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Hongchuan Zhao, Pu Sun, Wei Guo, Yi Wang, Ao Zhang, Linghua Meng, Chunyong Ding
There is great interest in developing small molecules agents capable of reversing tumor immune escape to restore the body's immune system. As an immunosuppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO-1) is considered a promising target for oncology immunotherapy. Currently, none of IDO-1 inhibitors have been launched for clinical practice yet. Thus, the discovery of new IDO-1 inhibitors is still in great demand. Herein, a series of diverse ortho -naphthaquinone containing natural product derivatives were synthesized as novel IDO-1 inhibitors...
March 18, 2019: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Vikram Mehraj, Rayoun Ramendra, Stephane Isnard, Franck P Dupuy, Rosalie Ponte, Jun Chen, Ido Kema, Mohammad-Ali Jenabian, Cecilia Costiniuk, Bertrand Lebouché, Réjean Thomas, Pierre Coté, Roger Leblanc, Jean-Guy Baril, Madeleine Durand, Carl Chartrand-Lefebvre, Cécile Tremblay, Petronela Ancuta, Nicole F Bernard, Donald C Sheppard, Jean-Pierre Routy
BACKGROUND: Microbial translocation from the gut to circulation contributes to immune activation during HIV infection and is usually assessed by measuring plasma levels of bacterial lipopolysaccharide (LPS). Gut fungal colonization increases during HIV infection and elevated systemic levels of the fungal polysaccharide (13)--D-Glucan (DG) have been reported in people living with HIV (PLWH). We assessed plasma DG in 146 early and chronic PLWH and investigated its contribution to systemic immune activation...
March 16, 2019: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Vikram Mehraj, Rayoun Ramendra, Stéphane Isnard, Franck P Dupuy, Bertrand Lebouché, Cecilia Costiniuk, Réjean Thomas, Jason Szabo, Jean-Guy Baril, Benoit Trottier, Pierre Coté, Roger LeBlanc, Madéleine Durand, Carl Chartrand-Lefebvre, Ido Kema, Yonglong Zhang, Malcolm Finkelman, Cécile Tremblay, Jean-Pierre Routy
Background: CXCL13 is preferentially secreted by Follicular Helper T cells (TFH ) to attract B cells to germinal centers. Plasma levels of CXCL13 have been reported to be elevated during chronic HIV-infection, however there is limited data on such elevation during early phases of infection and on the effect of ART. Moreover, the contribution of CXCL13 to disease progression and systemic immune activation have been partially defined. Herein, we assessed the relationship between plasma levels of CXCL13 and systemic immune activation...
2019: Frontiers in Immunology
Phyu P Aung, Edwin R Parra, Souptik Barua, Dawen Sui, Jing Ning, Barbara Mino, Debora A Ledesma, Jonathan L Curry, Priyadharsini Nagarajan, Carlos A Torres Cabala, Eleni Efstathiou, Anh Hoang, Michael K K Wong, Jennifer A Wargo, Alexander J Lazar, Arvind Rao, Victor G Prieto, Ignacio I Wistuba, Michael T Tetzlaff
PURPOSE: Merkel cell carcinoma is an aggressive cutaneous malignancy whose pathogenesis and prognosis are related to the integrity of the host immune system. Despite promising clinical responses to immune checkpoint blockade, response and resistance remain unpredictable, underscoring a critical need to delineate novel prognostic biomarkers and/or therapeutic targets for this disease. EXPERIMENTAL DESIGN: Expression of immune regulatory markers (PD-L2, B7-H3, B7-H4, IDO-1, ICOS, TIM3, LAG3, VISTA and OX-40) was assessed using singlet chromogenic immunohistochemistry in 10 primary MCCs...
February 26, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Joudy Alameddine, Emmanuelle Godefroy, Loukas Papargyris, Guillaume Sarrabayrouse, Julie Tabiasco, Chantal Bridonneau, Karina Yazdanbakhsh, Harry Sokol, Frédéric Altare, Francine Jotereau
The human colonic mucosa contains regulatory type 1-like (Tr1-like, i.e., IL-10-secreting and Foxp3-negative) T cells specific for the gut Clostridium Faecalibacterium prausnitzii (F. prausnitzii) , which are both decreased in Crohn's disease patients. These data, together with the demonstration, in mice, that colonic regulatory T cells (Treg) induced by Clostridium bacteria are key players in colon homeostasis, support a similar role for F. prausnitzii -specific Treg in the human colon. Here we assessed the mechanisms whereby F...
2019: Frontiers in Immunology
L B Jesus, A B Santos, E E V Jesus, R G D Santos, M S Grangeiro, A Bispo-da-Silva, M R Arruda, D S Argolo, A M Pinheiro, R S El-Bachá, S L Costa, M F D Costa
Central nervous system (CNS) is the main site for encystment of Neospora caninum in different animal species. In this tissue, glial cells (astrocytes and microglia) modulate responses to aggression in order to preserve homeostasis and neuronal function. Previous data showed that when primary cultures of glial cells are infected with N. caninum, they develop gliosis and the immune response is characterized by the release of TNF and IL-10, followed by the control of parasite proliferation. In order to elucidate this control, three enzymatic systems involved in parasite-versus-host interactions were observed on a model of neuron/glia co/cultures obtained from rat brains...
February 2019: Veterinary Parasitology
Mojtaba Haji Mazdarani, Milad Jafarikia, Fahimeh Nemati
INTRODUCTION: The aim of this study was to evaluate the expression of IDO-1 gene and cancerous grades of non-small cell lung cancer (NSCLC) and its subclasses among patients with lung cancer using real-time polymerase chain reaction (PCR). MATERIALS AND METHODS: A total of 35 clinical samples were collected from patients with NSCLC. To evaluate the IDO-1 gene after the extraction of RNA and complementary DNA (cDNA) synthesis using real-time PCR, the expression of the gene was investigated...
January 22, 2019: Journal of Cellular Physiology
Simon D Lytton, Marcin Osiecki, MałgorzataWoźniak, Bożena Cukrowska, Aldona Wierzbicka, Maria Goliszek, Piotr Socha, Wojciech Janczyk, Dilek Dayanakli, Dieter Abendroth, Sabine Kramp, Kai Fechner, Thomas Scheper, Michael Mahler, Chelsea Bentow, Dimietrios Bogdanos, Dietmar Fuchs, Marek Woynarowski
The impairment of regulatory T cells (Tregs) is a characteristic feature of autoimmune hepatitis (AIH), and the degradation of tryptophan (Trp) to kynurenine (Kyn), by gamma interferon-induced indoleamine-2,3-dioxygenase-1 (IDO-1), is a central metabolomics check point in the differentiation of Tregs. For this reason, we investigate whether or not Kyn and IDO activity is potentially useful biomarkers in pediatric AIH.Between January 2016 and January 2017, children of AIH type-1 (AIH-1, n = 37), AIH type-2 with liver kidney microsome-1 autoantibodies (AIH-2-LKM-1, n = 8), and autoantibody-negative Wilsons Disease (WD, n = 8) and alpha-1 anti-trypsin deficiency (AATD, n = 10), were enrolled in a cross-sectional survey of Kyn and Trp levels and Kyn/Trp ratios (IDO activity) by HPLC, and neopterin levels by ELISA...
January 21, 2019: Immunologic Research
Mayanne M T Zhu, Amanda R Dancsok, Torsten O Nielsen
PURPOSE OF REVIEW: This review focuses on the recent clinical development of indolamine-2,3-dioxygenase-1 (IDO-1) inhibitors. RECENT FINDINGS: IDO-1 alters tryptophan metabolism in a manner enhancing T-regulatory cell activity, but pre-clinical data show that its role in tumorigenesis is context-dependent on host and tumor interaction, highlighting some challenges in understanding the molecular oncology of this enzymatic drug target. Because results from phase I/II trials of IDO-1 inhibitor monotherapy have been disappointing, current clinical trials employ IDO-1 inhibitors in combination strategies with other immunotherapy agents or with chemotherapy ± radiation...
January 18, 2019: Current Oncology Reports
Songül Ünüvar, Duygu Erge, Bilge Kılıçarslan, Harika Gözde Gözükara Bağ, Ferhat Çatal, Gözde Girgin, Terken Baydar
BACKGROUND: Although Th2 immune activation is predominant in allergic diseases, neopterinlevels and indoleamine 2,3-dioxygenase (IDO)-1 activity (kynurenine:tryptophan ratio), which reflect Th1 immune activity, increase with interferon-gamma (IFN-γ) stimulation. We investigated neopterin, tryptophan, and kynurenine levels as biomarkersof the Th1 immune system activation and changes in IDO-1 activityin children with asthma, allergic rhinitis, and atopic dermatitis, as well as the relationship between these biomarkers and the total IgE level, age, and disease severity...
May 2019: Annals of Laboratory Medicine
Chang Chen, Cong Guo, Jian Gao, Kaifeng Shi, Jingtang Cheng, Jun Zhang, Sha Chen, Yan Liu, An Liu
BACKGROUND: Both Chuanxiong (Ligusticum chuanxiong Hort) and Tianma (Gastrodia elata Blume) have the effects of vasorelaxation and antihypertension. However, the effects of Tianshu Capsule (TSC, composed of Chuanxiong and Tianma in the mass ratio of 4:1) on antihypertensive activity have not been explored. This study aimed to investigate the eff ;ects of TSC on vascular tension and blood pressure in rats and to explore the underlying mechanisms. METHODS: The vasorelaxant effect of TSC was explored on thoracic aortic rings (both intact endothelium and denuded) preincubated with phenylephrine (Phe) or potassium chloride (KCL)...
December 21, 2018: Biomedicine & Pharmacotherapy
Laurence Booth, Jane L Roberts, Cindy Sander, Alshad S Lalani, John M Kirkwood, John F Hancock, Andrew Poklepovic, Paul Dent
There is no efficacious standard of care therapy for uveal melanoma. Unlike cutaneous disease, uveal melanoma does not exhibit RAS mutations but instead contains mutations with ~90% penetrance in either Gαq or Gα11 . Previously we demonstrated that neratinib caused ERBB1/2/4 and RAS internalization into autolysosomes which resulted in their proteolytic degradation. In PDX isolates of uveal melanoma, neratinib caused the internalization and degradation of Gαq and Gα11 in parallel with ERBB1 breakdown. These effects were enhanced by the HDAC inhibitor entinostat...
December 20, 2018: Cancer Biology & Therapy
Aline Talhouk, Heather Derocher, Pascal Schmidt, Samuel Leung, Katy Milne, Blake Gilks, Michael S Anglesio, Brad H Nelson, Jessica N McAlpine
PURPOSE: Tumors with high mutation load are thought to engender stronger immune responses which in turn promote prolonged patient survival. To investigate this, we assessed tumor-infiltrating lymphocytes (TIL) and immunosuppressive factors across the four molecular subtypes of endometrial cancer (EC), which have characteristic mutation rates ranging from low to ultra-high. EXPERIMENTAL DESIGN: 460 ECs were stratified by ProMisE (Proactive Molecular Risk Classifier in Endometrial cancer) into four molecular subtypes: mismatch repair-deficient (MMRd), POLE mutant (POLE), p53 abnormal (p53abn), and p53 wildtype (p53wt)...
December 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Mehdi Najar, Emerence Crompot, Gordana Raicevic, Etienne M Sokal, Mustapha Najimi, Laurence Lagneaux
Background: Being non-immunogenic and capable of achieving major metabolic liver functions, adult-derived human liver stem/progenitor cells (ADHLSCs) are of special interest in the field of liver cell therapy. The cytokine repertoire of engrafted cells may have critical impacts on the immune response balance, particularly during cell transplantation. Methods: In this work, we analyzed the cytokinome of ADHLSCs during hepatogenic differentiation (HD) following stimulation with a mixture of inflammatory cytokines (I) in vitro and compared it to that of mature hepatocytes...
October 2018: Hepatobiliary Surgery and Nutrition
Jianqin Lu, Xiangsheng Liu, Yu-Pei Liao, Xiang Wang, Ayman Ahmed, Wen Jiang, Ying Ji, Huan Meng, Andre E Nel
Immunotherapy provides the best approach to reduce the high mortality of metastatic breast cancer (BC). We demonstrate a chemo-immunotherapy approach, which utilizes a liposomal carrier to simultaneously trigger immunogenic cell death (ICD) as well as interfere in the regionally overexpressed immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO-1) at the BC tumor site. The liposome was constructed by self-assembly of a phospholipid-conjugated prodrug, indoximod (IND), which inhibits the IDO-1 pathway, followed by the remote loading of the ICD-inducing chemo drug, doxorubicin (DOX)...
November 27, 2018: ACS Nano
Rheal A Towner, Nataliya Smith, Debra Saunders, Chase A Brown, Xue Cai, Jadith Ziegler, Samantha Mallory, Mikhail G Dozmorov, Patricia Coutinho De Souza, Graham Wiley, Kyeongsoon Kim, Shinwook Kang, Doo-Sik Kong, Young-Tae Kim, Kar-Ming Fung, Jonathan D Wren, James Battiste
Treatment of glioblastoma (GBM) remains a challenge using conventional chemotherapy, such as temozolomide (TMZ), and is often ineffective as a result of drug resistance. We have assessed a novel nitrone-based agent, OKN-007, and found it to be effective in decreasing tumor volumes and increasing survival in orthotopic GBM xenografts by decreasing cell proliferation and angiogenesis and increasing apoptosis. In this study, we assessed combining OKN-007 with TMZ in vivo in a human G55 GBM orthotopic xenograft model and in vitro in TMZ-resistant and TMZ-sensitive human GBM cell lines...
November 20, 2018: Translational Oncology
Martina Mandarano, Guido Bellezza, Maria Laura Belladonna, Benoit J Van den Eynde, Rita Chiari, Jacopo Vannucci, Giada Mondanelli, Vienna Ludovini, Ivana Ferri, Fortunato Bianconi, Rachele Del Sordo, Lucio Cagini, Elisa Albini, Giulio Metro, Francesco Puma, Angelo Sidoni
Several cancers, especially non-small cell lung cancer (NSCLC), are able to escape the immunosurveillance of tumor-infiltrating lymphocytes (TILs); among the molecules involved, the indoleamine 2,3-dioxygenase 1 (IDO-1) and the programmed cell death ligand-1 (PD-L1) play a crucial role. These aspects are of great interest in the current immunotherapeutic era, therefore the current study analyses the TILs, IDO-1, and PD-L1 interactions and their correlations with clinicopathological parameters and prognosis in NSCLC...
November 17, 2018: Virchows Archiv: An International Journal of Pathology
Priyansha Choubey, Mohit Kwatra, Surya Narayan Pandey, Dinesh Kumar, Durgesh Kumar Dwivedi, Prabha Rajput, Abhishek Mishra, Mangala Lahkar, Ashok Jangra
BACKGROUND: Fisetin, a plant active polyphenol, is well known for its antioxidant and free radical scavenging activities. The present study was designed to explore the detailed molecular mechanism underlying its neuroprotective effects. METHODS: The young male mice were either administered a single dose of lipopolysaccharide (0.83 mg/kg) or subjected to restraint stress (6 h per day for 28 days) to induce behavioral deficits in different groups. Fisetin (15 mg/kg) was orally administered for the last 14 days of the study...
November 14, 2018: Psychopharmacology
Saeed Mohammadi, Ali Memarian, Sima Sedighi, Nasser Behnampour, Yaghoub Yazdani
Macrophages are versatile phagocytic cells in immune system with immunoregulatory functions. However, the removal of apoptotic cells by macrophages is disturbed in systemic lupus erythematosus (SLE). Aryl hydrocarbon receptor (AhR) is a ligand-activated cytoplasmic receptor and transcription factor with diverse effects on immune response. Indole-3-carbinol (I3C) is an AhR agonist which has been implicated as a beneficial factor in regulating inflammation and cytokine expression in murine models of SLE. However, the molecular mechanisms are not thoroughly studied...
October 5, 2018: Autoimmunity
Xiao-Jun Zhang, Zhong-Wen Yuan, Chang Qu, Xiu-Ting Yu, Tao Huang, Ping Vicky Chen, Zi-Ren Su, Yao-Xing Dou, Jia-Zhen Wu, Hui-Fang Zeng, Ying Xie, Jian-Nan Chen
Inflammatory bowel disease (IBD), majorly include Crohn's disease (CD) and ulcerative colitis (UC), is chronic and relapsing inflammatory disorders of the gastrointestinal tract, which treatment options remain limited. Here we examined the therapeutic effects of an isoquinoline alkaloid, Palmatine (Pal), on mice experimental colitis induced by dextran sulfate sodium (DSS) and explored underlying mechanisms. Colitis was induced in BALB/c mice by administering 3% DSS in drinking water for 7 days. Pal (50 and 100 mg kg-1 ) and the positive drug Sulfasalazine (SASP, 200 mg kg-1 ) were orally administered for 7 days...
September 19, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
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