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      Macrolactins from Marine-Derived Bacillus subtilis B5 Bacteria as Inhibitors of Inducible Nitric Oxide and Cytokines Expression

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          Abstract

          In order to find new natural products with anti-inflammatory activity, chemical investigation of a 3000-meter deep-sea sediment derived bacteria Bacillus subtilis B5 was carried out. A new macrolactin derivative was isolated and identified as 7,13-epoxyl-macrolactin A ( 1). Owing to the existence of the epoxy ring, 1 exhibited a significant inhibitory effect on the expression of inducible nitric oxide and cytokines, compared with previously isolated known macrolactins ( 25). Real-time Polymerase Chain Reaction (PCR) analysis showed that the new compound significantly inhibited the mRNA expressions of inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Reverse transcription-PCR analysis demonstrated that the new compound reduced the mRNA expression level of IL-1β in a concentration-dependent manner.

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          Most cited references 21

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          Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes.

          There is increasing evidence that an ongoing cytokine-induced acute-phase response (sometimes called low-grade inflammation, but part of a widespread activation of the innate immune system) is closely involved in the pathogenesis of type 2 diabetes and associated complications such as dyslipidemia and atherosclerosis. Elevated circulating inflammatory markers such as C-reactive protein and interleukin-6 predict the development of type 2 diabetes, and several drugs with anti-inflammatory properties lower both acute-phase reactants and glycemia (aspirin and thiazolidinediones) and possibly decrease the risk of developing type 2 diabetes (statins). Among the risk factors for type 2 diabetes, which are also known to be associated with activated innate immunity, are age, inactivity, certain dietary components, smoking, psychological stress, and low birth weight. Activated immunity may be the common antecedent of both type 2 diabetes and atherosclerosis, which probably develop in parallel. Other features of type 2 diabetes, such as fatigue, sleep disturbance, and depression, are likely to be at least partly due to hypercytokinemia and activated innate immunity. Further research is needed to confirm and clarify the role of innate immunity in type 2 diabetes, particularly the extent to which inflammation in type 2 diabetes is a primary abnormality or partly secondary to hyperglycemia, obesity, atherosclerosis, or other common features of the disease.
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            Inflammation and cancer: advances and new agents.

            Tumour-promoting inflammation is considered one of the enabling characteristics of cancer development. Chronic inflammatory disease increases the risk of some cancers, and strong epidemiological evidence exists that NSAIDs, particularly aspirin, are powerful chemopreventive agents. Tumour microenvironments contain many different inflammatory cells and mediators; targeting these factors in genetic, transplantable and inducible murine models of cancer substantially reduces the development, growth and spread of disease. Thus, this complex network of inflammation offers targets for prevention and treatment of malignant disease. Much potential exists in this area for novel cancer prevention and treatment strategies, although clinical research to support targeting of cancer-related inflammation and innate immunity in patients with advanced-stage cancer remains in its infancy. Following the initial successes of immunotherapies that modulate the adaptive immune system, we assert that inflammation and innate immunity are important targets in patients with cancer on the basis of extensive preclinical and epidemiological data. The adaptive immune response is heavily dependent on innate immunity, therefore, inhibiting some of the tumour-promoting immunosuppressive actions of the innate immune system might enhance the potential of immunotherapies that activate a nascent antitumour response.
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              Recent developments in anti-inflammatory natural products.

              Many of the inflammatory diseases are becoming common in aging society throughout the world. The clinically used anti-inflammatory drugs suffer from the disadvantage of side effects and high cost of treatment (in case of biologics). Alternative to these drugs are traditional medicines and natural products, which offer a great hope in the identification of bioactive lead compounds and their development into drugs for treating inflammatory diseases. Since ancient times traditional medicines and phytopharmaceuticals are being used for the treatment of inflammatory and other disorders. The present review article describes anti-inflammatory natural products derived from plants and marine sources reported during last decade. The compounds described belong to different chemical classes such as alkaloids, steroids, terpenoids, polyphenolics, phenylpropanoids, fatty acids and lipids, and various miscellaneous compounds. The attempt is also being made to enumerate the possible leads, e.g. curcumin, resveratrol, baicalein, boswellic acid, betulinic acid, ursolic acid, and oleanolic acid, for further development with the help of structure-activity relationship (SAR) studies and their current status. In addition SAR studies carried out on the anti-inflammatory activity of flavonoid compounds and clinical studies performed on anti-inflammatory natural products are also discussed.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Mar Drugs
                Mar Drugs
                marinedrugs
                Marine Drugs
                MDPI
                1660-3397
                26 October 2016
                November 2016
                : 14
                : 11
                Affiliations
                [1 ]Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, South Xiang-An Road, Xiamen 361102, China; yanxia1201@ 123456126.com (X.Y.); yunxiazhouxmu@ 123456163.com (Y.-X.Z.); liuxiuxiu6@ 123456126.com (X.-X.L.); fangmj@ 123456xmu.edu.cn (M.-J.F.); wuzhen@ 123456xmu.edu.cn (Z.W.)
                [2 ]Key Laboratory of Marine Biogenetic Resources, Third Institute of Oceanography State Oceanic Administration, Xiamen 361005, China; tangxixiang@ 123456tio.org.cn (X.-X.T.); yizhiwei@ 123456tio.org.cn (Z.-W.Y.)
                [3 ]South China Sea Bio-Resource Exploitation and Utilization Collaborative Innovation Center, Xiamen 361005, China
                Author notes
                [* ]Correspondence: jiangfq@ 123456xmu.edu.cn (F.-Q.J.); qyk@ 123456xmu.edu.cn (Y.-K.Q.); Tel./Fax: +86-592-218-9597 (F.-Q.J.); +86-592-218-9868 (Y.-K.Q.)
                [†]

                These authors contribute equally to this paper.

                [‡]

                Present address: West China School of Pharmacy, Sichuan University, Chengdu 610041, China.

                Article
                marinedrugs-14-00195
                10.3390/md14110195
                5128738
                27792158
                © 2016 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

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