650 results on '"Kazuo Umezawa"'
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2. Inhibitory effects of estetrol on the invasion and migration of immortalized human endometrial stromal cells
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Akihiko Wakatsuki, Yinzhi Lin, Shiori Kojima, Hiroshi Matsushita, Kosei Takeuchi, and Kazuo Umezawa
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17β estradiol ,estetrol ,endometriosis ,immortalized human endometrial stromal cells ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Endometriosis, a common gynecological disorder characterized by the growth of endometrial gland and stroma outside the uterus, causes several symptoms such as dysmenorrhea, hypermenorrhea, and chronic abdominal pain. 17β estradiol (E2) stimulates the growth of endometriotic lesions. Although estetrol (E4), produced by human fetal liver, is also a natural estrogen, it may have the opposite effects on endometriotic cells. We investigated different effects of E4 and E2 on the invasion and migration of immortalized human endometrial stromal cells (HESCs) and evaluated whether E4 affects the expression of Wiskott-Aldrich syndrome protein (WASP) family member 1 (WASF-1). We measured the invasion of HESCs by a Matrigel chamber assay. Cell migration was measured by wound healing assay and cell tracking analysis. The expression of WASF-1 was confirmed by independent real-time PCR analysis. Transfection of cells with siRNAs was carried out to knock down the expression of WASF-1 in HESCs. E4 significantly inhibited E2-induced invasion and migration of HESCs. WASF-1 was found to be a potential mediator based on metastasis PCR array. WASF-1 was upregulated by E2 and downregulated by E4. Knockdown of WASF-1 inhibited migration. Our results suggest that E4 may inhibit E2-induced growth of endometriotic lesions. Downregulation of WASF-1 is involved in the inhibitory effects of E4 on migration. The use of E4 combined with progestins as combined oral contraceptives may cause endometriotic lesions to regress in women with endometriosis.
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- 2023
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3. Methods of Cleaning Taps to Prevent Hospital-Associated Infections: An Environmental Survey-Based Study
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Masayoshi Hashimoto, Satomi Asai, Kazuo Umezawa, Ryosuke Tanitsu, Miki Miyazawa, Michiko Kobayashi, Yuji Kawakami, Yoshika Sekine, Yuji Suzuki, Hayato Miyachi, and Kenji Okami
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infection control ,water supply ,carbapenem-resistant Enterobacteriaceae ,disinfectants ,health facility environment ,Other systems of medicine ,RZ201-999 - Abstract
In hospitals, outbreaks can occur due to pathogens accumulating in the areas around the wards’ washbasins. Carbapenem-resistant Enterobacterales (CRE) was detected in an environmental survey in the high-care unit of a university hospital in Isehara, Japan, and effective cleaning methods were investigated. This study investigated methods of cleaning taps using commonly used detergents and disinfectants, and it assessed their effectiveness in removing hard scale and pathogens, including CRE. The taps were cleaned using various methods and cleaning agents, including environmentally neutral detergent, citric acid, baking soda, cleanser, 80% ethanol, 0.1% sodium hypochlorite, and a phosphoric acid-based environmental detergent (Space Shot). The cleaning effect was assessed based on the agent’s effectiveness at removing hard scale from taps. Biofilms and scale were identified on taps, and several bacterial species were cultured. Only phosphoric acid-based detergent was effective at removing hard scale. After cleaning with the phosphoric acid-based detergent, the bacterial count decreased, and no CRE or other pathogens were detected. These results provide a reference for other facilities considering introducing this cleaning method.
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- 2023
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4. Rapid profiling of drug-resistant bacteria using DNA-binding dyes and a nanopore-based DNA sequencer
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Ayumu Ohno, Kazuo Umezawa, Satomi Asai, Kirill Kryukov, So Nakagawa, Hayato Miyachi, and Tadashi Imanishi
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Medicine ,Science - Abstract
Abstract Spread of drug-resistant bacteria is a serious problem worldwide. We thus designed a new sequence-based protocol that can quickly identify bacterial compositions of clinical samples and their drug-resistance profiles simultaneously. Here we utilized propidium monoazide (PMA) that prohibits DNA amplifications from dead bacteria, and subjected the original and antibiotics-treated samples to 16S rRNA metagenome sequencing. We tested our protocol on bacterial mixtures, and observed that sequencing reads derived from drug-resistant bacteria were significantly increased compared with those from drug-sensitive bacteria when samples were treated by antibiotics. Our protocol is scalable and will be useful for quickly profiling drug-resistant bacteria.
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- 2021
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5. Influence of Ingestion of Lactulose on γ-Lactones Emanating from Human Skin Surface
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Yoshika Sekine, Shiori Uchiyama, Michihito Todaka, Yohei Sakai, Ryo Sakiyama, Hiroshi Ochi, Maho Muramatsu, Satomi Asai, and Kazuo Umezawa
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human skin gas ,γ-lactones ,prebiotic ,lactulose ,SCFAs ,Technology ,Engineering (General). Civil engineering (General) ,TA1-2040 ,Biology (General) ,QH301-705.5 ,Physics ,QC1-999 ,Chemistry ,QD1-999 - Abstract
Lactulose is known to grow health-promoting bacteria, with an increase in the production of beneficial metabolites, such as lactic acid and short-chain fatty acids (SCFAs) in the colon. Ingestion of lactulose powder at a food dosage level is known to reduce the dermal emanation of ammonia, a typical human skin gas which potentially affects body odour. However, no study has reported the effect of lactulose on human skin gases other than ammonia. In this study, the influence of lactulose ingestion on the dermal emissions of γ-lactones, volatile cyclic esters with sweet smells, was investigated in healthy subjects. Healthy participants ingested the lactulose powder with a food dosage of 4 g d−1 once a day for 2 weeks. γ-lactones emanating from the skin surface were collected from each participant’s forearm by using a passive flux sampler, and six kinds of γ-lactones, namely, γ-hexalactone (C6), γ-heptalactone (C7), γ-octalactone (C8), γ-nonalactone (C9), γ-decalactone (C10), and γ-undecalactone (C11), were determined by gas chromatography–mass spectrometry. Quantification of bifidobacteria in faeces collected before and after ingestion of lactulose for 2 weeks was carried out by using real-time PCR. The results showed a significant increase in the dermal emission fluxes of sweet-smelling C10 and C11 lactones as the number of bifidobacteria increased in the faeces, presumably mediated by SCFAs produced in the colon.
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- 2023
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6. Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat model
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Shinya Morita, Kazunobu Shinoda, Tadashi Yoshida, Masayuki Shimoda, Yoshihiko Kanno, Ryuichi Mizuno, Hidaka Kono, Hiroshi Asanuma, Ken Nakagawa, Kazuo Umezawa, and Mototsugu Oya
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Cyclosporine ,Nephrotoxicity ,NF-κB ,NF-κB inhibitor ,Therapeutics. Pharmacology ,RM1-950 ,Toxicology. Poisons ,RA1190-1270 - Abstract
Abstract Background Cyclosporine A (CsA) is an essential immunosuppressant in organ transplantation. However, its chronic nephrotoxicity is an obstacle to long allograft survival that has not been overcome. Nuclear factor-κB (NF-κB) is activated in the renal tissue in CsA nephropathy. In this study, we aimed to investigate the effect of the specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in a rat model of CsA nephrotoxicity. Methods We administered CsA (15 mg/kg) daily for 28 days to Sprague-Dawley rats that underwent 5/6 nephrectomy under a low-salt diet. We administered DHMEQ (8 mg/kg) simultaneously with CsA to the treatment group, daily for 28 days and evaluated its effect on CsA nephrotoxicity. Results DHMEQ significantly inhibited NF-κB activation and nuclear translocation due to CsA treatment. Elevated serum urea nitrogen and creatinine levels due to repeated CsA administration were significantly decreased by DHMEQ treatment (serum urea nitrogen in CsA + DHMEQ vs CsA vs control, 69 ± 6.4 vs 113.5 ± 8.8 vs 43.1 ± 1.1 mg/dL, respectively, p
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- 2020
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7. Cellular Anti-Inflammatory and Antioxidant Activities of Bamboo Sasa albomarginata Leaf Extract and Its Constituent Coumaric Acid Methyl Ester
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Shiori Kojima, Masatoshi Hakamata, Toshimichi Asanuma, Rie Suzuki, Jun-ichi Tsuruda, Takeshi Nonoyama, Yinzhi Lin, Hitomi Fukatsu, Naoki Koide, and Kazuo Umezawa
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Technology ,Medicine ,Science - Abstract
Background. Hot water extract of Sasa albomarginata (Kumazasa) leaves is commercially available and used as a dietary supplement or skincare cream. The extract possesses anti-inflammatory activity on the mouse atopic dermatitis model. To elucidate the mechanism of in vivo activity, we have studied the cellular anti-inflammatory and antioxidant activities of the extract and its constituents. Methods. Secretion of mouse and human IL-6 was measured by ELISA. ROS production was measured by a fluorescent reagent. Ultrahigh performance liquid chromatography (UHPLC)/MS was used for the ingredient analysis. Results. The Sasa albomarginata extract inhibited inflammatory mediators such as LPS-induced NO, IL-6, and ROS production in mouse monocyte leukemia RAW264.7 cells. It also inhibited iNOS, IL-6, and IL-1β expressions. Moreover, it inhibited LPS-induced IL-6 expression and production in human monocyte leukemia THP-1 cells differentiated into macrophages. The HPLC analysis of the extract revealed the existence of coumaric acid, ferulic acid, and coumaric acid methyl ester. Coumaric acid methyl ester but not coumaric acid or ferulic acid inhibited LPS-induced NO, IL-6, and ROS production in RAW264.7 cells and IL-6 production in differentiated THP-1 cells. Conclusion. The hot water extract of Sasa albomarginata leaves and one of its constituents possess cellular anti-inflammatory and antioxidant activities.
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- 2022
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8. Development of a wristband-type wearable device for the colorimetric detection of ammonia emanating from the human skin surface
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Shiro Ikeda, Satomi Asai, Kazuo Umezawa, Hayato Miyachi, Ai Nakamura, Yuichiro Kaifuku, and Yoshika Sekine
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Passive flux sampler ,Passive indicator ,Wearable device ,Ammonia ,Skin gas ,Fatigue odor ,Chemistry ,QD1-999 - Abstract
Human skin gas is the term used to describe gas emanating from the human skin surface. Ammonia, one such gas, has a pungent odor affecting body odor. As ammonia’s dermal emission increases with physical load and/or psychological stress, the resulting body odor is called “fatigue odor.” Previously, human skin gases were collected via direct contact or headspace sampling, using a homemade sampling probe or bag and passive flux sampler. We developed a wristband-type wearable device for rapid, on-site detection of dermal ammonia based on headspace passive sampling coupled with Alizarin red as a pH indicator. Color change was measured with a colorimetric indicator tested in an exposure chamber and calibrated using dermal emission flux measured with a passive flux sampler. The indicator was developed as a tablet-like device comprising a polyethylene terephthalate body with a transparent window, detection sheet, diffuser, and disk with concentric spaces. The detection sheet was prepared by pipetting 50 μL 0.1 % Alizarin red–1 % glycerol into a methanol solution onto a cellulose filter paper and drying. The colorimetric indicator was placed on the skin surface using a wristband. For quantitative evaluation, the color-change amount was evaluated using color difference (ΔE*ab), which was calculated from L*, a*, and b* measured using a spectrophotometer. The colorimetric response to ammonia on the colorimetric indicator was evaluated by comparison with the conventional passive flux sampler. Good correlations were obtained between the color change amounts and those collected with the passive flux sampler. To simulate living human-skin conditions, the influence of temperature and humidity was also tested, and the effect on the passive indicator was clarified. Compared to conventional dermal ammonia-measuring methods, this newly developed passive indicator was more user-friendly because the results were obtained on-site without external evaluation. The passive indicator was also found to be an effective and simplified instrument for dermal ammonia measurements.
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- 2022
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9. Evaluation of the basic assay performance of the GeneSoc® rapid PCR testing system for detection of severe acute respiratory syndrome coronavirus 2.
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Ryosuke Watanabe, Satomi Asai, Hidehumi Kakizoe, Hirofumi Saeki, Atsuko Masukawa, Miki Miyazawa, Kazumi Ohtagawa, Mend-Amar Ravzanaaadii, Mika Doi, Haruyo Atsumi, Kazuo Umezawa, and Hayato Miyachi
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Medicine ,Science - Abstract
In the ongoing coronavirus disease 2019 (COVID-19) pandemic, PCR has been widely used for screening patients displaying relevant symptoms. The rapid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enables prompt diagnosis and the implementation of proper precautionary and isolation measures for the patient. In the present study, we aimed to evaluate the basic assay performance of an innovative PCR system, GeneSoC® (Kyorin Pharmaceutical Co. Ltd., Tokyo, Japan). A total of 1,445 clinical samples were submitted to the clinical laboratory, including confirmed or suspected cases of COVID-19, from February 13 to August 31. Specimen types included nasopharyngeal swabs. The sampling was performed several times for each patient every 2-7 days. Using this system, sequences specific for SARS-CoV-2 RNA could be detected in a sample within 10-15 min using the microfluidic thermal cycling technology. Analytical sensitivity studies showed that GeneSoC® could detect the target sequence of the viral envelope and RNA-dependent RNA-polymerase (RdRp) genes at 5 and 10 copies/μL, respectively. The precision of the GeneSoC® measurements using clinical isolates of the virus at a concentration of 103 copies/μL was favorable for both the genes; within-run repeatability and between-run reproducibility coefficient of variation values were less than 3% and 2%, respectively; and the reproducibility of inter-detection units was less than 5%. Method comparison by LightCycler® 480 showed the positive and negative agreement to be 100% [(174/174) and (1271/1271), respectively]. GeneSoC® proved to be a rapid and reliable detection system for the prompt diagnosis of symptomatic COVID-19 patients and could help reduce the spread of infections and facilitate more rapid treatment of infected patients.
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- 2021
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10. Inhibition of Cellular and Animal Inflammatory Disease Models by NF-κB Inhibitor DHMEQ
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Jun Ma, Yuyang Zhang, Takeshi Sugai, Tetsuo Kubota, Hiroshi Keino, Magdy El-Salhy, Michitaka Ozaki, and Kazuo Umezawa
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NF-κB ,DHMEQ ,tacrolimus ,inflammation ,transplantation ,ointment ,Cytology ,QH573-671 - Abstract
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.
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- 2021
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11. Causes and mechanisms of peritoneal fibrosis and possible application of NF-κB inhibitor for prevention and treatment
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Andrzej Bręborowicz and Kazuo Umezawa
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fibrosis ,peritoneal dialysis ,NF-κB ,Medicine - Abstract
Peritoneal dialysis is an established form of the renal replacement therapy in patients with end stage renal failure. Continuous Ambulatory Peritoneal Dialysis developed by Moncrief and Popovich in 1975 was a revolutionary event, and contributed much to wide application of that form of treatment in uremic patients. On the other hand, the weak point of peritoneal dialysis is relatively short viability of the peritoneum as the dialysis membrane. Two main peritoneal pathologies are observed in patients treated with that form of renal replacement therapy: neovascularization of the membrane what causes increased peritoneal permeability to osmotic solutes and ultrafiltration failure, and fibrosis which results also in ultrafiltration failure due to its decreased hydraulic conductivity and reduced permeability to uremic toxins. Meanwhile, an NF-κB inhibitor DHMEQ was discovered in 2000 and has been successfully used to suppress various inflammatory and neoplastic disease models. NF-κB is likely to be involved in the mechanism of peritoneal inflammation and fibrosis. We have studied whether DHMEQ would inhibit cellular model of peritoneal inflammation and fibrosis. It inhibited inflammatory cytokine and collagen productions in primary culture of human peritoneal mesothelial cells, and intraperitoneal administration of NF-κB inhibitors would be useful to suppress peritoneal fibrosis.
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- 2019
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12. Growth Inhibitory Effects of Dipotassium Glycyrrhizinate in Glioblastoma Cell Lines by Targeting MicroRNAs Through the NF-κB Signaling Pathway
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Gabriel Alves Bonafé, Jéssica Silva dos Santos, Jussara Vaz Ziegler, Kazuo Umezawa, Marcelo Lima Ribeiro, Thalita Rocha, and Manoela Marques Ortega
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glioblastoma ,nuclear factor kappa-B ,dipotassium glycyrrhizinate ,miR16 ,miR146a ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
It has been shown that nuclear factor kappa-B (NF-κB) is constitutively activated in glioblastoma (GBM), suggesting that the pathway could be a therapeutic target. Glycyrrhetic acid (GA), a compound isolated from licorice (Glycyrrhiza glabra), has been shown to decrease cell viability and increases apoptosis in human cancer cell lines by NF-κB signaling pathway suppression. Dipotassium glycyrrhizinate (DPG), a dipotassium salt of GA, has anti-inflammatory properties without toxicity. The current study examined the effectiveness of DPG as an anti-tumor in U87MG and T98G GBM cell lines. Additionally, we assessed DPG as a candidate for combinational therapy in GBM with temozolomide (TMZ). Our results demonstrated that the viability of U87MG and T98G cells significantly decreased in a time- and dose-dependent manner after DPG treatment, and the apoptotic ratio of DPG-treated groups was significantly higher than that of control groups. In addition, DPG in combination with TMZ revealed synergistic effects. Furthermore, the expression of NF-κB-luciferase-reporter in transfected GBM cell lines was remarkably reduced after DPG exposure by up-regulating miR16 and miR146a, which down-regulate its target genes, IRAK2 and TRAF6. A reduced neuro-sphere formation was also observed after DPG in both GBM cells. In conclusion, DPG presented anti-tumoral effect on GBM cell lines through a decrease on proliferation and an increase on apoptosis. In addition, our data also suggest that DPG anti-tumoral effect is related to NF-κB suppression, where IRAK2- and TRAF6-mediating miR16 and miR146a, respectively, might be a potential therapeutic target of DPG.
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- 2019
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13. Conophylline inhibits high fat diet-induced non-alcoholic fatty liver disease in mice.
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Tomohiko Ohashi, Yukiomi Nakade, Mayu Ibusuki, Rena Kitano, Taeko Yamauchi, Satoshi Kimoto, Tadahisa Inoue, Yuji Kobayashi, Yoshio Sumida, Kiyoaki Ito, Haruhisa Nakao, Kazuo Umezawa, and Masashi Yoneda
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Medicine ,Science - Abstract
Conophylline (CnP), a vinca alkaloid extracted from the leaves of the tropical plant Tabernaemontana divaricate, attenuates hepatic fibrosis in mice. We have previously shown that CnP inhibits non-alcoholic steatohepatitis (NASH) using a methionine-choline-deficient (MCD) diet-fed mouse model. However, little is known about the CnP mediated inhibition of hepatic steatosis in high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) mouse models. CnP (0.5 and 1 μg/g/body weight) was co-administered along with a high-fat diet to male BALB/c mice. After nine weeks of administering the high-fat diet, hepatic steatosis, triglyceride, and hepatic fat metabolism-related markers were examined. Administration of a high-fat diet for 9 weeks was found to induce hepatic steatosis. CnP dose-dependently attenuated the high-fat diet-induced hepatic steatosis. The diet also attenuated hepatic peroxisome proliferator-activated receptor alpha (PPARA) mRNA levels. PPARA is known to be involved in β-oxidation. CnP upregulated the mRNA levels of hepatic PPARA and its target genes, such as carnitine palmitoyl transferase 1 (CPT1) and CPT2, in a dose-dependent manner in the liver. Furthermore, levels of hepatic β-hydroxybutyrate, which is a type of ketone body, were increased by CnP in a dose-dependent manner. Finally, CnP increased the expression of the autophagosomal marker LC3-II and decreased the expression of p62, which are known to be selectively degraded during autophagy. These results indicate that CnP inhibits hepatic steatosis through the stimulation of β-oxidation and autophagy in the liver. Therefore, CnP might prove to be a suitable therapeutic target for NAFLD.
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- 2019
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14. Cellular Signal Transductions and Their Inhibitors Derived from Deep-Sea Organisms
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Liyan Wang and Kazuo Umezawa
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cellular signal transduction ,bioactive metabolite ,deep-sea organisms ,anti-inflammatory agent ,anticancer agent ,Biology (General) ,QH301-705.5 - Abstract
Not only physiological phenomena but also pathological phenomena can now be explained by the change of signal transduction in the cells of specific tissues. Commonly used cellular signal transductions are limited. They consist of the protein–tyrosine kinase dependent or independent Ras-ERK pathway, and the PI3K-Akt, JAK-STAT, SMAD, and NF-κB-activation pathways. In addition, biodegradation systems, such as the ubiquitin–proteasome pathway and autophagy, are also important for physiological and pathological conditions. If we can control signaling for each by a low-molecular-weight agent, it would be possible to treat diseases in new ways. At present, such cell signaling inhibitors are mainly looked for in plants, soil microorganisms, and the chemical library. The screening of bioactive metabolites from deep-sea organisms should be valuable because of the high incidence of finding novel compounds. Although it is still an emerging field, there are many successful examples, with new cell signaling inhibitors. In this review, we would like to explain the current view of the cell signaling systems important in diseases, and show the inhibitors found from deep-sea organisms, with their structures and biological activities. These inhibitors are possible candidates for anti-inflammatory agents, modulators of metabolic syndromes, antimicrobial agents, and anticancer agents.
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- 2021
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15. Isolation and Characterization of New Anti-Inflammatory and Antioxidant Components from Deep Marine-Derived Fungus Myrothecium sp. Bzo-l062
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Xiaojie Lu, Junjie He, Yanhua Wu, Na Du, Xiaofan Li, Jianhua Ju, Zhangli Hu, Kazuo Umezawa, and Liyan Wang
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deep sea marine-derived fungus ,Myrothecium sp. ,myrothecol ,nitric oxide (NO) ,antioxidant activity ,Biology (General) ,QH301-705.5 - Abstract
In the present study, four new compounds including a pair of 2-benzoyl tetrahydrofuran enantiomers, namely, (−)-1S-myrothecol (1a) and (+)-1R-myrothecol (1b), a methoxy-myrothecol racemate (2), and an azaphilone derivative, myrothin (3), were isolated along with four known compounds (4–7) from cultures of the deep-sea fungus Myrothecium sp. BZO-L062. Enantiomeric compounds 1a and 1b were separated through normal-phase chiral high-performance liquid chromatography. The absolute configurations of 1a, 1b, and 3 were assigned by ECD spectra. Among them, the new compound 1a and its enantiomer 1b exhibited anti-inflammatory activity, inhibited nitric oxide formation in lipopolysaccharide-treated RAW264.7 cells, and exhibited antioxidant activity in the 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) and oxygen radical absorbance capacity assays.
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- 2020
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16. A national survey examining recognition, demand for antivenom, and overall level of preparedness for redback spider bites in Japan
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Toru Hifumi, Tomoya Okazaki, Arisa Manabe, Hideyuki Hamaya, Satoshi Egawa, Satoshi Fujimi, Akihiko Yamamoto, Yuichi Koido, Yuko Abe, Kenya Kawakita, Kazuo Umezawa, and Yasuhiro Kuroda
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Anaphylaxis ,antivenom ,questionnaire ,redback spiders ,spider bites ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
Aim Redback spiders are rapidly becoming a nationwide problem in Japan. The domestic production of antivenom for redback spider bites has been started because of extremely low supply. The purpose of this study was to investigate the ability of emergency physicians to recognize redback spider bites and to examine the demand for antivenom and identify the ideal choice for storage. Methods Questionnaires examining the ability to recognize redback spider bites, the demand for antivenom, and overall level of preparedness were sent to 271 emergency medical service centers in Japan in March 2015. Results Completed questionnaires were returned by 156 medical institutions (58%). Only 25% of the institutes correctly answered regarding the recognition of redback spider bites. A demand for the new, domestically produced antivenom was reported by 55% of the institutes. Antivenom demand was high and increased with the ability to recognize redback spider bites (0 correct answers, n = 24 [42.9%]; 1–2 answers, n = 32 [55.2%]; three answers, n = 28 [71.8%]; P = 0.02). The storage of antivenom within their prefectures or regions was the best option for initial supply planning. Approximately 90% of the emergency centers showed an ability to use the antivenom safely. Conclusion The recognition of redback spider bites was low; however, the demand for antivenom was high. The storage of antivenom within their own prefectures or regions was considered to be the best option for initial supply planning. Emergency medical service centers are also good candidates for storage and safe use of antivenom.
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- 2016
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17. Microenvironmental stromal cells abrogate NF-κB inhibitor-induced apoptosis in chronic lymphocytic leukemia
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Carl Philipp Simon-Gabriel, Katharina Foerster, Shifa Saleem, Dorothee Bleckmann, Marco Benkisser-Petersen, Nicolas Thornton, Kazuo Umezawa, Sarah Decker, Meike Burger, Hendrik Veelken, Rainer Claus, Christine Dierks, Justus Duyster, and Katja Zirlik
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) is known to play an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). Several NF-κB inhibitors were shown to successfully induce apoptosis of CLL cells in vitro. Since the microenvironment is known to be crucial for the survival of CLL cells, herein, we tested whether NF-κB inhibition may still induce apoptosis in these leukemic cells in the presence of protective stromal interaction. We used the specific NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ). Microenvironmental support was mimicked by co-culturing CLL cells with bone marrow-derived stromal cell lines (HS-5 and M2-10B4). NF-κB inhibition by DHMEQ in CLL cells could be confirmed in both the monoculture and co-culture setting. In line with previous reports, NF-κB inhibition induced apoptosis in the monoculture setting by activating the intrinsic apoptotic pathway resulting in poly (ADP-ribose) polymerase (PARP)-cleavage; however, it was unable to induce apoptosis in leukemic cells co-cultured with stromal cells. Similarly, small interfering ribonucleic acid (siRNA)-mediated RELA downregulation induced apoptosis of CLL cells cultured alone, but not in the presence of supportive stromal cells. B-cell activating factor (BAFF) was identified as a microenvironmental messenger potentially protecting the leukemic cells from NF-κB inhibition-induced apoptosis. Finally, we show improved sensitivity of stroma-supported CLL cells to NF-κB inhibition when combining the NF-κB inhibitor with the SYK inhibitor R406 or the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, agents known to inhibit the stroma-leukemia crosstalk. We conclude that NF-κB inhibitors are not promising as monotherapies in CLL, but may represent attractive therapeutic partners for ibrutinib and R406.
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- 2018
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18. Importance of Novel Intraperitoneal Therapy of NF-kappa B Inhibitor DHMEQ
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Sh. Kh. Gantsev and Kazuo Umezawa
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nf-kappa b ,cancer ,leukemia ,dehydroxymethylepoxyquinomicin ,dhmeq ,Surgery ,RD1-811 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2019
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19. Conophylline inhibits non-alcoholic steatohepatitis in mice.
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Yukiomi Nakade, Kazumasa Sakamoto, Taeko Yamauchi, Tadahisa Inoue, Yuji Kobayashi, Takaya Yamamoto, Norimitsu Ishii, Tomohiko Ohashi, Yoshio Sumida, Kiyoaki Ito, Haruhisa Nakao, Yoshitaka Fukuzawa, Kazuo Umezawa, and Masashi Yoneda
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Medicine ,Science - Abstract
Conophylline (CnP), a vinca alkaloid extracted from the leaves of the tropical plant Ervatamia microphylla, attenuates hepatic fibrosis in mice. However, little is known about whether CnP inhibits steatosis, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH) in mice. A methionine-choline-deficient (MCD) diet was administered to male db/db mice as a NASH model, and CnP (1 μg/kg/d) was co-administered. Eight weeks after the commencement of the MCD diet, hepatic steatosis, inflammation, and fibrosis, and hepatic fat metabolism-, inflammation-, and fibrosis-related markers were examined. Feeding on an MCD for 8 weeks induced hepatic steatosis, inflammation, and fibrosis. CnP significantly attenuated the MCD-induced increases in hepatic steatosis, as well as hepatic inflammation and fibrosis. The MCD diet increased hepatic transforming growth factor-β (TGF-β) mRNA levels, which are correlated with hepatic steatosis, inflammation, and fibrosis. The diet also attenuated acyl-coenzyme A oxidase 1 (ACOX1) and carnitine palmitoyltransferase 1 (CPT1) mRNA levels, which are involved in β-oxidation. The putative mechanism of the CnP effect involves reduced hepatic TGF-β mRNA levels, and increased mRNA levels of hepatic peroxisome proliferator-activated receptor (PPAR) α and its target genes ACOX1 and CPT1. The results of this study indicate that CnP inhibits steatohepatitis, possibly through the inhibition of hepatic TGF-β mRNA levels, and induces an increase in PPARα mRNA levels, resulting in the attenuation of hepatic steatosis, inflammation, and fibrosis in mice. CnP might accordingly be a suitable therapeutic option for NASH.
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- 2017
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20. Earthworm-Derived Pore-Forming Toxin Lysenin and Screening of Its Inhibitors
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Neelanun Sukumwang and Kazuo Umezawa
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Lysenin ,Eisenia foetida ,hemolysis ,pore formation ,sphingomyelin binding ,Dalbergia latifolia ,all-E-lutein ,tyrosylproline anhydride ,Medicine - Abstract
Lysenin is a pore-forming toxin from the coelomic fluid of earthworm Eisenia foetida. This protein specifically binds to sphingomyelin and induces erythrocyte lysis. Lysenin consists of 297 amino acids with a molecular weight of 41 kDa. We screened for cellular signal transduction inhibitors of low molecular weight from microorganisms and plants. The purpose of the screening was to study the mechanism of diseases using the obtained inhibitors and to develop new chemotherapeutic agents acting in the new mechanism. Therefore, our aim was to screen for inhibitors of Lysenin-induced hemolysis from plant extracts and microbial culture filtrates. As a result, we isolated all-E-lutein from an extract of Dalbergia latifolia leaves. All-E-lutein is likely to inhibit the process of Lysenin-membrane binding and/or oligomer formation rather than pore formation. Additionally, we isolated tyrosylproline anhydride from the culture filtrate of Streptomyces as an inhibitor of Lysenin-induced hemolysis.
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- 2013
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21. The NF-κB specific inhibitor DHMEQ prevents thrombus formation in a mouse model of antiphospholipid syndrome
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Misato Nishimura, Tokiko Nii, Gulzhan Trimova, Shuhei Miura, Kazuo Umezawa, Akira Ushiyama, and Tetsuo Kubota
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antiphospholipid syndrome ,nf-kappa b ,tissue factor ,thrombosis ,Pathology ,RB1-214 ,Internal medicine ,RC31-1245 ,Other systems of medicine ,RZ201-999 - Abstract
Background: β2-glycoprotein I (β2GPI)-dependent antiphospholipid antibodies (aPLs) are considered to play a pivotal pathogenic role in antiphospholipid syndrome (APS) by inducing the expression of tissue factor, inflammatory cytokines, and chemokines, most of which are dependent upon the NF-κB pathway. Therefore, the NF-κB is regarded as a promising target for the development of a novel therapeutic strategy. However, progress has been limited owing to the fact that there are no widely-used in vivo models, or highly specific inhibitors. Objective: This study aimed to test the effects of an NF-κB-specific inhibitor, DHMEQ, in preventing thrombus formation using an original mouse model of APS. Materials and Methods: Specificity of a monoclonal aPL WB-6 was examined by ELISA. WB-6 was injected into normal BALB/c mice with or without DHMEQ treatment. A pulse laser was radiated to a cutaneous vein in the window of a dorsal skinfold chamber attached to the mouse and thrombus formation was observed and recorded under a microscope. Results: WB-6 bound preferentially to the caldiolipin (CL)-β2GPI complex rather than to CL alone, or β2GPI alone. WB-6, but not isotype-matched control antibody, induced a prothrombotic state in the mice by inducing tissue factor expression upon circulating monocytes, resulting in thrombus formation at the site of laser-induced endothelial injury. This diathesis was almost completely ameliorated by DHMEQ treatment. Conclusions: Inhibition of the NF-κB pathway is a promising strategy for the development of a novel treatment for APS.
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- 2013
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22. The Neuroprotective Effect of Rapamycin as a Modulator of the mTOR-NF-κB Axis during Retinal Inflammation.
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Tomohiro Okamoto, Yoko Ozawa, Mamoru Kamoshita, Hideto Osada, Eriko Toda, Toshihide Kurihara, Norihiro Nagai, Kazuo Umezawa, and Kazuo Tsubota
- Subjects
Medicine ,Science - Abstract
The determination of the molecular mechanism underlying retinal pathogenesis and visual dysfunction during innate inflammation, and the treatment effect of rapamycin thereon.The endotoxin-induced uveitis and retinitis mouse model was established by injecting lipopolysaccharide. The mice were subsequently treated with rapamycin, a mammalian target of rapamycin (mTOR) inhibitor. The rhodopsin mRNA and protein expression level in the retina and the photoreceptor outer segment (OS) length in immunohistochemical stainings were measured, and visual function was recorded by electroretinography. Inflammatory cytokines, their related molecules, mTOR, and LC3 levels were measured by real-time PCR and/or immunoblotting. Leukocyte adhesion during inflammation was analyzed using concanavalin A lectin.The post-transcriptional reduction in the visual pigment of rod photoreceptor cells, rhodopsin, OS shortening, and rod photoreceptor cell dysfunction during inflammation were suppressed by rapamycin. Activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and induction of inflammatory cytokines, such as interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), and the activation of the downstream signaling protein, signal transducer and activator of transcription 3 (STAT3), which reduces rhodopsin in the retina during inflammation, were attenuated by rapamycin. Increased leukocyte adhesion was also attenuated by rapamycin. Interestingly, although mTOR activation was observed after NF-κB activation, mTOR inhibition suppressed NF-κB activation at the early phase, indicating that the basal level of activated mTOR was sufficient to activate NF-κB in the retina. In addition, the inhibition of NF-κB suppressed mTOR activation, suggesting a positive feedback loop of mTOR and NF-κB during inflammation. The ratio of LC3II to LC3I, which reflects autophagy induction, was not changed by inflammation but was increased by rapamycin.Our results propose the potential use of rapamycin as a neuroprotective therapy to suppress local activated mTOR levels, related inflammatory molecules, and the subsequent visual dysfunction during retinal inflammation.
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- 2016
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23. Inhibition of Late and Early Phases of Cancer Metastasis by the NF-κB Inhibitor DHMEQ Derived from Microbial Bioactive Metabolite Epoxyquinomicin: A Review
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Yinzhi Lin, Tamami Ukaji, Naoki Koide, and Kazuo Umezawa
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epoxyqinomicin ,DHMEQ ,metastasis ,invasion ,adhesion ,3D cell culture ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
We previously designed and synthesized dehydroxyepoxyquinomicin (DHMEQ) as an inhibitor of NF-κB based on the structure of microbial secondary metabolite epoxyquinomicin C. DHMEQ showed anti-inflammatory and anticancer activity in various in vivo disease models without toxicity. On the other hand, the process of cancer metastasis consists of cell detachment from the primary tumor, invasion, transportation by blood or lymphatic vessels, invasion, attachment, and formation of secondary tumor. Cell detachment from the primary tumor and subsequent invasion are considered to be early phases of metastasis, while tumor cell attachment to the tissue and secondary tumor formation the late phases. The assay system for the latter phase was set up with intra-portal-vein injection of pancreatic cancer cells. Intraperitoneal administration of DHMEQ was found to inhibit liver metastasis possibly by decreasing the expression of MMP-9 and IL-8. Also, when the pancreatic cancer cells treated with DHMEQ were inoculated into the peritoneal cavity of mice, the metastatic foci formation was inhibited. These results indicate that DHMEQ is likely to inhibit the late phase of metastasis. Meanwhile, we have recently employed three-dimensional (3D) culture of breast cancer cells for the model of early phase metastasis, since the 3D invasion just includes cell detachment and invasion into the matrix. DHMEQ inhibited the 3D invasion of breast cancer cells at 3D-nontoxic concentrations. In this way, DHMEQ was shown to inhibit the late and early phases of metastasis. Thus, DHMEQ is likely to be useful for the suppression of cancer metastasis.
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- 2018
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24. Induction of indoleamine 2, 3-dioxygenase in human dendritic cells by a cholera toxin B subunit-proinsulin vaccine.
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Jacques C Mbongue, Dequina A Nicholas, Kangling Zhang, Nan-Sun Kim, Brittany N Hamilton, Marco Larios, Guangyu Zhang, Kazuo Umezawa, Anthony F Firek, and William H R Langridge
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Medicine ,Science - Abstract
Dendritic cells (DC) interact with naïve T cells to regulate the delicate balance between immunity and tolerance required to maintain immunological homeostasis. In this study, immature human dendritic cells (iDC) were inoculated with a chimeric fusion protein vaccine containing the pancreatic β-cell auto-antigen proinsulin linked to a mucosal adjuvant the cholera toxin B subunit (CTB-INS). Proteomic analysis of vaccine inoculated DCs revealed strong up-regulation of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1). Increased biosynthesis of the immunosuppressive enzyme was detected in DCs inoculated with the CTB-INS fusion protein but not in DCs inoculated with proinsulin, CTB, or an unlinked combination of the two proteins. Immunoblot and PCR analyses of vaccine treated DCs detected IDO1mRNA by 3 hours and IDO1 protein synthesis by 6 hours after vaccine inoculation. Determination of IDO1 activity in vaccinated DCs by measurement of tryptophan degradation products (kynurenines) showed increased tryptophan cleavage into N-formyl kynurenine. Vaccination did not interfere with monocytes differentiation into DC, suggesting the vaccine can function safely in the human immune system. Treatment of vaccinated DCs with pharmacological NF-κB inhibitors ACHP or DHMEQ significantly inhibited IDO1 biosynthesis, suggesting a role for NF-κB signaling in vaccine up-regulation of dendritic cell IDO1. Heat map analysis of the proteomic data revealed an overall down-regulation of vaccinated DC functions, suggesting vaccine suppression of DC maturation. Together, our experimental data indicate that CTB-INS vaccine induction of IDO1 biosynthesis in human DCs may result in the inhibition of DC maturation generating a durable state of immunological tolerance. Understanding how CTB-INS modulates IDO1 activity in human DCs will facilitate vaccine efficacy and safety, moving this immunosuppressive strategy closer to clinical applications for prevention of type 1 diabetes autoimmunity.
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- 2015
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25. Inhibition of IGF-1-Mediated Cellular Migration and Invasion by Migracin A in Ovarian Clear Cell Carcinoma Cells.
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Tamami Ukaji, Yinzhi Lin, Kouji Banno, Shoshiro Okada, and Kazuo Umezawa
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Medicine ,Science - Abstract
Previously we isolated migracin A from a Streptomyces culture filtrate as an inhibitor of cancer cell migration. In the present research, we found that migracin A inhibited migration and invasion of ovarian clear cell carcinoma ES-2 cells. In the course of our mechanistic study, migracin A was shown to enhance vasohibin-1 expression in an angiogenesis array. We also confirmed that it increased the mRNA expression of this protein. Moreover, overexpression of vasohibin-1 lowered the migration but not the invasion of ES-2 cells. Then, we looked for another target protein employing a motility array, and found that migracin A lowered the IGF-1 expression. Knockdown of IGF-1 by siRNA decreased the migration and invasion of ES-2 cells. Migracin A also decreased Akt phosphorylation involved in the downstream signaling. Crosstalk analysis indicated that overexpression of vasohibin-1 decreased the IGF-1 expression. On the other hand, it showed no direct anticancer activity in terms of the ES-2 growth in agar. Migracin A inhibited the migration and IGF-1 expression in not only ES-2 but also another ovarian clear cell carcinoma JHOC-5 cells. In addition, it also inhibited capillary tube formation of human umbilical vein endothelial cells. Since its cytotoxicity is very low, migracin A may be a candidate for an anti-metastasis agent not exhibiting prominent toxicity.
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- 2015
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26. Galectin-3 up-regulation in hypoxic and nutrient deprived microenvironments promotes cell survival.
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Rafael Yamashita Ikemori, Camila Maria Longo Machado, Karina Mie Furuzawa, Suely Nonogaki, Eduardo Osinaga, Kazuo Umezawa, Marcelo Alex de Carvalho, Liana Verinaud, and Roger Chammas
- Subjects
Medicine ,Science - Abstract
Galectin-3 (gal-3) is a β-galactoside binding protein related to many tumoral aspects, e.g. angiogenesis, cell growth and motility and resistance to cell death. Evidence has shown its upregulation upon hypoxia, a common feature in solid tumors such as glioblastoma multiformes (GBM). This tumor presents a unique feature described as pseudopalisading cells, which accumulate large amounts of gal-3. Tumor cells far from hypoxic/nutrient deprived areas express little, if any gal-3. Here, we have shown that the hybrid glioma cell line, NG97ht, recapitulates GBM growth forming gal-3 positive pseudopalisades even when cells are grafted subcutaneously in nude mice. In vitro experiments were performed exposing these cells to conditions mimicking tumor areas that display oxygen and nutrient deprivation. Results indicated that gal-3 transcription under hypoxic conditions requires previous protein synthesis and is triggered in a HIF-1α and NF-κB dependent manner. In addition, a significant proportion of cells die only when exposed simultaneously to hypoxia and nutrient deprivation and demonstrate ROS induction. Inhibition of gal-3 expression using siRNA led to protein knockdown followed by a 1.7-2.2 fold increase in cell death. Similar results were also found in a human GBM cell line, T98G. In vivo, U87MG gal-3 knockdown cells inoculated subcutaneously in nude mice demonstrated decreased tumor growth and increased time for tumor engraftment. These results indicate that gal-3 protected cells from cell death under hypoxia and nutrient deprivation in vitro and that gal-3 is a key factor in tumor growth and engraftment in hypoxic and nutrient-deprived microenvironments. Overexpression of gal-3, thus, is part of an adaptive program leading to tumor cell survival under these stressing conditions.
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- 2014
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27. AMPK-NF-κB axis in the photoreceptor disorder during retinal inflammation.
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Mamoru Kamoshita, Yoko Ozawa, Shunsuke Kubota, Seiji Miyake, Chiduru Tsuda, Norihiro Nagai, Kenya Yuki, Shigeto Shimmura, Kazuo Umezawa, and Kazuo Tsubota
- Subjects
Medicine ,Science - Abstract
Recent progress in molecular analysis has revealed the possible involvement of multiple inflammatory signaling pathways in pathogenesis of retinal degeneration. However, how aberrant signaling pathways cause tissue damage and dysfunction is still being elucidated. Here, we focus on 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK), originally recognized as a key regulator of energy homeostasis. AMPK is also modulated in response to inflammatory signals, although its functions in inflamed tissue are obscure. We investigated the role of activated AMPK in the retinal neural damage and visual function impairment caused by inflammation. For this purpose, we used a mouse model of lipopolysaccharide-induced inflammation in the retina, and examined the effects of an AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). During inflammation, activated AMPK in the neural retina was decreased, but AICAR treatment prevented this change. Moreover, the electroretinogram (ERG) a-wave response, representing photoreceptor function, showed visual dysfunction in this model that was prevented by AICAR. Consistently, the model showed shortened photoreceptor outer segments (OSs) with reduced levels of rhodopsin, a visual pigment concentrated in the OSs, in a post-transcriptional manner, and these effects were also prevented by AICAR. In parallel, the level of activated NF-κB increased in the retina during inflammation, and this increase was suppressed by AICAR. Treatment with an NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) preserved the rhodopsin level during inflammation, suppressing NF-κB. These findings indicated that AMPK activation by AICAR and subsequent NF-κB inhibition had a protective effect on visual function, and that AMPK activation played a neuroprotective role during retinal inflammation.
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- 2014
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28. Amelioration of Severe TNBS Induced Colitis by Novel AP-1 and NF-κB Inhibitors in Rats
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Magdy El-Salhy, Kazuo Umezawa, Odd Helge Gilja, Jan G. Hatlebakk, Doris Gundersen, and Trygve Hausken
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Technology ,Medicine ,Science - Abstract
AP-1 and NF-κB inhibitors, namely, DTCM-G and DHMEQ, were investigated in male Wistar rats with severe colitis, induced by TNBS. The animals were randomized into 3 groups. The control group received 0.5 mL of 0.5% of the vehicle i.p., the DTCM-G group received 22.5 mg/kg body weight DTCM-G in 0.5% i.p., and the DHMEQ group received 15 mg/kg body weight DHMEQ i.p., all twice daily for 5 days. The body weight losses and mortality rates were significantly higher in the control group than those in DTCM-G-treated and DHMEQ-treated groups. The endoscopic inflammation scores in the control, DTCM-G-treated, and DHMEQ-treated groups were 6.3 ± 0.7, 1.0 ± 0.3, and 0.7 ± 0.3, respectively (P = 0.004 and 0.02, resp.). The inflammation scores as assessed by the macroscopic appearance were 4.3 ± 0.8, 0.7 ± 0.3, and 1.2 ± 0.4 in the control, DTCM-G-treated, and DHMEQ-treated groups, respectively (P = 0.01 and 0.009, resp.). The histopathological inflammation scores were 6.4 ± 0.7, 2.0 ± 1.0, and 2.2 ± 0.6 in the control, DTCM-G-treated, and DHMEQ-treated groups, respectively (P = 0.03 and 0.01, resp.). It was concluded that DTCM-G and DHMEQ exhibit strong anti-inflammatory and anticancer activities with no apparent toxicity, which make them excellent drug candidates for clinical use in inflammatory bowel diseases.
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- 2014
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29. Aberrant expression of NF-κB in liver fluke associated cholangiocarcinoma: implications for targeted therapy.
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Wunchana Seubwai, Chaisiri Wongkham, Anucha Puapairoj, Narong Khuntikeo, Ake Pugkhem, Chariya Hahnvajanawong, Jariya Chaiyagool, Kazuo Umezawa, Seiji Okada, and Sopit Wongkham
- Subjects
Medicine ,Science - Abstract
BACKGROUND: Up-regulation and association of nuclear factor kappa B (NF-κB) with carcinogenesis and tumor progression has been reported in several malignancies. In the current study, expression of NF-κB in cholangiocarcinoma (CCA) patient tissues and its clinical significance were determined. The possibility of using NF-κB as the therapeutic target of CCA was demonstrated. METHODOLOGY: Expression of NF-κB in CCA patient tissues was determined using immunohistochemistry. Dehydroxymethylepoxyquinomicin (DHMEQ), a specific NF-κB inhibitor, was used to inhibit NF-κB action. Cell growth was determined using an MTT assay, and cell apoptosis was shown by DNA fragmentation, flow cytometry and immunocytofluorescent staining. Effects of DHMEQ on growth and apoptosis were demonstrated in CCA cell lines and CCA-inoculated mice. DHMEQ-induced apoptosis in patient tissues using a histoculture drug response assay was quantified by TUNEL assay. PRINCIPAL FINDINGS: Normal bile duct epithelia rarely expressed NF-κB (subunits p50, p52 and p65), whereas all CCA patient tissues (n = 48) over-expressed all NF-κB subunits. Inhibiting NF-κB action by DHMEQ significantly inhibited growth of human CCA cell lines in a dose- and time-dependent manner. DHMEQ increased cell apoptosis by decreasing the anti-apoptotic protein expressions-Bcl-2, XIAP-and activating caspase pathway. DHMEQ effectively reduced tumor size in CCA-inoculated mice and induced cell apoptosis in primary histocultures of CCA patient tissues. CONCLUSIONS: NF-κB was over-expressed in CCA tissues. Inhibition of NF-κB action significantly reduced cell growth and enhanced cell apoptosis. This study highlights NF-κB as a molecular target for CCA therapy.
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- 2014
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30. A Local Community Outreach Educational Program on Genetic Testing: A Pilot Study.
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Haruyo ATSUMI, Anar DAMDINSUREN, Satomi ASAI, Hidefumi KAKIZOE, Asuka NAGAKAWA, Hideo IWASHITA, Kazuo UMEZAWA, and Hayato MIYACHI
- Subjects
EDUCATIONAL programs ,GENETIC testing ,HEALTH outcome assessment ,MEDICAL care ,GENETICS education - Abstract
Objective: To develop and implement a pilot educational program on genetic testing at the Tokai University School of Medicine with a public engagement approach through a local junior-high school outreach program. Methods: Seven medical students underwent 2 weeks of education and training to act as instructors for a one-day course on genetic testing for local junior-high school students. The one-day course comprised a lecture and an experimental lesson. The variation of UDP-glucuronosyltransferase 1A1 gene (UGT1A1) was selected as the teaching topic. A commercially available cultured human leukemia cell line was used as the source of human genomic DNA to circumvent the ethical concerns associated with obtaining samples from participants for genomic analysis. The medical students received instructions on the basics of conducting laboratory work and handling the equipment and reagents during the 2-week training. Results: The seven medical students completed the 2-week training. They then taught PCR and restriction enzyme experiments and the meaning of the results to junior-high school students. Conclusion: A pilot educational program on genetic testing with a local community outreach approach was successfully developed and implemented. [ABSTRACT FROM AUTHOR]
- Published
- 2024
31. Immune and allergenic effects of the microalga Coccomyxa sp. strain KJ in healthy humans: A pilot study.
- Author
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Satomi Asai, Kyoko Hayashi, Haruyo Atsumi, Mika Doi, Hidehumi Kakizoe, Kazuo Umezawa, Akihumi Hisada4,B, Tsukasa Nozaki, Akiko Kanno, Satoko Komatsu, Hitoshi Kuno, Kentaro Wakamatsu, Toshio Kawahara, Yoshiro Yamamoto, and Hayato Miyachi
- Subjects
LEUCOCYTES ,KILLER cells ,LYMPHOCYTE count ,PILOT projects ,HUMAN experimentation - Abstract
Background. The Coccomyxa sp. strain KJ (Coccomyxa KJ), a microalga found in Japan, has a potential function in controlling viral infections. Recently, its dry powder has been marketed as a health food product. Objectives. This pilot study investigated the effects of Coccomyxa KJ powder tablet intake on allergic reactions and immune functions in healthy participants. Materials and methods. Nine healthy volunteers (4 males and 5 females) who expressed interest in foods containing Coccomyxa KJ, and were willing to undergo blood tests, were recruited. Each individual was asked to take 2 Coccomyxa KJ powder tablets (0.3 g) before breakfast once a day for 4 weeks. The salivary immunoglobulin A (IgA) level and blood parameters (white blood cell (WBC) count, eosinophil and lymphocyte counts and percentages, natural killer (NK) cell activity, interleukin (IL)-6 level, and T helper (Th)1/Th2 cell ratio) were evaluated at baseline and weeks 2 and 4. Results. The 4-week intake of Coccomyxa KJ did not affect salivary IgA levels, WBC count, eosinophil and lymphocyte counts and percentages, or the Th1/Th2 ratio. There were significant differences in the NK cell activity after 4 weeks, with an average increase of 11.78 (95% confidence interval (95% CI): 6.80-16.76). None of the patients experienced adverse reactions during or after the study. Conclusions. Long-term Coccomyxa KJ intake improved NK cell activity without causing adverse effects on the indicators of local immunity, systemic inflammation and immune response balance. This study suggests that Coccomyxa KJ powder tablets can induce beneficial immune modifications without causing any adverse effects. [ABSTRACT FROM AUTHOR]
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- 2024
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32. Inhibitory effects of estetrol on the invasion and migration of immortalized human endometrial stromal cells.
- Author
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Akihiko Wakatsuki, Yinzhi Lin, Shiori Kojima, Hiroshi Matsushita, Kosei Takeuchi, and Kazuo Umezawa
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- 2024
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33. Isolation of the Anti-Inflammatory Agent Myceliostatin from a Methionine-Enriched Culture of Myceliophthora thermophila ATCC 42464
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Yanhua Wu, Junfeng Shen, Liyan Wang, Yinzhi Lin, Shiori Kojima, Shoshiro Okada, and Kazuo Umezawa
- Subjects
Pharmacology ,Complementary and alternative medicine ,Organic Chemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Analytical Chemistry - Published
- 2023
34. Survey of Infection Control Measures for COVID-19 (Current Coronavirus Infection) in Medical Facilities ~Questionnaire Results in the Metropolitan Area~
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Masamichi OGURA, Daisuke SAKURAI, Haruka OKABE, Natsuko OGINO, Takahiro KIKKAWA, Tomoko KUTSUZAWA, Satomi ASAI, and Kazuo UMEZAWA
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Epidemiology - Published
- 2022
35. A New 1,2-Naphthoquinone Derivative with Anti-lung Cancer Activity
- Author
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Riko Nakagawa, Hiroshi Tateishi, Mohamed O. Radwan, Takuma Chinen, Halilibrahim Ciftci, Kana Iwamaru, Nanami Baba, Yuna Tominaga, Ryoko Koga, Tsugumasa Toma, Jun-ichiro Inoue, Kazuo Umezawa, Mikako Fujita, and Masami Otsuka
- Subjects
Lung Neoplasms ,Drug Discovery ,NF-kappa B ,Humans ,Apoptosis ,General Chemistry ,General Medicine ,Naphthoquinones - Abstract
1,2-Naphthoquinone (2-NQ) is a nucleophile acceptor that non-selectively makes covalent bonds with cysteine residues in various cellular proteins, and is also found in diesel exhaust, an air pollutant. This molecule has rarely been considered as a pharmacophore of bioactive compounds, in contrast to 1,4-naphthoquinone. We herein designed and synthesized a compound named N-(7,8-dioxo-7,8-dihydronaphthalen-1-yl)-2-methoxybenzamide (MBNQ), in which 2-NQ was hybridized with the nuclear factor-κB (NF-κB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) as a nucleophile acceptor. Although 50 µM MBNQ did not inhibit NF-κB signaling, 10 µM MBNQ induced cell death in the lung cancer cell line A549, which was insensitive to 2-NQ (10 µM). In contrast, MBNQ was less toxic in normal lung cells than 2-NQ. A mechanistic study showed that MBNQ mainly induced apoptosis, presumably via the activation of p38 mitogen-activated protein kinase (MAPK). Collectively, the present results demonstrate that the introduction of an appropriate substituent into 2-NQ constitutes a new biologically active entity, which will lead to the development of 2-NQ-based drugs.
- Published
- 2022
36. Data from Conophylline Inhibits Hepatocellular Carcinoma by Inhibiting Activated Cancer-associated Fibroblasts Through Suppression of G Protein–coupled Receptor 68
- Author
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Ken Shirabe, Kazuo Umezawa, Kenichiro Araki, Norio Kubo, Akira Watanabe, Takamichi Igarashi, Mariko Tsukagoshi, Norihiro Ishii, Tadashi Handa, Dolgormaa Gantumur, Kei Hagiwara, Kouki Hoshino, Ryo Muranushi, Takehiko Yokobori, Norifumi Harimoto, and Takahiro Yamanaka
- Abstract
Treatment of hepatocellular carcinoma (HCC) is currently challenging. Cancer-associated fibroblasts (CAFs) promote the malignancy of HCC cells via production of cytokines. Conophylline (CnP), a vinca alkaloid obtained from Ervatamia microphylla leaves, has been reported to suppress activation of hepatic stellate cells and liver fibrosis in rats. We examined the efficacy of CnP in suppressing tumor growth in HCC. Specifically, we investigated whether CnP could inhibit CAFs, which were derived from HCC tissues in vitro and in vivo. Same as previous reports, CAFs promoted proliferative and invasive ability of HCC cells. CnP suppressed α-smooth muscle actin expression of CAFs, and inhibited their cancer-promoting effects. CnP significantly suppressed CAFs producting cytokines such as IL6, IL8, C-C motif chemokine ligand 2, angiogenin, and osteopontin (OPN). Combined therapy with sorafenib and CnP against HCC cells and CAFs in vivo showed to inhibit tumor growth the most compared with controls and single treatment with CnP or sorafenib. Transcriptome analysis revealed that GPR68 in CAFs was strongly suppressed by CnP. The cancer-promoting effects of cytokines were eliminated by knockdown of GPR68 in CAFs. CnP inhibited the HCC-promoting effects of CAFs by suppressing several HCC-promoting cytokines secreted by CAFs expressing GPR68. Combination therapy with CnP and existing anticancer agents may be a promising strategy for treating refractory HCC associated with activated CAFs.
- Published
- 2023
37. Figure S3 from Conophylline Inhibits Hepatocellular Carcinoma by Inhibiting Activated Cancer-associated Fibroblasts Through Suppression of G Protein–coupled Receptor 68
- Author
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Ken Shirabe, Kazuo Umezawa, Kenichiro Araki, Norio Kubo, Akira Watanabe, Takamichi Igarashi, Mariko Tsukagoshi, Norihiro Ishii, Tadashi Handa, Dolgormaa Gantumur, Kei Hagiwara, Kouki Hoshino, Ryo Muranushi, Takehiko Yokobori, Norifumi Harimoto, and Takahiro Yamanaka
- Abstract
ELISA of CAF-CM and CnP-treated CAF-CM
- Published
- 2023
38. Data from Impairment of Plasmacytoid Dendritic Cells for IFN Production by the Ligand for Immunoglobulin-Like Transcript 7 Expressed on Human Cancer Cells
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Yutaka Kawakami, Kazuo Umezawa, Yusuke Sasaki, Yoko Onami, Starlyn Okada, and Nobuo Tsukamoto
- Abstract
Purpose: Plasmacytoid dendritic cells (pDC) are specialized cells to produce type I IFN. Infiltration of pDCs in cancer tissues that have impaired ability to produce IFN-α has been suggested to play immunosuppressive roles in tumor immunity. To identify potential mechanisms causing pDC impairment in the cancer microenvironment, expression of immunoglobulin-like transcript 7 ligands (ILT7L), which inhibits pDC production of type I IFNs on the surface of various human cancer and noncancer cells, was examined.Experimental Design: To detect unidentified ILT7L, reporter cells, which express green fluorescent protein on interaction with ILT7L, were constructed. ILT7L expression on various human cancer cell lines as well as various noncancerous stromal cells and immune cells was examined. Cytokines and signals involved in the ILT7L expression were also investigated.Results: ILT7L was detected on all of the various types of human cancer cell lines tested. IFN-α, IFN-β, IFN-γ, tumor necrosis factor-α, interleukin-1β, transforming growth factor-β, lipopolysaccharide, and imiquimod induced ILT7L expression on cancer and noncancer cells. High ILT7L-expressing cancer cells inhibited production of IFN-α and tumor necrosis factor-α by pDC stimulated with CpG. ILT7L does not appear to be a member of classic or nonclassic HLAs. Additionally, NF-κB and mammalian target of rapamycin are involved in regulating ILT7L expression.Conclusions: ILT7L expression on cancer cells may be one of the mechanisms for impairment of pDCs in the cancer microenvironment. ILT7/ILT7L signaling may normally enable a negative immune response feedback following viral infection. Intervention of the ILT7L/ILT7 system may be useful for enhancing antitumor immunity as well as antiviral immunity. (Clin Cancer Res 2009;15(18):5733–43)
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- 2023
39. Supplementary Data from Impairment of Plasmacytoid Dendritic Cells for IFN Production by the Ligand for Immunoglobulin-Like Transcript 7 Expressed on Human Cancer Cells
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Yutaka Kawakami, Kazuo Umezawa, Yusuke Sasaki, Yoko Onami, Starlyn Okada, and Nobuo Tsukamoto
- Abstract
Supplementary Data from Impairment of Plasmacytoid Dendritic Cells for IFN Production by the Ligand for Immunoglobulin-Like Transcript 7 Expressed on Human Cancer Cells
- Published
- 2023
40. Effect of NF-κβ inhibitor – dehydroxymethylepoxyquinomicin on iron isomaltoside toxicity toward peritoneal mesothelial cells.
- Author
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Bręborowicz, Andrzej and Kazuo Umezawa
- Subjects
- *
IRON , *DEFEROXAMINE , *TISSUE plasminogen activator , *NF-kappa B - Abstract
This article, published in the journal Renal Failure, examines the impact of an NF-κβ inhibitor called DHMEQ on the toxicity of iron isomaltoside towards peritoneal mesothelial cells. Iron supplementation is commonly used in patients with uremia, but it can cause inflammation in the peritoneal cavity. The study found that DHMEQ reduced the inflammatory and fibrotic effects of iron on the mesothelial cells. More research is needed to determine the effectiveness of DHMEQ in a peritoneal dialysis setting. The article "Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method" by Livak and Schmittgen presents a method for analyzing gene expression data using real-time quantitative PCR. The authors explain the 2(-Delta Delta C(T)) method and its application in comparing gene expression levels between different samples. The article "Insights into iron and nuclear factor-kappa B (NF-kappaB) involvement in chronic inflammatory processes in peritoneal endometriosis" by Defrère et al. explores the role of iron and NF-kappaB in chronic inflammatory processes in peritoneal endometriosis. The authors discuss the mechanisms by which iron and NF-kappaB contribute to the development and progression of endometriosis. [Extracted from the article]
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- 2024
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41. Impact of ward pharmacist-led antimicrobial stewardship in intensive care units
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Masayoshi Hashimoto, Satomi Asai, Kazuo Umezawa, Kento Kohara, Miki Miyazawa, Yuji Suzuki, and Hayato Miyachi
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Pharmacology ,Infectious Diseases ,Oncology ,Pharmacology (medical) - Abstract
Various outcomes of mortality, medical costs, and antimicrobial usage result from antimicrobial stewardship (AS) programmes. Here, we clarified the effects of AS implementation by a well-trained pharmacist in an open intensive care unit (open ICU) through a retrospective, comparative study of 5123 open ICU patients of Tokai University Hospital. The 12 months before and after AS implementation were considered the control and study periods, respectively. After AS implementation, the number of AS cases increased significantly. The period until the implementation of therapeutic drug monitoring was significantly shortened, and antimicrobial drug usage increased significantly. The methicillin-resistant
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- 2022
42. Antitumour Activity of Dehydroxymethylepoxyquinomycin (DHMEQ): a Literature Review
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Kazuo Umezawa, R. A. Amirov, Sh. R. Kzyrgalin, E. I. Zhuk, R. S. Yamidanov, and Sh. Kh. Gantsev
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0301 basic medicine ,nf-kappa b ,RD1-811 ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,General Medicine ,dhmeq ,prostate cancer ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,ovarian cancer ,breast cancer ,030220 oncology & carcinogenesis ,Medicine ,Surgery ,business ,dehydroxymethylepoxyquinomycin ,antitumour activity ,carcinogenesis ,RC254-282 - Abstract
Carcinogenesis research uncovers new pathogenesis links as vulnerable targets of effective antitumour therapies. Among the key mediators of immune response, cell proliferation, cell apoptosis and inflammation is transcription factor NF-κB. Misregulation of an NF-κB-dependent pathway is found in solid and haematopoietic tumour cells. One of the best known NF-κB functions is expression regulation of genes involved in the apoptosis inhibition or activation and survival in both intact and malignant cells. The NF-κB-mediated pathways’ involvement in carcinogenesis, angiogenesis and tumour resistance to chemo- and radiotherapies makes this factor a promising target for drug anti-cancer interventions. This review summarises evidence on the antitumour and anti-inflammatory activity of a high-potent and specific low molecular-weight NF-κB inhibitor, dehydroxymethylhepoxyquinomycin (DHMEQ), as a candidate therapeutic agent in treatment for variant malignancies.
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- 2021
43. Abstract 3968: Conophylline-target ARL6ip1 regulates Ran-mediated cellular migration and invasion in human colorectal cancer cells
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Yinzhi Lin, Sivasundaram Karnan, Hideaki Ito, and Kazuo Umezawa
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Cancer Research ,Oncology - Abstract
Introduction: Conophylline is an alkaloid isolated from the leaves of Ervatamia microphylla. We isolated conophylline as an inhibitor of K-Ras functions. It is known to ameliorate various disease models in animals, including cancer, diabetes mellitus, NASH, and hepatic cirrhosis. On the other hand, its molecular target was determined to be ADP-ribosylation factor-like 6-interacting protein 1 (ARL6ip1) using a conophylline-biotin conjugate. ARL6ip1 is located in the endoplasmic reticulum (ER) membrane, and the conophylline-binding domain was determined by deletion mutation analysis. Known functions of ARL6ip1 include inhibition of apoptosis, inhibition of glutamate transporter, and modulation of the ER structure. However, whether ARL6ip1 is involved in the mechanisms of various biological activities of conophylline has not been proven, since knockdown of ARL6ip1 has often failed to change the cellular phenotypes. Therefore, in the present research, we knocked out ARL6ip1 in human colon carcinoma cells by CRISPR-Cas9 and studied the involvement and mechanism of ARL6ip1 in the anticancer activity of conophylline. Ran activity was measured by a pull-down assay with Ran-GTP antibody. Materials and Methods: Conophylline was isolated from the leaves of Ervatamia microphylla. We employed HCT116 and DLD1 cells as human colorectal cancer cells. Tumorigenicity was measured by soft agar colony formation. Cellular migration was measured by a wound healing assay and cell tracking analysis. Cellular invasion was measured by a Matrigel chamber assay. Results: Conophylline inhibited soft agar colony formation in HCT116 and DLD1 cells. It inhibited migration and invasion in HCT116 and DLD1 cells at nontoxic concentrations. Knockout of ARL6ip1 also decreased tumorigenicity, migration, and invasion in HCT116 and DLD1 cells. The mechanistic study was carried out with HCT116 cells. ARL6 and Ran are both G-proteins and are reported to interact with ARL6ip1. Although knockdown of ARL6 did not change the cell migratory activity, knockdown of Ran inhibited the migration. Conophylline inhibited the interaction of ARL6ip1 to Ran in the proximity ligation assay. Moreover, conophylline inhibited the Ran activity. Conclusion: CRISPR-Cas9 knockout of ARL6ip1 showed a similar anticancer activity as treatment with conophylline. It is likely that the anticancer activity of conophylline would be mediated by the ARL6ip1-Ran system. Thus, ARL6ip1 would be a useful molecular target for the treatment of cancer. Citation Format: Yinzhi Lin, Sivasundaram Karnan, Hideaki Ito, Kazuo Umezawa. Conophylline-target ARL6ip1 regulates Ran-mediated cellular migration and invasion in human colorectal cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3968.
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- 2023
44. Synergistic effect of 17-allylamino-17-demethoxygeldanamycin with dehydroxymethylepoxyquinomicin on the human anaplastic thyroid carcinoma cell line KTC2
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Shunichi Yamashita, Kazuo Umezawa, Boban Stanojevic, Biljana Vucetic-Tadic, Ana Bozovic, Lidija Todorović, and Gorana Stamenković
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NF-κB inhibitor ,Chemistry ,17-Allylamino-17-demethoxygeldanamycin ,targeted inhibitor ,nf-κb inhibitor ,synergy ,Hsp90 inhibitor ,General Biochemistry, Genetics and Molecular Biology ,3. Good health ,Anaplastic thyroid carcinoma ,Combined treatment ,lcsh:Biology (General) ,Cell culture ,Cancer research ,combined treatment ,General Agricultural and Biological Sciences ,lcsh:QH301-705.5 ,hsp90 inhibitor - Abstract
The use of targeted inhibitors has shown promise as an effective approach in cancer therapy. However, targeted therapies based only on one drug, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), have limited success, partly because cancer cells engage alternate pathways for survival and proliferation. In the present study, we evaluated whether dehydroxymethylepoxyquinomicin (DHMEQ), a nuclear factor ?B (NF-?B) inhibitor, can enhance the antitumor activities of 17-AAG, a 90 kDa heat shock protein (Hsp90) inhibitor, in the anaplastic thyroid cancer cell line KTC2. We examined the effect of combined drug treatment vs single drug treatment on cell survival. Isobologram analysis was performed to distinguish the additive vs synergistic effects of the drug combination. Western blotting was performed to investigate apoptosis markers: caspase 3, poly(ADP-ribose) polymerase-one (PARP-1), B-cell lymphoma-extra large (Bcl-XL), X-linked inhibitor of apoptosis (XIAP) and cellular inhibitor of apoptosis 2 (cIAP-2). Compared to monotherapy, the combined treatment enhanced growth-inhibitory effects in a synergistic manner and strongly potentiated apoptosis. These results demonstrate the first in vitro evidence that a combination of Hsp90 and NF-?B inhibitors is a more effective modality for inhibiting cell proliferation and survival in anaplastic thyroid carcinoma cells than either agent alone, warranting further investigations.
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- 2021
45. Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat model
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Hiroshi Asanuma, Ken Nakagawa, Mototsugu Oya, Kazuo Umezawa, Hidaka Kono, Shinya Morita, Yoshihiko Kanno, Tadashi Yoshida, Ryuichi Mizuno, Kazunobu Shinoda, and Masayuki Shimoda
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Male ,NF-κB inhibitor ,Combination therapy ,medicine.medical_treatment ,Renal function ,Pharmacology ,Kidney ,Protective Agents ,030226 pharmacology & pharmacy ,NF-κB ,Nephropathy ,Nephrotoxicity ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,lcsh:RA1190-1270 ,medicine ,Renal fibrosis ,Animals ,Pharmacology (medical) ,lcsh:Toxicology. Poisons ,Creatinine ,Cyclohexanones ,business.industry ,lcsh:RM1-950 ,NF-kappa B ,Immunosuppression ,DNA ,medicine.disease ,Nephrectomy ,lcsh:Therapeutics. Pharmacology ,chemistry ,Benzamides ,Cyclosporine ,Kidney Diseases ,business ,Immunosuppressive Agents ,Research Article - Abstract
Background Cyclosporine A (CsA) is an essential immunosuppressant in organ transplantation. However, its chronic nephrotoxicity is an obstacle to long allograft survival that has not been overcome. Nuclear factor-κB (NF-κB) is activated in the renal tissue in CsA nephropathy. In this study, we aimed to investigate the effect of the specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in a rat model of CsA nephrotoxicity. Methods We administered CsA (15 mg/kg) daily for 28 days to Sprague-Dawley rats that underwent 5/6 nephrectomy under a low-salt diet. We administered DHMEQ (8 mg/kg) simultaneously with CsA to the treatment group, daily for 28 days and evaluated its effect on CsA nephrotoxicity. Results DHMEQ significantly inhibited NF-κB activation and nuclear translocation due to CsA treatment. Elevated serum urea nitrogen and creatinine levels due to repeated CsA administration were significantly decreased by DHMEQ treatment (serum urea nitrogen in CsA + DHMEQ vs CsA vs control, 69 ± 6.4 vs 113.5 ± 8.8 vs 43.1 ± 1.1 mg/dL, respectively, p Conclusions These findings suggest that DHMEQ treatment in combination therapy with CsA-based immunosuppression is beneficial to prevent the development of CsA-induced nephrotoxicity.
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- 2020
46. Inhibition of cellular inflammatory mediator production and amelioration of learning deficit in flies by deep sea Aspergillus-derived cyclopenin
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Makoto Sawada, Zhenyu Liu, Yinzhi Lin, Shuwen Du, Liyan Wang, Hiromi Suzuki, Kazuo Umezawa, Mengjie Li, and Jianhua Ju
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Lipopolysaccharides ,0301 basic medicine ,Lipopolysaccharide ,Interleukin-1beta ,030106 microbiology ,Anti-Inflammatory Agents ,Nitric Oxide Synthase Type II ,Inflammation ,Pharmacology ,Nitric Oxide ,01 natural sciences ,Cell Line ,Nitric oxide ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Alzheimer Disease ,In vivo ,Drug Discovery ,medicine ,Animals ,Secretion ,Benzodiazepinones ,biology ,Microglia ,Learning Disabilities ,010405 organic chemistry ,Chemistry ,Diptera ,Macrophages ,NF-kappa B ,0104 chemical sciences ,Nitric oxide synthase ,Disease Models, Animal ,Aspergillus ,RAW 264.7 Cells ,medicine.anatomical_structure ,Cell culture ,biology.protein ,medicine.symptom - Abstract
In the course of screening lipopolysaccharide (LPS)-induced nitric oxide (NO) production inhibitors, two related benzodiazepine derivatives, cyclopenol and cyclopenin, were isolated from the extract of a deep marine-derived fungal strain, Aspergillus sp. SCSIOW2. Cyclopenol and cyclopenin inhibited the LPS-induced formation of NO and secretion of IL-6 in RAW264.7 cells at nontoxic concentrations. In terms of the mechanism underlying these effects, cyclopenol and cyclopenin were found to inhibit the upstream signal of NF-κB activation. These compounds also inhibited the expression of IL-1β, IL-6, and inducible nitric oxide synthase (iNOS) in mouse microglia cells, macrophages in the brain. In relation to the cause of Alzheimer's disease, amyloid-β-peptide is known to induce inflammation in the brain. Therefore, the present study investigated the ameliorative effects of these inhibitors on an in vivo Alzheimer's model using flies. Learning deficits were induced by the overexpression of amyloid-β42 in flies, and cyclopenin but not cyclopenol was found to rescue learning impairment. Therefore, novel anti-inflammatory activities of cyclopenin were identified, which may be useful as a candidate of anti-inflammatory agents for neurodegenerative diseases.
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- 2020
47. Virucidal effect of monogalactosyl diacylglyceride from a green microalga, Coccomyxa sp. KJ, against clinical isolates of SARS‐CoV‐2 as assessed by a plaque assay
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Satomi Asai, Masanobu Morita, Hidehumi Kakizoe, Hitoshi Kuno, Kyoko Hayashi, Takumi Watanabe, Takaaki Akaike, Satoko Komatsu, Hayato Miyachi, Kazuo Umezawa, and Toshio Kawahara
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Microbiology (medical) ,natural product ,Coronavirus disease 2019 (COVID-19) ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Clinical Biochemistry ,virucidal action ,Viral Plaque Assay ,Biology ,Antiviral Agents ,Rapid detection ,Virus ,Glycerides ,Microbiology ,Chlorophyta ,Chlorocebus aethiops ,Microalgae ,Animals ,Humans ,Immunology and Allergy ,Vero Cells ,Research Articles ,Infectious virus ,Virus quantification ,SARS-CoV-2 ,Biochemistry (medical) ,Public Health, Environmental and Occupational Health ,COVID-19 ,Galactose ,virus diseases ,Hematology ,biology.organism_classification ,quantification ,Medical Laboratory Technology ,Titer ,detection time ,Coccomyxa ,infectious virus ,Research Article - Abstract
Background Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the causative agent of coronavirus disease 2019 (COVID‐19) and is capable of human‐to‐human transmission and rapid global spread. Thus, the establishment of high‐quality viral detection and quantification methods, and the development of anti‐SARS‐CoV‐2 agents are critical. Methods Here, we present the rapid detection of infectious SARS‐CoV‐2 particles using a plaque assay with 0.5% agarose‐ME (Medium Electroosmosis) as an overlay medium. Results The plaques were capable of detecting the virus within 36–40 h post‐infection. In addition, we showed that a monogalactosyl diacylglyceride isolated from a microalga (Coccomyxa sp. KJ) could inactivate the clinical isolates of SARS‐CoV‐2 in a time‐ and concentration‐dependent manner. Conclusions These results would allow rapid quantification of the infectious virus titers and help develop more potent virucidal agents against SARS‐CoV‐2., We presented the rapid detection of SARS‐CoV‐2 using a plaque assay within 36–40 h post‐infection. In addition, we showed that a compound from a microalga inactivated the virus.
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- 2021
48. Cellular Anti-Inflammatory and Antioxidant Activities of Bamboo
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Shiori, Kojima, Masatoshi, Hakamata, Toshimichi, Asanuma, Rie, Suzuki, Jun-Ichi, Tsuruda, Takeshi, Nonoyama, Yinzhi, Lin, Hitomi, Fukatsu, Naoki, Koide, and Kazuo, Umezawa
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Lipopolysaccharides ,Leukemia ,Interleukin-6 ,Plant Extracts ,Anti-Inflammatory Agents ,Humans ,Water ,Esters ,Sasa ,Reactive Oxygen Species ,Nitric Oxide ,Antioxidants - Abstract
Hot water extract ofSecretion of mouse and human IL-6 was measured by ELISA. ROS production was measured by a fluorescent reagent. Ultrahigh performance liquid chromatography (UHPLC)/MS was used for the ingredient analysis.TheThe hot water extract of
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- 2021
49. Intravenous Administration of Dehydroxymethylepoxyquinomicin With Polymer Enhances the Inhibition of Pancreatic Carcinoma Growth in Mice
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Yasushi Hasegawa, Yuko Kitagawa, Sachiko Matsuda, Masayuki Tanaka, Minoru Kitago, Satoshi Kishino, Keiichi Suzuki, Shutaro Hori, Hiroshi Yagi, Hiroto Fujisaki, Tomohiro Konno, Yuta Abe, Kazuhiko Ishihara, Yutaka Nakano, Osamu Itano, Keiko Ohno, and Kazuo Umezawa
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Cancer Research ,Polymers ,Antineoplastic Agents ,Apoptosis ,Metastasis ,Mice ,Drug Delivery Systems ,In vivo ,Pancreatic cancer ,Cell Line, Tumor ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Protein Kinase Inhibitors ,Drug Carriers ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Cell growth ,Cyclohexanones ,Cell Cycle ,Cancer ,General Medicine ,medicine.disease ,Xenograft Model Antitumor Assays ,In vitro ,Disease Models, Animal ,Oncology ,Benzamides ,Cancer research ,Administration, Intravenous ,Ex vivo - Abstract
Background/aim Pancreatic cancer, which exhibits resistance to cytotoxic and molecular targeted drugs, has an extremely poor prognosis. Nuclear factor-κB (NF-κB) is constitutively activated in many pancreatic cancer cases. Although the NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) has exhibited anti-cancer effects in pancreatic cancer models, its poor solubility limits its use to intraperitoneal administration. Materials and methods Poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) (PMB) forms stable polymer aggregates with DHMEQ. The stability of DHMEQ aggregated with PMB in the human blood was measured by high-performance liquid chromatography-mass spectrometry (HPLC-MS) ex vivo. Anti-pancreatic cancer effects in AsPC-1 and MIA PaCa-2 pancreatic cancer cells were evaluated by cell growth inhibition assay in vitro and tumor growth inhibition assay in vivo. Results DHMEQ aggregated with PMB (PMB-DHMEQ) remained detectable after 60 min of incubation in the human blood, whereas DHMEQ aggregated with carboxymethyl cellulose (CMC-DHMEQ) was barely detectable. PMB-DHMEQ significantly inhibited AsPC-1 and MIA PaCa-2 cell growth in vitro compared to CMC-DHMEQ. Intravenous administration of PMB-DHMEQ reduced the tumor volume and liver metastasis compared to untreated or CMC-DHMEQ-treated mice. Conclusion Aggregation with PMB improved the solubility of DHMEQ, and effectively inhibited pancreatic cancer cell growth both in vitro and in vivo.
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- 2021
50. Dehydroxymethylepoxyquinomicin suppresses atopic dermatitis-like lesions in a stratum corneum-removed murine model through NF-κB inhibition
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Xiaoran Li, Huimin Wen, Zhehui Xie, Xin Li, Yuyang Zhang, Huan He, Xiaoxue Jiang, Jun Ma, and Kazuo Umezawa
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Keratinocytes ,0301 basic medicine ,Chemokine ,Immunology ,Anti-Inflammatory Agents ,Toxicology ,Cell Line ,Dermatitis, Atopic ,Lesion ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Dinitrochlorobenzene ,Stratum corneum ,medicine ,Animals ,Humans ,Immunology and Allergy ,CCL17 ,Pharmacology ,Mice, Inbred BALB C ,integumentary system ,biology ,Cyclohexanones ,Tumor Necrosis Factor-alpha ,Chemistry ,NF-kappa B ,General Medicine ,Disease Models, Animal ,HaCaT ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Benzamides ,biology.protein ,Cancer research ,Cytokines ,Female ,Tumor necrosis factor alpha ,Epidermis ,medicine.symptom ,CCL22 - Abstract
Background: Dehydroxymethylepoxyquinomicin (DHMEQ) is a specific and potent inhibitor of nuclear factor-kappa B (NF-κB) and has been shown to possess promising potential as an anti-inflammation including anti-atopic dermatitis (AD)-like skin lesions. Objective: To further evaluate the activity of DHMEQ in vivo modified AD-like lesion model in BALB/c mice and in vitro AD-like lesion cell model in human keratinocytes. Materials and methods: In this study, in vivo modified AD-like lesion model in BALB/c mice was chronically induced by the repetitive and alternative application of 2,4-dinitrochlorobenzene (DNCB) and oxazolone (OX) on ears, and stratum corneum of the ear skin was additionally stripped off with surgical tapes before each challenge with DNCB/OX. Moreover, in vitro AD-like lesion cell model in human keratinocytes (HaCaT) achieved by stimulating HaCaT cells with tumor necrosis factor (TNF)-α plus interferon (IFN)-γ was used to investigate mechanisms of the action. Results: The lesions derived from the stratum corneum-removed AD-like lesion model reaches to peak as well as DHMEQ arrives to its efficacy a week earlier than the data previously obtained from the common AD-like lesion model. Results showed that the drug reduced the ear thickness, epidermal thickness, mast cell infiltration, and gene expressions of interleukin (IL)-4, IL-13, and interferon (IFN)-γ in ear tissues. It significantly inhibited the expression of cytokines IL-6 and IL-1β, chemokines thymus and activation-regulated chemokine (TARC)/CCL17, and macrophage-derived chemokine (MDC)/CCL22 in the stimulated HaCaT cells. Discussion and conclusion: This study indicated that the action of DHMEQ's anti-AD like lesions might be related to its inhibition on NF-κB.
- Published
- 2019
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