Study of photoproducts of Chlorin-E6 and its effect in relation to fluorescence diagnosis and treatment in murine model of pancreatic cancer

Pallavi Gurung,Jun-Mo Lim,Sung-Ryoung Koo,Yong-Waun Kim 한국실험동물학회 2021 한국실험동물학회 학술발표대회 논문집 Vol.2021 No.7

Photodynamic diagnosis (PDD) and photodynamic therapy (PDT)-based on Chlorin-e6-trisodium (Ce6-3Na) offers a promising alternative treatment for pancreatic cancer, however, phototransformation of Ce6 and formation of photoproducts present a great challenge in its diagnosis and therapy. Therefore this study aims to examine the potential characteristics of the photoproducts of Ce6, and their influences in photodynamic diagnosis and therapeutic efficacy. The present study investigated the photosensitivity properties of the Ce6-3Na which was affected by different parameters like laser power and solution concentration. It was confirmed that Ce6 depicted highest Fluorescence (FL) intensity at concentration of 8-16 μM, which exponentially decreased dependent on time of exposure. The in vivo and in vitro formation of photoproduct due to the exposition of light at 405 and 660 nm wavelengths were monitored by High Performance Liquid Chromatography (HPLC). These findings were further verified by evaluating the cytotoxicity of photoproducts in PANC-1, AsPC-1 and MIA PaCa-2, pancreatic cancer cells. In accordance, FL diagnosis and cytotoxicity was also determined in murine pancreatic cancer to determine its accumulation, distribution in blood, tumor tissues with time and intensity variation by using tissue extraction and FL imaging techniques. The result obtained suggests that Ce6-3Na photoproducts at different conditions of laser power, irradiation time and treatments exhibits different FL tendency along with decreased photo-induced cytotoxicity in vivo and in vitro pancreatic cancer model than the original Ce6-Na.

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>

Immunomodulatory role of fermented garlic extract on macrophage cell proliferation, cytokine secretion and natural killer cell cytotoxicity

Pallavi Gurung,Junmo Lim,Yong-Wan Kim 한국실험동물학회 2022 한국실험동물학회 학술발표대회 논문집 Vol.2022 No.7

Synthesis and biological evaluation of pyridine-linked indanone derivatives: Potential agents for inflammatory bowel disease

Kadayat, Tara Man,Banskota, Suhrid,Bist, Ganesh,Gurung, Pallavi,Magar, Til Bahadur Thapa,Shrestha, Aarajana,Kim, Jung-Ae,Lee, Eung-Seok Elsevier 2018 Bioorganic & medicinal chemistry letters Vol.28 No.14

<P><B>Abstract</B></P> <P>A series of pyridine-linked indanone derivatives were designed and synthesized to discover new small molecules for the treatment of inflammatory bowel disease (IBD). Compounds <B>5b</B> and <B>5d</B> exhibited strongest inhibitory activity against TNF-α-induced monocyte adhesion to colon epithelial cells (an <I>in vitro</I> model of colitis). In TNBS (2,4,6-trinitrobenzenesulfonic acid)-induced rat colitis model, oral administration of the compounds <B>5b</B> and <B>5d</B> ameliorated colitis with significant recovery in altered expressions of E-cadherin, TNF-α and IL-1β expressions, indicating <B>5b</B> and <B>5d</B> as potential agents for therapeutics development against IBD.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Synthesis of pyridine-linked indanone derivatives <B>2</B>, <B>5a–l</B>, <B>8a–c</B> and <B>11a–c</B>. </LI> <LI> Potent anti-inflammatory effect by compounds <B>2</B>, <B>5a</B>, <B>5b</B>, <B>5d</B>, <B>5f</B>, and <B>5h</B>. </LI> <LI> Hydroxyl group substitution is favorable but alkoxy groups at indanone ring is less favored. </LI> <LI> <B>5b</B> and <B>5d</B> as potential agents for inflammatory bowel disease. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Serotonin disturbs colon epithelial tolerance of commensal <i>E. coli</i> by increasing NOX2-derived superoxide

Banskota, Suhrid,Regmi, Sushil Chandra,Gautam, Jaya,Gurung, Pallavi,Lee, Yu-Jeong,Ku, Sae Kwang,Lee, Jin-Hyung,Lee, Jintae,Chang, Hyeun Wook,Park, Sang Joon,Kim, Jung-Ae Elsevier 2017 FREE RADICAL BIOLOGY AND MEDICINE Vol.106 No.-

<P><B>Abstract</B></P> <P>Adherent-invasive <I>E. coli</I> colonization and Toll-like receptor (TLR) expression are increased in the gut of inflammatory bowel disease (IBD) patients. However, the underlying mechanism of such changes has not been determined. In the current study, it was examined whether gut serotonin (5-hydroxytryptamine, 5-HT) can induce adherent-invasive <I>E. coli</I> colonization and increase TLR expression. In a co-culture system, commensal <I>E. coli</I> strain (BW25113, BW) adhered minimally to colon epithelial cells, but this was significantly enhanced by 5-HT to the level of a pathogenic strain (EDL933). Without inducing bacterial virulence, such as, biofilm formation, 5-HT enhanced BW-induced signaling in colon epithelial cells, that is, NADPH oxidase (NOX)-dependent superoxide production, the up-regulations of IL-8, TLR2, TLR4, and ICAM-1, and the down-regulations of E-cadherin and claudin-2. In a manner commensurate with these gene modulations, BW induced an increase in NF-κB and a decrease in GATA reporter signals in colon epithelial cells. However, 5-HT-enhanced BW adhesion and colon epithelial responses were blocked by knock-down of NOX2, TLR2, or TLR4. In normal mice, 5-HT induced the invasion of BW into gut submucosa, and the observed molecular changes were similar to those observed <I>in vitro</I>, except for significant increases in TNFα and IL-1β, and resulted in death. In dextran sulfate sodium-induced colitis mice (an IBD disease model), in which colonic 5-HT levels were markedly elevated, BW administration induced death in along with large amount of BW invasion into colon submucosa, and time to death was negatively related to the amount of BW injected. Taken together, our results demonstrate that 5-HT induces the invasion of commensal <I>E. coli</I> into gut submucosa by amplifying commensal bacteria-induced epithelial signaling (superoxide production and the inductions of NOX2 and TLR2/TLR4). The authors suggest that these changes may constitute the molecular basis for the pathogenesis of IBD.</P> <P><B>Highlights</B></P> <P> <UL> <LI> 5-HT induces adhesive invasion of commensal <I>E. coli</I> to colon epithelial cells. </LI> <LI> Commensal <I>E. coli</I> induces colon epithelial NOX2 activation via TLR-2 and TLR-4. </LI> <LI> 5-HT amplifies commensal <I>E. coli</I>-induced up-regulation of TLR2/TLR4, IL-8, and ICAM-1 via NOX2. </LI> <LI> 5-HT enhances <I>E. coli</I>-induced down-regulation of E-cadherin. </LI> <LI> Inoculation of commensal <I>E.coli</I> with high 5-HT levels induces fatal colon inflammation in mice. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

BJ-1108,a 6-Amino-2,4,5-Trimethylpyridin-3-ol Analog, Inhibits Serotonin-Induced Angiogenesis and Tumor Growth through PI3K/NOX Pathway

( Suhrid Banskota ),( Jaya Gautam ),( Sushil C Regmi ),( Pallavi Gurung ),( Myo Hyeon Park ),( Seung Joo Kim ),( Tae Gyu Nam ),( Byeong Seon Jeong ),( Jung Ae Kim ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-

5-Hydroxytryptamine (5-HT) induces proliferation of cancer cells and vascular cells. In addition to 5-HT production by several cancer cells including gastrointestinal and breast cancer, a significant level of 5-HT is released from activated platelets in the thrombotic environment of tumors, suggesting that inhibition of 5-HT signaling may constitute a new target for antiangiogenic anticancer drug discovery. In the current study we clearly demon-strate that 5-HT-induced angiogenesis was mediated through the 5-HT, receptor-linked Gβγ/Src/PI3K pathway, but not through the MAPKIERKlp38 pathway. In addition, 5-HT induced production of NADPH oxidase (NOX)-derived reactive oxygen species (ROS). In an effort to develop new molecularly targeted anticancer agents against 5-HT action in tumor growth, we demonstrate that BJ-11 08, a derivative of 6-amino-2,4,5-trimethylpyri-oln-3-ol, significantly inhibited 5-HT-induced angiogenesis. In addition, BJ-11 08 induced a significant reduction in the size and weight of excised tumors in breast cancer ceil-inocu-lated CAM assay, showing proportionate suppression of tumor growth along with inhibition of angiogenesis. In human umbilical vein endothelial cells (HUVECs), BJ-11 08 signifi-cantly suppressed 5-HT-induced ROS generation and phosphorylation of P13K1Akt but not of Src. Unlike NOX inhibitors, BJ-11 08, which showed better antioxidant activity than vita-min C, barely suppressed superoxide anion induced by mevalonate or geranylgeranyl pyrophosphate which directly activates NOX without help from other signaling molecules in HUVECs, implying that the anti-angiogenic action of BJ-11 08 was not mediated through direct action on NOX activation, or free radical scavenging activity. In conclusion, BJ-1108 inhibited 5-HT-induced angiogenesis through PI3K1NOX signaling but not through Src, ERK, or p38.