dehydroxymethylepoxyquinomicin and Inflammation

General inflammatory diseases include skin inflammation, rheumatoid arthritis, inflammatory bowel diseases, sepsis, arteriosclerosis, and asthma. Although these diseases have been extensively studied, most of them are still difficult to treat. Meanwhile, NF-κB is a transcription factor promoting the expression of many inflammatory mediators. NF-κB is likely to be involved in the mechanism of most inflammatory diseases. We discovered a specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), about 20 years ago by molecular design from a natural product. It directly binds to and inactivates NF-κB components. It has been widely used to suppress cellular and animal inflammatory disease models and was shown to be potent in vivo anti-inflammatory activity without any toxicity. We have prepared ointment of DHMEQ for the treatment of severe skin inflammation. It inhibited inflammatory cytokine expressions and lowered the clinical score in mouse models of atopic dermatitis. Intraperitoneal (IP) administration of DHMEQ ameliorated various disease models of inflammation, such as rheumatoid arthritis, sepsis, and also graft rejection. It has been suggested that inflammatory cells in the peritoneal cavity would be important for most peripheral inflammation. In the present review, we describe the synthesis, mechanism of action, and cellular and in vivo anti-inflammatory activities and discuss the clinical use of DHMEQ for inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Benzamides; Cyclohexanones; Disease Models, Animal; Humans; Inflammation; Mice; NF-kappa B

NF-κB is a transcription factor and considered to be involved in the mechanisms of inflammation and cancer. We have designed the new NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ), which directly binds to a specific cysteine residue of Rel family proteins to inhibit their DNA-binding activity. DHMEQ showed potent anti-inflammatory and anticancer activities in many animal models. So far DHMEQ has been administered mainly into the peritoneal cavity of animals. According to the limited distribution of DHMEQ in the peritoneal cavity after intraperitoneal administration, it is likely that NF-κB in the peritoneal cells would be the main target of DHMEQ. Therefore, the inflammatory cells in the peritoneal cavity appear important for the regulation of peripheral inflammation and tumor growth in the body, and peritoneal NF-κB may be an important target for anti-inflammatory and anticancer agents in future.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cyclohexanones; Humans; Inflammation; Molecular Structure; Neoplasms; NF-kappa B; Peritoneum

Topics: Animals; Anti-Inflammatory Agents; Benzamides; Biological Products; Cell Differentiation; Cyclohexanones; Depsipeptides; Drug Design; Drug Evaluation, Preclinical; Inflammation; Inflammation Mediators; Lipopolysaccharides; Neoplasms; NF-kappa B; Osteoclasts; Piperidones; Signal Transduction

PM2.5 is a particle with a diameter <2.5 µm that is often involved in air pollution. Nanoparticles <100 nm are thought to invade the trachea and lungs to cause inflammation, possibly through the activation of macrophages. On the other hand, titanium dioxide (TiO2) particles can be used in models of nano‑micro‑sized particles, as one can prepare the particles with such sizes. TiO2 particles are classified into Rutile, Anatase, and Brookite types by their crystal structure. Among them, Anatase‑type TiO2 particles with a primary diameter of 50 nm (A50) were reported to induce interleukin (IL)‑1β production and secretion effectively in phorbol 12‑myristate 13‑acetate‑treated human monocytic leukemia THP‑1 cells (THP‑1 macrophages). We previously designed and synthesized dehydroxymethyl‑epoxyqinomicin (DHMEQ) as an inhibitor of NF‑κB. The present study investigated whether the NF‑κB inhibitor DHMEQ inhibits TiO2 nanoparticle‑induced IL‑1β production in THP‑1 macrophages, and determined the mechanism. As a result, DHMEQ inhibited A50‑induced IL‑1β secretion in ELISA assays at nontoxic concentrations. It decreased the expression of IL‑1β mRNA, which was dependent on NF‑κB. Although NLR family pyrin domain containing 3 (NLRP3)‑inflammasome‑caspase‑1 activation is required for the maturation of IL‑1β, and DHMEQ reduced the NLRP3 mRNA expression and caspase‑1 activity; a caspase‑1 inhibitor did not influence the A50‑induced IL‑1β production. Therefore, it is likely that inhibition of pro‑IL‑1β expression by DHMEQ may be sufficient to inhibit mature IL‑1β production. Thus, DHMEQ may be useful for the amelioration of inflammation in the trachea and lungs caused by inhalation of PM2.5.

Topics: Animals; Benzamides; Biomarkers; Caspase 1; Caspase Inhibitors; Cell Line; Cyclohexanones; Disease Models, Animal; Humans; Inflammation; Interleukin-1beta; Macrophages; Models, Molecular; Nanoparticles; NF-kappa B; Particulate Matter; Potassium; Titanium

Dehydroxymethylepoxyquinomicin (DHMEQ) is a newly developed compound that inhibits nuclear factor κB activation and is reported to ameliorate animal models of various inflammatory diseases without significant adverse effects. Because nuclear factor κB is a transcription factor that plays a critical role in the pathophysiology of asthma, DHMEQ may be of therapeutic benefit in asthma.. The purpose of this study was to evaluate the effects of DHMEQ on airway inflammation and remodelling in murine models of asthma.. The BALB/c mice were sensitized and then challenged acutely or chronically with ovalbumin and administered DHMEQ intraperitoneally before each challenge. Inflammation of airways, lung histopathology and airway hyper responsiveness to methacholine challenge were evaluated. In addition, the effect of DHMEQ on production of cytokines and eotaxin-1 by murine splenocytes, human peripheral blood mononuclear cells and bronchial epithelial cells was investigated.. Airway hyper responsiveness was ameliorated in both acutely and chronically challenged models by treatment with DHMEQ. DHMEQ significantly reduced eosinophilic airway inflammation and levels of Th2 cytokines in bronchoalveolar lavage fluid in the acute model. It also inhibited parameters of airway remodelling including mucus production, peribronchial fibrosis and the expression of α-smooth muscle actin. Moreover, the production of Th2 cytokines from murine splenocytes and human peripheral blood mononuclear cells and the production of eotaxin-1 by bronchial epithelial cells were inhibited by DHMEQ.. These results indicate that DHMEQ inhibits allergic airway inflammation and airway remodelling in murine models of asthma. DHMEQ may have therapeutic potential in the treatment of asthma.

Topics: Airway Remodeling; Animals; Asthma; Benzamides; Bronchoalveolar Lavage Fluid; Cells, Cultured; Cyclohexanones; Cytokines; Disease Models, Animal; Eosinophils; Epithelial Cells; Female; Humans; Inflammation; Inflammation Mediators; Leukocytes, Mononuclear; Mice; Mice, Inbred BALB C; NF-kappa B; Respiratory Hypersensitivity

1. The novel nuclear factor (NF)-kappaB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) is a derivative of the antibiotic epoxyquinomicin C from Amycolatopsis sp. that has been found to inhibit tumour necrosis factor (TNF)-alpha-induced activation of NF-kappaB by suppressing nuclear translocation of NF-kappaB. The aim of the present study was to determine the effects of DHMEQ on interferon (IFN)-gamma- and histamine-activated NCTC 2544 keratinocytes. 2. Keratinocytes were stimulated or not with 200 U/mL IFN-gamma and 10(-4) mol/L histamine in the absence or presence of different concentrations of DHMEQ (1, 5 and 10 microg/mL) or hydrocortisone (10(-5) mol/L), which was used as a reference anti-inflammatory drug. After 48 h, each sample was tested for the presence of intercellular adhesion molecule (ICAM)-1 by western blot analysis, as well as for the release of monocyte chemoattractant protein (MCP)-1, RANTES and interleukin (IL)-8 using specific sandwich ELISAs. To verify the effect of DHMEQ on cell viability of non-stimulated NCTC 2544 keratinocytes, the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used. 3. The results showed that 10 microg/mL DHMEQ potently inhibited ICAM-1 production (by 50%), as well as the release of MCP-1 (to 25% of control), RANTES (to 5% of control) and IL-8 (to 2% of control). The results of the MTT assay indicated that DHMEQ has no effect on cell viability. 4. In conclusion, DHMEQ inhibits the IFN-gamma- and histamine-induced activation of the keratinocyte cell line NCTC 2544. The anti-inflammatory effects of DHMEQ could be exploited by applying the drug topically alone or in combination with sub-toxic concentrations of anti-inflammatory drugs to producer a synergistic effect.

Topics: Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Benzamides; Cell Line; Chemokine CCL2; Chemokine CCL5; Cyclohexanones; Histamine; Humans; Hydrocortisone; Inflammation; Intercellular Adhesion Molecule-1; Interferon-gamma; Interleukin-8; Keratinocytes; NF-kappa B