Introduction of amino moiety enhances the inhibitory potency of 1-tetralone chalcone derivatives against LPS-stimulated reactive oxygen species production in RAW 264.7 macrophages

Katila, Pramila,Shrestha, Aastha,Shrestha, Aarajana,Shrestha, Ritina,Park, Pil-Hoon,Lee, Eung-Seok Elsevier 2019 Bioorganic chemistry Vol.87 No.-

<P><B>Abstract</B></P> <P>The design and synthesis of a series of thirty-two halogenated 1-tetralone or 6-amino-1-tetralone chalcone derivatives was achieved by the Claisen-Schmidt condensation reaction and were evaluated for their inhibitory effects against ROS production in LPS-stimulated RAW 264.7 macrophages. It was observed that the introduction of amino moiety into 1-tetralone skeleton greatly increased the inhibitory potency compared to corresponding 1-tetralone chalcones. Among the synthesized compounds, compound <B>18</B> which consists of 6-amino-1-tetralone skeleton together with <I>o</I>-fluorobenzylidene showed the most potent ROS inhibitory effect with IC<SUB>50</SUB> value of 0.25 ± 0.13 µM. SAR analysis revealed that amino moiety at the 6th position of 1-tetralone chalcones have an important role for exerting the greater ROS inhibitory potency in LPS-stimulated RAW 264.7 macrophages than those exhibited by 1-tetralone chalcones alone.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Halogenated 1-tetralone/6-amino-1-tetralone chalcone derivatives were synthesized. </LI> <LI> ROS Inhibitory effect in LPS-stimulated RAW 264.7 macrophages was examined. </LI> <LI> Compounds <B>18</B> showed the most potent ROS inhibition potency. </LI> <LI> Intro duction of amino group at the 6th position was enhanced the ROS inhibition. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Design and Synthesis of Fluorinated and/or Hydroxylated 2-Arylidene-1-indanone Derivatives as an Inhibitor of LPS-stimulated ROS Production in RAW 264.7 Macrophages with Structure–Activity Relationship Study

Pramila Katila,Aastha Shrestha,아라자나쉬레스타,Ritina Shrestha,박필훈,이응석 대한화학회 2018 Bulletin of the Korean Chemical Society Vol.39 No.12

A new series of thirty-two fluorinated and/or hydroxylated 2-arylidene-1-indanone derivatives were systematically designed, synthesized, and evaluated for their inhibitory activity against LPS-stimulated ROS production in RAW 264.7 macrophages. 5/6-Fluoro-1-indanone or 4-, 5-, 6-, or 7-hydroxyindanone moiety along with ortho-, meta-, or para-hydroxyphenyl, furanyl or thiophenyl moiety was prepared and evaluated. Among the synthesized compounds, compound 11 possessing 6-hydroxy-1-indanone moiety along with 5-chlorothiophenyl moiety was found to have the most potent inhibitory effect on the production of ROS in LPS-stimulated RAW 264.7 macrophages with an IC50 value of 3.29??M.

Mechanistic comparison between MPTP and rotenone neurotoxicity in mice

Bhurtel, Sunil,Katila, Nikita,Srivastav, Sunil,Neupane, Sabita,Choi, Dong-Young Elsevier BV 2019 NeuroToxicology Vol.71 No.-

<P><B>Abstract</B></P> <P>Animal models for Parkinson’s disease (PD) are very useful in understanding the pathogenesis of PD and screening for new therapeutic approaches. 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) and rotenone are common neurotoxins used for the development of experimental PD models, and both inhibit complex I of mitochondria; this is thought to be an instrumental mechanism for dopaminergic neurodegeneration in PD. In this study, we treated mice with MPTP (30 mg/kg/day) or rotenone (2.5 mg/kg/day) for 1 week and compared the neurotoxic effects of these toxins. MPTP clearly produced dopaminergic lesions in both the substantia nigra and the striatum as shown by loss of dopaminergic neurons, depletion of striatal dopamine, activation of glial cells in the nigrostriatal pathway and behavioral impairment. In contrast, rotenone treatment did not show any significant neuronal injury in the nigrostriatal pathway, but it caused neurodegeneration and glial activation only in the hippocampus. MPTP showed no such deleterious effects in the hippocampus suggesting the higher susceptibility of the hippocampus to rotenone than to MPTP. Interestingly, rotenone caused upregulation of the neurotrophic factors and their downstream PI3K-Akt pathway along with adenosine monophosphate-activated protein kinase (AMPK) activation. These results suggest that MPTP-induced dopaminergic neurotoxicity is more acute and specific in comparison to rotenone toxicity, and compensatory brain-derived neurotrophic factor (BDNF) induction and AMPK activation in the rotenone-treated brain might suppress the neuronal injury.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Neurotoxic property of MPTP and rotenone was compared. </LI> <LI> Neurotoxicity of MPTP was acute and selective to the dopaminergic neurons. </LI> <LI> Rotenone caused glial activation and neuronal loss in the hippocampus. </LI> </UL> </P>

Ameliorating effect of TI-1-162, a hydroxyindenone derivative, against TNBS-induced rat colitis is mediated through suppression of RIP/ASK-1/MAPK signaling

Gurung, Pallavi,Banskota, Suhrid,Katila, Nikita,Gautam, Jaya,Kadayat, Tara Man,Choi, Dong-Young,Lee, Eung Seok,Jeong, Tae Cheon,Kim, Jung-Ae Elsevier 2018 european journal of pharmacology Vol.827 No.-

<P>The pathogenesis of inflammatory bowel disease (IBD) is associated with production of immense pro-inflammatory cytokines including TNF-alpha. Once generated, TNF-alpha stimulates production of various pro-inflammatory cytokines and disrupts mucosal barrier by inducing inflamed mucosal epithelial cell death. In the present study, we investigated inhibitory effects of TI-1-162, a hydroxyindenone derivative, against TNF-alpha-induced and TNBS-induced colon inflammation. TI-1-162 showed inhibitory effect on the TNF-alpha-induced adhesion of U937 monocytic cells to HT-29 colonic epithelial cells (IC50 = 0.83 +/- 0.12 mu M), which is an in vitro model representing the initial step of colitis. In addition, TI-1-162 suppressed TNF-alpha-stimulated caspase-3 activation and HT-29 cell apoptosis. These in vitro inhibitory activities of TI-1-162 correlated to recovery changes in in vivo colon tissues, such as downregulation of adhesion molecules (ICAM-1, VCAM-1) and chemokines (CCL11, CXCL1, CXCL2, CXCL3, CX3CL1) revealed by gene expression array and Western blot analyses. Such molecular recovery of colon epithelium from TNBS-treated rats corresponded to the recovery in body weight, colon weight/length, and myeloperoxidase level by TI-1-162 (10 and 30 mg/kg/day, orally). In relation to action mechanism, TI-1-162 did not disturb TNF-alpha binding to its receptor, but suppressed phosphorylation of RIP-1, ASK-1, JNK and p38, and nuclear translocation of NF-kB and AP-1, which corresponded to down regulation of inflammatory cytokines in TNF-alpha-treated cells (HT-29 and U937) and TNBS-treated rat colon tissues. Taken together, the results indicate that the protective effects of TI-1-162 against colon inflammation and epithelial cell death are associated with its inhibitory action in RIP/ASK-1/MAPK signaling pathway downstream to TNF receptor 1.</P>

성상세포유래 신경영양인자의 자가생성 촉진에 의한 장기적 운동능력 향상 효과

니키타 카티라,최동영,Katila, Nikita,Choi, Dong-Young 대한약학회 2016 약학회지 Vol.60 No.4

We evaluated the effects of single infusion of glial cell derived neurotrophic factor (GDNF) on locomotor activity in aged rats. Enhanced activity for four weeks was accompanied by an increase in sizes of the nigral dopaminergic neurons, areas of their nuclei and cytoplasm. We found that increased level of neurotrophic factors sustained in the striatum up to four weeks. There was significant rise in the level of GDNF mRNA in the striatum following GDNF treatment. These results suggest that exogenous GDNF infusion stimulates expression of itself in the brain which is related to prolonged effects of the neurotrophic factor.

Neuroprotective Effects of N-Acetyldopamine Dimers from Cicadidae Periostracum

Punam Thapa,Nikita Katila,최혁재,한아름,최동영,남주원 한국생약학회 2021 Natural Product Sciences Vol.27 No.3

The chemical investigation of the 90% EtOH extract from Cicadidae Periostracum led to the isolation and identification of seven known N-acetyldopamine dimers (1-7). These compounds were identified by comparing mass spectrometry data and NMR spectroscopic data with those previously reported. In this study, complete interpretation of 1D and 2D NMR data of 1 and 2 were reported for the first time. In addition, compounds 3 and 4 were isolated from this material for the first time. All isolates were obtained as racemic mixtures, as confirmed by chiral HPLC. Furthermore, we evaluated the neuroprotective activities of compounds 1–7 and found that compounds 1, 5, and 6 significantly attenuated rotenone-induced death of SH-SY5Y neuroblastoma cells at a concentration of 100 mM. Parallel to this result, compounds 3 and 6 displayed antioxidant effects in the cytoplasm, as determined by CM-H2DCFDA fluorescence intensity, while compounds 1 and 5 showed antioxidant effects in the mitochondria, as assessed by MitoSox fluorescence intensity. Overall, these results suggest that some of these compounds protect neuroblastoma cells by ameliorating the release of reactive oxygen species. Further studies are warranted to elucidate the underlying mechanisms by which these compounds exhibit antioxidant and neuroprotective actions.

A new phenolic series of indenopyridinone as topoisomerase inhibitors: Design, synthesis, and structure-activity relationships

Shrestha, Aarajana,Park, Seojeong,Jang, Hae Jin,Katila, Pramila,Shrestha, Ritina,Kwon, Youngjoo,Lee, Eung-Seok Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.18

<P><B>Abstract</B></P> <P>DNA Topoisomerase IIα (topo IIα) is one of the most effective therapeutic targets to control cancer. In an effort to develop novel and effective topo IIα targeting anti-proliferative agent, a phenolic series of indenopyridinone and indenopyridinol were designed and prepared using efficient multi-component one pot synthetic method. Total twenty-two synthesized compounds were assessed for topo I and IIα inhibition, and anti-proliferation in three different human cancer cell lines. Overall structure-activity relationship study explored the significance of <I>meta-</I>phenolic group at 4-position and <I>para-</I>phenolic group at 2- and/or 4-position of indenopyridinone skeleton for strong topo IIα-selective inhibition and anti-proliferative activity against human cervix (HeLa) and colorectal (HCT15) cell lines. Compound <B>12</B> with excellent topo IIα inhibition (93.7%) was confirmed as a DNA intercalator that could be a new promising lead to develop effective topo IIα-targeted anticancer agents.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Phenolic series of indenopyridinone were synthesized. </LI> <LI> SAR study was performed by comparing topo inhibitory and anti-proliferative activity. </LI> <LI> <I>para-</I>Phenolic group at 2- and/or 4-position of indenopyridinones is important. </LI> <LI> Compound <B>12</B> acted as DNA-intercalative potent topo IIα inhibitor. </LI> <LI> Indenopyridinone as potential scaffold for anticancer activity. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Enhanced neuroinflammatory responses after systemic LPS injection in IL-32β transgenic mice

Neupane, Sabita,Srivastav, Sunil,Bhurtel, Sunil,Katila, Nikita,Shadfar, Sina,Park, Pil-Hoon,Hong, Jin Tae,Choi, Dong-Young Elsevier 2018 Journal of chemical neuroanatomy Vol.94 No.-

<P><B>Abstract</B></P> <P>IL-32 is a proinflammatory cytokine, and involved in various diseases including infection, inflammation, and cancer. However, effects of IL-32 on neuroinflammation remain obscure. Herein, we examined the effects of IL-32β on systemic LPS-induced neuroinflammation using IL-32β transgenic (Tg) mice. IL-32β wild type (WT) and Tg mice received LPS injection (5 mg/kg, i.p.), and then neuroinflammatory responses were evaluated. Systemic LPS caused remarkable gliosis in the brain at 12 h regardless of genotypes. The gliosis in WT mice was sustained by 24 h, whereas it became more severe in Tg mice by 24 h. Proinflammatory cytokines and proteins were increased at 12 h both in WT and Tg brains. The elevated levels of TNFα and VCAM-1were not altered over time, while levels of IL-6, IL-1β and iNOS were dropped in WT mice. In contrast, elevated levels IL-6, IL-1β, iNOS and VCAM-1 were sustained, and level of TNFα was augmented in Tg brains by 24 h. Interestingly, level of IL-10 mRNA in Tg mice was remarkably higher than in WT mice at 0 h, which was decreased at 12 h and maintained by 24 h. In WT brain, mRNA level of IL-10 was raised at 12 h after LPS injection, and further increased at 24 h. Activation of NF-κB signaling pathway was detected in glia cells after LPS injection which was exaggerated at 24 h in Tg mice in comparison to WT mice. These results indicate that IL-32β enhances neuroinflammatory responses caused by systemic LPS, and this might be attributable to prolonged activation of NF-κB signaling pathway.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Effects of IL-32β on neuroinflammation were evaluated. </LI> <LI> Enhanced neuroinflammation was observed in IL-32β transgenic mice. </LI> <LI> Prolonged activation of NF-κB might be related to extended neuroinflammation. </LI> </UL> </P>

Neuroprotective Effects of Antidepressants via Upregulation of Neurotrophic Factors in the MPTP Model of Parkinson’s Disease

Shadfar, S.,Kim, Y. G.,Katila, N.,Neupane, S.,Ojha, U.,Bhurtel, S.,Srivastav, S.,Jeong, G. S.,Park, P. H.,Hong, J. T. HUMANA PRESS INC 2018 Molecular Neurobiology Vol.55 No.1

<P>Neurotrophic factors are essential for neuronal survival, plasticity, and development and have been implicated in the action mechanism of antidepressants. In this study, we assessed the neurotrophic factor-inducing and neuroprotective properties of antidepressants. In the first part of the study, we found that fluoxetine, imipramine, and milnacipran (i.p., 20 mg/kg/day for 1 week or 3 weeks) upregulated brain-derived neurotrophic factor in the striatum and substantia nigra both at 1 week and 3 weeks. In contrast, an increase in the glial-derived neurotrophic factor was more obvious at 3 weeks after the antidepressants treatment. Specifically, it was found that fluoxetine and imipramine are more potent in raising the levels of neurotrophic factors than milnacipran. Furthermore, antidepressants elevated the phosphorylation of extracellular signal-regulated-protein kinase (ERK1/2) and the serine/threonine kinase Akt. In the second part of the study, we compared the neuroprotective effects of fluoxetine, imipramine, and milnacipran in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Pretreament with fluoxetine, imipramine or milnacipran for 3 weeks reduced MPTP-induced dopaminergic neurodegeneration and microglial activation in the nigrostriatal pathway. Neurochemical analysis by HPLC exhibited that antidepressants attenuated the depletion of striatal dopamine. In consistent, beam test showed that behavioral impairment was ameliorated by antidepressants. Neuroprotective effects were more prominent in the fluoxetine or imipramine treatment group than in milnacipran treatment group. Finally, we found that neuroprotection of the antidepressants against 1-methyl-4-phenylpyridinium neurotoxicity in SH-SY5Y cells was attenuated by ERK or Akt inhibitor. These results indicate that neuroprotection by antidepressants might be associated with the induction of neurotrophic factors, and antidepressant could be a potential therapeutic intervention for treatment of Parkinson's disease.</P>

Lodopyridones B and C from a marine sediment-derived bacterium <i>Saccharomonospora</i> sp.

Le, Tu Cam,Yim, Chae-Yoon,Park, Songhee,Katila, Nikita,Yang, Inho,Song, Myoung Chong,Yoon, Yeo Joon,Choi, Dong-Young,Choi, Hyukjae,Nam, Sang-Jip,Fenical, William Elsevier 2017 Bioorganic & medicinal chemistry letters Vol.27 No.14

<P><B>Abstract</B></P> <P>HPLC-UV guided isolation of the culture broth of a marine bacterium <I>Saccharomonospora</I> sp. CNQ-490 has led to the isolation of two new natural products, lodopyridones B and C (<B>1</B> and <B>2</B>) along with the previously reported lodopyridone A (<B>3</B>). Their chemical structures were established from the interpretation of 2D NMR spectroscopic data and the comparison of NMR data with the lodopyridone A (<B>3</B>). Lodopyridones B and C (<B>1</B> and <B>2</B>) possess the thiazole, and chloroquinoline groups which are characteristic features of these molecules. Lodopyridones A–C show weak inhibitory activities on the β-site amyloid precursor protein cleaving enzyme 1 (BACE1).</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>