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T cell inhibitory pathway

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https://www.readbyqxmd.com/read/28810531/mir-146a-overexpression-effectively-improves-experimental-allergic-conjunctivitis-through-regulating-cd4-cd25-t-cells
#1
Yang Yang, Xiaolong Yin, Jinglin Yi, Xiaowei Peng
OBJECTIVE: To study the mechanism of miR-146a in the regulation of allergic conjunctivitis (AC) through CD4(+)CD25(-)T cells. METHODS: BALB/c mice were sensitized with ragweed pollen (RW) and alum, and then challenged with RW. Eosinophil infiltration was determined using Giemsa assay. ELISA assay was performed to examine the level of antigen-specific IgE in the serum and cytokine levels in splenocytes. The expression of miR-146a was measured by qRT-PCR. Flow cytometric analysis was used to analyze the percentage of CD4(+)CD25(-)T cells and Tregs...
August 11, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28802252/exploiting-radiation-induced-signaling-to-increase-the-susceptibility-of-resistant-cancer-cells-to-targeted-drugs-akt-and-mtor-inhibitors-as-an-example
#2
Iris Eke, Adeola Y Makinde, Molykutty J Aryankalayil, Veit Sandfort, Sanjeewani T Palayoor, Barbara H Rath, Lance Liotta, Mariaelena Pierobon, Emanuel F Petricoin, Matthew F Brown, Jayne M Stommel, Mansoor M Ahmed, C Norman Coleman
Implementing targeted drug therapy in radio-oncologic treatment regimens has greatly improved the outcome of cancer patients. However, the efficacy of molecular targeted drugs such as inhibitory antibodies or small molecule inhibitors essentially depends on target expression and activity, which both can change during the course of treatment. Radiotherapy has previously been shown to activate pro-survival pathways which can help tumor cells to adapt and thereby survive treatment. Therefore, we aimed to identify changes in signaling induced by radiation and evaluate the potential of targeting these changes with small molecules to increase the therapeutic efficacy on cancer cell survival...
August 11, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28802125/novel-4-3-4-oxo-5-2-oxoindolin-3-ylidene-thiazolidin-2-ylidene-amino-benzenesulfonamides-synthesis-carbonic-anhydrase-inhibitory-activity-anticancer-activity-and-molecular-modelling-studies
#3
Wagdy M Eldehna, Mahmoud F Abo-Ashour, Alessio Nocentini, Paola Gratteri, Ibrahim H Eissa, Mohamed Fares, Omnia E Ismael, Hazem A Ghabbour, Mahmoud M Elaasser, Hatem A Abdel-Aziz, Claudiu T Supuran
Herein we report the synthesis of two series of novel 4/3-((4-oxo-5-(2-oxoindolin-3-ylidene)thiazolidin-2-ylidene)amino)benzenesulfonamides (4a-m and 7a-g). All the newly prepared sulfonamides were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. In particular, hCA isoforms II and IX (tumor-associated) were more susceptible to inhibition by the synthesized derivatives, with KIs in the range of 2...
August 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28792938/m-6-a-mrna-methylation-controls-t-cell-homeostasis-by-targeting-the-il-7-stat5-socs-pathways
#4
Hua-Bing Li, Jiyu Tong, Shu Zhu, Pedro J Batista, Erin E Duffy, Jun Zhao, Will Bailis, Guangchao Cao, Lina Kroehling, Yuanyuan Chen, Geng Wang, James P Broughton, Y Grace Chen, Yuval Kluger, Matthew D Simon, Howard Y Chang, Zhinan Yin, Richard A Flavell
N(6)-methyladenosine (m(6)A) is the most common and abundant messenger RNA modification, modulated by 'writers', 'erasers' and 'readers' of this mark. In vitro data have shown that m(6)A influences all fundamental aspects of mRNA metabolism, mainly mRNA stability, to determine stem cell fates. However, its in vivo physiological function in mammals and adult mammalian cells is still unknown. Here we show that the deletion of m(6)A 'writer' protein METTL3 in mouse T cells disrupts T cell homeostasis and differentiation...
August 9, 2017: Nature
https://www.readbyqxmd.com/read/28792090/distinct-activation-mechanisms-trigger-the-trypanocidal-activity-of-dna-damaging-prodrugs
#5
Emma Louise Meredith, Ambika Kumar, Aya Konno, Joanna Szular, Sam Alsford, Karin Seifert, David Horn, Shane R Wilkinson
Quinone-based compounds have been exploited to treat infectious diseases and cancer, with such chemicals often functioning as inhibitors of key metabolic pathways or as prodrugs. Here, we screened an aziridinyl-1,4-benzoquinone (ABQ) library against the causative agents of trypanosomiasis, and cutaneous leishmaniasis, identifying several potent structures that exhibited EC50 values of <100 nM. However, these compounds also displayed significant toxicity towards mammalian cells indicating that they are not suitable therapies for systemic infections...
August 9, 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28791126/investigation-of-sphingosine-kinase-1-in-interferon-responses-during-dengue-virus-infection
#6
Amanda L Aloia, Julie K Calvert, Jennifer N Clarke, Lorena T Davies, Karla J Helbig, Stuart M Pitson, Jillian M Carr
Dengue virus (DENV) regulates sphingosine kinase (SK)-1 activity and chemical inhibition of SK1 reduces DENV infection. In primary murine embryonic fibroblasts (pMEFs) lacking SK1 however, DENV infection is enhanced and this is associated with induction of normal levels of interferon beta (IFN-β) but reduced levels of IFN-stimulated genes (ISGs). We have further investigated this link between SK1 and type I IFN responses. DENV infection downregulates cell-surface IFN-alpha receptor (IFNAR)1 in both wild-type (WT) and SK1(-)(/-) pMEF, but, consistent with poor ISG responses, shows reduced induction of phosphorylated (p)-STAT1 and key IFN regulatory factors (IRF)1 and -7 in SK1(-/-) pMEF...
July 2017: Clinical & Translational Immunology
https://www.readbyqxmd.com/read/28783703/lag3-limits-regulatory-t-cell-proliferation-and-function-in-autoimmune-diabetes
#7
Qianxia Zhang, Maria Chikina, Andrea L Szymczak-Workman, William Horne, Jay K Kolls, Kate M Vignali, Daniel Normolle, Maria Bettini, Creg J Workman, Dario A A Vignali
Inhibitory receptors (IRs) are pivotal in controlling T cell homeostasis because of their intrinsic regulation of conventional effector T (Tconv) cell proliferation, viability, and function. However, the role of IRs on regulatory T cells (Tregs) remains obscure because they could be required for suppressive activity and/or limit Treg function. We evaluated the role of lymphocyte activation gene 3 (LAG3; CD223) on Tregs by generating mice in which LAG3 is absent on the cell surface of Tregs in a murine model of type 1 diabetes...
March 31, 2017: Science Immunology
https://www.readbyqxmd.com/read/28780985/9-19-cycloartenol-glycoside-g3-from-cimicifuga-simplex-regulates-immune-responses-by-modulating-th17-treg-ratio
#8
Yang Su, Lun Wu, Guangrui Mu, Qiuhong Wang, Bingyou Yang, Genhong Cheng, Haixue Kuang
Cimicifuga simplex is a medicinal herb which has a wide range of biological activities. We isolated seven 9,19-cycloartenol glycosides from the roots of C. simplex, and among the glycosides, G3 exhibited the strongest inhibitory effect on immune responses, including suppressing the differentiation of CD(4+) T cells and directly suppressing the cytokine-induced JAK/STAT signaling pathways. In the IL-23-induced mouse ear model of skin disease, G3 repressed disease development by inhibiting the expression of pro-inflammatory mediators in murine ear skin...
July 27, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28775208/a-multikinase-and-dna-pk-inhibitor-combination-immunomodulates-melanomas-suppresses-tumor-progression-and-enhances-immunotherapies
#9
Alexander K Tsai, Asra Y Khan, Christina E Worgo, Lucy L Wang, Yuanyuan Liang, Eduardo Davila
Combination therapies have the potential to improve outcomes in melanoma patients but have not yet been clinically efficacious. Here, we used high-throughput flow cytometry-based screening to identify and characterize candidate therapies that might synergize with and augment T-cell immunotherapy efficacy. Two lead therapies, regorafenib and NU7441, were selected based on their ability to alter a variety of immunomodulatory proteins, including CD55, CD73, CD155, programmed death-ligand 1 (PD-L1), nerve growth factor receptor (NGFR), and HLA class I in a heterogeneous panel of melanomas...
August 3, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28770269/the-pd-1-pd-l1-inhibitory-pathway-is-altered-in-primary-glomerulonephritides
#10
Ewelina Grywalska, Iwona Smarz-Widelska, Ewelina Krasowska-Zajac, Izabela Korona-Glowniak, Karolina Zaluska-Patel, Michal Mielnik, Martyna Podgajna, Anna Malm, Jacek Rolinski, Wojciech Zaluska
The pathogenesis of primary proliferative and non-proliferative glomerulonephritides (PGN and NPGN) is still not fully understood, however, current evidence suggests that most cases of PGN and NPGN are the results of immunologic response to different etiologic agents that activates various biological processes leading to glomerular inflammation and injury. Programmed cell death protein 1 (PD-1) is the major inhibitory receptor regulating T cell exhaustion. The aim of this study was to evaluate the frequencies of PD-1-positive and PD-ligand 1 (PD-L1)-positive T and B lymphocytes in patients with NPGN and PGN in relation to clinical parameters for the first time...
August 2, 2017: Archivum Immunologiae et Therapiae Experimentalis
https://www.readbyqxmd.com/read/28768861/positive-and-negative-regulation-of-type-i-interferons-by-the-human-t-cell-leukemia-virus-antisense-protein-hbz
#11
Manraj Singh Narulla, Ahlam Alsairi, Lucie Charmier, Stephen Noonan, David Conroy, William W Hall, Noreen Sheehy
The pathogenesis of human T-cell leukemia virus type 1 (HTLV-1) is strongly linked to the viral regulatory proteins Tax1 and HBZ, whose opposing functions contribute to the clinical outcome of infection. Type I interferons α and β (IFNα and IFNβ) are key cytokines involved in innate immunity and IFNα, in combination with other antivirals, is extensively used in the treatment of HTLV-1 infection. The relationship between HTLV-1 and IFN signaling is unclear and to date the effect of HBZ on this pathway has not been examined...
August 2, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28768188/blockage-of-core-fucosylation-reduces-cell-surface-expression-of-pd-1-and-promotes-anti-tumor-immune-responses-of-t-cells
#12
Masahiro Okada, Shunsuke Chikuma, Taisuke Kondo, Sana Hibino, Hiroaki Machiyama, Tadashi Yokosuka, Miyako Nakano, Akihiko Yoshimura
Programmed cell death 1 (PD-1) is highly expressed on exhausted T cells and inhibits T cell activation. Antibodies that block the interaction between PD-1 and its ligand prevent this inhibitory signal and reverse T cell dysfunction, providing beneficial anti-tumor responses in a substantial number of patients. Mechanisms for the induction and maintenance of high PD-1 expression on exhausted T cells have not been fully understood. Utilizing a genome-wide loss-of-function screening method based on the CRISPR-Cas9 system, we identified genes involved in the core fucosylation pathway as positive regulators of cell-surface PD-1 expression...
August 1, 2017: Cell Reports
https://www.readbyqxmd.com/read/28761757/mechanisms-of-action-and-rationale-for-the-use-of-checkpoint-inhibitors-in-cancer
#13
REVIEW
Clemence Granier, Eleonore De Guillebon, Charlotte Blanc, Helene Roussel, Cecile Badoual, Elia Colin, Antonin Saldmann, Alain Gey, Stephane Oudard, Eric Tartour
The large family of costimulatory molecules plays a crucial role in regulation of the immune response. These molecules modulate TCR signalling via phosphorylation cascades. Some of the coinhibitory members of this family, such as PD-1 and CTLA-4, already constitute approved targets in cancer therapy and, since 2011, have opened a new area of antitumour immunotherapy. Many antibodies targeting other inhibitory receptors (Tim-3, VISTA, Lag-3 and so on) or activating costimulatory molecules (OX40, GITR and so on) are under evaluation...
2017: ESMO Open
https://www.readbyqxmd.com/read/28745235/effects-of-ascorbic-acid-on-tax-nf-%C3%AE%C2%BAb-and-mmp-9-in-human-t-cell-lymphotropic-virus-type-1-positive-malignant-t-lymphocytes
#14
Steve Harakeh, Jihane Khalife, Elias Baydoun, Rania Azar, Ahmed Al-Hejin, Elie Barbour, Esam Azhar, Aleksandra Niedzwiecki, Soad Al Jaouni, Mona Diab-Assaf, Mohammad Amjad Kamal, Mathias Rath
BACKGROUND: HTLV-1 is a retrovirus that infects CD4-positive cells and leads to Adult T-cell leukemia by constitutive activation of nuclear factor kappa B. Ascorbic acid (AA) is an essential nutrient that possess anti-proliferative and pro-apoptotic activity against a number of malignant cell lines. This study delineates the effect of AA on Tax protein expression as well as NF-κB and MMP9 activity in two HTLV-1-positive leukemia cells (HuT-102 and C91-PL). METHODS: The cytotoxic and antiproliferative effect of AA were studied by LDH release and MTT tests respectively...
July 25, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28744711/calcitriol-ameliorates-angiotensinii-induced-renal-injury-partly-via-upregulating-a20
#15
Hongfei Zhao, Yunfeng Xia, Hua Gan
Inflammation and reactive oxygen species (ROS) play crucial roles in the progression of chronic kidney diseases. Vitamin D has been shown anti-inflammatory effects, but the underlying mechanism is not fully understood. Here, we investigated whether calcitriol exerts protective effects via upregulating A20 in angiotensinII (AngII)-induced renal injury. Male C57BL/6 mice were infused with vehicle or AngII for 10 days. Calcitriol reduced infiltration of T lymphocytes and macrophages. This reduction of inflammatory cells was accompanied by elevated A20 and decreased pro-inflammatory cytokines (PICs) and reactive oxygen species (ROS)...
July 25, 2017: Inflammation
https://www.readbyqxmd.com/read/28742189/novel-endogenous-negative-modulators-of-platelet-function-as-potential-anti-thrombotic-targets
#16
Y-J Li, H-X Zhu, D Zhang, H-C Li, P Ma, L-Y Huang
Platelets are megakaryocyte-derived nuclear-free fragments that participate in cardiovascular diseases including acute myocardial infarction, ischemic stroke, hypertension, and atherosclerosis. At the endothelium damage site, platelets interact with sub-endothelial matrix proteins such as glycoprotein VI/Fc receptor γ-chain (GPVI/FcRγ), G protein-coupled receptor/phospholipase Cγ(β) (GPCR/PLCγ(β)), Rho/RhoK and integrin. The activation of these signaling pathways triggers intracellular calcium increase and causes platelet adhesion, aggregation, granule release and finally thrombus formation...
July 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28738836/metabolism-associated-danger-signal-induced-immune-response-and-reverse-immune-checkpoint-activated-cd40-monocyte-differentiation
#17
REVIEW
Jin Dai, Pu Fang, Jason Saredy, Hang Xi, Cueto Ramon, William Yang, Eric T Choi, Yong Ji, Wei Mao, Xiaofeng Yang, Hong Wang
Adaptive immunity is critical for disease progression and modulates T cell (TC) and antigen-presenting cell (APC) functions. Three signals were initially proposed for adaptive immune activation: signal 1 antigen recognition, signal 2 co-stimulation or co-inhibition, and signal 3 cytokine stimulation. In this article, we propose to term signal 2 as an immune checkpoint, which describes interactions of paired molecules leading to stimulation (stimulatory immune checkpoint) or inhibition (inhibitory immune checkpoint) of an immune response...
July 24, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28738491/-establishment-of-a-model-of-hydrogen-peroxide-induced-injury-in-pulmonary-artery-endothelium-cells-and-relevant-mechanisms-of-oxidative-stress
#18
J Ye, Y Y He, Y Yan, J H Zhao, T Y Lian, X J Wang, Y Yan, S J Zhang, S H Yang, Z C Jing
Objective: To establish a hydrogen peroxide (H(2)O(2)) induced injury model of pulmonary artery endothelial cells (PAECs) and explore the molecular mechanisms of oxidative stress on the structure and function of PAECs in this model. Methods: Human PAECs were treated with H(2)O(2) at different concentrations (25, 50, 100, 200, 400, 800, 1 600, 3 200, 6 400 μmol/L) for 4 and 24 h, respectively. The PAECs survival curve was obtained according to the cell viability measured by CCK-8 assay. The cell apoptosis of PAECs was detected by flow cytometry...
July 24, 2017: Zhonghua Xin Xue Guan Bing za Zhi
https://www.readbyqxmd.com/read/28736117/modulation-of-dendritic-cell-and-t-cell-cross-talk-during-aging-the-potential-role-of-checkpoint-inhibitory-molecules
#19
REVIEW
Joanne K Gardner, Cyril D S Mamotte, Connie Jackaman, Delia J Nelson
Dendritic cells (DCs) undergo continuous changes throughout life, and there is evidence that elderly DCs have a reduced capacity to stimulate T cells, which may contribute to impaired anti-tumour immune responses in elderly people with cancer. Changes in checkpoint inhibitory molecules/pathways during aging may be one mechanism that impairs the ability of elderly DCs to activate T cells. However, little is currently known regarding the combined effects of aging and cancer on DC and T cell inhibitory molecules/pathways...
July 20, 2017: Ageing Research Reviews
https://www.readbyqxmd.com/read/28732877/enhanced-antitumor-activity-of-gemcitabine-by-polysaccharide-induced-nk-cell-activation-and-immune-cytotoxicity-reduction-in-vitro-vivo
#20
Xin Xie, Yiran Zhou, Xue Wang, Jian Guo, Jingwen Li, Hongye Fan, Jie Dou, Baiyong Shen, Changlin Zhou
The polysaccharide SEP has been reported to activate NK and T cells via TLR2/4. Here, the combination of gemcitabine (GEM) and SEP against HepG-2 was investigated. SEP apparently enhanced antitumor activity of gemcitabine against liver cancer through stimulating NKG2D and DAP10/Akt pathway to activate NK cells. The NKG2D upregulation could improve the sensitivity of NK-92 cells targeting to its ligand MICA expressed on HepG-2 cells. Meanwhile, GEM up-regulated MICA expression and attenuated soluble MICA secretion through inhibiting ADAM10 expression, which in turn enhanced the cytotoxicity of NK-92 cells against cancer cells...
October 1, 2017: Carbohydrate Polymers
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