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Cell cycle arrest mediated by WEE1 is involved in the unfolded protein response in plants
고기성,유재용,Nirmal Kumar Ramasamy,RIKNOHARMOKO,Bích Ngọc Thị Vũ,박지예,이균오 한국식물생명공학회 2018 Plant biotechnology reports Vol.12 No.5
Activation of the unfolded protein response (UPR) in mammalian cells leads to cell cycle arrest at the G1 phase (Thomas et al., J Biol Chem 288:7606–7617, 2013). However, how UPR signaling affects cell cycle arrest remains largely unknown in plants. Here, we examined UPR and endoreduplication in Col-0, wee1, and ER stress sensing-deficient ire1a&b plants during DNA replication and ER stress conditions. We found that WEE1, an essential negative regulator of the cell cycle, is involved in the maintenance of ER homeostasis during genotoxic stress and the ER stress hypersensitivity of ire1a&b is alleviated by loss-of-function mutation in WEE1. WEE1-mediated cell cycle arrest was required for IRE1–bZIP60 pathway activation during ER stress. In contrast, loss-of-function mutation in WEE1 caused increased expression of UPR-related genes during DNA replication stress. WEE1 and IRE1 were required for endoreduplication during DNA replication stress and ER stress, respectively. Taken together, these findings suggest that cell cycle regulation is associated with UPR activation in different manners during ER stress and DNA replication stress in Arabidopsis.
( Tuan Hiep Tran ),( Thiruganesh Ramasamy ),( Bijay Kumar Poudel ),( Nirmal Marasini ),( Bo Kyung Moon ),( Hyuk Jun Cho ),( Han Gon Choi ),( Chul Soon Yong ),( Jong Oh Kim ) 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0
The aim of this study was to prepare ganciclovir (GCV)-loaded cross-linked gelatin microspheres byspray-drying method. The microspheres were characterized in terms of particle size, surface morphology, loadingefficiency, thermal behavior, physical characteristics, swelling properties, and the release profile in vitro. The majorprocess and formulation parameters were optimized to obtain smaller particles with high loading capacity. The physicalstate examination confirmed the molecular-level dispersion of drug in the polymer. The loading efficiency determinedby high-performance liquid chromatography (HPLC) was around 68%. The in vitro release experimentsrevealed that the GCV released from the gelatin microspheres was related to the extent of swelling, which was proportionalto the drug-to-polymer ratio. These results suggest that cross-linked gelatin microspheres could be a suitabledrug-delivery system for GCV.
Cho, Hyuk Jun,Lee, Dong Won,Marasini, Nirmal,Poudel, Bijay Kumar,Kim, Jeong Hwan,Ramasamy, Thiruganesh,Yoo, Bong Kyu,Choi, Han-Gon,Yong, Chul Soon,Kim, Jong Oh Pharmaceutical Society of Great Britain 2013 Journal of pharmacy and pharmacology Vol.65 No.10
<P>To develop and optimize the novel self-microemulsifying drug delivery system (SMEDDS) formulation for enhanced water solubility and bioavailability of telmisartan (TMS) using the Box-Behnken design (BBD) and desirability function.</P>
Preparation and Characterization of Spray-Dried Gelatin Microspheres Encapsulating Ganciclovir
Tuan Hiep Tran,김종오,Thiruganesh Ramasamy,Bijay Kumar Poudel,Nirmal Marasini,문보경,조혁준,최한곤,용철순 한국고분자학회 2014 Macromolecular Research Vol.22 No.2
The aim of this study was to prepare ganciclovir (GCV)-loaded cross-linked gelatin microspheres byspray-drying method. The microspheres were characterized in terms of particle size, surface morphology, loadingefficiency, thermal behavior, physical characteristics, swelling properties, and the release profile in vitro. The majorprocess and formulation parameters were optimized to obtain smaller particles with high loading capacity. The physicalstate examination confirmed the molecular-level dispersion of drug in the polymer. The loading efficiency determinedby high-performance liquid chromatography (HPLC) was around 68%. The in vitro release experimentsrevealed that the GCV released from the gelatin microspheres was related to the extent of swelling, which was proportionalto the drug-to-polymer ratio. These results suggest that cross-linked gelatin microspheres could be a suitabledrug-delivery system for GCV.
( Hyuk Jun Cho ),( Dong Won Lee ),( Nirmal Marasini ),( Bijay Kumar Poudel ),( Jeong Hwan Kim ),( Thiruganesh Ramasamy ),( Bong Kyu Yoo ),( Han Gon Choi ),( Chul Soon Yong ),( Jong Oh Kim ) 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0
Objectives: To develop and optimize the novel self-microemulsifying drug delivery system (SMEDDS) formulation for enhanced water solubility and bioavailability of telmisartan (TMS) using the Box-Behnken design (BBD) and desirability function. Method: TMS-SMEDDS formulation consisted of the mixture of oil (Peceol), surfactant (Labrasol), co-surfactant (Transcutol), TMS and triethanolamine. A three-level BBD was applied to explore the main effect, interaction effect and quadratic effect of three independent variables, including the amount of Peceol (X1), Labrasol (X2) and Transcutol (X3). Determined conditions were 20<X1 <40, 50<X2 <80 and 5<X3 <30. The response variables were droplet size (Y1), polydispersity index (Y2) and dissolution percentage of TMS after 15min (Y3). KEY FINDINGS: The optimized conditions were 28.93, 80 and 28.08 (mg) for X1 , X2 and X3 , respectively, and the response variables were predicted to be 159.8nm, 0.241 and 85.8% for Y1 , Y2 and Y3 , respectively. The actual values from the optimized formulation showed good agreement with predicted values. The optimized TMS-SMEDDS formulation showed faster drug dissolution rate and higher bioavailability than TMS powder. Conclusions: Our results suggest that response surface methodology using BBD and desirability function is a promising approach to understand the effect of SMEDDS variables and to optimize the formulation.
Eun Ji Lee,Jae Yong Yoo,Rikno Harmoko,Ki Seong Ko,Nirmal Kumar Ramasamy,Bo Young Hwang,Sang Yeol Lee,Kyun Oh Lee 한국당과학회 2016 한국당과학회 학술대회 Vol.2016 No.01
The predominant N-glycan in plants is paucimannosidic N-glycan with core β1,2-xylose and α 1,3-fucose residues (PNGXF). Here, We hypothesized that additions of the core β1,2-xylose, α 1,3-fucose, and 6-arm β1,2-GlcNAc residues to the common acceptor (GlcNAcMan3GlcNAc2) are relatively determined by the different activity and/or substrate occupancy of the enzymes of the corresponding genes in plants. As a result, we describe a mechanism in Arabidopsis thaliana that effectively form the largest N-glycan in plants. Genetic and biochemical evidence suggest that the addition of the 6-arm β1,2-GlcNAc residue by N-acetylglucosaminyltransferase II (GnTII) is less effective than additions of the core β1,2-xylose and α1,3-fucose residues by XylT, FucTA, and FucTB in Arabidopsis thaliana. Moreover, analysis of gnt2 mutant and 35S: GnTII transgenic plants indicates that the additions of the core β1,2-xylose and α1,3-fucose residues to the common acceptor (GlcNAcMan3GlcNAc2) are partially inhibited by the addition of the 6-arm β1,2-GlcNAc residue. Our findings show that plants control the rate of the addition of the 6-arm GlcNAc residue to the common N-glycan acceptor as a mechanism to facilitate formation of the general N-glycans with Man3XylFucGlcNAc2 and GlcNAc2Man3XylFucGlcNAc2 structures by hexosaminidase activity and the regulated sharing of the common acceptor GlcNAcMan3GlcNAc2.
Expression of a human glucocerebrosidase in a customized N-glycan producing plant
Bo Young Hwang,Ki Seong Ko,Jae Yong Yoo,Rikno Harmoko,Nirmal Kumar Ramasamy,Eun Ji Lee,Sang Yeol Lee,Kyun Oh Lee 한국당과학회 2016 한국당과학회 학술대회 Vol.2016 No.01
Gaucher’s disease is a lysosomal storage disorder by mutations in the gene encoding glucocerebrosidase (GC). Gaucher’s disease is currently treated by enzyme replacement therapy using recombinant GC (CerezymeⓇ) expressed in Chinese hamster ovary (CHO) cells. As complex glycans in mammalian cells have not terminate in mannose residues, which are essential for the biological absorption of GC via macrophage mannose receptors in human patient with Gaucher’s disease, glycan modification in vitro is required in order to expose the mannose residues on the glycans of CerezymeⓇ. Notably, the recombinant human GC (rhGC) expressed in the plant cells unaffectedly contains terminal mannose residues on its complex glycan. Hence, the plant-produced rhGC does not require exposure of mannose residues in vitro, which is a requirement for the production of CerezymeⓇ. However, The presence of β1,2-xylose and core α1,3-fucose residues on plant type complex N-glycans are potentially allergic in mammals. In this study, to remove the plant specific sugar residues and customize the N-glycan structure in plant, we isolated mutants of the corresponding plant specific glycosyltransferase genes and used for multiple-mutants construction. The resulting mutants was transformed by a human α 1,6-fucosyltransferase gene to accomplish customized N-glycosylation in plant. In consequence, the production of a rhGC in a humanized N-glycosylation plant is described.
N-acetylglucosaminyltransferase II (GnTII) is required for stress tolerance in plants
Eun Ji Lee,Jae Yong Yoo,Ki Seong Ko,Nirmal Kumar Ramasamy,Bo Young Hwang,Sang Yeol Lee,Kyun Oh Lee 한국당과학회 2016 한국당과학회 학술대회 Vol.2016 No.07
The most abundant N-glycan in plants is the paucimannosidic N-glycan with core β1,2-xylose and α 1,3-fucose residues Man3XylFucGlcNAc2. Here, we report a mechanism in Arabidopsis thaliana that efficiently produces the largest N-glycan in plants. Genetic and biochemical evidence indicates that the addition of the 6-arm β1,2-GlcNAc residue by N-acetylglucosaminyltransferase II (GnTII) is less effective than additions of the core β1,2-xylose and α1,3-fucose residues by XylT, FucTA, and FucTB in Arabidopsis. Furthermore, analysis of gnt2 mutant and 35S:GnTII transgenic plants shows that the addition of the 6-arm non-reducing GlcNAc residue to the common N-glycan acceptor GlcNAcMan3GlcNAc2 inhibits additions of the core β1,2-xylose and α1,3-fucose residues. Our findings indicate that plants limit the rate of the addition of the 6-arm GlcNAc residue to the common N-glycan acceptor as a mechanism to facilitate formation of the prevalent N-glycans with Man3XylFucGlcNAc2 and GlcNAc2Man3XylFucGlcNAc2 structures. To investigate the physiological effects of the addition of the 6-arm GlcNAc residue to the N-glycans in plants, phenotypes of Col-0, gnt2, 35S:GnTII and a triple-knockout mutant with mutated alleles of N-acetyl-beta-D-hexosaminidases (Hex1, Hex2 and Hex3) were analysed in the absence or presence of exogenously supplied tunicamycin (TM) or sodium chloride (NaCl). gnt2, compared with Col-0, 35S:GnTII and the triple mutant, displayed increased sensitivity to TM and NaCl during germination and seedling development, indicating that GnTII is important to confer stress tolerance on plants.