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pi3k AND autoimmune

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https://www.readbyqxmd.com/read/29760711/selective-modulation-of-tnf-tnfrs-signaling-insights-for-multiple-sclerosis-treatment
#1
REVIEW
Valentina Pegoretti, Wia Baron, Jon D Laman, Ulrich L M Eisel
Autoimmunity develops when self-tolerance mechanisms are failing to protect healthy tissue. A sustained reaction to self is generated, which includes the generation of effector cells and molecules that destroy tissues. A way to restore this intrinsic tolerance is through immune modulation that aims at refurbishing this immunologically naïve or unresponsive state, thereby decreasing the aberrant immune reaction taking place. One major cytokine has been shown to play a pivotal role in several autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS): tumor necrosis factor alpha (TNFα) modulates the induction and maintenance of an inflammatory process and it comes in two variants, soluble TNF (solTNF) and transmembrane bound TNF (tmTNF)...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29760047/nanoparticles-that-reshape-the-tumor-milieu-create-a-therapeutic-window-for-effective-t-cell-therapy-in-solid-malignancies
#2
Fan Zhang, Sirkka B Stephan, Chibawanye I Ene, Tyrel T Smith, Eric C Holland, Matthias T Stephan
A major obstacle to the success rate of chimeric antigen receptor (CAR-) T cell therapy against solid tumors is the microenvironment antagonistic to T cells that solid tumors create. Conventional checkpoint blockade can silence lymphocyte anti-survival pathways activated by tumors, but because they are systemic, these treatments disrupt immune homeostasis and induce autoimmune side effects. Thus, new technologies are required to remodel the tumor milieu without causing systemic toxicities. Here we demonstrate that targeted nanocarriers that deliver a combination of immune-modulatory agents can remove pro-tumor cell populations and simultaneously stimulate anti-tumor effector cells...
May 14, 2018: Cancer Research
https://www.readbyqxmd.com/read/29728568/egr2-independent-klf1-mediated-induction-of-pd-l1-in-cd4-t-cells
#3
Shuzo Teruya, Tomohisa Okamura, Toshihiko Komai, Mariko Inoue, Yukiko Iwasaki, Shuji Sumitomo, Hirofumi Shoda, Kazuhiko Yamamoto, Keishi Fujio
Programmed death ligand 1 (PD-L1)-mediated induction of immune tolerance has been vigorously investigated in autoimmunity and anti-tumor immunity. However, details of the mechanism by which PD-L1 is induced in CD4+ T cells are unknown. Here, we revealed the potential function of Klf1 and Egr2-mediated induction of PD-L1 in CD4+ T cells. We focused on the molecules specifically expressed in CD4+ CD25- LAG3+ regulatory T cells (LAG3+ Tregs) highly express of PD-L1 and transcription factor Egr2. Although ectopic expression of Egr2 induced PD-L1, a deficiency of Egr2 did not affect its expression, indicating the involvement of another PD-L1 induction mechanism...
May 4, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29724464/class-i-pi3k-inhibitor-zstk474-attenuates-experimental-autoimmune-neuritis-by-decreasing-the-frequency-of-th1-th17-cells-and-reducing-the-production-of-proinflammatory-cytokines
#4
Xiuju Chen, Ying Guo, Ranran Han, Haijie Liu, Yanan Ding, Yanchao Shi, Dexin Kong, Xiaofeng Ma
The Class I phosphatidylinositol 3-kinase inhibitor, 2-(2-difluoromethy lbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine (ZSTK474), has anti-inflammatory and immunoregulatory properties. However, whether it can be used to treat Guillain-Barré syndrome (GBS)-a neuroinflammatory disorder-is unknown. We induced experimental autoimmune neuritis (EAN) in Lewis rats, an established model of GBS. Orally administered ZSTK474 decreased neurological deficits in the GBS model, as demonstrated by diminished inflammatory cell infiltration, and ameliorated demyelination of sciatic nerves...
April 26, 2018: Cellular Immunology
https://www.readbyqxmd.com/read/29710540/effects-of-artesunate-on-chondrocyte-proliferation-apoptosis-and-autophagy-through-the-pi3k-akt-mtor-signaling-pathway-in-rat-models-with-rheumatoid-arthritis
#5
Fa-Bo Feng, Hai-Yan Qiu
BACKGROUND: Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily results in warm, swollen, and painful joints. In this study, we investigate the potentially therapeutic role of artesunate (Art) on chondrocyte proliferation, apoptosis and autophagy in rheumatoid arthritis (RA) via the PI3K/AKT/mTOR signaling pathway. METHODS: Rat model of RA was successfully established through subcutaneous injection of emulsion. Positive protein expression rates of PI3K, AKT and mTOR were determined by immunohistochemistry...
April 7, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29681901/putting-on-the-brakes-regulatory-kinases-and-phosphatases-maintaining-b-cell-anergy
#6
REVIEW
S Elizabeth Franks, John C Cambier
B cell antigen receptor (BCR) signaling is a tightly regulated process governed by both positive and negative mediators/regulators to ensure appropriate responses to exogenous and autologous antigens. Upon naïve B cell recognition of antigen CD79 [the immunoreceptor tyrosine-based activation motif (ITAM)-containing signaling subunit of the BCR] is phosphorylated and recruits Src and Syk family kinases that then phosphorylate proximal intermediaries linked to downstream activating signaling circuitry. This plasma membrane localized signalosome activates PI3K leading to generation of PIP3 critical for membrane localization and activation of plecktrin homology domain-containing effectors...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29581356/icos-signaling-controls-induction-and-maintenance-of-collagen-induced-arthritis
#7
Vincent Panneton, Sahar Bagherzadeh Yazdchi, Mariko Witalis, Jinsam Chang, Woong-Kyung Suh
ICOS is a key costimulatory receptor facilitating differentiation and function of follicular helper T cells and inflammatory T cells. Rheumatoid arthritis patients were shown to have elevated levels of ICOS+ T cells in the synovial fluid, suggesting a potential role of ICOS-mediated T cell costimulation in autoimmune joint inflammation. In this study, using ICOS knockout and knockin mouse models, we found that ICOS signaling is required for the induction and maintenance of collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis...
May 1, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29518396/effects-of-as2541019-a-novel-selective-pi3k%C3%AE-inhibitor-on-antibody-production-and-hamster-to-rat-xenotransplantation
#8
Takanori Marui, Hidehiko Fukahori, Tomoko Kawashima, Misato Ito, Masahiko Akamatsu, Yoko Kaneko, Fumie Takahashi, Sunao Imada, Tatsuaki Morokata
B cell-mediated antibodies play a critical role in protecting the body from infections; however, excessive antibody production is involved in the pathogenesis of autoimmune diseases and transplanted organ rejection. Regulation of antibody production is therefore crucial for overcoming these complications. Phosphatidylinositol-3-kinase p110δ (PI3Kδ), a member of the family of PI3K lipid kinases, is a key mediator of B cell activation and proliferation, with a small molecule PI3Kδ inhibitor having been approved for the treatment of B cell lymphoma...
May 5, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29492193/preclinical-evaluation-of-the-pi3k-akt-mtor-pathway-in-animal-models-of-multiple-sclerosis
#9
Santa Mammana, Placido Bramanti, Emanuela Mazzon, Eugenio Cavalli, Maria Sofia Basile, Paolo Fagone, Maria Cristina Petralia, James Andrew McCubrey, Ferdinando Nicoletti, Katia Mangano
The PI3K/AKT/mTOR pathway is an intracellular signalling pathway that regulates cell activation. proliferation, metabolism and apoptosis. Increasing body of data suggests that alterations in the PI3K/AKT/mTOR pathway may result in an enhanced susceptibility to autoimmunity. Multiple Sclerosis (MS) is one of the most common chronic inflammatory diseases of the central nervous system leading to demyelination and neurodegeneration. In the current study, we have firstly evaluated in silico the involvement of the mTOR network on the generation and progression of MS and on oligodendrocyte function, making use of currently available whole-genome transcriptomic data...
February 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29491183/fast-direct-neuronal-signaling-via-the-il-4-receptor-as-therapeutic-target-in-neuroinflammation
#10
Christina F Vogelaar, Shibajee Mandal, Steffen Lerch, Katharina Birkner, Jerome Birkenstock, Ulrike Bühler, Andrea Schnatz, Cedric S Raine, Stefan Bittner, Johannes Vogt, Jonathan Kipnis, Robert Nitsch, Frauke Zipp
Ongoing axonal degeneration is thought to underlie disability in chronic neuroinflammation, such as multiple sclerosis (MS), especially during its progressive phase. Upon inflammatory attack, axons undergo pathological swelling, which can be reversible. Because we had evidence for beneficial effects of T helper 2 lymphocytes in experimental neurotrauma and discovered interleukin-4 receptor (IL-4R) expressed on axons in MS lesions, we aimed at unraveling the effects of IL-4 on neuroinflammatory axon injury. We demonstrate that intrathecal IL-4 treatment during the chronic phase of several experimental autoimmune encephalomyelitis models reversed disease progression without affecting inflammation...
February 28, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29475723/umbralisib-a-novel-pi3k%C3%AE-and-casein-kinase-1%C3%AE%C2%B5-inhibitor-in-relapsed-or-refractory-chronic-lymphocytic-leukaemia-and-lymphoma-an-open-label-phase-1-dose-escalation-first-in-human-study
#11
Howard A Burris, Ian W Flinn, Manish R Patel, Timothy S Fenske, Changchun Deng, Danielle M Brander, Martin Gutierrez, James H Essell, John G Kuhn, Hari P Miskin, Peter Sportelli, Michael S Weiss, Swaroop Vakkalanka, Michael R Savona, Owen A O'Connor
BACKGROUND: Umbralisib (TGR-1202) is a novel next-generation inhibitor of phosphatidylinositol 3-kinase (PI3K) isoform p110δ (PI3Kδ), which is structurally distinct from other PI3Kδ inhibitors and shows improved isoform selectivity. Umbralisib also uniquely inhibits casein kinase-1ε, a major regulator of protein translation. The aim of this first-in-human phase 1 study was to establish the safety and preliminary activity profile of umbralisib in patients with haematological malignancies...
April 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29444704/hpmsc-transplantation-restoring-ovarian-function-in-premature-ovarian-failure-mice-is-associated-with-change-of-th17-tc17-and-th17-treg-cell-ratios-through-the-pi3k-akt-signal-pathway
#12
Na Yin, Yanlin Wang, Xueyan Lu, Ranran Liu, Lianshuang Zhang, Wei Zhao, Wendan Yuan, Qianqian Luo, Hao Wu, Xiying Luan, Hongqin Zhang
BACKGROUND: Human placenta-derived mesenchymal stem cell (hPMSC) transplantation has been demonstrated to be an effective way of recovering ovarian function in mice with autoimmune induced premature ovarian failure (POF). But the exact mechanism remains unclear. The goal of the present study is to investigate the role of immune factors (T-helper 17 (Th17), cytotoxic T (Tc17) and regulatory T (Treg) cells) in the recovery of ovarian function and whether the phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway is involved in the regulation...
February 14, 2018: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/29383139/dihydroartemisinin-attenuates-autoimmune-thyroiditis-by-inhibiting-the-cxcr3-pi3k-akt-nf-%C3%AE%C2%BAb-signaling-pathway
#13
Huijuan Liu, Qin Tian, Xiaoyu Ai, Yuan Qin, Zhanhong Cui, Meng Li, Jiahuan Yang, Denghui Zhai, Yanrong Liu, Shuang Chen, Jing Meng, Tao Sun, Honggang Zhou, Cheng Yang
Dihydroartemisinin (DHA) is the first generation of naturally occurring artemisinin derivatives with antimalarial activity. Recent research showed that this drug also features immunosuppressive and anti-inflammatory properties. Autoimmune thyroiditis (AIT) is a common organ-specific autoimmune disease with no available effective drug treatment. In this study, we investigated effects of DHA on AIT in vitro and in vivo . Results showed that DHA can visibly reduce antithyroglobulin antibody and thyroid peroxidase antibody levels and regulate T helper cells (Th) 1/Th2 imbalance of experimental AIT mice...
December 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29313959/cardiolipin-activates-antigen-presenting-cells-via-tlr2-pi3k-pkn1-akt-p38-nf-kb-signaling-to-prime-antigen-specific-na%C3%A3-ve-t-cells-in-mice
#14
Jung-Ah Cho, Tae-Joo Kim, Hye-Jung Moon, Young-Joo Kim, Hye-Kyung Yoon, Seung-Yong Seong
Mitochondrial defects and antimitochondrial cardiolipin (CL) antibodies are frequently detected in autoimmune disease patients. CL from dysregulated mitochondria activates various pattern recognition receptors, such as NLRP3. However, the mechanism by which mitochondrial CL activates APCs as a damage-associated molecular pattern to prime antigen-specific naïve T cells, which is crucial for T-cell-dependent anticardiolipin IgG antibody production in autoimmune diseases is unelucidated. Here, we show that CL increases the expression of costimulatory molecules in CD11c+ APCs both in vitro and in vivo...
January 4, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/29311560/a-central-role-for-pi3k-akt-signaling-pathway-in-linking-samhd1-deficiency-to-the-type-i-interferon-signature
#15
Changhoon Oh, Jeongmin Ryoo, Kiwon Park, Baek Kim, Michele B Daly, DongYeon Cho, Kwangseog Ahn
The autoimmune disorder Aicardi-Goutières syndrome (AGS) is characterized by a constitutive type I interferon response. SAMHD1 possesses both dNTPase and RNase activities and mutations in SAMHD1 cause AGS; however, how SAMHD1-deficiency causes the type I interferon response in patients with AGS remains unknown. Here, we show that endogenous RNA substrates accumulated in the absence of SAMHD1 act as a major immunogenic source for the type I interferon response. Reconstitution of SAMHD1-negative human cells with wild-type but not RNase-defective SAMHD1 abolishes spontaneous type I interferon induction...
January 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29298866/a-mirna181a-nfat5-axis-links-impaired-t-cell-tolerance-induction-with-autoimmune-type-1-diabetes
#16
Isabelle Serr, Martin G Scherm, Adam M Zahm, Jonathan Schug, Victoria K Flynn, Markus Hippich, Stefanie Kälin, Maike Becker, Peter Achenbach, Alexei Nikolaev, Katharina Gerlach, Nicole Liebsch, Brigitta Loretz, Claus-Michael Lehr, Benedikt Kirchner, Melanie Spornraft, Bettina Haase, James Segars, Christoph Küper, Ralf Palmisano, Ari Waisman, Richard A Willis, Wan-Uk Kim, Benno Weigmann, Klaus H Kaestner, Anette-Gabriele Ziegler, Carolin Daniel
Molecular checkpoints that trigger the onset of islet autoimmunity or progression to human type 1 diabetes (T1D) are incompletely understood. Using T cells from children at an early stage of islet autoimmunity without clinical T1D, we find that a microRNA181a (miRNA181a)-mediated increase in signal strength of stimulation and costimulation links nuclear factor of activated T cells 5 (NFAT5) with impaired tolerance induction and autoimmune activation. We show that enhancing miRNA181a activity increases NFAT5 expression while inhibiting FOXP3+ regulatory T cell (Treg ) induction in vitro...
January 3, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29246441/roquin-suppresses-the-pi3k-mtor-signaling-pathway-to-inhibit-t-helper-cell-differentiation-and-conversion-of-treg-to-tfr-cells
#17
Katharina Essig, Desheng Hu, Joao C Guimaraes, Dominik Alterauge, Stephanie Edelmann, Timsse Raj, Jan Kranich, Gesine Behrens, Alexander Heiseke, Stefan Floess, Juliane Klein, Andreas Maiser, Susan Marschall, Martin Hrabĕ de Angelis, Heinrich Leonhardt, Cornelis F Calkhoven, Elfriede Noessner, Thomas Brocker, Jochen Huehn, Anne B Krug, Mihaela Zavolan, Dirk Baumjohann, Vigo Heissmeyer
Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17∼92 binding to an overlapping cis-element in the Pten 3' UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch...
December 19, 2017: Immunity
https://www.readbyqxmd.com/read/29202478/%C3%AE-%C3%AE-tcr-recruits-the-syk-pi3k-axis-to-drive-proinflammatory-differentiation-program
#18
Ryunosuke Muro, Takeshi Nitta, Kenta Nakano, Tadashi Okamura, Hiroshi Takayanagi, Harumi Suzuki
γδT cells produce inflammatory cytokines and have been implicated in the pathogenesis of cancer, infectious diseases, and autoimmunity. The T cell receptor (TCR) signal transduction that specifically regulates the development of IL-17-producing γδT (γδT17) cells largely remains unclear. Here, we showed that the receptor proximal tyrosine kinase Syk is essential for γδTCR signal transduction and development of γδT17 in the mouse thymus. Zap70, another tyrosine kinase essential for the development of αβT cells, failed to functionally substitute for Syk in the development of γδT17...
January 2, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29179250/pi3k-inhibitors-understanding-toxicity-mechanisms-and-management
#19
REVIEW
I Brian Greenwell, Andrew Ip, Jonathon B Cohen
The phosphatidylinositol 3-kinase (PI3K) pathway has attracted immense interest as a therapeutic target for cancer treatment. Idelalisib was the first PI3K inhibitor approved by the US Food and Drug Administration and is utilized in the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. Copanlisib has subsequently been approved for relapsed follicular lymphoma in patients who have received at least two prior systemic therapies. There are multiple other PI3K agents currently in development; these target various combinations of PI3K isoforms...
November 15, 2017: Oncology (Williston Park, NY)
https://www.readbyqxmd.com/read/29127843/ifn-%C3%AE-regulates-th17-differentiation-partly-through-the-inhibition-of-osteopontin-in-experimental-autoimmune-encephalomyelitis
#20
Qing Zhao, Wenjing Cheng, Yebin Xi, Zheyi Cao, Yunzhi Xu, Ting Wu, Chengzhen Li, Xiaoyin Niu, Guangjie Chen
Multiple sclerosis (MS) and the corresponding animal model, experimental autoimmune encephalomyelitis (EAE), are chronic neuroinflammatory autoimmune diseases. Increased activation of CD4+T cells, especially the Th1 and Th17 subsets, is thought to play a causal role in this disease. IFN-β is widely used in the treatment of MS and is found to decrease IL-17 and OPN production in MS patients and EAE mice. However, a definitive molecular mechanism has not yet been fully elucidated. In this study, we investigated the immunomodulatory effect of IFN-β on the EAE model...
January 2018: Molecular Immunology
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