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Liping Chen, Chunhui Huang, Jieyi Shentu, Minjun Wang, Sicheng Yan, Fei Zhou, Zaijun Zhang, Chuang Wang, Yifan Han, Qinwen Wang, Wei Cui
Indirubins are natural occurring alkaloids extracted from indigo dye-containing plants. Indirubins could inhibit various kinases, and might be used to treat chronic myelocytic leukemia, cancer and neurodegenerative disorders. 7-bromoindirubin-3-oxime (7Bio), an indirubin derivative derived from indirubin-3-oxime, possesses inhibitory effects against cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3β (GSK3β), two pharmacological targets of Alzheimer's disease (AD). In this study, we have discovered that 2...
2017: Frontiers in Molecular Neuroscience
Yasuhiro Kosuge, Hiroaki Saito, Tatsuki Haraguchi, Yoshimi Ichimaru, Sachiyo Ohashi, Hiroko Miyagishi, Shunsuke Kobayashi, Kumiko Ishige, Shinichi Miyairi, Yoshihisa Ito
Indirubin and its derivatives have been reported to exhibit anti-cancer and anti-inflammatory activities. Recently, some of its derived analogs have been shown to have neuroprotective potential. Endoplasmic reticulum (ER) stress has been demonstrated to contribute to the pathogenesis of various neurodegenerative diseases, whereas the effects of indirubin derivatives on ER stress-induced cell death have not been addressed. In the present study, a series of 44 derivatives of indirubin was prepared to search for a novel class of neuroprotective agents against ER stress-induced neuronal death...
October 28, 2017: Bioorganic & Medicinal Chemistry Letters
Kunping Liu, Jinbang Li, Xuefang Wu, Meixiang Chen, Feng Luo, Jun Li
Multi-targets inhibitor 6-bromo-indirubin-3'-oxime (BIO) has diverse biological effects on cancer cells. The key component of the β-catenin destruction complex glycogen synthase kinase 3β (GSK-3β), one of the major target for BIO, polyubiquitination and degradation of the main oncoprotein β-catenin in colorectal cancer (CRC). In the present study, we evaluated the effect of BIO on drug resistance and biological properties of CRC cells. Whole-genome transcriptional profiling revealed that differentially expressed genes were mainly centered on well-characterized signaling pathways including stem cell, cell adhesion and cell growth in BIO-treated CRC cells...
October 16, 2017: International Journal of Oncology
Aimilia D Sklirou, Nicolas Gaboriaud-Kolar, Issidora Papassideri, Alexios-Leandros Skaltsounis, Ioannis P Trougakos
As genetic interventions or extended caloric restriction cannot be applied in humans, many studies have been devoted to the identification of natural products that can prolong healthspan. 6-bromoindirubin-3'-oxime (6BIO), a hemi-synthetic derivative of indirubins found in edible mollusks and plants, is a potent inhibitor of Glycogen synthase kinase 3β (Gsk-3β). This pleiotropic kinase has been implicated in various age-related diseases including tumorigenesis, neurodegeneration and diabetes. Accordingly, 6BIO has shown anti-tumor and anti-neurodegenerative activities; nevertheless, the potential role of 6BIO in normal human cells senescence remains largely unknown...
September 15, 2017: Scientific Reports
Sandra Medina-Moreno, Thomas C Dowling, Juan C Zapata, Nhut M Le, Edward Sausville, Joseph Bryant, Robert R Redfield, Alonso Heredia
Successful propagation of HIV in the human host requires entry into a permissive cell, reverse transcription of viral RNA, integration into the human genome, transcription of the integrated provirus, and assembly/release of new virus particles. Currently, there are antiretrovirals against each of these viral steps, except for provirus transcription. An inhibitor of HIV transcription could both increase potency of treatment and suppress drug-resistant strains. Cellular cyclin-dependent kinase 9 (CDK9) serves as a cofactor for the HIV Tat protein and is required for effective transcription of the provirus...
2017: PloS One
Y K Lin, L C See, Y H Huang, C C Chi, R C Y Hui
BACKGROUND: Indigo naturalis and its refined formulation, Lindioil, are effective in treating psoriatic symptoms topically. Indirubin is the active ingredient in indigo naturalis. OBJECTIVES: To determine the efficacy and safety of different concentrations of indirubin in Lindioil ointment for treating psoriasis. METHODS: In this randomized, double-blind trial, adult patients presenting with chronic plaque psoriasis for >1 year and with <20% of the body surface area (BSA) affected were randomized to apply Lindioil ointment containing 200 μg/g, 100 μg/g, 50 μg/g, or 10 μg/g of indirubin twice daily for 8 weeks followed by an additional 12-week safety/extension period...
August 17, 2017: British Journal of Dermatology
Yoshimi Ichimaru, Takeshi Fujii, Hiroaki Saito, Makoto Sano, Taketo Uchiyama, Shinichi Miyairi
Indirubin 3'-oxime (Indox (1b)) suppresses cancer cell growth (IC50: 15μM towards HepG2 cells) and inhibits cell cycle-related kinases such as cyclin-dependent kinases and glycogen synthase kinase-3β. We have previously reported that the conjugation of 1b with oxirane, a protein-reactive component, enhanced the cytotoxic activity of Indox as determined from the IC50 value (1.7μM) of indirubin 3'-(O-oxiran-2-ylmethyl)oxime (Epox/Ind (1c)). Here we prepared Epox/Ind derivatives with one or two halogen atoms or a methoxy group on the aromatic ring(s) of an Indox moiety and studied the structure-activity relationships of the substituent(s)...
September 1, 2017: Bioorganic & Medicinal Chemistry
Manoela Viar Fogaça, Priscila de Matos Cândido-Bacani, Lucas Milanez Benicio, Lara Martinelli Zapata, Priscilla de Freitas Cardoso, Marcelo Tempesta de Oliveira, Tamara Regina Calvo, Eliana Aparecida Varanda, Wagner Vilegas, Ilce Mara de Syllos Cólus
CONTEXT: Indigofera suffruticosa Miller (Fabaceae) and I. truxillensis Kunth produce compounds, such as isatin (ISA) and indirubin (IRN), which possess antitumour properties. Their effects in mammalian cells are still not very well understood. OBJECTIVE: We evaluated the activities of ISA and/or IRN on cell viability and apoptosis in vitro, their genotoxic potentials in vitro and in vivo, and the IRN- and ISA-induced expression of ERCC1 or BAX genes. MATERIALS AND METHODS: HeLa and/or CHO-K1 cell lines were tested (3 or 24 h) in the MTT, Trypan blue exclusion, acridine orange/ethidium bromide, cytokinesis-blocked micronucleus (CBMN) and comet (36, 24 and 72 h) tests after treatment with IRN (0...
December 2017: Pharmaceutical Biology
Alexander Minges, Georg Groth
Pyruvate phosphate dikinase (PPDK) is an essential enzyme of C4 photosynthesis in plants, catalyzing the ATP-driven conversion of pyruvate to phosphoenolpyruvate (PEP). It is further used by some bacteria and unicellular protists in the reverse, ATP-forming direction. Many weed species use C4 photosynthesis in contrast to world's major crops, which are C3 plants. Hence inhibitors of PPDK may be used as C4-specific herbicides. By screening a library of 80 commercially available kinase inhibitors, we identified compounds derived from bisindolylmaleimide (bisindolylmaleimide IV, IC50 = 0...
2017: PloS One
J X Chu, Y L Chu
No abstract text is available yet for this article.
June 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Susann Kugel, Martin Baunach, Philipp Baer, Mie Ishida-Ito, Srividhya Sundaram, Zhongli Xu, Michael Groll, Christian Hertweck
Terpenoid natural products comprise a wide range of molecular architectures that typically result from C-C bond formations catalysed by classical type I/II terpene cyclases. However, the molecular diversity of biologically active terpenoids is substantially increased by fully unrelated, non-canonical terpenoid cyclases. Their evolutionary origin has remained enigmatic. Here we report the in vitro reconstitution of an unusual flavin-dependent bacterial indoloterpenoid cyclase, XiaF, together with a designated flavoenzyme-reductase (XiaP) that mediates a key step in xiamycin biosynthesis...
June 15, 2017: Nature Communications
Andong Zhou, Lei Yan, Fangfang Lai, Xiaoguang Chen, Masuo Goto, Kuo-Hsiung Lee, Zhiyan Xiao
The indolin-2-one core is a privileged structure for antitumor agents, especially kinase inhibitors. Twenty-three novel indolin-2-ones were designed by molecular dissection of the anticancer drug indirubin. Seventeen of them exhibited significant inhibition against the tested cell lines, and two of them (1c and 1h) showed IC50 values at the submicromolar level against HCT-116 cells. Compounds 1c and 2c were also potent inhibitors of the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Flow cytometry was utilized to explore the antitumor mechanism of 1c and 2c with MDA-MB-231 cells, and distinct effects were observed on 2c...
August 1, 2017: Bioorganic & Medicinal Chemistry Letters
Xinlai Cheng, Karl-Heinz Merz, Sandra Vatter, Jochen Zeller, Stephan Muehlbeyer, Andrea Thommet, Jochen Christ, Stefan Wölfl, Gerhard Eisenbrand
Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5- and 3'-position have been extensively investigated, but the impact of substituents in 5'-position is not equally well-studied. Here, we report the synthesis of new indirubin 3'- and 5'-derivatives in the search of water-soluble indirubins by introducing basic centers. Antiproliferative activity of all compounds in tumor cells was evaluated along with kinase inhibition of selected compounds...
June 22, 2017: Journal of Medicinal Chemistry
Tianjie Qi, Haitao Li, Shuai Li
Indirubin, a traditional Chinese medicine formulation from the Muricidae family, has been reported to exhibit abroad anti-cancer and anti-inflammation activities and mediate nuclear factor-κB (NF-κB) signal. Thus, this study aimed to investigate the protective effects of indirubin on LPS-induced acute lung injury and the potential mechanism in mice. The results showed that LPS treatment caused oxidative stress and inflammation in mice. Indirubin alleviated LPS-caused oxidative stress and inflammation via reducing MDA abundance and IL-1β and TNF-α expressions in mice...
May 30, 2017: Oncotarget
Junzhi Lin, Martha Hlafka, Omar Vargas, Mukul Bhattarai
Purple urine bag syndrome (PUBS) is a unique phenomenon characterized by purple discoloration of the urinary catheter bag and tubing following urinary catheterization lasting for hours to days. The purple discoloration is a mixture of indirubin dissolved in plastic with indigo on its surface. PUBS is most commonly associated with urinary tract infection (UTI) caused by bacteria with indoxyl phosphatase/sulfatase activity. It occurs predominantly in chronically catheterized, constipated elderly female patients...
November 2016: CEN Case Reports
Karyn Muzinga Ndolo, Kyeong Ryang Park, Hyo Jeong Lee, Kyoung Bin Yoon, Yong-Chul Kim, Sun-Young Han
Aurora kinase A plays an essential role in mitosis including chromosome separation and cytokinesis. Aberrant expression and activity of Aurora kinase A is associated with numerous malignancies including colorectal cancer followed by poor prognosis. The aim of this study is to determine the inhibitory effects of LDD970, an indirubin derivative, on Aurora kinase A in HT29 colorectal cancer cells. In vitro kinase assay revealed that, LDD970 inhibited levels of activated Aurora kinase A (IC50=0.37 mM). The inhibitory effects of LDD970 on Aurora kinase A, autophosphorylation and phosphorylation of histone H3 (Ser10), were confirmed by immunoblot analysis...
April 2017: Immune Network
Makoto Sano, Yoshimi Ichimaru, Masahiro Kurita, Emiko Hayashi, Taku Homma, Hiroaki Saito, Shinobu Masuda, Norimichi Nemoto, Akihiro Hemmi, Takashi Suzuki, Shinichi Miyairi, Hiroyuki Hao
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis. To identify potential effective therapeutic drugs for PDAC, we established a screening system based on spheroid formation using 170#3 mouse PDAC cells with or without fibroblasts. We found that indirubin 3'-oxime (Indox) and 5-methoxyindirubin 3'-oxime (5MeOIndox) inhibited PDAC cell proliferation. Furthermore, PDAC xenograft growth was also inhibited in BALB/c nu/nu mice after administration of Indox and 5MeOIndox. Both phosphorylated CDK1 and cyclin B1 levels in 170#3 cells were significantly reduced by treatment with Indox and 5MeOIndox in vitro and in vivo...
July 1, 2017: Cancer Letters
Mingcheng Huang, Lihui Wang, Shan Zeng, Qian Qiu, Yaoyao Zou, Maohua Shi, Hanshi Xu, Liuqin Liang
OBJECTIVES: To evaluate the inhibition of indirubin in FLSs migration, invasion, activation, and proliferation in RA FLSs. METHODS: The levels of IL-6 and IL-8 in cultural supernatants were measured by ELISA. RA FLS migration and invasion in vitro were measured by the Boyden chamber method and the scratch assay. Signal transduction protein expression was measured by western blot. FLS proliferation was detected by Edu incorporation. F-actin was measured by immunofluorescence staining...
May 2017: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
Jin-Lun Lai, Yu-Hui Liu, Yong-Chong Peng, Pan Ge, Chen-Fei He, Chang Liu, Ying-Yu Chen, Ai-Zhen Guo, Chang-Min Hu
Indirubin is a Chinese medicine extracted from indigo and known to be effective for treating chronic myelogenous leukemia, neoplasia, and inflammatory disease. This study evaluated the in vivo anti-inflammatory activity of indirubin in a lipopolysaccharide- (LPS-) induced mouse mastitis model. The indirubin mechanism and targets were evaluated in vitro in mouse mammary epithelial cells. In the mouse model, indirubin significantly attenuated the severity of inflammatory lesions, edema, inflammatory hyperemia, milk stasis and local tissue necrosis, and neutrophil infiltration...
2017: Mediators of Inflammation
Eleni N Tsakiri, Nicolas Gaboriaud-Kolar, Kalliopi K Iliaki, Job Tchoumtchoua, Eleni-Dimitra Papanagnou, Sofia Chatzigeorgiou, Konstantinos D Tallas, Emmanuel Mikros, Maria Halabalaki, Alexios-Leandros Skaltsounis, Ioannis P Trougakos
AIMS: Organismal aging can be delayed by mutations that either activate stress responses or reduce the nutrient-sensing pathway signaling; thus, by using Drosophila melanogaster as an in vivo experimental screening platform, we searched for compounds that modulate these pathways. RESULTS: We noted that oral administration of the glycogen synthase kinase 3 (Gsk-3) inhibitor 6-bromoindirubin-3'-oxime (6BIO) in Drosophila flies extended healthy life span. 6BIO is not metabolized in fly tissues, modulated bioenergetic pathways, decreased lipid and glucose tissue load, activated antioxidant and proteostatic modules, and enhanced resistance to stressors...
November 10, 2017: Antioxidants & Redox Signaling
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