Stc1: A Critical Link between RNAi and Chromatin Modification Required for Heterochromatin Integrity

Bayne, Elizabeth H.,White, Sharon A.,Kagansky, Alexander,Bijos, Dominika A.,Sanchez-Pulido, Luis,Hoe, Kwang-Lae,Kim, Dong-Uk,Park, Han-Oh,Ponting, Chris P.,Rappsilber, Juri,Allshire, Robin C. Cell Press 2010 Cell Vol.140 No.5

<P><B>Summary</B></P><P>In fission yeast, RNAi directs heterochromatin formation at centromeres, telomeres, and the mating type locus. Noncoding RNAs transcribed from repeat elements generate siRNAs that are incorporated into the Argonaute-containing RITS complex and direct it to nascent homologous transcripts. This leads to recruitment of the CLRC complex, including the histone methyltransferase Clr4, promoting H3K9 methylation and heterochromatin formation. A key question is what mediates the recruitment of Clr4/CLRC to transcript-bound RITS. We have identified a LIM domain protein, Stc1, that is required for centromeric heterochromatin integrity. Our analyses show that Stc1 is specifically required to establish H3K9 methylation via RNAi, and interacts both with the RNAi effector Ago1, and with the chromatin-modifying CLRC complex. Moreover, tethering Stc1 to a euchromatic locus is sufficient to induce silencing and heterochromatin formation independently of RNAi. We conclude that Stc1 associates with RITS on centromeric transcripts and recruits CLRC, thereby coupling RNAi to chromatin modification.</P>

Selected aryl thiosemicarbazones as a new class of multi-targeted monoamine oxidase inhibitors

Mathew, Bijo,Baek, Seung Cheol,Grace Thomas Parambi, Della,Pil Lee, Jae,Joy, Monu,Annie Rilda, P. R.,Randev, Rugma V.,Nithyamol, P.,Vijayan, Vijitha,Inasu, Sini T.,Mathew, Githa Elizabeth,Lohidakshan, The Royal Society of Chemistry 2018 MedChemComm Vol.9 No.11

<P>A series of 13 phenyl substituted thiosemicarbazones (SB1-SB13) were synthesized and evaluated for their inhibitory potential towards human recombinant monoamine oxidase A and B (MAO-A and MAO-B, respectively) and acetylcholinesterase. The solid state structure of SB4 was ascertained by the single X-ray diffraction technique. Compounds SB5 and SB11 were potent for MAO-A (IC50 1.82 ± 0.14) and MAO-B (IC50 0.27 ± 0.015 μM), respectively. Furthermore, SB11 showed a high selectivity index (SI > 37.0) for MAO-B. The effects of fluorine orientation revealed that SB11 (<I>m</I>-fluorine) showed 28.2 times higher inhibitory activity than SB12 (<I>o</I>-fluorine) against MAO-B. Furthermore, inhibitions by SB5 and SB11 against MAO-A and MAO-B, respectively, were recovered to near reference levels in reversibility experiments. Both SB5 and SB11 showed competitive inhibition modes, with <I>K</I>i values of 0.97 ± 0.042 and 0.12 ± 0.006 μM, respectively. These results indicate that SB5 and SB11 are selective, reversible and competitive inhibitors of MAO-A and MAO-B, respectively. Compounds SB5, SB7 and SB11 showed moderate inhibition against acetylcholinesterase with IC50 values of 35.35 ± 0.47, 15.61 ± 0.057 and 26.61 ± 0.338 μM, respectively. Blood-brain barrier (BBB) permeation was studied using the parallel artificial membrane permeation assay (PAMPA) method. Molecular docking studies were carried out using AutoDock 4.2.</P>

한국개신교의 목회자 자녀로 살아가는 삶에 대한 내러티브 탐구 : 20대 미혼 청년의 경험을 중심으로

이비조(Bijo Lee),한영주(Youngju Han) 한국질적탐구학회 2020 질적탐구 Vol.6 No.3

This narrative inquiry is to comprehend what stories of life Protestantism pastor’s children form in their lives. For this purpose, the study analyzed the data, collected via 3∼5 times of in-depth interviews, according to narrative inquiry procedure proposed by Clandinin and Connelly(2000). The result was reconstituted into three themes - ‘Family and I’, ‘Church and I’, ‘My current self’. For participant Lee Myungjoo, helping her father’s church duty was the top priority in life. However after meeting a friend who listened to her stories with full heart, she came to have different dream and now she is dreaming of establishing a church community of her own. Participant Lim Dongwoo has spent his adolescence, trying to brake the intangible expectation for a pastor’s child. But after his parents changed their way of nurturing, to allow him to do what he wanted, their relationship took a new turn. As he came to have his own way of belief in the God, he was able to understand his father. Currently, he has let go of the path to become a minister and seek a new path. Participant Kim Jinhee has experienced that her father’s caring for her during childhood, became a burden, forcing to be a good child. She accepted the value of universal happiness by expressing her experiences of being pressured to share what she had as a pastor’s child, and now lives as a teacher who conveys the value to students. Unlike the existing studies, the study allowed pastors’ children who are now living their own lives in their position, to speak up about their life experience in detail. It is meaningful in that it added the understanding on the life of pastors. 본 연구는 목회자 자녀로 살아가는 사람들이 어떠한 삶의 이야기들을 형성하며 살아내는지를 이해하려는 내러티브 탐구이다. 본 연구는 한국개신교의 목회자 가정에서 목회자 자녀로 살아온 3인의 연구 참여자들과 3∼5 회에 걸친 심층면담을 통해 수집된 자료를 Clandinin과 Connelly(2000)가 제시한 내러티브 탐구절차에 따라 분석하였다. 분석결과는 ‘가족과 나’, ‘교회와 나’, ‘현재의 나’의 세 가지 주제로 재구성되었다. 참여자[이명주]는 부의 사역을 돕는 역할에 우선순위를 두고 살아가다가 온전히 마음을 들어준 선배와의 만남을 통해 자신을 위한 선택을 하게 되었으며, 현재는 자신이 꿈꾸는 교회공동체를 세워가고 싶다는 목표를 바라보며 살아가고 있다. 참여자[임동우]는 목회자 자녀로 느끼는 실체 없는 기대를 깨뜨리고자 금기시된 행동을 시도하는 청소년기를 보냈지만, 원하는 바를 시도하게 허용한 부모님의 양육방식의 변화로 관계의 새로운 국면을 맞이하였으며, 주어진 삶의 조건이던 신앙이 자신의 것이 되면서 아버지를 이해하는 경험을 하였다. 현재는 가정에서 지지받는 선택이던 사역자라는 진로를 내려놓고 새롭게 길을 찾아가고자 고민하고 있다. [김진희]는 아이로서 살아갈 수 있도록 울타리가 되어준 부의 배려를 통해 바른 아이여야 한다는 부담을 내려놓는 경험을 하였으며, 목회자 자녀이기에 때로 자신의 것을 내어줘야 했던 경험들을 조금씩 나눔으로써 모두 행복할 수 있다는 가치로 받아들이며 교사로서 학생들에게 이를 삶으로 전하는 현재를 살아가고 있다. 이 연구는 목회자 자녀의 적응과 극복을 전제하는 기존연구와 달리, 각자의 삶의 영역에서 자신의 삶을 살아내는 목회자 자녀들의 구체적 삶의 경험을 그들 자신의 생생한 목소리로 이야기할 수 있었다는 점에서 목회자 자녀로 살아가는 삶에 대한 이해를 더했다는 것에 그 의의가 있다.

Inhibition of monoamine oxidases by benzimidazole chalcone derivatives

Krishna Athulya,Lee Jiseong,Kumar Sunil,Sudevan Sachithra Thazhathuveedu,Uniyal Prerna,Pappachen Leena K.,Kim Hoon,Mathew Bijo 한국응용생명화학회 2023 Applied Biological Chemistry (Appl Biol Chem) Vol.66 No.-

Ten benzimidazole chalcone derivatives were synthesized, and their monoamine oxidase (MAO) inhibitory activity was evaluated. Most compounds showed higher inhibitory activity against MAO-B than MAO-A. Compound BCH2 exhibited an IC50 value of 0.80 μM, thereby showing the most potent inhibition amongst all. In addition, BCH2 showed the highest MAO-B selectivity index (SI) with an SI value of 44.11 compared to MAO-A. Among the substituents, the halogen group showed the best MAO-B inhibition, and the ortho-position of the B ring showed better inhibitory activity than the para-site. In comparison with ortho-substituents, the inhibitory activity increased in the order, -Cl > -Br > -F > -H. BCH2 was found to be a competitive inhibitor of the enzyme with optimum inhibition kinetics, where Ki was found to be 0.25 ± 0.014 μM. In the reversibility experiment, BCH2 showed a recovery pattern after MAO-B inhibition, similar to that of lazabemide. Thus, BCH2 is a potent, reversible, and selective MAO-B inhibitor and has been suggested as a candidate for the treatment of neurological disorders.

Inhibitions of monoamine oxidases by ferulic acid hydrazide derivatives: synthesis, biochemistry, and computational evaluation

Peedikayil Arshida Thottile,Lee Jiseong,Abdelgawad Mohamed A.,Ghoneim Mohammed M.,Shaker Mohamed E.,Selim Samy,Kumar Sunil,Dev Sanal,Kim Hoon,Mathew Bijo 한국응용생명화학회 2023 Applied Biological Chemistry (Appl Biol Chem) Vol.66 No.-

Monoamine oxidases (MAOs) regulate neurotransmitters, and changes in their regulation lead to neurogenerative diseases (NDs). Therefore, MAO inhibitors are used to treat NDs. Ferulic acid, a phenolic compound found in various plant species, has been demonstrated to have a variety of biological functions, including anti-inflammatory, anticancer, and neuroprotective effects. In this study, ten ferulic acid hydrazide derivatives (FA1–FA10) were synthesized, and their ability to inhibit monoamine oxidase (MAO) enzymes was tested. Six candidates demonstrated a more pronounced pattern of inhibitory action against MAO-B than against MAO-A. FA3 had the highest inhibitory efficacy in MAO-B inhibition (IC50 value of 1.88 μM), followed by FA9 (2.08 μM). FA3 has a Ki of 1.92 ± 0.73 μM. A reversibility experiment of MAO-B inhibition by FA3 was conducted using dialysis, and the recovery pattern showed FA3 was a reversible MAO-B inhibitor with a similar recovery to safinamide, a reversible reference inhibitor. These results indicate that FA3 is an effective reversible MAO-B inhibitor. In molecular dynamics and docking, FA3 paired with pi-pi stacking helped stabilize the protein ligand in the active site of MAO-B. According to this study, lead compounds can be used as therapeutic agents to treat neurological conditions, such as Parkinson's disease (PD).

Development of morpholine ring-bearing halogenated α,β-unsaturated ketones as selective monoamine oxidase-B inhibitors

Lee Jiseong,Parmbil Saranya Kattil,Pandit Nagendar Kumar,Kumar Sunil,Syed Asad,Elgorban Abdallah M.,Wong Ling Shing,Ranjana,Kim Hoon,Mathew Bijo 한국응용생명화학회 2024 Applied Biological Chemistry (Appl Biol Chem) Vol.67 No.-

Nine morpholine-derived halogenated chalcone derivatives ( MHC1 - MHC9 ) were synthesized, and their inhibitory activity against monoamine oxidase (MAO) was evaluated. MHC5 showed the highest inhibitory activity against MAO-B with an IC 50 value of 0.065 μM, followed by MHC7 (IC 50  = 0.078 μM) and MHC6 (IC 50  = 0.082 μM). The para -F substituent MHC4 was also potent (IC 50  = 0.095 μM). The selectivity index values of all the compounds were high for MAO-B over MAO-A, and the values for MHC5 and MHC4 were 66.15 and 80.11, respectively. MHC5 and MHC4 were competitive MAO-B inhibitors with K i values of 0.024 ± 0.00062 and 0.041 ± 0.0028 μM, respectively. In reversibility tests, the changes in residual activity before and after the dialysis of MHC5 and MHC4 were similar to those of safinamide, a reversible MAO-B reference inhibitor. Additionally, molecular docking and dynamic simulations predicted that the lead molecules MHC5 and MHC4 could strongly bind to the MAO-B active site with docking scores of –10.92 ± 0.08 and –10.64 ± 0.14 kcal/mol, respectively. Additionally, MHC4 and MHC5 exhibited favorable ADME features, including blood–brain barrier permeability. The experiments confirmed that MHC5 and MHC4 are reversible and potent selective inhibitors of MAO-B and are promising candidates for the treatment of neurodegenerative diseases (human health).