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https://www.readbyqxmd.com/read/29793020/epha2-stimulates-vcam-1-expression-through-calcium-dependent-nfat1-activity
#1
Steven Daniel Funk, Alexandra C Finney, Arif Yurdagul, Christopher B Pattillo, A Wayne Orr
Endothelial cell activation by proinflammatory stimuli drives leukocyte recruitment through enhanced expression of counter-receptors such as vascular cell adhesion molecule-1 (VCAM-1). We previously demonstrated that activation of the receptor tyrosine kinase EphA2 with its ligand ephrin-A1 induces VCAM-1 expression. Here, we sought to characterize the proinflammatory signaling pathways involved. Analysis of over-represented transcription factors in ephrin-A1-induced genes identified multiple potential transcriptional regulators, including the Rel family members nuclear factor-κB (NF-κB/p65) and nuclear factor of activated T-cells (NFAT)...
May 21, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29792714/docking-screens-for-dual-inhibitors-of-disparate-drug-targets-for-parkinson-s-disease
#2
Mariama Jaiteh, Alexey Zeifman, Marcus Saarinen, Per Svenningsson, José M Brea, Maria Isabel Loza, Jens Carlsson
Modulation of multiple biological targets with a single drug can lead to synergistic therapeutic effects and has been demonstrated to be essential for efficient treatment of CNS disorders. However, rational design of compounds that interact with several targets is very challenging. Here, we demonstrate that structure-based virtual screening can guide the discovery of multi-target ligands of unrelated proteins relevant for Parkinson's disease. A library with 5.4 million molecules was docked to crystal structures of the A2A adenosine receptor (A2AAR) and monoamine oxidase B (MAO-B)...
May 24, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29792386/disparate-effects-of-shb-gene-deficiency-on-disease-characteristics-in-murine-models-of-myeloid-b-cell-and-t-cell-leukemia
#3
Maria Jamalpour, Xiujuan Li, Karin Gustafsson, Jeffrey W Tyner, Michael Welsh
The Src homology-2 domain protein B is an adaptor protein operating downstream of tyrosine kinases. The Shb gene knockout has been found to accelerate p210 Breakpoint cluster region-cAbl oncogene 1 tyrosine kinase-induced leukemia. In human myeloid leukemia were tumors with high Src homology-2 domain protein B mRNA content, tumors were, however, associated with decreased latency and myeloid leukemia exhibiting immune cell characteristics. Thus, the aim of this study was to investigate the effects of Shb knockout on the development of leukemia in three additional models, that is, colony stimulating factor 3 receptor-T618I-induced neutrophilic leukemia, p190 Breakpoint cluster region-cAbl oncogene 1 tyrosine kinase-induced B-cell leukemia, and G12D-Kras-induced T-cell leukemia/thymic lymphoma...
April 2018: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/29791852/melanopsin-retinal-ganglion-cells-regulate-cone-photoreceptor-lamination-in-the-mouse-retina
#4
Adele R Tufford, Jessica R Onyak, Katelyn B Sondereker, Jasmine A Lucas, Aaron M Earley, Pierre Mattar, Samer Hattar, Tiffany M Schmidt, Jordan M Renna, Michel Cayouette
Newborn neurons follow molecular cues to reach their final destination, but whether early life experience influences lamination remains largely unexplored. As light is among the first stimuli to reach the developing nervous system via intrinsically photosensitive retinal ganglion cells (ipRGCs), we asked whether ipRGCs could affect lamination in the developing mouse retina. We show here that ablation of ipRGCs causes cone photoreceptors to mislocalize at different apicobasal positions in the retina. This effect is partly mediated by light-evoked activity in ipRGCs, as dark rearing or silencing of ipRGCs leads a subset of cones to mislocalize...
May 22, 2018: Cell Reports
https://www.readbyqxmd.com/read/29791797/modulating-macrophage-polarization-through-ccr2-inhibition-and-multivalent-engagement
#5
Michael B Deci, Scott W Ferguson, Sydney L Scatigno, Juliane Nguyen
Excessive or prolonged recruitment of inflammatory monocytes to damaged tissue can significantly worsen patient outcomes. Monocytes migrate to sites of tissue inflammation in response to high local concentrations of CCL2, a chemokine that binds to and signals through the CCR2 receptor. While the role of CCR2 in cellular migration is well studied, it is unclear how CCR2 inhibition affects macrophage polarization and if multivalency can increase downstream signaling effects. Using affinity selection with a phage library, we identified a novel scFv (58C) that binds specifically and with high affinity to the N-terminal domain of CCR2 (KD = 59...
May 23, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29791754/atp-triggers-a-robust-intracellular-ca-2-mediated-signalling-pathway-in-human-synovial-fibroblasts
#6
Kondo C, R B Clark, T Y Kim, Belke D, Banderali U, R T Szerencsei, A H Jalloul, P P M Schnetkamp, Spitzer Kw, Giles Wr
NEW FINDINGS: What is the central question of this study? In human articular joints, the synovial fibroblast HSF cell population has essential functions including secretion of lubricants. We address some remaining questions concerning activation-secretion coupling by characterizing the main [Ca2+ ]i signalling pathways activated by ATP. What is the main finding and its importance? In HSF ATP acts through a linked G-protein (Gq ) and phospholipase C signalling mechanisms to produce IP-3 which markedly enhances release of Ca2+ from the endoplasmic reticulum...
May 23, 2018: Experimental Physiology
https://www.readbyqxmd.com/read/29791585/protective-effect-and-mechanism-of-lactobacillus-on-cerebral-ischemia-reperfusion-injury-in-rats
#7
Shi Wanchao, Ma Chen, Su Zhiguo, Xie Futang, Shi Mengmeng
The present study was designed to investigate the protective effects and mechanism of inactivated lactobacillus (ILA) on cerebral ischemia reperfusion injury (CIRI) in rats. In this experiment, 30 male Sprague Dawley rats were randomly divided into control group, IRI groups, and ILA group. A middle cerebral artery occlusion and reperfusion model was prepared. The rats were killed after 24 hours of recovery of blood flow of cerebral ischemia resulting from 60-min occlusion. The cerebral infarction volume and neurological scores were assayed by staining and behavioral observation...
2018: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
https://www.readbyqxmd.com/read/29791566/cytidine-phosphate-guanosine-oligodeoxynucleotides-in-combination-with-cd40-ligand-decrease-periodontal-inflammation-and-alveolar-bone-loss-in-a-tlr9-independent-manner
#8
Qian Zhao, Yang Hu, Shu Deng, Pei Yu, Bowen Chen, Zuomin Wang, Xiaozhe Han
Local administration of toll-like receptor 9 (TLR9), agonist cytidine-phosphate-guanosine oligodeoxynucleotide (CpG ODNs), and CD40 ligand (CD40L) can decrease ligature-induced periodontal inflammation and bone loss in wild type (WT) mouse. OBJECTIVE: This study aimed to explore whether such effect is dependent on TLR9 signaling. MATERIAL AND METHODS: Purified spleen B cells isolated from WT C57BL/6J mice and TLR9 knockout (KO) mice were cultured for 48 hours under the following conditions: CD40L, CpG+CD40L, CpG at low, medium and high doses...
2018: Journal of Applied Oral Science: Revista FOB
https://www.readbyqxmd.com/read/29791021/immtac-anti-pd-1-combination-to-enhance-killing-of-cancer-cells-by-reversing-treg-mediated-immunosuppression
#9
Huanling Zhang, Yanyan Li, Xiaoping Liu, Zhaoduan Liang, Mengyong Yan, Qiang Liu, Anan Chen, Yifeng Bao, Chengzhi Zhou, Shiyue Li, Cassian Yee, Yi Li
Recently, bi-functional molecules that can redirect immune effectors to tumor cells have emerged as potentially robust mediators of tumor regression in clinical trials. Two modalities, in particular, bi-specific antibodies for T cell redirection and activation (BiTe) and immune-mobilizing monoclonal T-cell receptors against cancer (ImmTAC) are being evaluated in efficacy studies as 'off-the-shelf' reagents. Optimal therapy will require an understanding and means to address regulatory mechanisms of limiting efficacy...
May 23, 2018: Immunology
https://www.readbyqxmd.com/read/29790498/rooibos-tea-extracts-inhibit-osteoclast-formation-and-activity-through-the-attenuation-of-nf-%C3%AE%C2%BAb-activity-in-raw264-7-murine-macrophages
#10
Shaakirah Moosa, Abe E Kasonga, Vishwa Deepak, Sumari Marais, Innocentia B Magoshi, Megan J Bester, Marlena C Kruger, Magdalena Coetzee
Rooibos tea is a naturally sweet and aromatic tea that is native to the Western Cape province of South Africa. Rooibos is usually fermented to produce the traditional reddish brown colour and has been found to have numerous health benefits. These include beneficial effects on osteoblasts; however, its effects on osteoclast formation and activity are unknown. Osteoclasts are large, multinucleated cells responsible for bone resorption. Binding of RANKL to its receptor on osteoclast precursors triggers the NF-κB signalling pathway leading to the formation of osteoclasts...
May 23, 2018: Food & Function
https://www.readbyqxmd.com/read/29790390/collecting-duct-principal-but-not-intercalated-cell-prorenin-receptor-regulates-renal-sodium-and-water-excretion
#11
Nirupama Ramkumar, Deborah Stuart, Elena Mironova, Nikita Abraham, Yang Gao, Shuping Wang, Jayalakshmi Lakshmipathi, James D Stockand, Donald E Kohan
The collecting duct is the predominant nephron site of prorenin and prorenin receptor (PRR) expression. We previously demonstrated that the collecting duct PRR regulates epithelial Na+ channel (ENaC) activity and water transport; however, which cell type is involved remains unclear. Herein, we examined the effects of principal cell (PC) or intercalated cell (IC) PRR deletion on renal Na+ and water handling. PC or IC PRR KO mice were obtained by crossing floxed PRR mice with mice harboring Cre recombinase under the control of the AQP2 or B-1 subunit of the H+ ATPase promoters, respectively...
May 23, 2018: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/29790086/testosterone-mediated-activation-of-androgenic-signalling-sustains-in-vitro-the-transformed-and-radioresistant-phenotype-of-rhabdomyosarcoma-cell-lines
#12
S Giannattasio, F Megiorni, V Di Nisio, A Del Fattore, R Fontanella, S Camero, C Antinozzi, C Festuccia, G L Gravina, S Cecconi, C Dominici, L Di Luigi, C Ciccarelli, P De Cesaris, A Riccioli, B M Zani, A Lenzi, R G Pestell, A Filippini, C Crescioli, V Tombolini, F Marampon
PURPOSE: Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in childhood, rarely affects adults, preferring male. RMS expresses the receptor for androgen (AR) and responds to androgen; however, the molecular action of androgens on RMS is unknown. METHODS: Herein, testosterone (T) effects were tested in embryonal (ERMS) and alveolar (ARMS) RMS cell lines, by performing luciferase reporter assay, RT-PCR, and western blotting experiments. RNA interference experiments or bicalutamide treatment was performed to assess the specific role of AR...
May 22, 2018: Journal of Endocrinological Investigation
https://www.readbyqxmd.com/read/29789639/fludarabine-and-neurotoxicity-in-engineered-t-cell-therapy
#13
Kate L Lowe, Crystal L Mackall, Elliot Norry, Rafael Amado, Bent K Jakobsen, Gwendolyn Binder
Adoptive T-cell therapy, incorporating engineered T cell receptors (TCRs) or chimeric antigen receptors (CARs), target tumor antigens with high affinity and specificity. To increase the potency of adoptively transferred T cells, patients are conditioned with lymphodepleting chemotherapy regimens prior to adoptive T-cell transfer (ACT), and data suggest that fludarabine is an important component of an effective regimen. In a recent clinical trial using CAR-T cells engineered to target the CD19 B-cell antigen to treat acute lymphoblastic leukemia, JCAR-015 (NCT02535364), two patient deaths due to cerebral edema led to trial suspension...
May 7, 2018: Gene Therapy
https://www.readbyqxmd.com/read/29789608/downregulation-of-endothelin-receptor-b-contributes-to-defective-b-cell-lymphopoiesis-in-trisomy-21-pluripotent-stem-cells
#14
Glenn A MacLean, Jennifer McEldoon, Jialiang Huang, Jeremy Allred, Matthew C Canver, Stuart H Orkin
Individuals with Trisomy 21 (T21) exhibit numerous hematological abnormalities, including reductions in numbers of circulating B and T lymphocytes. To elucidate molecular mechanisms underlying these phenotypes, we differentiated human isogenic disomic and trisomic pluripotent cells, and observed that trisomic cells showed defects in B cell, but not T cell differentiation. Global gene expression of differentiated, trisomic B cells revealed reduced expression of genes encoding endothelin signaling components, namely the Endothelin Receptor B (EDNRB), and its ligand Endothelin1 (EDN1)...
May 22, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29789259/synthesis-characterization-and-cytotoxicity-studies-of-1-2-3-triazoles-and-1-2-4-triazolo-1-5-a-pyrimidines-in-human-breast-cancer-cells
#15
Maryam Gilandoust, Kachigere B Harsha, Chakrabhavi Dhananjaya Mohan, Ainiah Rushdiana Raquib, Shobith Rangappa, Vijay Pandey, Peter E Lobie, Basappa, Kanchugarakoppal S Rangappa
Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) is essential for physiological functions of tissues and neovasculature. VEGFR signaling is associated with the progression of pathological angiogenesis in various types of malignancies, making it an attractive therapeutic target in cancer treatment. In the present work, we report the synthesis of 1,4-disubstituted 1,2,3-triazoles and 1,2,4-triazolo[1, 5-a]pyrimidine derivatives via copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and screened for their anticancer activity against MCF7 cells...
May 9, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29788325/ancestral-tcdd-exposure-induces-multigenerational-histologic-and-transcriptomic-alterations-in-gonads-of-male-zebrafish
#16
Danielle N Meyer, Bridget B Baker, Tracie R Baker
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), the classic AhR (aryl hydrocarbon receptor) agonist, is a potent environmental toxicant and endocrine-disrupting chemical (EDC) with known developmental toxicity in humans, rodents, and fish. Early life exposure to some EDCs, including TCDD, is linked to the occurrence of adult-onset and multigenerational disease. Previous work exposing juvenile F0 zebrafish (Danio rerio) to 50 ppt (parts per trillion) TCDD during reproductive development has shown male-mediated transgenerational decreases in fertility (F0-F2) and histological and transcriptomic alterations in F0 testes...
May 21, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29787950/macroporous-silica-nanoparticles-for-delivering-bcl2-function-converting-peptide-to-treat-multidrug-resistant-cancer-cells
#17
Weixia Xu, Pengjin Ge, Boning Niu, Xiaokun Zhang, Jie Liu, Jingjing Xie
The abundance of B cell lymphoma gene 2 (Bcl-2) is closely correlated with the resistance of cancer cells to chemotherapeutic agents, and a peptide derived from orphan nuclear receptor Nur77 can convert Bcl-2 from a protector to a killer of cancer cells. However, successful application of the Bcl-2-converting peptide to treat drug-resistant cancer cells depends on an efficient delivery carrier. Mesoporous silica nanoparticles (MSNs) have been extensively studied as promising candidates for small molecule drug delivery...
May 15, 2018: Journal of Colloid and Interface Science
https://www.readbyqxmd.com/read/29787770/lateral-hypothalamic-orexin-glucose-inhibited-neurons-may-regulate-reward-based-feeding-by-modulating-glutamate-transmission-in-the-ventral-tegmental-area
#18
Suraj B Teegala, Zhenyu Sheng, Miloni S Dalal, Pamela R Hirschberg, Kevin D Beck, Vanessa H Routh
Glucose inhibits ∼60% of lateral hypothalamic (LH) orexin neurons. Fasting increases the activation of LH orexin glucose-inhibited (GI) neurons in low glucose. Increases in spontaneous glutamate excitatory postsynaptic currents (sEPSCs) onto putative VTA DA neurons in low glucose are orexin dependent (Sheng et al., 2014). VTA DA neurons modulate reward-based feeding (Aston-Jones et al., 2010). We tested the hypothesis that increased activation of LH orexin-GI neurons in low glucose increases glutamate signaling onto VTA DA neurons and contributes to reward-based feeding in food restricted animals...
May 19, 2018: Brain Research
https://www.readbyqxmd.com/read/29787571/rnai-screening-of-subtracted-transcriptomes-reveals-tumor-suppression-by-taurine-activated-gabaa-receptors-involved-in-volume-regulation
#19
Camiel L C Wielders, Pim van Nierop, Tinke L Vormer, Floris Foijer, Joanne Verheij, Johannes C Lodder, Jesper B Andersen, Huibert D Mansvelder, Hein Te Riele
To identify coding and non-coding suppressor genes of anchorage-independent proliferation by efficient loss-of-function screening, we have developed a method for enzymatic production of low complexity shRNA libraries from subtracted transcriptomes. We produced and screened two LEGO (Low-complexity by Enrichment for Genes shut Off) shRNA libraries that were enriched for shRNA vectors targeting coding and non-coding polyadenylated transcripts that were reduced in transformed Mouse Embryonic Fibroblasts (MEFs)...
2018: PloS One
https://www.readbyqxmd.com/read/29787277/targeting-of-egfr-vegfr2-and-akt-by-engineered-dual-drug-encapsulated-mesoporous-silica-gold-nanoclusters-sensitizes-tamoxifen-resistant-breast-cancer
#20
Bn Prashanth Kumar, Nagaprasad Puvvada, Shashi Rajput, Siddik Sarkar, Madhusudan Kr Mahto, Murali M Yallapu, Amita Pathak, Luni Emdad, Swadesh K Das, Rui L Reis, Subhas C Kundu, Paul B Fisher, Mahitosh Mandal
Tamoxifen has improved overall disease-free survival and reduced mortality rates in cancer patients. However, breast cancer patients often fail to respond to tamoxifen therapy due to the development of a drug-resistant phenotype. Functional analysis and molecular studies suggest that protein mutation and dysregulation of survival signaling molecules such as epidermal growth factor receptor, vascular endothelial growth factor receptor 2 and Akt contribute to tamoxifen resistance. Various strategies, including combinatorial therapies, show to chemo-sensitize tamoxifen-resistant cancers...
May 22, 2018: Molecular Pharmaceutics
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