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Sushila Maharjan,Chang Boem Lee,Ye Rim Kim,Hei Chan Lee,Kwangkyoung Liou,Jae Kyung Sohng. 한국당과학회 2011 한국당과학회 학술대회 Vol.2011 No.1
Polyketides are a large class of natural products that include clinically important antibiotics, antitumor compounds, immunosuppressants, pigments and herbicides. Herboxidiene is a polyketide natural product that was found to control several important biannual weeds at relatively low application rates (<250 g/hectare) without damaging wheat. Early study indicated that the epoxide and the C-18 hydroxyl groups are important for the activity of herboxidiene. While Sakai et al., 2002 reported that herboxidiene showed antitumor activity against human tumor cell lines, Koguchi et al., 1997 reported that herboxidiene up-regulated the gene expression of low density lipoprotein receptors. The interesting biological profile of this natural product has prompted us to produce its glycosylated analogues so as to alter its activity. It is well known that bioactive natural products are often complexed with sugar moieties which are essential for activity of the compound. In this study, we carried out in vitro experiments to generate glucosyl-herboxidiene.
Metabolic engineering of Nocardia sp. CS682 for enhanced production of nargenicin A1.
Maharjan, Sushila,Koju, Dinesh,Lee, Hei Chan,Yoo, Jin Cheol,Sohng, Jae Kyung Humana Press 2012 Applied biochemistry and biotechnology Vol.166 No.3
<P>A number of secondary metabolites having therapeutic importance have been reported from the genus Nocardia. One of the polyketide antibiotic compounds isolated from Nocardia is nargenicin A(1). Recently, nargenicin A(1) has been isolated from Nocardia sp. CS682, a new Nocardia strain isolated from soil in Jeonnam, South Korea. It possesses strong antibacterial activity against methicillin-resistant Staphylococcus aureus. In this study, we applied a metabolic engineering approach based on recombinant DNA technology in order to boost the production of nargenicin A(1) from Nocardia sp. CS682. Initially, we optimized the transformation of this new strain by electroporation method. Heterologous expression of S-adenosylmethionine synthetase (MetK1-sp) in Nocardia sp. CS682 enhanced the production of nargenicin A(1) by about 2.8 times due to transcriptional activation of biosynthetic genes as revealed by reverse transcription polymerase chain reaction analysis. Similarly, expression of acetyl-CoA carboxylase genes improved nargenicin A(1) production by about 3.8 times in Nocardia sp. ACC18 compared to that in Nocardia sp. CS682 and Nocardia sp. NV18 by increasing precursor pool. Thus, enhanced production of nargenicin A(1) from Nocardia sp. CS682 can be achieved by expression of transcriptional activator genes and precursor genes from Streptomyces strains.</P>
Maharjan, Sushila,Singh, Bijay,Jiang, Tao,Yoon, So-Yeon,Li, Hui-Shan,Kim, Girak,Gu, Min Jeong,Kim, Soo Ji,Park, Ok-Jin,Han, Seung Hyun,Kang, Sang-Kee,Yun, Cheol-Heui,Choi, Yun-Jaie,Cho, Chong-Su Elsevier 2016 Biomaterials Vol.84 No.-
<P><B>Abstract</B></P> <P>A successful delivery of antigen through oral route requires to overcome several barriers, such as enzymatic barrier of gastrointestinal tract and epithelial barrier that constitutes of microfold cells (M cells) for antigen uptake. Although each barrier represents a critical step in determining the final efficiency of antigen delivery, the transcytosis of antigen by M cells in the follicle-associated epithelium (FAE) to Peyer's patches appears to be a major bottleneck. Considering the systemic administration of receptor activator of nuclear factor (NF)-ĸB ligand (RANKL) induces differentiation of receptor activator of nuclear factor (NF)-ĸB (RANK)-expressing enterocytes into M cells, here, we illustrated a promising approach of antigen delivery using full length transmembrane RANKL (mRANKL). The results showed that the intraperitoneal injection of mRANKL increased the population of dendritic cells and macrophages in mesenteric lymph nodes and spleen. Subsequently, systemic administration of mRANKL resulted in significantly higher number of functional GP2<SUP>+</SUP> M cells leading higher transcytosis of fluorescent beads through them. To corroborate the effect of mRANKL in antigen delivery through M cells, we orally delivered microparticulate antigen to mice treated with mRANKL. Oral immunization induced strong protective IgA and systemic IgG antibody responses against orally delivered antigen in mRANKL-treated mice. The higher antibody responses are attributed to the higher transcytosis of antigens through M cells. Ultimately, the higher memory B cells and effector memory CD4 T cells after oral immunization in RANKL-treated mice confirmed potency of RANKL-mediated antigen delivery. To the best of our knowledge, this is the first study to demonstrate significant induction of mucosal and humoral immune responses to M cell targeted oral vaccines after the systemic administration of RANKL.</P>
( Koju Dinesh ),( Sushila Maharjan ),( Dipesh Dhakal ),( Jin Cheol Yoo ),( Jae Kyung Sohng ) 한국미생물 · 생명공학회 2012 Journal of microbiology and biotechnology Vol.22 No.8
Nargenicin A1 is a 28-membered polyketide macrolide, with antibacterial activity against methicillin-resistant Staphylococcus aureus, produced by Nocardia sp. CS682. In this study, the production of nargenicin A1 was improved by enhancing the supply of different biosynthetic precursors. In Nocardia sp. CS682 (KCTC11297BP), this improvement was ~4.62-fold with the supplementation of 30 mM methyl oleate, 4.25-fold with supplementation of 15mM sodium propionate, and 2.81-fold with supplementation of 15 mM sodium acetate. In Nocardia sp. metK18 and Nocardia sp. CS682 expressing S-adenosylmethionine synthetase (MetK), the production of nargenicin A1 was improved by ~5.57-fold by supplementation with 30 mM methyl oleate, 5.01-fold by supplementation with 15 mM sodium propionate, and 3.64-fold by supplementation with 15 mM sodium acetate. Furthermore, supplementing the culture broth of Nocardia sp. ACC18 and Nocardia sp. CS682 expressing the acetyl-CoA carboxylase complex (AccA2 and AccBE) with 30 mM methyl oleate, 15 mM sodium propionate, or 15 mM sodium acetate resulted in ~6.99-, 6.46-, and 5.58-fold increases, respectively, in nargenicin A1 production. Our overall results showed that among the supplements, methyl oleate was the most effective precursor supporting the highest titers of nargenicin A1 in Nocardia sp. CS682, Nocardia sp. metK18, and Nocardia sp. ACC18.
Chitosan-based particulate systems for the delivery of mucosal vaccines against infectious diseases
Singh, Bijay,Maharjan, Sushila,Cho, Ki-Hyun,Cui, LianHua,Park, In-Kyu,Choi, Yun-Jaie,Cho, Chong-Su Elsevier 2018 International journal of biological macromolecules Vol.110 No.-
<P><B>Abstract</B></P> <P>Given that most pathogens enter the body at mucosal surfaces for infection and mucosal immune responses act as the first line of defense against the invading pathogens, mucosal vaccination is the most effective method to prevent infectious diseases. However, the development of mucosal vaccines requires an efficient antigen delivery system which should protect the antigens from physical elimination and enzymatic degradation, target mucosal inductive sites, and appropriately stimulate the mucosal and systemic immunity. Accordingly, polymeric particles have garnered much attention because the physicochemical properties of polymers can be adjusted to resolve the issues associated with mucosal vaccine delivery. Particularly, chitosan-based polymeric carriers are the most promising vehicles for mucosal vaccine delivery because chitosan is biodegradable, biocompatible and mucoadhesive in nature. Similarly, chitosan can be modified with chemical and biological molecules to develop delivery carriers for controlled or targeted therapy. Moreover, they can be converted to various formulations, such as solid, liquid and gel, with a wide range of particle sizes. In this review, we highlight and discuss advances in the development of chitosan-based particulate systems, specifically for the delivery of mucosal vaccines against infections.</P>
Needle-Free Immunization with Chitosan-Based Systems
Singh, Bijay,Maharjan, Sushila,Sindurakar, Princy,Cho, Ki-Hyun,Choi, Yun-Jaie,Cho, Chong-Su MDPI 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.11
<P>Despite successful use, needle-based immunizations have several issues such as the risk of injuries and infections from the reuse of needles and syringes and the low patient compliance due to pain and fear of needles during immunization. In contrast, needle-free immunizations have several advantages including ease of administration, high level of patient compliance and the possibility of mass vaccination. Thus, there is an increasing interest on developing effective needle-free immunizations via cutaneous and mucosal approaches. Here, we discuss several methods of needle-free immunizations and provide insights into promising use of chitosan systems for successful immunization.</P>
조기현,비제이,Sushila Maharjan,장윤정,최윤재,조종수 한국조직공학과 재생의학회 2017 조직공학과 재생의학 Vol.14 No.3
Healing process in scarring inevitably produces a considerable amount of non-organized dense collagen-rich matrix called scar thus impairing the native structure of skin. Connective tissue growth factor (CTGF) overexpression within healing tissues is known to play an imperative role in collagen production stimulated by transforming growth factor-beta in cutaneous wound healing. Undoubtedly, the knockdown of CTGF expression through siRNA-mediated gene silencing could simply impede the scarring process. However, the less stability and low transfection of siRNAs themselves urge a safe carrier to protect and transfect them into cells at a high rate avoiding toxicities. Here, we developed a degradable poly(sorbitol-co- PEI) (PSPEI), prepared by polymerization of sorbitol diacrylate with low molecular weight polyethylenimine, which has high transfection efficiency but low cytotoxicity, and utilized it in siCTGF delivery to silence the expression of CTGF in an animal model of cutaneous wound healing. Unlike contracted scar in normal healing, there was no or less contraction in the healed skin of mice treated with siCTGF using PSPEI. Histologically, the healed tissues also had distinct papillary structures and dense irregular connective tissues that were lacking in the control scar tissues. This study exemplifies a successful treatment of cutaneous wound healing using a polymer system coupled with RNA interference. Hence, the approach holds a great promise for developing new treatments with novel targets in regenerative medicines.