myc in multiple myeloma (MM)cells induced cell death and growth inhibition, and downregulated expression of miR-17-92 cluster. Overexpression of miR-17 or miR-18 could partly abrogated Myc-knockdown-induced MM cell apoptosis. One of the mechanism of Myc inhibiting MM cell apoptosis is through Myc activates miR-17-92 cluster and subsequently down-modulates proapoptotic protein Bim. Although miR-17-92 cluster are located at 13q31.3, the expression of miR-18, miR-19 and miR-20 (especially miR-19) in patients with del(13q14) was higher than those without del(13q14). Patients with miR-17, miR-20 and miR-92 high-expression had shorter PFS compared to those with miR-17, miR-20 and miR-92 low-expression. These results suggest the Myc-inducible miR-17-92 cluster miRNAs contribute to tumorigenesis and poor prognosis in multiple myeloma. © 2011 Elsevier Ireland Ltd. Source


Liu H.,Nanjing University | Gu L.-B.,Jiangsu Province Institute of Geriatrics | Tu Y.,Nanjing University | Hu H.,Nanjing University | And 2 more authors.
Acta Pharmacologica Sinica | Year: 2016

Aim:A previous report shows that emodin extracted from the Chinese herbs rhubarb and giant knotweed rhizome can ameliorate the anticancer drug cisplatin-induced injury of HEK293 cells. In this study, we investigated whether and how emodin could protect renal tubular epithelial cells against cisplatin-induced nephrotoxicity in vitro.Methods:The viability and apoptosis of normal rat renal tubular epithelial cells (NRK-52E) were detected using formazan assay and flow cytometry analysis, respectively. The expression levels of cleaved caspase-3, autophagy maker LC3 I/II, and AMPK/mTOR signaling pathway-related proteins were measured with Western blot analysis. The changes of morphology and RFP-LC3 fluorescence were observed under microscopy.Results:Cisplatin (10-50 μmol/L) dose-dependently induced cell damage and apoptosis in NRK-52E cells, whereas emodin (10 and 100 μmol/L) significantly ameliorated cisplatin-induced cell damage, apoptosis and caspase-3 cleavage. Emodin dose-dependently increased LC3-II levels and induced RFP-LC3-containing punctate structures in NRK-52E cells. Furthermore, the protective effects of emodin were abolished by bafilomycin A1 (10 nmol/L), and mimicked by rapamycin (100 nmol/L). Moreover, emodin increased the phosphorylation of AMPK and suppressed the phosphorylation of mTOR. The AMPK inhibitor compound C (10 μmol/L) not only abolished emodin-induced autophagy activation, but also emodin-induced anti-apoptotic effects.Conclusion:Emodin ameliorates cisplatin-induced apoptosis of rat renal tubular cells in vitro through modulating the AMPK/mTOR signaling pathways and activating autophagy. Emodin may have therapeutic potential for the prevention of cisplatin-induced nephrotoxicity. © 2016 CPS and SIMM All rights reserved. Source


Gu L.,Yamanashi University | Gu L.,Jiangsu Province Institute of Geriatrics | Kitamura M.,Yamanashi University
PLoS ONE | Year: 2012

Senescence-associated secretory phenotype (SASP) is characterized by abundant secretion of various proteins in senescent cells and implicated in tumor progression and inflammatory responses. However, the profile of secreted proteins in SASP is different from cell type to cell type, and currently, universal markers for SASP have not been reported. In the present investigation, we show that SASP-responsive alkaline phosphatase (SASP-RAP) serves as a sensitive, general and convenient marker for SASP. Etoposide-treated cells exhibited a senescent phenotype characterized by senile morphology, positive staining for senescence-associated β-galactosidase, growth arrest and induction of p53 and p21WAF1/CIP1. In SASP-RAP-transfected cells, exposure to etoposide increased secretion of SASP-RAP time-dependently. The kinetics of secretion was closely correlated with that of activation of the p21WAF1/CIP1 promoter and the p16INK4a promoter. The enhanced secretion of SASP-RAP by senescence was also observed in cells treated with other senescence inducers such as trichostatin A, doxorubicin and 4-phenylbutylic acid. The induction of SASP-RAP by senescence was similarly observed in natural replicative senescence. To confirm selectivity of the SASP-RAP response, cells were treated with senescence-related and -unrelated stimuli (IL-1β, LPS, TNF-α and TGF-β), and induction of senescence markers and activity of SASP-RAP were evaluated in parallel. Unlike etoposide, senescence-unrelated stimuli did not induce p53 and p21WAF1/CIP1, and it was correlated with lack of induction of SASP-RAP. In contrast, senescence-unrelated stimuli up-regulated conventional indicators for SASP, e.g., MMP-3, IL-6 and TIMP, without induction of senescence. SASP-RAP thus serves as a selective, convenient and general marker for detection and monitoring of SASP during cellular senescence. © 2012 Gu, Kitamura. Source


Ouyang X.,Nanjing Medical University | Ouyang X.,Oklahoma Medical Research Foundation | Ouyang X.,Jiangsu Province Institute of Geriatrics | Ouyang X.,University of Oklahoma | And 8 more authors.
Neurogastroenterology and Motility | Year: 2015

Background: Hyperglycemia is known to induce dysrhythmias in the stomach; however, it is unknown whether they are also induced in the small intestine. Autonomic dysfunction is commonly noted in diabetes but the role it plays in hyperglycemia-induced dysrhythmias remains unknown. This study aimed to explore the effects of hyperglycemia on intestinal myoelectrical activity and the role of autonomic functions in hyperglycemia. Methods: Small intestinal myoelectrical activity (slow wave and spike activity) and autonomic functions (assessed by the spectral analysis of heart rate variability) were measured in Goto-Kakizaki diabetic rats and control rats treated with acute glucagon. Blood glucose was measured and its correlation with intestinal slow waves was determined. Key Results: (1) The diabetic rats showed reduced regularity in intestinal slow waves in fasting and fed states (p < 0.001 for both), and increased sympathovagal balance (p < 0.05) in comparison with the control rats. The regularity in intestinal slow waves was negatively correlated with the HbA1c level in all rats (r = -0.663, p = 0.000). (2) Glucagon injection in the control rats induced transient hyperglycemia, intestinal slow wave dysrhythmias and impaired autonomic functions, similar to those observed in the diabetic rats. The increase in blood glucose was correlated with the decrease in the regularity of intestinal slow waves (r = -0.739, p = 0.015). Conclusions & Inferences: Both spontaneous and glucagon-induced hyperglycemia results in slow wave dysrhythmias in the small intestine. Impairment in autonomic functions (increased sympathovagal balance) may play a role in hyperglycemia-induced dysrhythmias. This study suggests that hyperglycemia results in slow wave dysrhythmias in the small intestine. Impairment in autonomic functions is believed to play a role in hyperglycemia-induced slow wave dysrhythmias. © 2015 John Wiley & Sons Ltd. Source


Gu L.,Yamanashi University | Gu L.,Jiangsu Province Institute of Geriatrics | Johno H.,Yamanashi University | Nakajima S.,Yamanashi University | And 4 more authors.
Laboratory Investigation | Year: 2013

Cordyceps militaris has been used in Eastern countries for the treatment of various diseases including chronic kidney diseases. However, there are no reports that identified its active entities and molecular mechanisms underlying its therapeutic effectiveness. 3′-Deoxyadenosine is a major nucleoside derivative isolated from C. militaris. Some reports suggested that both C. militaris and 3′-deoxyadenosine have anti-inflammatory and anti-fibrotic effects. In the present report, we investigated whether and how 3′-deoxyadenosine interferes with fibrogenic processes in the kidney. For this purpose, we examined effects of 3′-deoxyadenosine on the expression of collagens triggered by transforming growth factor-β (TGF-β1) and bone morphogenetic protein-4 (BMP-4), especially focusing on the regulation of Smad signaling in vitro and in vivo. We found that 3′-deoxyadenosine suppressed expression of collagens induced by TGF-β1 and BMP-4 dose dependently. This suppression occurred at the transcriptional level and was correlated with blunted activation of the CAGA box and the BMP-responsive element. The suppressive effect on the TGF-β/BMP signaling was mediated mainly by adenosine transporter and partially by the A3 adenosine receptor, but not A1/A2 adenosine receptors. 3′-Deoxyadenosine reduced levels of both phosphorylated and total Smad proteins (Smad1, 2 and 3) dose dependently. It was mainly ascribed to transcriptional suppression, but not to enhanced protein degradation and eIF2α-mediated translational suppression. Consistent with the in vitro results, in vivo administration with 3′-deoxyadenosine reduced the levels of phosphorylated and total Smad proteins, as well as the levels of Smad mRNAs, in the kidney subjected to unilateral ureteral obstruction. It was associated with blunted induction of type I collagen and α-smooth muscle actin, a decrease in the number of interstitial myofibroblasts and reduced fibrotic area. These results suggest that 3′-deoxyadenosine interferes with the TGF-β and BMP signaling via downregulation of Smads, which may underlie the anti-fibrotic effect of this agent. 3′-Deoxyadenosine may be useful for therapeutic intervention in various TGF-β-related fibrotic disorders. Source

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