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Maheshwor Thapa,Hye-Ran Yoon 대한약학회 2018 약학회지 Vol.62 No.1
A rapid and simple screening method was developed for the simultaneous analysis of 6 sulfur-containing amino acids from human plasma at ng level. The procedure involves simple protein precipitation followed by direct analysis using UPLC-MS/MS. Calibration curves showed an excellent linear relationship with coefficients of determination (r 2 ) of 0.9989-0.9998. LOD and LOQ were between 1-50 ng/mL and 10-100 ng/mL, respectively. When sulfur amino acids spiked into plasma sample, excellent linearity of detection response was demonstrated over the range between 10-10,000 ng/mL. This new analytical method is suitable for simultaneous screening of large number of samples in clinical application and metabolomics research.
Maheshwor Thapa,Suraj Adhikari,나승훈,윤혜란,이원재 대한화학회 2020 Bulletin of the Korean Chemical Society Vol.41 No.5
Enantioseparation of thyroxine using chiral crown ether type column.
Amelioration of DSS-induced colitis by BJ-2223 through the inhibition of Th17 cell differentiation
Maheshwor Timilshina,Jae Hoon Chang 대한약학회 2018 약학회지 Vol.62 No.5
CD4+ T cells differentiate into T helper (Th) 1 and Th17 cells, which are key mediators of several inflammatory and autoimmune diseases. Inhibition of Th1 and Th17 cell differentiation helps attenuate several inflammatory conditions. Th17 cells are highly pro-inflammatory cells that orchestrate tissue inflammation and ulcerative colitis (UC). Thus, novel compounds that inhibit Th17 cell differentiation are required for the effective treatment of inflammatory and autoimmune diseases. By extensive screening of several synthetic compounds, we found that BJ-2223 inhibits Th17 cell differentiation without affecting Th1 and regulatory T (Treg) cell differentiation in vitro. Furthermore, BJ-2223 does not induce apoptosis and does not affect T cell proliferation and viability. Mechanistically, BJ-2223 inhibits Th17 cell differentiation through inhibition of the Janus-activated kinase (JAK)/signal transducer and activator of transcription protein (STAT) signaling pathway. Moreover, BJ-2223 ameliorates dextran sulfate sodium (DSS)-induced colitis, protects intestinal tissue, and decreases the percentage of Th17 cells in vivo. Thus, BJ-2223 is a novel compound that inhibits in vitro Th17 differentiation and attenuates DSS-induced colitis by reducing the percentage of Th17 cells.
Kang, Youra,Timilshina, Maheshwor,Nam, Tae-gyu,Jeong, Byeong-Seon,Chang, Jae-Hoon BioMed Central 2017 BIOLOGICAL RESEARCH Vol.50 No.-
<P><B>Background</B></P><P>CD4<SUP>+</SUP> T cells play an important role in the initiation of an immune response by providing help to other cells. Among the helper T subsets, interferon-γ (IFN-γ)-secreting T helper 1 (Th1) and IL-17-secreting T helper 17 (Th17) cells are indispensable for clearance of intracellular as well as extracellular pathogens. However, Th1 and Th17 cells are also associated with pathogenesis and contribute to the progression of multiple inflammatory conditions and autoimmune diseases.</P><P><B>Results</B></P><P>In the current study, we found that BJ-1108, a 6-aminopyridin-3-ol analogue, significantly inhibited Th1 and Th17 differentiation in vitro in a concentration-dependent manner, with no effect on proliferation or apoptosis of activated T cells. Moreover, BJ-1108 inhibited differentiation of Th1 and Th17 cells in ovalbumin (OVA)-specific OT II mice. A complete Freund’s adjuvant (CFA)/OVA-induced inflammatory model revealed that BJ-1108 can reduce generation of proinflammatory Th1 and Th17 cells. Furthermore, in vivo studies showed that BJ-1108 delayed onset of disease and suppressed experimental autoimmune encephalomyelitis (EAE) disease progression by inhibiting differentiation of Th1 and Th17 cells.</P><P><B>Conclusions</B></P><P>BJ-1108 treatment ameliorates inflammation and EAE by inhibiting Th1 and Th17 cells differentiation. Our findings suggest that BJ-1108 is a promising novel therapeutic agent for the treatment of inflammation and autoimmune disease.</P>
AMPK suppresses Th2 cell responses by repressing mTORC2
Pandit Mahesh,Timilshina Maheshwor,Gu Ye,Acharya Suman,Chung Yeonseok,Seo Sang-Uk,Chang Jae-Hoon 생화학분자생물학회 2022 Experimental and molecular medicine Vol.54 No.-
Allergic inflammation is a T helper 2 (Th2) cell-driven pathophysiological phenomenon, but the mechanism by which the metabolic cascade affects Th2 cell differentiation remains unclear. In this study, we investigated the roles of AMP-activated protein kinase (AMPK) and intracellular energy sensors in Th2 cell differentiation and the pathogenesis of allergic inflammation. Accordingly, T-cell-specific AMPK or Sirtuin 1 (Sirt1)-knockout mice were subjected to allergic inflammation, and their Th2 cell responses were investigated. The results demonstrated that inducing allergic inflammation in AMPK- and Sirt1-knockout mice increased Th2 cell responses and exacerbated allergic phenotypes. Furthermore, treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMPK, ameliorated allergic inflammation in mice. Mechanistically, our findings revealed that AMPK repressed mechanistic target of rapamycin complex 2 (mTORC2), which downregulated the expression of suppressor of cytokine signaling 5 (SOCS5) in CD4+ T cells. In addition, the loss of AMPK signaling reduced SOCS5 expression and increased interleukin-4-STAT6–GATA3 axis-mediated Th2 cell differentiation. Finally, the T-cell-specific deletion of Rictor, a member of mTORC2, in Sirt1T-KO mice led to the reversal of allergic exacerbation to the level in control mice. Overall, our findings suggest that AMPK in CD4+ T cells inhibits the differentiation of Th2 cells by repressing mTORC2 and thus serves as a potential target for Th2 cell-associated diseases.
윤혜란,타파마헤샬,Yoon, Hye-Ran,Thapa, Maheshwor The Korean Society of Inherited Metabolic Disease 2017 대한유전성대사질환학회지 Vol.17 No.2
Purpose: A sensitive gas chromatography mass spectrometry (GC-MS) method was developed for screening of fatty acid oxidation disorders. Methods: The assay utilized a simple protein precipitation with sulfosalicylic acid followed by tert-butyl dimethylsilyl (TBDMS) derivatization of hydroxyl functional group by N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide (MTBSTFA). Results: Calibration curves of spiked pooled plasma showed a linear relationship in the range of 0.01 ng -2 mg with correlation coefficient value greater than 0.98. Limits of detection (LOD) and limits of quantification (LOQ) were found in the range of 0.9-8.8 ng and 9-88 ng, respectively. Conclusion: The new developed method might be useful for a rapid, sensitive screening of inherited fatty acid oxidation disorders. In addition, the method expected to be one of the alternative method for screening newborns of metabolic disorders in the laboratories where expensive MS/MS is unavailable.
윤혜란,마헤샬타파,Yoon, Hye-Ran,Thapa, Maheshwor The Korean Society of Inherited Metabolic Disease 2015 대한유전성대사질환학회지 Vol.15 No.3
Purpose: If early diagnosis is not made, patients with metabolic disorders as homocystinemia rapidly progress to physical defect or mental retardation resulted in storage of the toxic material into the brain. Therefore, it is necessary to develop an analytical method for a rapid screening and/or correct confirmation diagnosis. Methods: The standard solution of sulfur amino acids spiked plasma was subjected to protein precipitation with methanol, and then consecutively derivatized with trimethylsilyl (TMS) and trifluoroacyl (TFA) and determined by GC-MS. The formation of TMS derivative of the hydroxyl and TFA derivative of amino functional group was performed by BSTFA and MBTFA, respectively. Selective ion monitoring (SIM) mode was used for quantification with selected specific ions. Results: A calibration curve on standard spiked pooled plasma showed a linear relationship with correlation coefficient of 0.9936-0.9992 for all compounds over the range of 0.1-300 ng. The precision and accuracy were within S.D. of 1-15% and RSD of 1-15% for intra-day assay at 2 ng/mL, 15 ng/mL and 30 ng/mL. LOD and LOQ was 0.4 ng/mL and 4 ng/mL respectively. Conclusion: A rapid analytical method was developed to quantify sulfur amino acids and methyl malonic acid, after two-step derivatization procedure with good sensitivity and specificity on human plasma. Advantages of a new method are simplicity and rapidity. The method could be useful for routine analysis, diagnosis of homocysteinemia.
Phung, Cao Dai,Nguyen, Hanh Thuy,Choi, Ju Yeon,Pham, Thanh Tung,Acharya, Suman,Timilshina, Maheshwor,Chang, Jae-Hoon,Kim, Ju-Hyun,Jeong, Jee-Heon,Ku, Sae Kwang,Choi, Han-Gon,Yong, Chul Soon,Kim, Jong Elsevier 2019 Journal of controlled release Vol.315 No.-
<P><B>Abstract</B></P> <P>In this study, dual drug-loaded nanoparticles were constructed to co-deliver low-dose doxorubicin (DOX) and miR-200c (DOX/miR-NPs) to inhibit programmed death-1 receptor (PD-L1) expression and trigger immunogenic cell death (ICD) in cancer cells. Two block copolymers, folic acid (FA)-conjugated PLGA-PEG (PLGA-PEG-FA) and PLGA-PEI, were formulated as folate-targeted NPs and loaded with DOX and miR-200c. The NPs, which were formed as nanosize objects (110.4 ± 2.1) with narrow size distribution (0.19 ± 0.02), effectively protected the miR-200c from degradation in serum. Modifying the NPs with FA increased not only their uptake by cancer cells <I>in vitro</I> but also their accumulation in tumor microenvironments <I>in vivo</I>, as compared with those properties of non-FA-modified NPs. The DOX/miR-NPs also exhibited efficacious inhibition of PD-L1 expression and robust induction of ICD in cancer cells <I>in vitro</I> and <I>in vivo</I>, resulting in increased dendritic cell maturation and CD8<SUP>+</SUP> T cell response towards cancer cells. Furthermore, tumor growth was significantly inhibited by folate-targeted NPs loaded with the low-dose DOX/miR-200c combination, but not by treatments with free DOX, miR-NPs or DOX-NPs. Thus, our results suggest that simultaneous PD-L1 inhibition via microRNAs and the induction of an immunogenic tumor microenvironment via low-dose cytotoxic drugs may improve cancer therapy efficacy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A folate receptor-targeted nanoparticle was prepared for co-delivery of doxorubicin and miR-200c (DOX/miR-NPs). </LI> <LI> The DOX/miR-NPs inhibited PD-L1 expression and robustly induced immunogenic cell death in cancer cells <I>in vitro</I> and <I>in vivo</I>. </LI> <LI> The treatment with DOX/miR-NPs significantly increased tumor-infiltrated dendritic cells and cytotoxic T cells. </LI> <LI> The tumor growth was remarkably inhibited by DOX/miR-NPs. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>