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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.
Chemokine Expression in Inflamed Adipose Tissue Is Mainly Mediated by NF-κB  [PDF]
Franck Tourniaire, Beatrice Romier-Crouzet, Jong Han Lee, Julie Marcotorchino, Erwan Gouranton, Jerome Salles, Christiane Malezet, Julien Astier, Patrice Darmon, Eric Blouin, Stephane Walrand, Jianping Ye, Jean-Francois Landrier
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066515
Abstract: Immune cell infiltration of expanding adipose tissue during obesity and its role in insulin resistance has been described and involves chemokines. However, studies so far have focused on a single chemokine or its receptor (especially CCL2 and CCL5) whereas redundant functions of chemokines have been described. The objective of this work was to explore the expression of chemokines in inflamed adipose tissue in obesity. Human and mouse adipocytes were analyzed for expression of chemokines in response to inflammatory signal (TNF-α) using microarrays and gene set enrichment analysis. Gene expression was verified by qRT-PCR. Chemokine protein was determined in culture medium with ELISA. Chemokine expression was investigated in human subcutaneous adipose tissue biopsies and mechanism of chemokine expression was investigated using chemical inhibitors and cellular and animal transgenic models. Chemokine encoding genes were the most responsive genes in TNF-α treated human and mouse adipocytes. mRNA and protein of 34 chemokine genes were induced in a dose-dependent manner in the culture system. Furthermore, expression of those chemokines was elevated in human obese adipose tissue. Finally, chemokine expression was reduced by NF-κB inactivation and elevated by NF-κB activation. Our data indicate that besides CCL2 and CCL5, numerous other chemokines such as CCL19 are expressed by adipocytes under obesity-associated chronic inflammation. Their expression is regulated predominantly by NF-κB. Those chemokines could be involved in the initiation of infiltration of leukocytes into obese adipose tissue.
The Early Nutritional Environment of Mice Determines the Capacity for Adipose Tissue Expansion by Modulating Genes of Caveolae Structure  [PDF]
Leslie P. Kozak,Susan Newman,Pei-Min Chao,Tamra Mendoza,Robert A. Koza
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011015
Abstract: While the phenomenon linking the early nutritional environment to disease susceptibility exists in many mammalian species, the underlying mechanisms are unknown. We hypothesized that nutritional programming is a variable quantitative state of gene expression, fixed by the state of energy balance in the neonate, that waxes and wanes in the adult animal in response to changes in energy balance. We tested this hypothesis with an experiment, based upon global gene expression, to identify networks of genes in which expression patterns in inguinal fat of mice have been altered by the nutritional environment during early post-natal development. The effects of over- and under-nutrition on adiposity and gene expression phenotypes were assessed at 5, 10, 21 days of age and in adult C57Bl/6J mice fed chow followed by high fat diet for 8 weeks. Under-nutrition severely suppressed plasma insulin and leptin during lactation and diet-induced obesity in adult mice, whereas over-nourished mice were phenotypically indistinguishable from those on a control diet. Food intake was not affected by under- or over-nutrition. Microarray gene expression data revealed a major class of genes encoding proteins of the caveolae and cytoskeleton, including Cav1, Cav2, Ptrf (Cavin1), Ldlr, Vldlr and Mest, that were highly associated with adipose tissue expansion in 10 day-old mice during the dynamic phase of inguinal fat development and in adult animals exposed to an obesogenic environment. In conclusion gene expression profiles, fat mass and adipocyte size in 10 day old mice predicted similar phenotypes in adult mice with variable diet-induced obesity. These results are supported by phenotypes of KO mice and suggest that when an animal enters a state of positive energy balance adipose tissue expansion is initiated by coordinate changes in mRNA levels for proteins required for modulating the structure of the caveolae to maximize the capacity of the adipocyte for lipid storage.
Raloxifene Suppresses Experimental Autoimmune Encephalomyelitis and NF-κB-Dependent CCL20 Expression in Reactive Astrocytes  [PDF]
Rui Li, Wen Xu, Ying Chen, Wei Qiu, Yaqing Shu, Aimin Wu, Yongqiang Dai, Jian Bao, Zhengqi Lu, Xueqiang Hu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094320
Abstract: Recent clinical data have led to the consideration of sexual steroids as new potential therapeutic tools for multiple sclerosis. Selective estrogen receptor modulators can exhibit neuroprotective effects like estrogen, with fewer systemic estrogen side effects than estrogen, offering a more promising therapeutic modality for multiple sclerosis. The important role of astrocytes in a proinflammatory effect mediated by CCL20 signaling on inflammatory cells has been documented. Their potential contribution to selective estrogen receptor modulator-mediated protection is still unknown. Using a mouse model of chronic neuroinflammation, we report that raloxifene, a selective estrogen receptor modulator, alleviated experimental autoimmune encephalomyelitis–an animal model of multiple sclerosis–and decreased astrocytic production of CCL20. Enzyme-linked immunosorbent assay, immunohistochemistry imaging and transwell migration assays revealed that reactive astrocytes express CCL20, which promotes Th17 cell migration. In cultured rodent astrocytes, raloxifene inhibited IL-1β-induced CCL20 expression and chemotaxis ability for Th17 migration, whereas the estrogen receptor antagonist ICI 182,780 blocked this effect. Western blotting further indicated that raloxifene suppresses IL-1β-induced NF-κB activation (phosphorylation of p65) and translocation but does not affect phosphorylation of IκB. In conclusion, these data demonstrate that raloxifene provides robust neuroprotection against experimental autoimmune encephalomyelitis, partially via an inhibitory action on CCL20 expression and NF-κB pathways in reactive astrocytes. Our results contribute to a better understanding of the critical roles of raloxifene in treating experimental autoimmune encephalomyelitis and uncover reactive astrocytes as a new target for the inhibitory action of estrogen receptors on chemokine CCL20 expression.
A Smac-mimetic sensitizes prostate cancer cells to TRAIL-induced apoptosis via modulating both IAPs and NF-kappaB
Yao Dai, Meilan Liu, Wenhua Tang, Yongming Li, Jiqin Lian, Theodore S Lawrence, Liang Xu
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-392
Abstract: The potential of Smac-mimetics to bind XIAP or cIAP-1 was examined by pull-down assay. Cytotoxicity of TRAIL and/or Smac-mimetics was determined by a standard cell growth assay. Silencing of XIAP or cIAP-1 was achieved by transient transfection of short hairpin RNA. Apoptosis was detected by Annexin V-PI staining followed by flow cytometry and by Western Blot analysis of caspases, PARP and Bid. NF-kappaB activation was determined by subcellular fractionation, real time RT-PCR and reporter assay.SH122, but not its inactive analog, binds to XIAP and cIAP-1. SH122 significantly sensitized prostate cancer cells to TRAIL-mediated cell death. Moreover, SH122 enhanced TRAIL-induced apoptosis via both the death receptor and the mitochondrial pathway. Knockdown of both XIAP and cIAP-1 sensitized cellular response to TRAIL. XIAP-knockdown attenuated sensitivity of SH122 to TRAIL-induced cytotoxicity, confirming that XIAP is an important target for IAP-inhibitor-mediated TRAIL sensitization. SH122 also suppressed TRAIL-induced NF-kappaB activation by preventing cytosolic IkappaB-alpha degradation and RelA nuclear translocation, as well as by suppressing NF-kappaB target gene expression.These results demonstrate that SH122 sensitizes human prostate cancer cells to TRAIL-induced apoptosis by mimicking Smac and blocking both IAPs and NF-kappaB. Modulating IAPs may represent a promising approach to overcoming TRAIL-resistance in human prostate cancer with constitutively active NF-kappaB signaling.Primary or acquired resistance of prostate cancer to current treatment protocols has been associated with apoptosis-resistance in cancer cells, leading to therapy failure [1,2]. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that is in clinical trials for the treatment of prostate cancer, either alone or in combination with other treatments [3]. TRAIL selectively induces apoptosis in prostate cancer cells compared to normal prostate epithelia
Tripeptidyl Peptidase II Regulates Sperm Function by Modulating Intracellular Ca2+ Stores via the Ryanodine Receptor  [PDF]
Yuchuan Zhou, Yanfei Ru, Chunmei Wang, Shoulin Wang, Zuomin Zhou, Yonglian Zhang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066634
Abstract: Recent studies have identified Ca2+ stores in sperm cells; however, it is not clear whether these Ca2+ stores are functional and how they are mobilized. Here, in vitro and in vivo, we determined that tripeptidyl peptidase II antagonists strongly activated the cAMP/PKA signaling pathway that drives sperm capacitation-associated protein tyrosine phosphorylation. We demonstrated that in the absence of Ca2+, TPIII antagonists elevated the intracellular Ca2+ levels in sperm, resulting in a marked improvement in sperm movement, capacitation, acrosome reaction, and the in vitro fertilizing ability. This antagonist-induced release of intracellular Ca2+ could be blocked by the inhibitors of ryanodine receptors (RyRs) which are the main intracellular Ca2+ channels responsible for releasing stored Ca2+. Consistent with these results, indirect immunofluorescence assay using anti-RyR antibodies further validated the presence of RyR3 in the acrosomal region of mature sperm. Thus, TPPII can regulate sperm maturation by modulating intracellular Ca2+ stores via the type 3 RyR.
Two Phosphodiesterase Genes, PDEL and PDEH, Regulate Development and Pathogenicity by Modulating Intracellular Cyclic AMP Levels in Magnaporthe oryzae  [PDF]
Haifeng Zhang,Kaiyue Liu,Xing Zhang,Wei Tang,Jiansheng Wang,Min Guo,Qian Zhao,Xiaobo Zheng,Ping Wang,Zhengguang Zhang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017241
Abstract: Cyclic AMP (cAMP) signaling plays an important role in regulating multiple cellular responses, such as growth, morphogenesis, and/or pathogenicity of eukaryotic organisms such as fungi. As a second messenger, cAMP is important in the activation of downstream effector molecules. The balance of intracellular cAMP levels depends on biosynthesis by adenylyl cyclases (ACs) and hydrolysis by cAMP phosphodiesterases (PDEases). The rice blast fungus Magnaporthe oryzae contains a high-affinity (PdeH/Pde2) and a low-affinity (PdeL/Pde1) PDEases, and a previous study showed that PdeH has a major role in asexual differentiation and pathogenicity. Here, we show that PdeL is required for asexual development and conidial morphology, and it also plays a minor role in regulating cAMP signaling. This is in contrast to PdeH whose mutation resulted in major defects in conidial morphology, cell wall integrity, and surface hydrophobicity, as well as a significant reduction in pathogenicity. Consistent with both PdeH and PdeL functioning in cAMP signaling, disruption of PDEH only partially rescued the mutant phenotype of ΔmagB and Δpka1. Further studies suggest that PdeH might function through a feedback mechanism to regulate the expression of pathogenicity factor Mpg1 during surface hydrophobicity and pathogenic development. Moreover, microarray data revealed new insights into the underlying cAMP regulatory mechanisms that may help to identify potential pathogenicity factors for the development of new disease management strategies.
Fish Oil Suppresses Cell Growth and Metastatic Potential by Regulating PTEN and NF-κB Signaling in Colorectal Cancer  [PDF]
Shevali Kansal, Archana Bhatnagar, Navneet Agnihotri
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0084627
Abstract: Homeostasis in eukaryotic tissues is tightly regulated by an intricate balance of the prosurvival and antisurvival signals. The tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10), a dual-specificity phosphatase, plays a functional role in cell cycle arrest and apoptosis. NF-κB and its downstream regulators (such as VEGF) play a central role in prevention of apoptosis, promotion of inflammation and tumor growth. Therefore, we thought to estimate the expression of PTEN, Poly-ADP-ribose polymerase (PARP), NF-κBp50, NF-κBp65 and VEGF to evaluate the effect of supplementation of fish oil on apoptotic and inflammatory signaling in colon carcinoma. Male wistar rats in Group I received purified diet while Group II and III received modified diet supplemented with FO:CO(1:1)&FO:CO(2.5:1) respectively. These were further subdivided into controls receiving ethylenediamine-tetra acetic-acid and treated groups received dimethylhydrazine-dihydrochloride (DMH)/week for 4 weeks. Animals sacrificed 48 hours after last injection constituted initiation phase and that sacrificed after 16 weeks constituted post-initiation phase. We have analysed expression of PTEN, NF-κBp50, NF-κBp65 by flowcytometer and nuclear localization of NF-κB by immunofluorescence. PARP and VEGF were assessed by immunohistochemistry. In the initiation phase, animals receiving DMH have shown increased % of apoptotic cells, PTEN, PARP, NF-κBp50, NF-κBp65 and VEGF however in post-initiation phase no significant alteration in apoptosis with decreased PTEN and increased PARP, NF-κBp50, NF-κBp65 and VEGF were observed as compared to control animals. On treatment with both ratios of fish oil in both the phases, augmentation in % of apoptotic cells, decreased PTEN, PARP, NF-κBp50, NF-κBp65 and VEGF were documented with respect to DMH treated animals with effect being more exerted with higher ration in post-initiation phase. Hence, fish oil activates apoptosis, diminishes DNA damage and inhibits inflammatory signalling in a dose and time dependent manner so as to inhibit progression of colon cancer.
Hepatitis B Virus Polymerase Suppresses NF-κB Signaling by Inhibiting the Activity of IKKs via Interaction with Hsp90β  [PDF]
Dan Liu, An’dong Wu, Lei Cui, Ruidong Hao, Yuan Wang, Jing He, Deyin Guo
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091658
Abstract: Nuclear factor-κB (NF-κB) plays a central role in the regulation of diverse biological processes, including immune responses, development, cell growth, and cell survival. To establish persistent infection, many viruses have evolved strategies to evade the host’s antiviral immune defenses. In the case of hepatitis B virus (HBV), which can cause chronic infection in the liver, immune evasion strategies used by the virus are not fully understood. It has recently been reported that the polymerase of HBV (Pol) inhibits interferon-β (IFN-β) activity by disrupting the interaction between IKKε and the DDX3. In the current study, we found that HBV Pol suppressed NF-κB signaling, which can also contribute to IFN-β production. HBV Pol did not alter the level of NF-κB expression, but it prevented NF-κB subunits involved in both the canonical and non-canonical NF-κB pathways from entering the nucleus. Further experiments demonstrated that HBV Pol preferentially suppressed the activity of the IκB kinase (IKK) complex by disrupting the association of IKK/NEMO with Cdc37/Hsp90, which is critical for the assembly of the IKK complex and recruitment of the IKK complex to the tumor necrosis factor type 1 receptor (TNF-R1). Furthermore, we found that HBV Pol inhibited the NF-κB-mediated transcription of target genes. Taken together, it is suggested that HBV Pol could counteract host innate immune responses by interfering with two distinct signaling pathways required for IFN-β activation. Our studies therefore shed light on a potential therapeutic target for persistent infection with HBV.
Curcumin suppresses gastric NF-κB activation and macromolecular leakage in Helicobacter pylori-infected rats  [cached]
Kawiya Sintara, Duangporn Thong-Ngam, Suthiluk Patumraj, Naruemon Klaikeaw, Tanittha Chatsuwan
World Journal of Gastroenterology , 2010,
Abstract: AIM: To investigate whether curcumin could attenuate nuclear factor (NF)-κB p65 expression and macromolecular leakage in the gastric mucosa of Helicobacter pylori (H. pylori)-infected rats.METHODS: Twenty-five male Sprague-Dawley rats were equally divided into five groups: control rats (Control), control rats supplemented with 600 mg/kg curcumin, H. pylori-infected rats (Hp), H. pylori-infected rats supplemented with 200 mg/kg curcumin (Hp + curI), and H. pylori-infected rats supplemented with 600 mg/kg curcumin (Hp + curII). In H. pylori-infected groups, rats were inoculated with H. pylori suspension twice a day at an interval of 4 h for 3 d. Two weeks later, 200 or 600 mg/kg curcumin was given once daily to curcumin-supplemented groups for 7 d. On the day of the experiment, macromolecular leakage in gastric mucosa was examined by intravital fluorescence microscopy. The stomach tissue was removed to examine NF-κB p65 expression in gastric epithelial cells by immunohistochemistry.RESULTS: The expression of NF-κB p65 in gastric epithelial cells and the macromolecular leakage from gastric mucosal microcirculation significantly increased in the Hp group compared with the Control group. The percentages of NF-κB p65 immunoreactive cells in Control and Hp groups were 10.72% ± 2.10% vs 16.02% ± 2.98%, P = 0.004, respectively. The percentages of macromolecular leakage in Control and Hp groups were 10.69% ± 1.43% vs 15.41% ± 2.83%, P = 0.001, respectively. Curcumin supplementation in Hp + curI and Hp + curII groups significantly decreased NF-κB p65 immunoreactive cells and macromolecular leakage compared with results in the Hp group. The percentages of NF-κB p65 immunoreactive cells in Hp + curI and Hp + curII groups were 11.79% ± 2.13% (P = 0.017) and 11.42% ± 1.68% (P = 0.010), respectively. The percentages of macromolecular leakage in Hp + curI and Hp + curII groups were 12.32% ± 2.13% (P = 0.025) and 12.14% ± 1.86% (P = 0.018), respectively.CONCLUSION: H. pylori-induced gastric inflammation in rats is associated with increased NF-κB activation and macromolecular leakage which can be reduced by curcumin supplementation.
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