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Agonist triggering

José Miguel Arcas, Alejandro González, Katharina Gers-Barlag, Omar González-González, Federico Bech, Lusine Demirkhanyan, Eleonora Zakharian, Carlos Belmonte, Ana Gomis, Félix Viana
TRPM8 is a polymodal, non-selective cation channel activated by cold temperature and cooling agents that plays a critical role in the detection of environmental cold. We found that TRPM8 is a pharmacological target of tacrolimus (FK506), a macrolide immunosuppressant with several clinical uses, including the treatment of organ rejection following transplants, treatment of atopic dermatitis and dry eye disease. Tacrolimus is an inhibitor of the phosphatase calcineurin, an action shared with cyclosporine.Tacrolimus activates TRPM8 channels in different species, including humans, and sensitizes their response to cold temperature by inducing a leftward shift in the voltage-dependent activation curve...
December 13, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Johanna P van Geffen, Sanne L N Brouns, Joana Batista, Harriet McKinney, Carly Kempster, Magdolna Nagy, Suthesh Sivapalaratnam, Constance C F M J Baaten, Nikki Bourry, Mattia Frontini, Kerstin Jurk, Manuela Krause, Daniele Pillitteri, Frauke Swieringa, Remco Verdoold, Rachel Cavill, Marijke J E Kuijpers, Willem H Ouwehand, Kate Downes, Johan W M Heemskerk
In combination with microspotting, whole-blood microfluidics can provide high-throughput information on multiple platelet functions in thrombus formation. Based on assessment of the inter- and intra-subject variability in parameters of microspot-based thrombus formation, we aimed to determine the platelet factors contributing to this variation. Blood samples from 94 genotyped healthy subjects were analysed for conventional platelet phenotyping: i.e. haematological parameters, platelet glycoprotein expression levels and activation markers (24 parameters)...
December 13, 2018: Haematologica
Sebastian Klobuch, Tim Steinberg, Emanuele Bruni, Carina Mirbeth, Bernhard Heilmeier, Lina Ghibelli, Wolfgang Herr, Albrecht Reichle, Simone Thomas
Effective and tolerable salvage therapies for elderly patients with chemorefractory acute myeloid leukemia (AML) are limited and usually do not change the poor clinical outcome. We recently described in several chemorefractory elderly AML patients that a novel biomodulatory treatment regimen consisting of low-dose azacitidine (AZA) in combination with PPARγ agonist pioglitazone (PGZ) and all- trans retinoic acid (ATRA) induced complete remission of leukemia and also triggered myeloid differentiation with rapid increase of peripheral blood neutrophils...
2018: Frontiers in Pharmacology
Enrrico Bloise, Pasquapina Ciarmela, Cynthia Dela Cruz, Stefano Luisi, Felice Petraglia, Fernando M Reis
Activins are dimeric glycoproteins belonging to the transforming growth factor beta superfamily and resulting from the assembly of two beta subunits, which may also be combined with alpha subunits to form inhibins. Activins were discovered in 1986 following the isolation of inhibins from porcine follicular fluid, and were characterized as ovarian hormones that stimulate follicle stimulating hormone (FSH) release by the pituitary gland. In particular, activin A was shown to be the isoform of greater physiological importance in humans...
January 1, 2019: Physiological Reviews
Li Wu, Yu Tai, Shanshan Hu, Mei Zhang, Rui Wang, Weijie Zhou, Juan Tao, Yongsheng Han, Qingtong Wang, Wei Wei
Disorder of the sympathetic nervous system (SNS) is closely related to the pathogenesis of various autoimmune diseases (ADs). Catecholamine triggered beta2-adrenergic receptor (β2-AR) signaling is important in creating a bidirectional response in the progression of ADs due to factors including diverse expression patterns, single nucleotide polymorphisms (SNPs), biased signals, and desensitization of β2-AR, as well as different subtypes of Gα binding to β2-AR. In this review, we summarize the actions of β2-AR signaling in regulating the functions of immunocytes and in the pathogenesis of ADs, and the application of β2-AR agonists or antagonists in treating major types of ADs is also discussed...
2018: Frontiers in Pharmacology
Yusuke Narita, Tatsuki Uchiyama, Chisaki Mizumoto, Tomoharu Takeoka, Kenjiro Tomo, Masaaki Tsuji, Tatsuharu Ohno
A 44-year-old woman in the first remission phase of mixed-phenotype acute leukemia (T-lymphoid and myeloid lineages) suddenly exhibited thrombocytopenia (1.1×104 /µl) with generalized petechiae approximately 150 days after bone marrow transplantation (BMT) from a one-locus (HLA-B) mismatched unrelated donor. Until then, the donor bone marrow had smoothly engrafted, and the platelet count had promptly normalized. Despite extensively searching for the triggering agent such as GVHD, graft failure, relapsed leukemia, or adverse drug effects, it could not be determined...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
David R Zhou, Rawan Eid, Eric Boucher, Katie A Miller, Craig A Mandato, Michael T Greenwood
The prevailing models of stress induced Programmed Cell Death (PCD) posit that excess extracellular chemicals interact with or enter cells and disrupts cellular homeostasis. This activates signalling cascades involving the mitochondria, an increase in the steady state levels of Reactive Oxygen Species (ROS) as well as the activation of Bax and caspases. Further, the increased ROS also causes cellular damage that triggers or enhances PCD responses. The models have been modified in a number of ways, for example to include the existence of caspase and Bax independent forms of PCD...
December 5, 2018: Biochimica et biophysica acta. Molecular cell research
Vahid Reza Askari, Reza Shafiee-Nick
Myelin loss subsequent to oligodendrocyte death has been reported in a variety of myelin-associated disorders such as multiple sclerosis (MS). Lipopolysaccharide (LPS) has been shown to elicit cellular responses in the central nervous system (CNS) and trigger immune infiltrates and glial cells to release a variety of inflammatory cytokines and mediators. LPS-induced oligodendrocytes toxicity may be chosen as an efficient model to evaluate the role of oligodendrocytes in neuroprotective activities of compounds...
December 5, 2018: Biochemical Pharmacology
Nannan Lai, Qing Min, Ermeng Xiong, Jun Liu, Lumin Zhang, Shoya Yasuda, Ji-Yang Wang
CD40 ligand (CD40 L) expressed by activated T cells interacts with CD40 on B cells and triggers B cell survival, proliferation and differentiation. Deficiency in CD40 L or CD40 in humans causes hyper IgM syndrome due to a defect in T-B interaction that is essential for Ig gene class switch recombination (CSR). CD40 L belongs to the tumor necrosis factor family and normally forms a homotrimer on the cell surface, which is important for its biological activity. To generate a multimeric CD40 L that can be used to stimulate both mouse and human B cells, we fused the extracellular domain of mouse CD40 L, which is known to also bind human CD40, with streptavidin (SA) that forms a stable tetramer under physiological conditions...
December 6, 2018: Molecular Immunology
Yung-Chang Lin, Chen-Yu Hsu, Sheng-Kai Huang, Yun-Han Fan, Chien-Hao Huang, Chan-Keng Yang, Wan-Ting Su, Po-Chia Chang, Avijit Dutta, Yu-Jen Liu, Ching-Tai Huang, Tse-Ching Chen, Chun-Yen Lin
Toll-Like Receptor 9 (TLR9) stimulation selectively triggers the formation of a cell cluster termed intrahepatic myeloid aggregation for T cell expansion" (iMATE) in a mouse chronic viral hepatitis model. iMATE expands cytotoxic T cells and controls viral hepatitis infection. The liver-specific immune response prompted this investigation of whether the effect could control tumor growth in the murine hepatic tumor model. Murine hepatic BNL cells were used to establish an orthotropic liver tumor model. We found that intravenous infusion of TLR 9 agonist, CpG oligodeoxynucleotide (ODN) induced iMATE formation in non-tumor parts of liver and suppressed the murine BNL tumor growth...
2018: Oncoimmunology
C Gerónimo-Olvera, L Tristán-López, J C Martínez-Lazcano, L García-Lara, A Sánchez-Mendoza, A Morales-Martínez, M A Hernández-Melesio, L Arregui, C Ríos, F Pérez-Severiano
Under pathological conditions, nitric oxide can become a mediator of oxidative cellular damage, generating an unbalance between oxidant and antioxidant systems. The participation of neuronal nitric oxide synthase (nNOS) in the neurodegeneration mechanism has been reported; the activation of N-methyl-D-aspartate (NMDA) receptors by agonist quinolinic acid (QUIN) triggers an increase in nNOS function and promotes oxidative stress. The aim of the present work was to elucidate the participation of nNOS in QUIN-induced oxidative stress in knock-out mice (nNOS-/-)...
December 6, 2018: Neurochemical Research
Enhui Pan, Zirun Zhao, James O McNamara
Hippocampal mossy fiber axons simultaneously activate CA3 pyramidal cells and stratum lucidum interneurons (SLIN), the latter providing feedforward inhibition to control CA3 pyramidal cell excitability. Filopodial extensions of giant boutons of mossy fibers provide excitatory synaptic input to the SLIN. These filopodia undergo extraordinary structural plasticity causally linked to executing memory tasks, leading us to seek the mechanisms by which activity regulates these synapses. High frequency stimulation of the mossy fibers induces LTD of their calcium permeable-AMPA receptor synapses with SLINs; previous work localized site of induction to be postsynaptic and site of expression to be presynaptic...
December 5, 2018: Journal of Neurophysiology
Erin J Campbell, Jeremy P M Flanagan, Leigh C Walker, Mitchell K R I Hill, Nathan J Marchant, Andrew J Lawrence
Humans with alcohol use disorder typically abstain due to the negative consequences associated with excessive drinking, and exposure to contexts previously associated with alcohol use can trigger relapse. We employed a rat model that captures a characteristic of this human condition: namely voluntary abstinence from alcohol use due to contingent punishment. There is substantial variability in the propensity to relapse following extended periods of abstinence, and this is a critical feature preventing the successful treatment of alcohol use disorder...
December 3, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Jingjing Shen, Liu Tu, Di Chen, Ting Tan, Yan Wang, Shali Wang
Individuals with intracerebral hemorrhage (ICH) suffer varying degrees of neurological dysfunction as a result of neuronal apoptosis, and thus, maintenance of neuronal survival may be crucial to prevent ICH brain injury. Here, we report that the expression of transient receptor potential vanilloid 4 (TRPV4) was upregulated in mouse neurons after ICH. The selective TRPV4 agonist GSK1016790 A aggravated neuronal death whereas the TRPV4 antagonist HC-067047 promoted neuronal survival after ICH. We found that GSK1016790 A triggered Ca2+ signals that were amplified and propagated by Ca2+ -induced Ca2+ release (CICR) from the endoplasmic reticulum (ER) in the neurons...
November 30, 2018: Brain Research Bulletin
Madeline J Foertsch, Jessica B Winter, Abigail G Rhoades, Lukas T Martin, Christopher A Droege, Neil E Ernst
Alcohol withdrawal syndrome (AWS) is a complex neurologic disorder that develops after an acute reduction in or cessation of chronic alcohol consumption that alters neurotransmitter conduction. The incidence of AWS in the intensive care unit varies, but has been associated with poor outcomes. This is primarily driven by downregulation of gamma-aminobutyric acid (GABA) leading to autonomic excitability and psychomotor agitation. No clinical assessment tools have been validated to assess for AWS in the intensive care unit, particularly for patients requiring mechanical ventilation...
January 2019: Critical Care Nursing Quarterly
Anna E Oja, Berber Piet, David van der Zwan, Hans Blaauwgeers, Mark Mensink, Sander de Kivit, Jannie Borst, Martijn A Nolte, René A W van Lier, Regina Stark, Pleun Hombrink
Resident memory T cells (TRM ) inhabit peripheral tissues and are critical for protection against localized infections. Recently, it has become evident that CD103+ TRM are not only important in combating secondary infections, but also for the elimination of tumor cells. In several solid cancers, intratumoral CD103+ CD8+ tumor infiltrating lymphocytes (TILs), with TRM properties, are a positive prognostic marker. To better understand the role of TRM in tumors, we performed a detailed characterization of CD8+ and CD4+ TIL phenotype and functional properties in non-small cell lung cancer (NSCLC)...
2018: Frontiers in Immunology
Lauren K Dobbs, Alanna R Kaplan, Roland Bock, Khanhky Phamluong, J Hoon Shin, Miriam E Bocarsly, Lindsay Eberhart, Dorit Ron, Veronica A Alvarez
Vulnerability for cocaine abuse in humans is associated with low dopamine D2 receptor (D2R) availability in the striatum. The mechanisms driving this vulnerability are poorly understood. In this study, we found that downregulating D2R expression selectively in striatal indirect-pathway neurons triggers a multitude of changes in D1 receptors (D1R)-expressing direct-pathway neurons, which comprise the other main subpopulation of striatal projection neurons. These changes include a leftward shift in the dose-response to D1-like agonist that indicates a behavioral D1R hypersensitivity, a shift from PKA to ERK intracellular signaling cascades upon D1R activation, and a reduction in the density of bridging collaterals from D1R-expressing neurons to pallidal areas...
December 1, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Yunfang Zhang, Junxia Feng, Qi Wang, Shili Zhao, Shen Yang, Lu Tian, Ping Meng, Jingchun Li, Hongyan Li
BACKGROUND/AIMS: Hyperglycaemia stress-induced renal injury is closely associated with mitochondrial dysfunction through poorly understood mechanisms. The aim of our study is to explore the upstream trigger and the downstream effector driving diabetic nephropathy via modulating mitochondrial homeostasis. METHODS: A diabetic nephropathy model was generated in wild-type (WT) mice and MAP Kinase phosphatase 1 transgenic (MKP1-TG) mice using STZ injection. Cell experiments were conducted via high-glucose treatment in the human renal mesangial cell line (HRMC)...
November 30, 2018: Cellular Physiology and Biochemistry
Dominique de Ziegler, Paul Pirtea, Marie Carbonnel, Marine Poulain, Ettore Cicinelli, Carlo Bulletti, Konstantinos Kostaras, George Kontopoulos, David Keefe, Jean Marc Ayoubi
Endometriosis - a disease causing pain and infertility - is encountered in nearly 50% of infertile women. While medical treatment is effective on pain and recurrence of symptoms after surgical excision, it is of no help for treating infertility for which the only options considered are surgery and ART. Surgery enhances the chances of conceiving naturally during the 12-18 ensuing months irrespective of the stage of the disease. Surgery however is of no help when ART is considered, as it does not improve outcome and can only harm the ovarian response to stimulation...
November 3, 2018: Best Practice & Research. Clinical Endocrinology & Metabolism
M E Sales, A J Español, A R Salem, P Pulido Martínez, Y Sanchez, F Sanchez
BACKGROUND: Muscarinic acetylcholine receptors (mAChRs) have attracted interest as targets for therapeutic interventions in different illnesses like Alzheimer´s disease, viral infections and different tumors. Regarding the latter, many authors have studied each subtype of mAChRs, which seem to be involved in the progression of distinct types of malignancies. METHODS: We carefully revised research literature focused on mAChRs expression and signaling as well as in their involvement in cancer progression and treatment...
December 2, 2018: Current Clinical Pharmacology
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