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B Inhibition (b + inhibition)

Distribution by Scientific Domains

Medical Sciences	66%

Selected Abstracts

PRECLINICAL STUDY: Ecstasy-induced oxidative stress to adolescent rat brain mitochondria in vivo: influence of monoamine oxidase type A

ADDICTION BIOLOGY, Issue 2 2009
Ema Alves
ABSTRACT The administration of a neurotoxic dose of 3,4-methylenedioxymethamphetamine (MDMA; ,ecstasy') to the rat results in mitochondrial oxidative damage in the central nervous system, namely lipid and protein oxidation and mitochondrial DNA deletions with subsequent impairment of the correspondent protein expression. Although these toxic effects were shown to be prevented by monoamine oxidase B inhibition, the role of monoamine oxidase A (MAO-A) in MDMA-mediated mitochondrial damage remains to be evaluated. Thus, the aim of the present study was to clarify the potential interference of a specific inhibition of MAO-A by clorgyline, on the deleterious effects produced by a binge administration of a neurotoxic dose of MDMA (10 mg MDMA/kg of body weight, intraperitoneally, every 2 hours in a total of four administrations) to an adolescent rat model. The parameters evaluated were mitochondrial lipid peroxidation, protein carbonylation and expression of the respiratory chain protein subunits II of reduced nicotinamide adenine dinucleotide dehydrogenase (NDII) and I of cytochrome oxidase (COXI). Considering that hyperthermia has been shown to contribute to the neurotoxic effects of MDMA, another objective of the present study was to evaluate the body temperature changes mediated by MDMA with a MAO-A selective inhibition by clorgyline. The obtained results demonstrated that the administration of a neurotoxic binge dose of MDMA to an adolescent rat model previously treated with the specific MAO-A inhibitor, clorgyline, resulted in synergistic effects on serotonin- (5-HT) mediated behaviour and body temperature, provoking high mortality. Inhibition of MAO-A by clorgyline administration had no protective effect on MDMA-induced alterations on brain mitochondria (increased lipid peroxidation, protein carbonylation and decrease in the expression of the respiratory chain subunits NDII and COXI), although it aggravated MDMA-induced decrease in the expression of COXI. These results reinforce the notion that the concomitant use of MAO-A inhibitors and MDMA is counter indicated because of the resulting severe synergic toxicity. [source]

Modulation of Activation-Induced Cytidine Deaminase by Curcumin in Helicobacter pylori -Infected Gastric Epithelial Cells

HELICOBACTER, Issue 6 2009
Syed Faisal Haider Zaidi
Abstract Background:, Anomalous expression of activation-induced cytidine deaminase (AID) in Helicobacter pylori -infected gastric epithelial cells has been postulated as one of the key mechanisms in the development of gastric cancer. AID is overexpressed in the cells through nuclear factor (NF)-,B activation by H. pylori and hence, inhibition of NF-,B pathway can downregulate the expression of AID. Curcumin, a spice-derived polyphenol, is known for its anti-inflammatory activity via NF-,B inhibition. Therefore, it was hypothesized that curcumin might suppress AID overexpression via NF-,B inhibitory activity in H. pylori -infected gastric epithelial cells. Materials and Methods:, MKN-28 or MKN-45 cells and H. pylori strain 193C isolated from gastric cancer patient were used for co-culture experiments. Cells were pretreated with or without nonbactericidal concentrations of curcumin. Apoptosis was determined by DNA fragmentation assay. Enzyme-linked immunosorbent assay was performed to evaluate the anti-adhesion activity of curcumin. Real-time polymerase chain reaction was employed to evaluate the expression of AID mRNA. Immunoblot assay was performed for the analysis of AID, NF-,B, inhibitors of NF-,B (I,B), and I,B kinase (IKK) complex regulation with or without curcumin. Results:, The adhesion of H. pylori to gastric epithelial cells was not inhibited by curcumin pretreatment at nonbactericidal concentrations (,10 ,mol/L). Pretreatment with nonbactericidal concentration of curcumin downregulated the expression of AID induced by H. pylori. Similarly, NF-,B activation inhibitor (SN-50) and proteasome inhibitor (MG-132) also downregulated the mRNA expression of AID. Moreover, curcumin (,10 ,mol/L) has suppressed H. pylori -induced NF-,B activation via inhibition of IKK activation and I,B degradation. Conclusion:, Nonbactericidal concentrations of curcumin downregulated H. pylori -induced AID expression in gastric epithelial cells, probably via the inhibition of NF-,B pathway. Hence, curcumin can be considered as a potential chemopreventive candidate against H. pylori -related gastric carcinogenesis. [source]

Nuclear factor-,B inhibition improves myocardial contractility in rats with cirrhotic cardiomyopathy

LIVER INTERNATIONAL, Issue 5 2008
Hongqun Liu
Abstract Background/Aims: Cytokines such as tumour necrosis factor (TNF-,) contribute to the pathogenesis of cirrhotic cardiomyopathy. Nuclear factor-,B (NF-,B) is crucial for cytokine regulation, and induces cardiac dysfunction in several heart disease models. We aimed to elucidate possible NF-,B involvement in cirrhotic cardiomyopathy. Methods: Rats were bile duct ligated (BDL) to produce cirrhosis; controls received sham operation. Animals were studied 4 weeks later. Two NF-,B inhibitors were used: pyrrolidine dithiocarbamate (PDTC) and Bay 11-7082. Four groups were studied in most protocols: sham control, sham+PDTC, BDL and BDL+PDTC. Additional contractility studies were performed with Bay 11-7082. Myocardial NF-,B and TNF-, expression was measured by Western blot and ELISA. The contractility of isolated cardiomyocytes was observed under direct microscopy. Results: Nuclear factor-,B and TNF-, levels were increased in cirrhotic hearts compared with controls. PDTC significantly reduced NF-,B activity and TNF-, expression in cirrhotic hearts; controls were unaffected. Cirrhotic cardiomyocytes showed decreased systolic and diatolic velocity compared with sham controls. Both PDTC and Bay 11-7082 restored contractile function in cirrhotic cardiomyocytes, but did not affect controls. Conclusions: Inhibition of the increased NF-,B activity in cirrhotic hearts was associated with improvement of attenuated cardiomyocyte contractility. NF-,B, via effects on cytokine expression, may contribute to the pathogenesis of cirrhotic cardiomyopathy. [source]

Inhibition of NF-,B activation with designed ankyrin-repeat proteins targeting the ubiquitin-binding/oligomerization domain of NEMO

PROTEIN SCIENCE, Issue 9 2007
Emanuel Wyler
Abstract The link between the NF-,B signal transduction pathway and cancer is now well established. Inhibiting this pathway is therefore a promising approach in the treatment of certain cancers through a pro-apoptotic effect in malignant cells. Owing to its central role in the pathway, the I,B kinase (IKK) complex is a privileged target for designing inhibitors. Previously, we showed that oligomerization of NEMO is necessary for IKK activation and defined a minimal oligomerization domain (CC2-LZ) for NEMO, and we developed NEMO peptides inhibiting NF-,B activation at the level of the IKK complex. To improve the low-affinity inhibitors, we used ribosome display to select small and stable proteins with high affinity against the individual CC2-LZ because the entire NEMO protein is poorly soluble. Several binders with affinities in the low nanomolar range were obtained. When expressed in human cells, some of the selected molecules, despite their partial degradation, inhibited TNF-,-mediated NF-,B activation while having no effect on the basal activity. Controls with a naive library member or null plasmid had no effect. Furthermore, we could show that this NF-,B inhibition occurs through a specific interaction between the binders and the endogenous NEMO, resulting in decreased IKK activation. These results indicate that in vitro selections with the NEMO subdomain alone as a target may be sufficient to lead to interesting compounds that are able to inhibit NF-,B activation. [source]

Differential mechanism of NF-,B inhibition by two glucocorticoid receptor modulators in rheumatoid arthritis synovial fibroblasts

ARTHRITIS & RHEUMATISM, Issue 11 2009
Valerie Gossye
Objective To investigate and compare the molecular mechanisms by which 2 glucocorticoid receptor (GR),activating compounds, dexamethasone (DEX) and Compound A (CpdA), interfere with the NF-,B activation pathway in rheumatoid arthritis (RA) synovial cells. Methods Quantitative polymerase chain reaction was performed to detect the tumor necrosis factor , (TNF,),induced cytokine gene expression of interleukin-1, (IL-1,) and to investigate the effects of DEX and CpdA in RA fibroblast-like synoviocytes (FLS) transfected with small interfering RNA (siRNA) against GR (siGR) compared with nontransfected cells. Immunofluorescence analysis was used to detect the subcellular distribution of NF-,B (p65) under the various treatment conditions, and active DNA-bound p65 was measured using a TransAM assay and by chromatin immunoprecipitation analysis of IL-1,. Signaling pathways were studied via Western blotting of siGR-transfected cells, compared with nontransfected and nontargeting siRNA,transfected control cells, to detect the regulation of phospho-IKK, I,B,, phospho-p38, phospho-ERK, and phospho-JNK. Results Both DEX and CpdA efficiently inhibited IL-1, gene expression in a GR-dependent manner. In addition, CpdA attenuated the TNF,-induced nuclear translocation and DNA binding of p65 in RA FLS, via the attenuation of IKK phosphorylation and subsequent I,B, degradation. CpdA also displayed profound effects on TNF,-induced MAPK activation. The effects of CpdA on TNF,-induced kinase activities occurred independently of the presence of GR. In sharp contrast, DEX did not affect TNF,-induced IKK phosphorylation, I,B, degradation, p65 nuclear translocation, or MAPK activation in RA FLS. Conclusion DEX and CpdA display a dissimilar molecular mechanism of interaction with the NF-,B activation pathway ex vivo. A dual pathway, partially dependent and partially independent of GR (nongenomic), may explain the gene-inhibitory effects of CpdA in RA FLS. [source]

The NF (Nuclear factor)-,B inhibitor parthenolide interacts with histone deacetylase inhibitors to induce MKK7/JNK1-dependent apoptosis in human acute myeloid leukaemia cells

BRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2010
Yun Dai
Summary Interactions between the nuclear factor (NF)-,B inhibitor parthenolide and the pan-histone deacetylase inhibitors (HDACIs) vorinostat and LBH589 were investigated in human acute myeloid leukaemia (AML) cells, including primary AML blasts. Co-administration of parthenolide blocked HDACI-mediated phosphorylation/activation of IKK and RelA/p65 in association with increased JNK1 activation in various AML cell types. These events were accompanied by an increase in apoptosis in multiple AML cell lines (e.g. U937, HL-60, NB4, MV-4-11, and MOLM-13). Significantly, parthenolide also increased HDACI-mediated cell death in haematopoietic cells transduced with the MLL - MLLT1 fusion gene, which exhibit certain leukaemia-initiating cell characteristics, as well as primary AML blasts. Exposure to parthenolide/HDACI regimens clearly inhibited the growth of AML-colony-forming units but was relatively sparing toward normal haematopoietic progenitors. Notably, blockade of c-Jun N-terminal kinase (JNK) signalling by either pharmacological inhibitors or genetic means (e.g. dominant-negative JNK1 or JNK1 shRNA) diminished parthenolide/HDACI-mediated lethality. Moreover, dominant-negative MKK7, but not dominant-negative MKK4/SEK1, blocked JNK1 activation and apoptosis induced by parthenolide/HDACI regimens. Together, these findings indicate that parthenolide potentiates HDACI lethality in human AML cells through a process involving NF-,B inhibition and subsequent MKK7-dependent activation of the SAPK/JNK pathway. They also raise the possibility that this strategy may target leukaemic progenitor cells. [source]