Inhibition Of Nuclear factor-κB Activation Research Articles

Anti-Inflammatory Effect of Ebractenoid F, a Major Active Compound of Euphorbia ebracteolata Hayata, through Inhibition of Nuclear Factor-κB Activation.

Euphorbia ebracteolata Hayata (Euphorbiaceae family) is a perennial plant that is widely distributed in Korea, Japan, and China. Its roots contain bioactive diterpenes that have anti-inflammatory properties. However, the anti-inflammatory mechanisms are not yet fully understood. This study aimed to identify the most active anti-inflammatory compound from the roots of E. ebracteolata Hayata, using bioassay-guided fractionation and a combinative method of high-speed countercurrent chromatography (HSCCC) and preparative high-performance liquid chromatography (HPLC). Then, we investigated its anti-inflammatory mechanism in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Ebractenoid F was identified as the most potent bioactive compound of E. ebracteolata Hayata. Ebractenoid F significantly decreased nitric oxide (NO) production and nuclear factor-κB (NF-κB) activation induced by LPS in RAW 264.7 macrophages. Moreover, ebractenoid F decreased the degradation of inhibitory κB-α, the nuclear translocation of the p65 and p50 subunits of NF-κB, and the expression of NF-κB downstream genes. Furthermore, ebractenoid F inhibited the phosphorylation of Akt and mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase (ERK) and c-Jun NH2 terminal kinase (JNK), in LPS-stimulated RAW 264.7 cells. In conclusion, ebractenoid F exerts the most potent anti-inflammatory effect by suppressing NF-κB-mediated NO production in LPS-stimulated RAW 264.7 cells. Ebractenoid F may be a useful therapeutic compound for the prevention or treatment of inflammation-associated diseases.

73 Therapeutic Effects of Melittin Against Acetaminophen-Induced Liver Injury in Mice

Study Objective: An overdose of acetaminophen (APAP) frequently causes severe liver injury, but the treatment options remain limited. Melittin is a bioactive peptide derived from bee venom and possesses anti-oxidative, anti- apoptotic, and anti-inflammatory properties. Emerging evidence suggests that this peptide exerts beneficial effects on several inflammatory disorders. However, whether melittin has a protective effect on APAP toxicity remains undetermined. The purpose of the current study was to investigate the effect of melittin on APAP-induced hepatotoxicity.Methods: Melittin was intraperitoneally administered at a dose of 0.01 mg/kg to mice 1 hour after APAP injection (400 mg/kg).Results: Administration of melittin after APAP injection reduced serum aspartate aminotransferase and alanine aminotransferase levels and alleviated histological alterations in APAP-injected mice. Melittin inhibited lipid peroxidation and DNA oxidation with restoration of glutathione content and upregulation of antioxidant enzymes. Melittin also attenuated hepatocyte apoptosis with inhibition of caspase-3 activation. In addition, serum and hepatic levels of cytokines were reduced by melittin. This effect was associated with inhibition of nuclear factor-κB activation. Furthermore, melittin attenuated infiltration of neutrophils and macrophages into the liver.Conclusion: Altogether, these data suggest that melittin might be served as a treatment agent for APAP-induced hepatotoxicity.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)No, authors do not have interests to disclose Study Objective: An overdose of acetaminophen (APAP) frequently causes severe liver injury, but the treatment options remain limited. Melittin is a bioactive peptide derived from bee venom and possesses anti-oxidative, anti- apoptotic, and anti-inflammatory properties. Emerging evidence suggests that this peptide exerts beneficial effects on several inflammatory disorders. However, whether melittin has a protective effect on APAP toxicity remains undetermined. The purpose of the current study was to investigate the effect of melittin on APAP-induced hepatotoxicity. Methods: Melittin was intraperitoneally administered at a dose of 0.01 mg/kg to mice 1 hour after APAP injection (400 mg/kg). Results: Administration of melittin after APAP injection reduced serum aspartate aminotransferase and alanine aminotransferase levels and alleviated histological alterations in APAP-injected mice. Melittin inhibited lipid peroxidation and DNA oxidation with restoration of glutathione content and upregulation of antioxidant enzymes. Melittin also attenuated hepatocyte apoptosis with inhibition of caspase-3 activation. In addition, serum and hepatic levels of cytokines were reduced by melittin. This effect was associated with inhibition of nuclear factor-κB activation. Furthermore, melittin attenuated infiltration of neutrophils and macrophages into the liver. Conclusion: Altogether, these data suggest that melittin might be served as a treatment agent for APAP-induced hepatotoxicity. No, authors do not have interests to disclose

Mulberry vinegar attenuates lipopolysaccharide and interferon gamma-induced inflammatory responses in C6 glial cells.

The present study evaluated the effect of mulberry vinegar (MV) on the regulation of the inflammatory responses using C6 glial cells. Treatment with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) induced the nitric oxide and reactive oxygen species generation, while pre-incubation with MV inhibited these formations in a concentration-dependent manner. MV treatment also decreased the production of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α in C6 glial cells stimulated by LPS/IFN-γ. Compared to the LPS/IFN-γ-treated control group, the MV-treated group exerts downregulation in the protein expressions of inducible nitric oxide synthase and cyclooxygenase-2, through inhibition of nuclear factor-κB activation. Protein expressions of glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 were also decreased in the MV-treated group. These findings suggest that MV prevents neuroinflammation by regulating the NF-κB signaling pathway and glial activation. PRACTICAL APPLICATION: Mulberry fruits (Morus alba L.) have been commonly consumed as juice or jam. It is a rich source of anthocyanins that might be associated with beneficial effects on human health, including the anti-oxidant, anti-inflammatory, anti-obesity, and anti-diabetic effects. Mulberry vinegar was produced by alcohol and acetic fermentation of mulberry juice, and they possessed a protective effect against LPS/IFN-γ-stimulated inflammatory responses in glial cells via regulation of glial activation and NF-κB signaling pathway (i.e., downregulation of iNOS, COX-2, TLR4, p-IκB, and NF-κB p65 protein expressions). Although further research especially animal and clinical trials are still necessary, the present study will be helpful to scale-up the production of functional vinegar with neuroprotective and anti-inflammatory properties using mulberry.

Anti-inflammatory effects of Phaeodactylum tricornutum extracts on human blood mononuclear cells and murine macrophages

The microalgae Phaeodactylum tricornutum (PT) is known for its high content of omega-3 fatty acids, which are known to attenuate inflammation. Additionally, this microalga contains other nutrients such as carbohydrates, vitamins, proteins, and carotenoids and therefore could be of interest for animal and human nutrition. Here, we investigated the effects of hexane, ethanolic, and aqueous extracts on lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMCs) and on the murine macrophage cell line RAW 264.7. Further, the cytotoxicity of the extracts was studied using the MTT assay. The production of pro-inflammatory cytokines was significantly inhibited by the ethanolic and aqueous P. tricornutum extracts but not by the hexane extract. Both at the mRNA and at the protein levels, the aqueous extract inhibited LPS-induced IL-6, IL-1β, TNFα, and COX-2 expression and release by up to 96% (mRNA) and 79% (protein) in a dose-dependent manner. Compared to the aqueous extract, the ethanolic extract was less effective in cytokine inhibition. The production of nitric oxide in RAW 264.7 cells was significantly reduced by all extracts. We showed that the anti-inflammatory effect of P. tricornutum is exerted through inhibition of nuclear factor-κB activation and dependent on the mitogen-activated protein (MAP) kinase pathway. Our data indicate anti-inflammatory effects of the aqueous P. tricornutum extract and provide a basis information on the safety and potential health benefits of P. tricornutum usage for future animal and human nutrition.

Coumarins from the roots of Angelica dahurica cause anti-allergic inflammation.

Allergic inflammation is induced by allergens and leads to various allergic diseases, including rhinitis, asthma and conjunctivitis. Histamine is important in the pathogenesis of an immunoglobulin E-dependent allergic reaction and results in the secretion of cytokines associated with inflammation. Angelica dahurica (A. dahurica) is a medicinal plant widely used in China for the treatment of symptoms related to allergic inflammation. The present study investigated the chemical constituents from A. dahurica and evaluated their reductive effect on allergic inflammation. As a result, 15 compounds including 13 coumarins have been identified as isoimperatorin (1), imperatorin (2), oxypeucedanin (3), oxypeucedanin hydrate (4), bergapten (5), byakangelicin (6), phellopterin (7), byakangelicol (8), isopimpinellin (9), xanthotoxol (10), xanthotoxin (11), pimpinellin (12), scopoletin (13), β-sitosterol (14) and daucosterol (15). Compounds 1-13 were able to reduce the release of histamine, with compounds 4-6 exhibiting the most potent activity. Furthermore, compounds 1-12 were able to inhibit the secretion of tumor necrosis factor-α, interleukin (IL)-1β and IL-4, with compounds 5 and 7 exhibiting the strongest inhibitory effects. These compounds implemented the inhibitory effects on the expression of inflammatory cytokine genes through the inhibition of nuclear factor-κB activation. Virtual screening by a docking program indicated that compound 3 is a potent histamine H1 receptor antagonist. Additionally, the calculated physicochemical properties of these compounds support most furanocoumarins to be delivered to binding sites and permeate the cell membrane. The present findings contribute to understanding how A. dahurica attenuates allergic inflammation.

Chicory, a typical vegetable in Mediterranean diet, exerts a therapeutic role in established atherosclerosis in apolipoprotein E-deficient mice.

Since protocatechuic acid exerts an atheroprotective role, we investigated how chicory (Cichorium intybus L. var. foliosum, Belgian endive) rich in protocatechuic acid, a typical vegetable in Mediterranean diet, affects preestablished atherosclerosis progression. Apolipoprotein E-deficient mice fed AIN diets containing 0.5% freeze-dried chicory for 10 weeks displayed a reduction in lesion size with a concomitant improvement in lesion stability indicated by fewer macrophages and more collagen content. Chicory consumption suppressed aortic cholesterol accumulation and intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1 expression, whereas it increased aortic ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) expression. Furthermore, chicory consumption improved peritoneal macrophage phenotype with less cellular cholesterol associated with an enhancement of cholesterol efflux capacity through upregulation of ABCA1 and ABCG1, less cellular oxidative stress associated with an inhibition of nicotinamide adenine dinucleotide phosphate oxidase activity, and weaker inflammatory responses associated with an inhibition of nuclear factor-κB activation. Interestingly, ABCA1 and ABCG1 silencing tended to completely block beneficial effects of chicory in peritoneal macrophages. Chicory exerts an atheroprotective role in mice possibly by regulating lesional macrophage content and phenotype, suggesting that chicory is one underrated contributor to Mediterranean Diet-induced atheroprotection.

Marine Diterpenoids as Potential Anti-Inflammatory Agents.

The inflammatory response is a highly regulated process, and its dysregulation can lead to the establishment of chronic inflammation and, in some cases, to death. Inflammation is the cause of several diseases, including rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, and asthma. The search for agents inhibiting inflammation is a great challenge as the inflammatory response plays an important role in the defense of the host to infections. Marine invertebrates are exceptional sources of new natural products, and among those diterpenoids secondary metabolites exhibit notable anti-inflammatory properties. Novel anti-inflammatory diterpenoids, exclusively produced by marine organisms, have been identified and synthetic molecules based on those structures have been obtained. The anti-inflammatory activity of marine diterpenoids has been attributed to the inhibition of Nuclear Factor-κB activation and to the modulation of arachidonic acid metabolism. However, more research is necessary to describe the mechanisms of action of these secondary metabolites. This review is a compilation of marine diterpenoids, mainly isolated from corals, which have been described as potential anti-inflammatory molecules.

Evaluating the anti-neuroinflammatory capacity of raw and steamed garlic as well as five organosulfur compounds.

The anti-neuroinflammatory capacities of raw and steamed garlic extracts as well as five organosulfur compounds (OSCs) were examined in lipopolysaccharide (LPS)-stimulated BV2 microglia. According to those results, steaming pretreatment blocked the formation of alliinase-catalyzed OSCs such as allicin and diallyl trisulfide (DATS) in crushed garlic. Raw garlic, but not steamed garlic, dose-dependently attenuated the production of LPS-induced nitric oxide (NO), interleukin-1β (IL-1β), tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein-1 (MCP-1). DATS and diallyl disulfide at 200 and 400 μM, respectively, displayed significant anti-neuroinflammatory activity. Meanwhile, even at 1 mM, diallyl sulfide, S-allyl cysteine and alliin did not display such activity. Inhibition of nuclear factor-κB activation was the mechanism underlying this protective effect of raw garlic and DATS. Analysis results indicated that the anti-neuroinflammatory capacity of raw garlic is due to the alliin-derived OSCs. Importantly, DATS is a highly promising therapeutic candidate for treating inflammation-related neurodegenerative diseases.

Emodin has a protective effect in cases of severeacute pancreatitis via inhibition of nuclear factor‑κB activation resulting in antioxidation.

Severe acute pancreatitis (SAP) accounts for up to 20% of acute pancreatitis (AP) cases. The absence of effective treatment options has resulted in a high rate of morbidity and mortality. Emodin is a major component of the Chinese herb rhubarb, which has been widely used in the treatment of numerous diseases, including inflammation and cancer. There are a limited number of studies however, that have investigated the effectiveness of emodin in the treatment of SAP. The present study used a rat model of SAP, to investigate the effect and molecular mechanisms of emodin treatment. Administration of emodin was identified to significantly attenuate SAP, as determined by serum amylase analysis and histological assessment of edema, vacuolization, inflammation and necrosis (P<0.01). Furthermore, treatment with emodin markedly inhibited nuclear factor (NF)‑κB DNA‑binding activity (P<0.01) and the serum expression levels of tumor necrosis factor‑α, interleukin (IL)‑6 and IL‑1β (P<0.05). This attenuation was associated with decreased malondialdehyde and increased superoxide dismutase levels in the pancreatic tissues and serum (P<0.05). This study indicated that administration of exogenous emodin had therapeutic effects on the severity of SAP. The mechanism may be due to inhibition of NF‑κB activation resulting in an antioxidation response, which can subsequently suppress the expression of cytokines.

Ginsenoside Rb1 Reduces Nitric Oxide Production via Inhibition of Nuclear Factor-κB Activation in Interleukin-1β- Stimulated SW1353 Chondrosarcoma Cells

Purpose: To investigate the effect and the potential mechanisms of ginsenoside Rb1 on nitric oxide (NO) production in chondrocytes.Methods: SW1353 chondrosarcoma cells were stimulated with interleukin-1β (IL-1β) in the presence of 20, 40, 80 μM ginsenoside Rb1. NO concentration was assessed by the Griess reaction. Expression of inducible nitric oxide synthase (iNOS), content of inhibitor of NF-κB (IκB)α and nuclear level of nuclear factor (NF)-κB p65 were determined by Western blot. DNA binding activity of NF-κB was evaluated with Trans AM™ kit for NF-κB p65.Results: Ginsenoside Rb1 (40 and 80 μM) significantly decreased NO level by 24 (p &lt; 0.05) and 46 % (p &lt; 0.01), as well as iNOS protein expression by 40 and 55 % (p &lt; 0.01), respectively, in IL-1β- stimulated SW1353 cells. Ginsenoside Rb1 (40 and 80 μM) also markedly elevated IκBα protein content by 200 and 260 % (p &lt; 0.01), reduced the nuclear level of p65 protein by 30 and 40 % (p &lt; 0.01), as well as decreased the DNA binding activity of NF-κB by 40 and 50 % (both p &lt; 0.01), respectively, in IL- 1β-stimulated SW1353 cells.Conclusion: These results suggest that ginsenoside Rb1 inhibits IL-1β-induced NO production through downregulation of NF-κB-dependent iNOS expression in chondrocytes, and also underlines the potential mechanisms of ginseng activity in OA treatment of TCM. Keywords: Ginsenoside Rb1, Nitric oxide, Nuclear factor-κB, Chondrocytes, Osteoarthritis

Sanguinarine protects against pressure overload‑induced cardiac remodeling via inhibition of nuclear factor-κB activation.

Cardiac remodeling is a major determinant of heart failure characterized by cardiac hypertrophy and fibrosis. Sanguinarine exerts widespread pharmacological effects, including antitumor and anti‑inflammatory responses. In the present study, the effect of sanguinarine on cardiac hypertrophy, fibrosis and heart function was determined using the model induced by aortic banding (AB) in mice. AB surgery and sham surgery were performed on male wild‑type C57 mice, aged 8‑10weeks, with or without administration of sanguinarine from one week after surgery for an additional seven weeks. Sanguinarine protected against the cardiac hypertrophy, fibrosis and dysfunction induced by AB, as assessed by the heart weight/body weight, lung weight/body weight and heart weight/tibia length ratios, echocardiographic and hemodynamic parameters, histological analysis, and the gene expression levels of hypertrophic and fibrotic markers. The inhibitory effect of sanguinarine on cardiac remodeling was mediated by inhibiting nuclear factor (NF)‑κB signaling pathway activation. The findings indicated that sanguinarine protected against cardiac hypertrophy and fibrosis via inhibiting NF‑κB activation. These findings may be used to develop a potential therapeutic drug for treating cardiac remodeling and heart failure.

Methanol Extract ofArtemisia apiaceaHance Attenuates the Expression of Inflammatory Mediators via NF-κB Inactivation

Artemisia apiacea Hance is one of the most widely used herbs for the treatment of malaria, jaundice, and dyspeptic complaint in oriental medicine. This study investigated the effects of methanol extracts of A. apiacea Hance (MEAH) on the induction of inducible nitric oxide synthase (iNOS) and proinflammatory mediators by lipopolysaccharide (LPS) in Raw264.7 macrophage cells and also evaluated the in vivo effect of MEAH on carrageenan-induced paw edema in rats. MEAH treatment in Raw264.7 cells significantly decreased LPS-inducible nitric oxide production and the expression of iNOS in a concentration-dependent manner, while MEAH (up to 100 μg/mL) had no cytotoxic activity. Results from immunoblot analyses and ELISA revealed that MEAH significantly inhibited the expression of cyclooxygenase-2, tumor necrosis factor-α, interleukin-1β, and interleukin-6 in LPS-activated cells. As a plausible molecular mechanism, increased degradation and phosphorylation of inhibitory-κBα and nuclear factor-κB accumulation in the nucleus by LPS were partly blocked by MEAH treatment. Finally, MEAH treatment decreased the carrageenan-induced formation of paw edema and infiltration of inflammatory cells in rats. These results demonstrate that MEAH has an anti-inflammatory therapeutic potential that may result from the inhibition of nuclear factor-κB activation, subsequently decreasing the expression of proinflammatory mediators.

Conditioned Media from Adipose-Tissue-Derived Mesenchymal Stem Cells Downregulate Degradative Mediators Induced by Interleukin-1βin Osteoarthritic Chondrocytes

Osteoarthritis (OA) is the most frequent joint disorder and an important cause of disability. Recent studies have shown the potential of adipose-tissue-derived mesenchymal stem cells (AD-MSC) for cartilage repair. We have investigated whether conditioned medium from AD-MSC (CM) may regulate in OA chondrocytes a number of key mediators involved in cartilage degeneration. CM enhanced type II collagen expression in OA chondrocytes while decreasing matrix metalloproteinase (MMP) activity in cell supernatants as well as the levels of MMP-3 and MMP-13 proteins and mRNA in OA chondrocytes stimulated with interleukin- (IL-) 1β. In addition, CM increased IL-10 levels and counteracted the stimulating effects of IL-1β on the production of tumor necrosis factor-α, IL-6, prostaglandin E2, and NO measured as nitrite and the mRNA expression of these cytokines, CCL-2, CCL-3, CCL-4, CCL-5, CCL-8, CCL-19, CCL-20, CXCL-1, CXCL-2, CXCL-3, CXCL-5, CXCL-8, cyclooxygenase-2, microsomal prostaglandin E synthase-1, and inducible NO synthase. These effects may be dependent on the inhibition of nuclear factor-κB activation by CM. Our data demonstrate the chondroprotective actions of CM and provide support for further studies of this approach in joint disease.

The Effects of Green Tea on Obesity and Type 2 Diabetes

The Effects of Green Tea on Obesity and Type 2 Diabetes

Endothelial Nuclear Factor-κB–Dependent Regulation of Arteriogenesis and Branching

Arteriogenesis and collateral formation are complex processes requiring integration of multiple inputs to coordinate vessel branching, growth, maturation, and network size. Factors regulating these processes have not been determined. We used an inhibitor of NFκB activation (IκBαSR) under control of an endothelial-specific inducible promoter to selectively suppress endothelial nuclear factor-κB activation during development, in the adult vasculature, or in vitro. Inhibition of nuclear factor-κB activation resulted in formation of an excessively branched arterial network that was composed of immature vessels and provided poor distal tissue perfusion. Molecular analysis demonstrated reduced adhesion molecule expression leading to decreased monocyte influx, reduced hypoxia-inducible factor-1α levels, and a marked decrease in δ-like ligand 4 expression with a consequent decrease in Notch signaling. The latter was the principal cause of increased vascular branching as treatment with Jagged-1 peptide reduced the size of the arterial network to baseline levels. These findings identify nuclear factor-κB as a key regulator of adult and developmental arteriogenesis and collateral formation. Nuclear factor-κB achieves this by regulating hypoxia-inducible factor-1α-dependent expression of vascular endothelial growth factor-A and platelet-derived growth factor-BB, which are necessary for the development and maturation of the arterial collateral network, and by regulating δ-like ligand 4 expression, which in turn determines the size and complexity of the network.

Dietary supplementation with geranylgeraniol suppresses lipopolysaccharide-induced inflammation via inhibition of nuclear factor-κB activation in rats

The isoprenoid geranylgeraniol (GGOH) inhibits nuclear factor-kappa B (NF-κB) activation in the liver, yet the mechanism remains unclear. We investigated the modulation and inhibition of lipopolysaccharide (LPS)-induced NF-κB signaling in the liver of rats fed a GGOH-supplemented diet. Rats were fed a diet supplemented with or without GGOH for 10 days. Rats were then intraperitoneally injected with 0.5 mg/kg LPS or vehicle (sterilized saline) and fasted for 18 h. Plasma levels of the inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, and the liver damage indicators alanine and aspartate aminotransferases (ALT and AST) were assessed. Liver mRNA and proteins were assayed for changes in NF-κB target genes and signal transduction genes. Rats fed a high-dose, GGOH-supplemented diet showed significantly lower levels of plasma inflammatory cytokines and ALT and AST activities. In the liver, GGOH significantly suppressed NF-κB activation and mRNA expression of its pro-inflammatory target genes. Furthermore, GGOH supplementation substantially suppressed mRNA expression of signal transducer genes upstream of the IκB kinase complex. Western blotting of liver extracts further demonstrated the substantial decrease in total IL-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6), leading to lower signal transduction and inhibition of NF-κB after LPS. A 10-day, high-dose, GGOH-supplemented diet was sufficient to inhibit LPS-induced inflammation and activation of NF-κB in rat livers. GGOH significantly modulated NF-κB signaling molecules, inhibiting its signal transduction and activation in the liver, thus protecting against liver damage.

Imatinib enhances docetaxel-induced apoptosis through inhibition of nuclear factor-κB activation in anaplastic thyroid carcinoma cells

Imatinib enhances docetaxel-induced apoptosis through inhibition of nuclear factor-κB activation in anaplastic thyroid carcinoma cells

Imatinib Enhances Docetaxel-Induced Apoptosis Through Inhibition of Nuclear Factor-κB Activation in Anaplastic Thyroid Carcinoma Cells

We previously reported the partial effectiveness of imatinib (also known as STI571, Glivec, or Gleevec) on anaplastic thyroid cancer (ATC) cells. Imatinib is a selective tyrosine kinase inhibitor that has been used for various types of cancer treatments. Recently, several reports have demonstrated that imatinib enhanced the sensitivity of cancer cells to other anticancer drugs. In this study, therefore, we investigated whether imatinib enhances the antitumor activity of docetaxel in ATC cells. Two ATC cell lines, FRO and KTC-2, were treated with imatinib and/or docetaxel. Cell survival assay and flow cytometry for annexin V were used to assess the induction of apoptosis. Changes of pro- and antiapoptotic factors were determined by Western blot. Nuclear factor-κB (NF-κB) activity was measured by DNA-binding assay. Tumor growth was also investigated in vivo. The combined treatment significantly enhanced apoptosis compared with single treatment. ATC cells themselves expressed high levels of antiapoptotic factors, X-linked inhibitor of apoptosis (XIAP), and survivin. The treatment with docetaxel alone further increased their expressions; however, the combined treatment blocked the inductions. Although imatinib alone had no effect on NF-κB background levels, combined treatment significantly suppressed the docetaxel-induced NF-κB activation. Further, the combined administration of the drugs also showed significantly greater inhibitory effect on tumor growth in mice xenograft model. Imatinib enhanced antitumor activity of docetaxel in ATC cells. Docetaxel seemed to induce both pro- and antiapoptotic signaling pathways in ATC cells, and imatinib blocked the antiapoptotic signal. Thus, docetaxel combined with imatinib emerges as an attractive strategy for the treatment of ATC.

Inflammation, Endoplasmic Reticulum Stress, Autophagy, and the Monocyte Chemoattractant Protein-1/CCR2 Pathway

Numerous inflammatory cytokines have been implicated in the pathogenesis of cardiovascular diseases. Monocyte chemoattractant protein (MCP)-1/CCL2 is expressed by mainly inflammatory cells and stromal cells such as endothelial cells, and its expression is upregulated after proinflammatory stimuli and tissue injury. MCP-1 can function as a traditional chemotactic cytokine and also regulates gene transcription. The recently discovered novel zinc-finger protein, called MCPIP (MCP-1-induced protein), initiates a series of signaling events that causes oxidative and endoplasmic reticulum (ER) stress, leading to autophagy that can result in cell death or differentiation, depending on the cellular context. After a brief review of the basic processes involved in inflammation, ER stress, and autophagy, the recently elucidated role of MCP-1 and MCPIP in inflammatory diseases is reviewed. MCPIP was found to be able to control inflammatory response by inhibition of nuclear factor-κB activation through its deubiquitinase activity or by degradation of mRNA encoding a set of inflammatory cytokines through its RNase activity. The potential inclusion of such a novel deubiquitinase in the emerging anti-inflammatory strategies for the treatment of inflammation-related diseases such as cardiovascular diseases and type 2 diabetes is briefly discussed.

Heme oxygenase-1 mediates protective effects on inflammatory, catabolic and senescence responses induced by interleukin-1β in osteoarthritic osteoblasts

Osteoarthritis (OA) is a chronic degenerative joint disease showing altered bone metabolism. Osteoblasts contribute to the regulation of cartilage metabolism and bone remodeling. We have shown previously that induction of heme oxygenase-1 (HO-1) protects OA cartilage against inflammatory and degradative responses. In this study, we investigated the effects of HO-1 induction on OA osteoblast metabolism. HO-1 was induced with cobalt protoporphyrin IX (CoPP) and by transduction with LV-HO-1. In osteoblasts stimulated with interleukin (IL)-1β, CoPP enhanced mineralization, the expression of a number of markers of osteoblast differentiation such as Runx2, bone morphogenetic protein-2, osteocalcin, and collagen 1A1 and 1A2, as well as the ratio osteoprotegerin/receptor activator of nuclear factor-κB ligand. HO-1 induction significantly reduced the expression of matrix metalloproteinase (MMP)-1, MMP-2 and MMP-3, and the production of pro-inflammatory cytokines such as tumor necrosis factor-α and IL-6 whereas IL-10 levels increased. HO-1 also exerted inhibitory effects on prostaglandin (PG)E 2 production which could be dependent on cyclooxygenase-2 and microsomal PGE synthase-1 down-regulation. The activity of senescence-associated β-galactosidase and the expression of the senescence marker caveolin-1 were significantly decreased after HO-1 induction. The inhibition of nuclear factor-κB activation induced by IL-1β in OA osteoblasts may contribute to some HO-1 effects. Our results have shown that HO-1 decreases the production of relevant inflammatory and catabolic mediators that participate in OA pathophysiology thus eliciting protective effects in OA osteoblasts.