Search Results: 1 - 10 of 100 matches for " "
All listed articles are free for downloading (OA Articles)
Page 1 /100
Display every page Item
Celastrol Blocks Interleukin-6 Gene Expression via Downregulation of NF-κB in Prostate Carcinoma Cells  [PDF]
Kun-Chun Chiang, Ke-Hung Tsui, Li-Chuan Chung, Chun-Nan Yeh, Wen-Tsung Chen, Phei-Lang Chang, Horng-Heng Juang
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0093151
Abstract: Interleukin-6 (IL-6), a multifunctional cytokine, contributes to proliferation or differentiation of prostate carcinoma cells in a highly cell type-specific manner. Celastrol (3-hydroxy-24-nor-2oxo-1(10),3,5,7-fried?elatetrane-29-oicacid), also named as tripterine, is extracted from root of Chinese traditional herb Tripterygiumwilfordii Hook f with potent anti-inflammatory and anti-cancer activities. In this study, we evaluated the molecular mechanisms of celastrol on cell proliferation and IL-6 gene expression in prostate carcinoma cells. 3H-thymidine incorporation and flow cytometric analysis indicated that celastrol treatments arrested the cell cycle at the G0/G1 phase, thus attenuating cell proliferation in prostate carcinoma PC-3 cells; moreover, celastrol induced cell apoptosis at higher dosage. Knockdown of IL-6 attenuated the anti-proliferative effect of celastrol on PC-3 cells. Results from ELISA and 5’-deletion transient gene expression assays indicated that celastrol treatment decreased IL-6 secretion and gene expression, and this effect is dependent on the NF-κB response element within IL-6 promoter area since mutation of the NF-κB response element from AAATGTCCCATTTTCCC to AAATGTTACATTTTCCC by site-directed mutagenesis abolished the inhibition of celastrol on the IL-6 promoter activity. Celastrol also attenuated the activation of PMA and TNFα on the gene expression and secretion of IL-6 in PC-3 cells. Immunoblot assays revealed that celastrol treatment downregulated the expressions of IKKα, p50 and p65, supporting the 5’-deletion transient gene expression assay result that celastrol blocked IL-6 expression through the NF-κB pathway in PC-3 cells. For the first time, our results concluded that celastrol attenuates PC-3 cell proliferation via downregulation of IL-6 gene expression through the NF-κB-dependent pathway.
NF-Kappa B Modulation Is Involved in Celastrol Induced Human Multiple Myeloma Cell Apoptosis  [PDF]
Haiwen Ni, Wanzhou Zhao, Xiangtu Kong, Haitao Li, Jian Ouyang
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0095846
Abstract: Celastrol is an active compound extracted from the root bark of the traditional Chinese medicine Tripterygium wilfordii Hook F. To investigate the effect of celastrol on human multiple myeloma cell cycle arrest and apoptosis and explore its molecular mechanism of action. The activity of celastrol on LP-1 cell proliferation was detected by WST-8 assay. The celastrol-induced cell cycle arrest was analyzed by flow cytometry after propidium iodide staining. Nuclear translocation of the nuclear factor kappa B (NF-κB) was observed by fluorescence microscope. Celastrol inhibited cell proliferation of LP-1 myeloma cell in a dose-dependent manner with IC50 values of 0.8817 μM, which was mediated through G1 cell cycle arrest and p27 induction. Celastrol induced apoptosis in LP-1 and RPMI 8226 myeloma cells in a time and dose dependent manner, and it involved Caspase-3 activation and NF-κB pathway. Celastrol down-modulated antiapoptotic proteins including Bcl-2 and survivin expression. The expression of NF-κB and IKKa were decreased after celastrol treatment. Celastrol effectively blocked the nuclear translocation of the p65 subunit and induced human multiple myeloma cell cycle arrest and apoptosis by p27 upregulation and NF-kB modulation. It has been demonstrated that the effect of celastrol on NF-kB was HO-1-independent by using zinc protoporphyrin-9 (ZnPPIX), a selective heme oxygenase inhibitor. From the results, it could be inferred that celastrol may be used as a NF-kB inhibitor to inhibit myeloma cell proliferation.
Natural Proteasome Inhibitor Celastrol Suppresses Androgen-Independent Prostate Cancer Progression by Modulating Apoptotic Proteins and NF-kappaB  [PDF]
Yao Dai,Jeffrey DeSano,Wenhua Tang,Xiaojie Meng,Yang Meng,Ezra Burstein,Theodore S. Lawrence,Liang Xu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014153
Abstract: Celastrol is a natural proteasome inhibitor that exhibits promising anti-tumor effects in human malignancies, especially the androgen-independent prostate cancer (AIPC) with constitutive NF-κB activation. Celastrol induces apoptosis by means of proteasome inhibition and suppresses prostate tumor growth. However, the detailed mechanism of action remains elusive. In the current study, we aim to test the hypothesis that celastrol suppresses AIPC progression via inhibiting the constitutive NF-κB activity as well as modulating the Bcl-2 family proteins.
The NF-kappa B inhibitor, celastrol, could enhance the anti-cancer effect of gambogic acid on oral squamous cell carcinoma
Di He, Qin Xu, Ming Yan, Ping Zhang, Xiaojian Zhou, Zhiyuan Zhang, Wenhu Duan, Laiping Zhong, Dongxia Ye, Wantao Chen
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-343
Abstract: Three human oral squamous cell carcinoma cell lines, Tca8113, TSCC and NT, were treated with GA alone, celastrol alone or GA plus celastrol. Cytotoxicity was assessed by MTT assay. The rate of apoptosis was examined with annexin V/PI staining as well as transmission electronic microscopy in Tca8113 cells. The level of constitutive NF-kappa B activity in oral squamous cell carcinoma cell lines was determined by immunofluorescence assays and nuclear extracts and electrophoretic mobility shift assays (EMSAs) in vitro. To further investigate the role of NF-kappa B activity in GA and celastrol treatment in oral squamous cell carcinoma, we used the dominant negative mutant SR-IκBα to inhibit NF-kappa B activity and to observe its influence on the effect of GA.The results showed that GA could inhibit the proliferation and induce the apoptosis of the oral squamous cell carcinoma cell lines and that the NF-kappa B pathway was simultaneously activated by GA treatment. The minimal cytotoxic dose of celastrol was able to effectively suppress the GA-induced NF-kappa B pathway activation. Following the combined treatment with GA and the minimal cytotoxic dose of celastrol or the dominant negative mutant SR-IκBα, proliferation was significantly inhibited, and the apoptotic rate of Tca8113 cells was significantly increased.The combination of GA and celastrol has a synergistic antitumor effect. The effect can be primarily attributed to apoptosis induced by a decrease in NF-kappa B pathway activation. The NF-kappa B signaling pathway plays an important role in this process. Therefore, combining GA and celastrol may be a promising modality for treating oral squamous cell carcinoma.Despite improvements in surgery and radiation, the overall survival rate of patients with oral squamous cell carcinoma (OSCC) has not improved over the past two decades[1]. Chemotherapy (pre- or post-surgery) does not appear to be beneficial for local control and survival improvement in the patients with OSC
Celastrol Suppresses Tumor Cell Growth through Targeting an AR-ERG-NF-κB Pathway in TMPRSS2/ERG Fusion Gene Expressing Prostate Cancer  [PDF]
Longjiang Shao, Zhansong Zhou, Yi Cai, Patricia Castro, Olga Dakhov, Ping Shi, Yaoxia Bai, Huixiang Ji, Wenhao Shen, Jianghua Wang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0058391
Abstract: The TMPRSS2/ERG (T/E) fusion gene is present in the majority of all prostate cancers (PCa). We have shown previously that NF-kB signaling is highly activated in these T/E fusion expressing cells via phosphorylation of NF-kB p65 Ser536 (p536). We therefore hypothesize that targeting NF-kB signaling may be an efficacious approach for the subgroup of PCas that carry T/E fusions. Celastrol is a well known NF-kB inhibitor, and thus may inhibit T/E fusion expressing PCa cell growth. We therefore evaluated Celastrol’s effects in vitro and in vivo in VCaP cells, which express the T/E fusion gene. VCaP cells were treated with different concentrations of Celastrol and growth inhibition and target expression were evaluated. To test its ability to inhibit growth in vivo, 0.5 mg/kg Celastrol was used to treat mice bearing subcutaneous VCaP xenograft tumors. Our results show Celastrol can significantly inhibit the growth of T/E fusion expressing PCa cells both in vitro and in vivo through targeting three critical signaling pathways: AR, ERG and NF-kB in these cells. When mice received 0.5 mg/kg Celastrol for 4 times/week, significant growth inhibition was seen with no obvious toxicity or significant weight loss. Therefore, Celastrol is a promising candidate drug for T/E fusion expressing PCa. Our findings provide a novel strategy for the targeted therapy which may benefit the more than half of PCa patients who have T/E fusion expressing PCas.
Celastrol Inhibits Lipopolysaccharide-Stimulated Rheumatoid Fibroblast-Like Synoviocyte Invasion through Suppression of TLR4/NF-κB-Mediated Matrix Metalloproteinase-9 Expression  [PDF]
Guoqing Li, Dan Liu, Yu Zhang, Yayun Qian, Hua Zhang, Shiyu Guo, Masataka Sunagawa, Tadashi Hisamitsu, Yanqing Liu
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0068905
Abstract: Invasion of fibroblast-like synoviocytes (FLSs) is critical in the pathogenesis of rheumatoid arthritis (RA). The metalloproteinases (MMPs) and activator of Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway play a critical role in RA-FLS invasion induced by lipopolysaccharide (LPS). The present study aimed to explore the anti-invasive activity of celastrol on LPS-stimulated human RA-FLSs, and to elucidate the mechanism involved. We investigated the effect of celastrol on LPS-induced FLS migration and invasion as well as MMP expression and explored the upstream signal transduction. Results showed that celastrol suppressed LPS-stimulated FLS migration and invasion by inhibiting MMP-9 expression and activity. Furthermore, our results revealed that celastrol inhibited the transcriptional activity of MMP-9 by suppressing the binding activity of NF-κB in the MMP-9 promoter, and suppressed the TLR4/MyD88/NF-κB pathway. Administration of celastrol (0.5 mg/kg and 1 mg/kg, intraperitoneally) daily for 3 weeks in a collagen-induced arthritis rat model markedly alleviated the clinical signs, synovial hyperplasia and inflammatory cell infiltration of joints. In conclusion, celastrol might inhibit FLS migration and invasion induced by LPS by suppressing TLR4/NF-κB-mediated MMP-9 expression, providing a theoretical foundation for the clinical treatment of RA with celastrol.
Rosiglitazone Treatment of Type 2 Diabetic db/db Mice Attenuates Urinary Albumin and Angiotensin Converting Enzyme 2 Excretion  [PDF]
Harshita Chodavarapu, Nadja Grobe, Hari K. Somineni, Esam S. B. Salem, Malav Madhu, Khalid M. Elased
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0062833
Abstract: Alterations within the renal renin angiotensin system play a pivotal role in the development and progression of cardiovascular and renal disease. Angiotensin converting enzyme 2 (ACE2) is highly expressed in renal tubules and has been shown to be renoprotective in diabetes. The protease, a disintegrin and metalloprotease (ADAM) 17, is involved in the ectodomain shedding of several transmembrane proteins including ACE2. Renal ACE2 and ADAM17 were significantly increased in db/db mice compared to controls. We investigated the effect of the insulin sensitizer, rosiglitazone, on albuminuria, renal ADAM17 protein expression and ACE2 shedding in db/db diabetic mice. Rosiglitazone treatment of db/db mice normalized hyperglycemia, attenuated renal injury and decreased urinary ACE2 and renal ADAM17 protein expression. Urinary excreted ACE2 is enzymatically active. Western blot analysis of urinary ACE2 demonstrated two prominent immunoreactive bands at approximately 70 & 90 kDa. The predominant immunoreactive band is approximately 20 kDa shorter than the one demonstrated for kidney lysate, indicating possible ectodomain shedding of active renal ACE2 in the urine. Therefore, it is tempting to speculate that renoprotection of rosiglitazone could be partially mediated via downregulation of renal ADAM17 and ACE2 shedding. In addition, there was a positive correlation between blood glucose, urinary albumin, plasma glucagon, and triglyceride levels with urinary ACE2 excretion. In conclusion, urinary ACE2 could be used as a sensitive biomarker of diabetic nephropathy and for monitoring the effectiveness of renoprotective medication.
Diacerhein attenuates the inflammatory response and improves survival in a model of severe sepsis
Kelly L Calisto, Angélica C Camacho, Francine C Mittestainer, Bruno M Carvalho, Dioze Guadagnini, José B Carvalheira, Mario J Saad
Critical Care , 2012, DOI: 10.1186/cc11478
Abstract: Diffuse sepsis was induced by cecal ligation and puncture surgery (CLP) in male Wistar rats. Blood glucose and inflammatory cytokine levels were assessed 24 hours after CLP. The effect of diacerhein on survival of septic animals was investigated in parallel with insulin signaling and its modulators in liver, muscle, and adipose tissue.Here we demonstrated that diacerhein treatment improves survival during peritoneal-induced sepsis and inhibits sepsis-induced insulin resistance by improving insulin signaling via increased insulin-receptor substrate-1-associated phosphatidylinositol 3-kinase activity and Akt phosphorylation. Diacerhein also decreases the activation of endoplasmic reticulum stress signaling that involves upregulation of proinflammatory pathways, such as the I kappa B kinase and c-Jun NH2-terminal kinase, which blunts insulin-induced insulin signaling in liver, muscle, and adipose tissue. Additionally, our data show that this drug promoted downregulation of proinflammatory signaling cascades that culminate in transcription of immunomodulatory factors such interleukin (IL)-1β, IL-6, and tumor necrosis factor-α.This study demonstrated that diacerhein treatment increases survival and attenuates the inflammatory response with a significant effect on insulin sensitivity. On the basis of efficacy and safety profile, diacerhein represents a novel antiinflammatory therapy for management of insulin resistance in sepsis and a potential approach for future clinical trials.Sepsis is defined as a systemic inflammatory response syndrome caused by the body's response to an infection [1]. During the onset of sepsis, the inflammatory system becomes hyperactive, leading to a production of proinflammatory molecules and cytokine release [2], which contribute to septic shock, multiple organ failure, and death. Hyperglycemia and insulin resistance occur as a consequence of the metabolic effects of stress hormones and the overproduction of proinflammatory mediators in sepsis
Astaxanthin Attenuates the Apoptosis of Retinal Ganglion Cells in db/db Mice by Inhibition of Oxidative Stress  [PDF]
Ling-Yan Dong,Jie Jin,Gao Lu,Xiao-Li Kang
Marine Drugs , 2013, DOI: 10.3390/md11030960
Abstract: Diabetic retinopathy is a common diabetic eye disease caused by changes in retinal ganglion cells (RGCs). It is an ocular manifestation of systemic disease, which affects up to 80% of all patients who have had diabetes for 10 years or more. The genetically diabetic db / db mouse, as a model of type-2 diabetes, shows diabetic retinopathy induced by apoptosis of RGCs. Astaxanthin is a carotenoid with powerful antioxidant properties that exists naturally in various plants, algae and seafood. Here, astaxanthin was shown to reduce the apoptosis of RGCs and improve the levels of oxidative stress markers, including superoxide anion, malondialdehyde (MDA, a marker of lipid peroxidation), 8-hydroxy-2-deoxyguanosine (8-OHdG, indicator of oxidative DNA damage) and MnSOD (manganese superoxide dismutase) activity in the retinal tissue of db / db mouse. In addition, astaxanthin attenuated hydrogen peroxide(H 2O 2)-induced apoptosis in the transformed rat retinal ganglion cell line RGC-5. Therefore, astaxanthin may be developed as an antioxidant drug to treat diabetic retinopathy.
Fenofibrate Improves Renal Lipotoxicity through Activation of AMPK-PGC-1α in db/db Mice  [PDF]
Yu Ah Hong, Ji Hee Lim, Min Young Kim, Tae Woo Kim, Yaeni Kim, Keun Suk Yang, Hoon Suk Park, Sun Ryoung Choi, Sungjin Chung, Hyung Wook Kim, Hye Won Kim, Bum Soon Choi, Yoon Sik Chang, Cheol Whee Park
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0096147
Abstract: Peroxisome proliferator-activated receptor (PPAR)-α, a lipid-sensing transcriptional factor, serves an important role in lipotoxicity. We evaluated whether fenofibrate has a renoprotective effect by ameliorating lipotoxicity in the kidney. Eight-week-old male C57BLKS/J db/m control and db/db mice, divided into four groups, received fenofibrate for 12 weeks. In db/db mice, fenofibrate ameliorated albuminuria, mesangial area expansion and inflammatory cell infiltration. Fenofibrate inhibited accumulation of intra-renal free fatty acids and triglycerides related to increases in PPARα expression, phosphorylation of AMP-activated protein kinase (AMPK), and activation of Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-estrogen-related receptor (ERR)-1α-phosphorylated acetyl-CoA carboxylase (pACC), and suppression of sterol regulatory element-binding protein (SREBP)-1 and carbohydrate regulatory element-binding protein (ChREBP)-1, key downstream effectors of lipid metabolism. Fenofibrate decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and FoxO3a phosphorylation in kidneys, increasing the B cell leukaemia/lymphoma 2 (BCL-2)/BCL-2-associated X protein (BAX) ratio and superoxide dismutase (SOD) 1 levels. Consequently, fenofibrate recovered from renal apoptosis and oxidative stress, as reflected by 24 hr urinary 8-isoprostane. In cultured mesangial cells, fenofibrate prevented high glucose-induced apoptosis and oxidative stress through phosphorylation of AMPK, activation of PGC-1α-ERR-1α, and suppression of SREBP-1 and ChREBP-1. Our results suggest that fenofibrate improves lipotoxicity via activation of AMPK-PGC-1α-ERR-1α-FoxO3a signaling, showing its potential as a therapeutic modality for diabetic nephropathy.
Page 1 /100
Display every page Item

Copyright © 2008-2017 Open Access Library. All rights reserved.