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https://www.readbyqxmd.com/read/28646511/control-of-autoimmune-inflammation-using-liposomes-to-deliver-positive-allosteric-modulators-of-metabotropic-glutamate-receptors
#1
Joshua M Gammon, Arjun R Adapa, Christopher M Jewell
Multiple sclerosis (MS) is an autoimmune disease where myelin is incorrectly recognized as foreign and attacked by the adaptive immune system. Dendritic cells (DCs) direct adaptive immunity by presenting antigens to T cells, therefore serving as a target for autoimmune therapies. N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), a positive allosteric modulator of metabotropic glutamate receptor 4 (mGluR4), can promote regulatory T cells by altering cytokine secretion to bias T cell differentiation...
June 24, 2017: Journal of Biomedical Materials Research. Part A
https://www.readbyqxmd.com/read/28646487/immunotoxic-effects-of-thymus-in-mice-following-exposure-to-nanoparticulate-tio2
#2
Fashui Hong, Yaoming Zhou, Yingjun Zhou, Ling Wang
Titanium dioxide nanoparticles (TiO2 NPs) have been extensively used in industry, medicine, and daily life, and have shown potential toxic effects for animals or humans. We noted that the effects of TiO2 NPs on the immune system and its mechanism of action in animals or humans have not been elucidated. Thus, mice were exposed to the TiO2 NPs (0, 1.25, 2.5, or 5 mg kg(-1) body weight) for 9 consecutive months. Exposure to TiO2 NPs was accumulated in the thymus, leading to a decrease in body weight and increases in the weight of the thymus or thymus indices...
June 24, 2017: Environmental Toxicology
https://www.readbyqxmd.com/read/28646220/angiotensin-ii-synergizes-with-baff-to-promote-atheroprotective-regulatory-b-cells
#3
Padmapriya Ponnuswamy, Jeremie Joffre, Olivier Herbin, Bruno Esposito, Ludivine Laurans, Christoph J Binder, Thomas F Tedder, Lynda Zeboudj, Xavier Loyer, Andreas Giraud, Yujiao Zhang, Alain Tedgui, Ziad Mallat, Hafid Ait-Oufella
Angiotensin II (AngII) promotes hypertension, atherogenesis, vascular aneurysm and impairs post-ischemic cardiac remodeling through concerted roles on vascular cells, monocytes and T lymphocytes. However, the role of AngII in B lymphocyte responses is largely unexplored. Here, we show that chronic B cell depletion (Baffr deficiency) significantly reduces atherosclerosis in Apoe (-/-) mice infused with AngII. While adoptive transfer of B cells in Apoe (-/-) /Baffr (-/-) mice reversed atheroprotection in the absence of AngII, infusion of AngII in B cell replenished Apoe (-/-) /Baffr (-/-) mice unexpectedly prevented the progression of atherosclerosis...
June 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28646160/loss-of-g%C3%AE-i-proteins-impairs-thymocyte-development-disrupts-t-cell-trafficking-and-leads-to-an-expanded-population-of-splenic-cd4-pd-1-cxcr5-t-cells
#4
Il-Young Hwang, Kathleen Harrison, Chung Park, John H Kehrl
Thymocyte and T cell trafficking relies on signals initiated by G-protein coupled receptors. To address the importance of the G-proteins Gαi2 and Gαi3 in thymocyte and T cell function, we developed several mouse models. Gαi2 deficiency in hematopoietic progenitors led to a small thymus, a double negative (DN)1/DN2 thymocyte transition block, and an accumulation of mature single positive (SP) thymocytes. Loss at the double positive (DP) stage of thymocyte development caused an increase in mature cells within the thymus...
June 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28646117/cyclin-dependent-kinase-9-is-a-novel-specific-molecular-target-in-adult-t-cell-leukemia-lymphoma
#5
Tomoko Narita, Takashi Ishida, Asahi Ito, Ayako Masaki, Shiori Kinoshita, Susumu Suzuki, Hisashi Takino, Takashi Yoshida, Masaki Ri, Shigeru Kusumoto, Hirokazu Komatsu, Kazunori Imada, Yuetsu Tanaka, Takaori-Kondo Akifumi, Hiroshi Inagaki, Arne Scholz, Philip Lienau, Taruho Kuroda, Ryuzo Ueda, Shinsuke Iida
Cyclin-dependent kinase 9 (CDK9), a subunit of the positive transcription elongation factor b (P-TEFb) complex, regulates gene transcription elongation by phosphorylating the carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII).  The deregulation of CDK9/P-TEFb has important implications for many cancer types.  BAY 1143572 is a novel and highly selective CDK9/P-TEFb inhibitor currently being investigated in phase I studies. We evaluated the therapeutic potential of BAY 1143572 in adult T-cell leukemia/lymphoma (ATL)...
June 23, 2017: Blood
https://www.readbyqxmd.com/read/28646041/concurrent-ox40-and-cd30-ligand-blockade-abrogates-the-cd4-driven-autoimmunity-associated-with-ctla4-and-pd1-blockade-while-preserving-excellent-anti-cd8-tumor-immunity
#6
Maher G Nawaf, Maria H Ulvmar, David R Withers, Fiona M McConnell, Fabrina M Gaspal, Gwilym J Webb, Nick D Jones, Hideo Yagita, James P Allison, Peter J L Lane
Although strategies that block FOXP3-dependent regulatory T cell function (CTLA4 blockade) and the inhibitory receptor PD1 have shown great promise in promoting antitumor immune responses in humans, their widespread implementation for cancer immunotherapy has been hampered by significant off-target autoimmune side effects that can be lethal. Our work has shown that absence of OX40 and CD30 costimulatory signals prevents CD4 T cell-driven autoimmunity in Foxp3-deficient mice, suggesting a novel way to block these side effects...
June 23, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28646040/il-23-limits-the-production-of-il-2-and-promotes-autoimmunity-in-lupus
#7
Hong Dai, Fan He, George C Tsokos, Vasileios C Kyttaris
The IL-23/IL-17 pathway is important in multiple autoimmune diseases, but its effect on lupus pathology remains unclear, with opposing trials in murine models of the disease. In this study, we show a disease activity-related upregulation of serum IL-23 and IL-23 receptor in patients with systemic lupus erythematosus (SLE) as compared with healthy controls. When added in SLE T cell in vitro cultures, IL-23 induced IL-17 and limited IL-2 production, whereas T follicular helper and double negative (DN) T cells significantly expanded...
June 23, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28646017/ror%C3%AE-modulates-semaphorin-3e-transcription-and-neurovascular-interaction-in-pathological-retinal-angiogenesis
#8
Ye Sun, Chi-Hsiu Liu, Zhongxiao Wang, Steven S Meng, Samuel B Burnim, John Paul SanGiovanni, Theodore M Kamenecka, Laura A Solt, Jing Chen
Pathological proliferation of retinal blood vessels commonly causes vision impairment in proliferative retinopathies, including retinopathy of prematurity. Dysregulated crosstalk between the vasculature and retinal neurons is increasingly recognized as a major factor contributing to the pathogenesis of vascular diseases. Class 3 semaphorins (SEMA3s), a group of neuron-secreted axonal and vascular guidance factors, suppress pathological vascular growth in retinopathy. However, the upstream transcriptional regulators that mediate the function of SEMA3s in vascular growth are poorly understood...
June 23, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28645940/t-cell-receptors-for-clinical-therapy-in-vitro-assessment-of-toxicity-risk
#9
Andre Kunert, Matthias Obenaus, Cor Hj Lamers, Thomas Blankenstein, Reno Debets
Adoptive therapy with T cell receptor (TCR)-engineered T cells has shown promising results in the treatment of patients with tumors, and the number of TCRs amenable for clinical testing is expanding rapidly. Notably, adoptive therapy with T cells is challenged by treatment-related side effects, which calls for cautious selection of target antigens and TCRs that goes beyond their mere ability to induce high T cell reactivity. Here, we propose a sequence of in vitro assays to improve selection of TCRs, and exemplify risk assessments of on-target as well as off-target toxicities using TCRs directed against Cancer Germline Antigens...
June 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28645743/role-of-trpc3-and-trpc6-channels-in-the-myocardial-response-to-stretch-linking-physiology-and-pathophysiology
#10
REVIEW
Yohei Yamaguchi, Gentaro Iribe, Motohiro Nishida, Keiji Naruse
Transient receptor potential (TRP) channels constitute a large family of versatile multi-signal transducers. In particular, TRP canonical (TRPC) channels are known as receptor-operated, non-selective cation channels. TRPC3 and TRPC6, two members in the TRPC family, are highly expressed in the heart, and participate in the pathogenesis of cardiac hypertrophy and heart failure as a pathological response to chronic mechanical stress. In the pathological response, myocardial stretch increases intracellular Ca(2+) levels and activates nuclear factor of activated T cells to induce cardiac hypertrophy...
June 20, 2017: Progress in Biophysics and Molecular Biology
https://www.readbyqxmd.com/read/28645733/low-interleukin-2-concentration-favors-generation-of-early-memory-t-cells-over-effector-phenotypes-during-chimeric-antigen-receptor-t-cell-expansion
#11
Tanja Kaartinen, Annu Luostarinen, Pilvi Maliniemi, Joni Keto, Mikko Arvas, Heini Belt, Jonna Koponen, Petri I Mäkinen, Angelica Loskog, Satu Mustjoki, Kimmo Porkka, Seppo Ylä-Herttuala, Matti Korhonen
No abstract text is available yet for this article.
June 20, 2017: Cytotherapy
https://www.readbyqxmd.com/read/28645718/optimizing-adjuvants-for-intradermal-delivery-of-menc-glycoconjugate-vaccine
#12
Agnese Donadei, Cristiana Balocchi, Maria R Romano, Luigi Panza, Roberto Adamo, Francesco Berti, Derek T O'Hagan, Simona Gallorini, Barbara C Baudner
Intradermal vaccine delivery is a promising alternative to the conventional intramuscular route. The skin layer is immunologically supported by a densely network of antigen presenting cells, while the skeletal muscle is loaded with a relatively sparse population of APCs. Nevertheless, the vaccine to be suitable for intradermal delivery needs a new formulation to facilitate either smaller injection volumes or the introduction into new delivery devises as micro-needles. This study presents a proof of concept for intradermal delivery of the MenC-CRM197 glycoconjugate vaccine using a mouse model...
June 20, 2017: Vaccine
https://www.readbyqxmd.com/read/28645613/regulation-of-testicular-steroidogenesis-by-foxa3-via-transcriptional-modulation-of-er%C3%AE-signaling-in-type-2-diabetes-mellitus-t2dm
#13
Yong Zhao, Hong-Xin Li, Ke Wang, Bin-Yuan Yan, Wei Li
Although both insulin and estrogen receptor α (ERα) are known to exert inhibitory effects on testicular steroidogenesis, it remains unknown whether these pathways regulate testosterone (T) production under certain pathological conditions [e.g., type 2 diabetes mellitus (T2DM)] in a coordinated manner. Here, we found that the expression of forkhead box protein A3 (Foxa3), an essential transcriptional regulator engaged in adipogenesis and energy metabolism, was significantly down-regulated in the Leydig cells (LCs) from T-deficient T2DM mice...
June 20, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28645565/from-the-outside-from-within-biological-and-therapeutic-relevance-of-signal-transduction-in-t-cell-acute-lymphoblastic-leukemia
#14
REVIEW
Mariana L Oliveira, Padma Akkapeddi, Isabel Alcobia, Afonso R Almeida, Bruno A Cardoso, Rita Fragoso, Teresa L Serafim, João T Barata
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer that arises from clonal expansion of transformed T-cell precursors. In this review we summarize the current knowledge on the external stimuli and cell-intrinsic lesions that drive aberrant activation of pivotal, pro-tumoral intracellular signaling pathways in T-cell precursors, driving transformation, leukemia expansion, spread or resistance to therapy. In addition to their pathophysiological relevance, receptors and kinases involved in signal transduction are often attractive candidates for targeted drug development...
June 20, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28645307/aberrant-intestinal-microbiota-due-to-il-1-receptor-antagonist-deficiency-promotes-il-17-and-tlr4-dependent-arthritis
#15
Rebecca Rogier, Thomas H A Ederveen, Jos Boekhorst, Harm Wopereis, Jose U Scher, Julia Manasson, Sanne J C M Frambach, Jan Knol, Johan Garssen, Peter M van der Kraan, Marije I Koenders, Wim B van den Berg, Sacha A F T van Hijum, Shahla Abdollahi-Roodsaz
BACKGROUND: Perturbation of commensal intestinal microbiota has been associated with several autoimmune diseases. Mice deficient in interleukin-1 receptor antagonist (Il1rn (-/-) mice) spontaneously develop autoimmune arthritis and are susceptible to other autoimmune diseases such as psoriasis, diabetes, and encephalomyelitis; however, the mechanisms of increased susceptibility to these autoimmune phenotypes are poorly understood. We investigated the role of interleukin-1 receptor antagonist (IL-1Ra) in regulation of commensal intestinal microbiota, and assessed the involvement of microbiota subsets and innate and adaptive mucosal immune responses that underlie the development of spontaneous arthritis in Il1rn (-/-) mice...
June 23, 2017: Microbiome
https://www.readbyqxmd.com/read/28644608/targeting-cpg-adjuvant-to-lymph-node-via-dextran-conjugate-enhances-anti-tumor-immunotherapy
#16
Weidong Zhang, Myunggi An, Jingchao Xi, Haipeng Liu
Nucleic acids based adjuvants recognized by Toll-like receptors (TLR) are potent immune system stimulants that can augment the anti-tumor immune responses in an antigen-specific manner. However, their clinical uses as vaccine adjuvants are limited primarily due to lack of accumulation in the lymph nodes, the anatomic sites where the immune responses are initiated. Here, we showed that chemical conjugation of type B CpG DNA, a TLR9 agonist to dextran polymer dramatically enhanced CpG's lymph node accumulation in mice...
June 23, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28644496/the-role-of-soybean-extracts-and-isoflavones-in-hormone-dependent-breast-cancer-aromatase-activity-and-biological-effects
#17
Cristina Amaral, Maria Regina T Toloi, Luis Daniel Vasconcelos, Maria José V Fonseca, Georgina Correia-da-Silva, Natércia Teixeira
Estrogen receptor-positive (ER(+)) breast cancer is the most common cause of cancer death in women worldwide. Nowadays, the relationship between soya diet and breast cancer is controversial due to the unknown role of its isoflavones, genistein (G) and daidzein (D). In this work, we investigated not only the anti-tumor properties of a soybean extract (NBSE) but also whether the biotransformation of extract (BSE) by the fungus Aspergillus awamori increased its effectiveness. The BSE showed a stronger anti-aromatase activity and anti-proliferative efficacy in ER(+) aromatase-overexpressing breast cancer cells...
June 23, 2017: Food & Function
https://www.readbyqxmd.com/read/28644433/ctla-4-mediated-posttranslational-modifications-direct-cytotoxic-t-lymphocyte-differentiation
#18
Holger Lingel, Josef Wissing, Aditya Arra, Denny Schanze, Stefan Lienenklaus, Frank Klawonn, Mandy Pierau, Martin Zenker, Lothar Jänsch, Monika C Brunner-Weinzierl
The blockade of inhibitory receptors such as CTLA-4 (CD152) is being used as immune-checkpoint therapy, offering a powerful strategy to restore effective immune responses against tumors. To determine signal components that are induced under the control of CTLA-4 we analyzed activated murine CD8(+) T cells by quantitative proteomics. Accurate mass spectrometry revealed that CTLA-4 engagement led to central changes in the phosphorylation of proteins involved in T-cell differentiation. Beside other targets, we discovered a CTLA-4-mediated induction of the translational inhibitor programmed cell death-4 (PDCD4) as a result of FoxO1 nuclear re-localization...
June 23, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28644354/development-and-function-of-immune-cells-in-an-adolescent-patient-with-a-deficiency-in-the-interleukin-10-receptor
#19
Sharon Veenbergen, Marieke A van Leeuwen, Gertjan J Driessen, Rogier Kersseboom, Lilian F de Ruiter, Rolien H C Raatgeep, Dicky J Lindenbergh-Kortleve, Ytje Simons-Oosterhuis, Katharina Biermann, Dicky J J Halley, Lissy de Ridder, Johanna C Escher, Janneke N Samsom
OBJECTIVE: Monogenic defects in the interleukin-10 (IL-10) pathway are extremely rare and cause infantile-onset inflammatory bowel disease (IBD)-like pathology. Understanding how immune responses are dysregulated in monogenic IBD-like diseases can provide valuable insight in "classical" IBD pathogenesis. Here, we studied long-term immune cell development and function in an adolescent IL-10 receptor (IL10RA)-deficient patient who presented in infancy with severe colitis and fistulizing perianal disease and is currently treated with immune suppressants...
July 2017: Journal of Pediatric Gastroenterology and Nutrition
https://www.readbyqxmd.com/read/28644030/a-plc-%C3%AE-1-feedback-pathway-regulates-lck-substrate-phosphorylation-at-the-t-cell-receptor-and-slp-76-complex
#20
Judson Belmont, Tao Gu, Ashley Marie Mudd, Arthur R Salomon
Phospholipase C gamma 1 (PLC-γ1) occupies a critically important position in the T cell signaling pathway. While its functions as a regulator of both Ca2+ signaling and PKC-family kinases are well characterized, PLC-γ1's role in the regulation of early T cell receptor signaling events is incompletely understood. Activation of the T cell receptor leads to the formation of a signalosome complex between SLP-76, LAT, PLC-γ1, Itk, and Vav1. Recent studies have revealed the existence of both positive and negative feedback pathways from SLP-76 to the apical kinase in the pathway, Lck...
June 23, 2017: Journal of Proteome Research
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