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https://www.readbyqxmd.com/read/28748611/apelin-induced-cardioprotection-against-ischemia-reperfusion-injury-roles-of-epidermal-growth-factor-and-src
#1
Anna Folino, Lisa Accomasso, Claudia Giachino, Pier Giorgio Montarolo, Gianni Losano, Pasquale Pagliaro, Raffaella Rastaldo
AIM: Apelin, the ligand of the G-protein-coupled-receptor (GPCR) APJ, exerts a postconditioning-like protection against ischemia-reperfusion injury through activation of PI3K-Akt-NO signalling. The pathway connecting APJ to PI3K is still unknown. Since other GPCR ligands act through transactivation of epidermal growth factor receptor (EGFR) via a matrix-metalloproteinase (MMP) or Src kinase, we investigated whether EGFR transactivation is involved in the following three features of apelin-induced cardioprotection: limitation of infarct size, suppression of contracture, and improvement of post-ischemic contractile recovery...
July 27, 2017: Acta Physiologica
https://www.readbyqxmd.com/read/28746882/a-landscape-of-therapeutic-cooperativity-in-kras-mutant-cancers-reveals-principles-for-controlling-tumor-evolution
#2
Grace R Anderson, Peter S Winter, Kevin H Lin, Daniel P Nussbaum, Merve Cakir, Elizabeth M Stein, Ryan S Soderquist, Lorin Crawford, Jim C Leeds, Rachel Newcomb, Priya Stepp, Catherine Yip, Suzanne E Wardell, Jennifer P Tingley, Moiez Ali, Mengmeng Xu, Meagan Ryan, Shannon J McCall, Autumn J McRee, Christopher M Counter, Channing J Der, Kris C Wood
Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tissue-specific sensitizing combinations involving inhibitors of cell cycle, metabolism, growth signaling, chromatin regulation, and transcription...
July 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28746311/prolonged-mek1-2-suppression-impairs-the-developmental-potential-of-embryonic-stem-cells
#3
Jiho Choi, Aaron J Huebner, Kendell Clement, Ryan M Walsh, Andrej Savol, Kaixuan Lin, Hongcang Gu, Bruno Di Stefano, Justin Brumbaugh, Sang-Yong Kim, Jafar Sharif, Christopher M Rose, Arman Mohammad, Junko Odajima, Jean Charron, Toshi Shioda, Andreas Gnirke, Steven Gygi, Haruhiko Koseki, Ruslan I Sadreyev, Andrew Xiao, Alexander Meissner, Konrad Hochedlinger
Concomitant activation of the Wnt pathway and suppression of Mapk signalling by two small molecule inhibitors (2i) in the presence of leukaemia inhibitory factor (LIF) (hereafter termed 2i/L) induces a naive state in mouse embryonic stem (ES) cells that resembles the inner cell mass (ICM) of the pre-implantation embryo. Since the ICM exists only transiently in vivo, it remains unclear how sustained propagation of naive ES cells in vitro affects their stability and functionality. Here we show that prolonged culture of male mouse ES cells in 2i/L results in irreversible epigenetic and genomic changes that impair their developmental potential...
July 26, 2017: Nature
https://www.readbyqxmd.com/read/28740236/reduced-expression-of-the-murine-hla-g-homolog-qa-2-is-associated-with-malignancy-epithelial-mesenchymal-transition-and-stemness-in-breast-cancer-cells
#4
Istéfani L da Silva, Lucía Montero-Montero, Ester Martín-Villar, Jorge Martin-Pérez, Bruno Sainz, Jaime Renart, Renata Toscano Simões, Émerson Soares Veloso, Cláudia Salviano Teixeira, Mônica C de Oliveira, Enio Ferreira, Miguel Quintanilla
Qa-2 is believed to mediate a protective immune response against cancer; however, little is known about the role of Qa-2 in tumorigenesis. Here, we used 4T1 breast cancer cells to study the involvement of Qa-2 in tumor progression in a syngeneic host. Qa-2 expression was reduced during in vivo tumor growth and in cell lines derived from 4T1-induced tumors. Tumor-derived cells elicited an epithelial-mesenchymal transition associated with upregulation of Zeb1 and Twist1/2 and enhanced tumor initiating and invasive capacities...
July 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28736554/differential-requirements-for-src-family-kinases-in-syk-or-zap70-mediated-slp-76-phosphorylation-in-lymphocytes
#5
Frank Fasbender, Maren Claus, Sabine Wingert, Mina Sandusky, Carsten Watzl
In a synthetic biology approach using Schneider (S2) cells, we show that SLP-76 is directly phosphorylated at tyrosines Y113 and Y128 by SYK in the presence of ITAM-containing adapters such as CD3ζ, DAP12, or FcεRγ. This phosphorylation was dependent on at least one functional ITAM and a functional SH2 domain within SYK. Inhibition of Src-kinases by inhibitors PP1 and PP2 did not reduce SLP-76 phosphorylation in S2 cells, suggesting an ITAM and SYK dependent, but Src-kinase independent signaling pathway...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28732195/fake-inhibitors-ampk-activation-trumps-inhibition
#6
Christopher G Langendorf, John W Scott, Bruce E Kemp
Protein kinase inhibitors have become increasingly important therapeutic drugs for the treatment of human diseases; however, resistance and off-target effects can limit their use. In this issue of Cell Chemical Biology, Ross et al. (2017) reveal a novel off-target mechanism where the Src kinase inhibitor SU6656 paradoxically primes AMPK for phosphorylation and activation by the upstream kinase LKB1.
July 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28730474/allosteric-modulation-of-src-family-kinases-with-atp-competitive-inhibitors
#7
Ames C Register, Sujata Chakraborty, Dustin J Maly
The Src family kinases (SFKs) are an important family of tyrosine kinases that are allosterically regulated by their SH2 and SH3 domains. Engagement of SFK SH2 and SH3 domains with their intramolecular ligands leads to reduced kinase activity by stabilizing an inactive ATP-binding site conformation. Disruption of these intramolecular interactions stabilizes a more active ATP-binding site conformation and restores SFK activity. Interestingly, this allosteric relationship is bidirectional in that ATP-competitive ligands that stabilize distinct active site conformations can divergently modulate the abilities of the regulatory SH2 and SH3 domains to participate in intermolecular interactions...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28729967/tesevatinib-ameliorates-progression-of-polycystic-kidney-disease-in-rodent-models-of-autosomal-recessive-polycystic-kidney-disease
#8
William E Sweeney, Philip Frost, Ellis D Avner
AIM: To investigate the therapeutic potential of tesevatinib (TSV), a unique multi-kinase inhibitor currently in Phase II clinical trials for autosomal dominant polycystic kidney disease (ADPKD), in well-defined rodent models of autosomal recessive polycystic kidney disease (ARPKD). METHODS: We administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.P. to the well characterized bpk model of polycystic kidney disease starting at postnatal day (PN) 4 through PN21 to assess efficacy and toxicity in neonatal mice during postnatal development and still undergoing renal maturation...
July 6, 2017: World Journal of Nephrology
https://www.readbyqxmd.com/read/28729437/estradiol-induced-regulation-of-glut4-in-3t3-l1-cells-involvement-of-esr1-and-akt-activation
#9
Raquel Campello, Luciana Fátima, João Barreto-Andrade, Thais Fg Lucas, Rosana Cristina Tieko Mori, Catarina Segreti Porto, Ubiratan Fabres Machado
Impaired insulin-stimulated glucose uptake involves reduced expression of the GLUT4 (solute carrier family 2 facilitated glucose transporter member 4, SLC2A4 gene). 17β-estradiol (E2) modulates SLC2A4/GLUT4 expression, but the involved mechanisms are unclear. Although E2 exerts its biological effects by binding to estrogen receptors 1/2 (ESR1/2), which are nuclear transcriptional factors; extranuclear effects have also been proposed. We hypothesize that E2 regulates GLUT4 through a mechanism related to extranuclear ESR1...
July 20, 2017: Journal of Molecular Endocrinology
https://www.readbyqxmd.com/read/28716707/non-oxidizable-hmgb1-induces-cardiac-fibroblasts-migration-via-cxcr4-in-a-cxcl12-independent-manner-and-worsens-tissue-remodeling-after-myocardial-infarction
#10
Stefania Di Maggio, Giuseppina Milano, Francesco De Marchis, Alessandro D'Ambrosio, Matteo Bertolotti, Blanca Soler Palacios, Ileana Badi, Elena Sommariva, Giulio Pompilio, Maurizio C Capogrossi, Angela Raucci
Myocardial infarction (MI) is a major health burden worldwide. Extracellular High mobility group box 1 (HMGB1) regulates tissue healing after injuries. The reduced form of HMGB1 (fr-HMGB1) exerts chemotactic activity by binding CXCL12 through CXCR4, while the disulfide form, (ds-HMGB1), induces cytokines expression by TLR4. Here, we assessed the role of HMGB1 redox forms and the non-oxidizable mutant (3S) on human cardiac fibroblast (hcFbs) functions and cardiac remodeling after infarction. Among HMGB1 receptors, hcFbs express CXCR4...
July 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28713919/ganetespib-induces-g2-m-cell-cycle-arrest-and-apoptosis-in-gastric-cancer-cells-through-targeting-of-receptor-tyrosine-kinase-signaling
#11
Harry Lee, Nipun Saini, Amanda B Parris, Ming Zhao, Xiaohe Yang
Heat shock protein 90 (HSP90) regulates several important cellular processes via its repertoire of 'client proteins'. These client proteins have been found to play fundamental roles in signal transduction, cell proliferation, cell cycle progression and survival, as well as other features of malignant cells, such as invasion, tumor angiogenesis and metastasis. Thus, HSP90 is an emerging target for cancer therapy. To this end, we evaluated ganetespib (STA-9090), a novel and potent HSP90 inhibitor, for its activity in gastric cancer cell lines...
July 13, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28709498/targeting-fyn-kinase-in-alzheimer-s-disease
#12
REVIEW
Haakon B Nygaard
The past decade has brought tremendous progress in unraveling the pathophysiology of Alzheimer's disease (AD). While increasingly sophisticated immunotherapy targeting soluble and aggregated brain amyloid-beta (Aβ) continues to dominate clinical research in AD, a deeper understanding of Aβ physiology has led to the recognition of distinct neuronal signaling pathways linking Aβ to synaptotoxicity and neurodegeneration and to new targets for therapeutic intervention. Identifying specific signaling pathways involving Aβ has allowed for the development of more precise therapeutic interventions targeting the most relevant molecular mechanisms leading to AD...
June 13, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/28708578/hyperglycemia-and-advanced-glycation-end-products-ages-suppress-the-differentiation-of-3t3-l1-preadipocytes
#13
Chia-Chu Chang, Chen-Yu Chen, Geen-Dong Chang, Ting-Huan Chen, Woan-Ling Chen, Hui-Chin Wen, Chih-Yang Huang, Chung-Ho Chang
Aging is characterized by mild hyperglycemia and accumulation of advanced glycation end products (AGEs). Effects of chronic exposure to hyperglycemia or AGEs on the adipogenic differentiation of 3T3-L1 preadipocytes remain unclear. We examined the chronic effect of AGEs and high glucose on the differentiation of 3T3-L1 cells by culturing 3T3-L1 cells in the presence of AGEs or 25 mM glucose for 1 month. Chronic incubation of 3T3-L1 cells with AGEs or high glucose blocked their differentiation into mature adipocytes as evidenced by reduced levels of adipocyte markers such as accumulated oil droplets, GPDH, aP2, adiponectin and of adipogenesis regulators PPARγ and C/EBPα...
July 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28707014/doxycycline-and-its-quaternary-ammonium-derivative-for-adjuvant-therapies-of-chondrosarcoma
#14
Imen Miladi, Magali Vivier, Marie-Mélanie Dauplat, Morgane Chatard, Sophie Besse, Aurélien Vidal, Karine Chassain, Betty Jean, Christiane Forestier, Jean-Michel Chezal, Francoise Rédini, Francoise Degoul, Elisabeth Miot-Noirault
PURPOSE: This study was conducted during the development of innovative treatment targeting the microenvironment of chondrosarcoma. In this context, MMP inhibitors were conjugated with a quaternary ammonium (QA) function as a targeting ligand to proteoglycans of chondrosarcoma extracellular matrix. Here we report the proof of concept of this strategy applied to the MMP13 inhibitor, doxycycline (Dox). METHODS: A quaternary ammonium derivative of the MMP13 inhibitor doxycycline (QA-Dox) was synthesized, and its anticancer activity was evaluated in the Swarm rat chondrosarcoma (SRC) model compared with the parent drug doxycycline, in vitro and in vivo...
July 13, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28705934/gq-pathway-regulates-proximal-c-type-lectin-like-receptor-2-clec-2-signaling-in-platelets
#15
Rachit Badolia, Vaishali Inamdar, Bhanu Kanth Manne, Carol Dangelmaier, Satya P Kunapuli
Platelets play a key role in the physiological hemostasis or pathological process of thrombosis. Rhodocytin, an agonist of the C-type lectin like receptor-2 (CLEC-2), elicits powerful platelet activation signals in conjunction with Src family kinases (SFKs), spleen tyrosine kinase (Syk), and phospholipase γ2 (PLCγ2). Previous reports have shown that rhodocytin-induced platelet aggregation depends on secondary mediators such as thromboxane (TxA2) and ADP, which are agonists for G protein coupled receptors (GPCRs) on platelets...
July 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28704617/resveratrol-prevents-angiotensin-ii-induced-hypertrophy-of-vascular-smooth-muscle-cells-through-the-transactivation-of-growth-factor-receptors
#16
Ekhtear Hossain, Madhu B Anand-Srivastava
We previously showed that the augmented levels of endogenous angiotensin II (Ang II) contribute to vascular smooth muscle cell (VSMC) hypertrophy through the transactivation of growth factor receptors in spontaneously hypertensive rats. Resveratrol (RV), a polyphenolic component of red wine, has also been shown to attenuate Ang II-evoked VSMC hypertrophy, however, the molecular mechanism mediating this response is obscure. The present study is therefore undertaken to examine if RV could prevent Ang II-induced VSMC hypertrophy through the transactivation of growth factor receptor and associated signaling pathways...
July 13, 2017: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/28699511/striatal-enriched-tyrosine-protein-phosphatase-step-in-the-mechanisms-of-depressive-disorders
#17
Elizabeth Kulikova, Alexander Kulikov
Striatal-enriched tyrosine protein phosphatase (STEP) is expressed mainly in the brain. Its dysregulation is associated with Alzheimer's and Huntington's diseases, schizophrenia, fragile X syndrome, drug abuse and stroke/ischemia. However, an association between STEP and depressive disorders is still obscure. The review discusses the theoretical foundations and experimental facts concerning possible relationship between STEP dysregulation and depression risk. STEP dephosphorylates and inactivates several key neuronal signaling proteins such as extracellular signal-regulating kinase 1 and 2 (ERK1/2), stress activated protein kinases p38, the Src family tyrosine kinases Fyn, Pyk2, NMDA and AMPA glutamate receptors...
July 10, 2017: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/28698313/hiv-and-hiv-tat-inhibit-lps-induced-il-27-production-in-human-macrophages-by-distinct-intracellular-signaling-pathways
#18
Niranjala Gajanayaka, Shifawn O'Hara, Yulia Konarski, Jason Fernandes, Kar Muthumani, Maya Kozlowski, Jonathan B Angel, Ashok Kumar
Monocyte-derived Mϕs (MDMs) from HIV-infected patients and MDM infected in vitro with HIV exhibit a reduced ability to secrete various cytokines, including IL-12. Recently, IL-27, an IL-12 family cytokine, was shown to inhibit HIV replication in Mϕ. Whether HIV infection or HIV accessory protein(s) impact IL-27 production in Mϕs remains unknown. Herein, we show that in vitro HIV infection, as well as intracellular HIV-Tat (Tat) and Tat peptides, inhibit LPS-induced IL-27 production in human MDMs, suggesting impairment of the TLR4 signaling pathway...
July 11, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28697919/fatty-acid-translocase-promoted-hepatitis-b-virus-replication-by-upregulating-the-levels-of-hepatic-cytosolic-calcium
#19
Jian Huang, Lei Zhao, Ping Yang, Zhen Chen, Xiong Z Ruan, Ailong Huang, Ni Tang, Yaxi Chen
Hepatitis B virus (HBV) is designated a "metabolovirus" due to the intimate connection between the virus and host metabolism. The nutrition state of the host plays a relevant role in the severity of HBV infection. Metabolic syndrome (MS) is prone to increasing HBV DNA loads and accelerating the progression of liver disease in patients with chronic hepatitis B (CHB). Cluster of differentiation 36 (CD36), also named fatty acid translocase, is known to facilitate long-chain fatty acid uptake and contribute to the development of MS...
July 8, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28695794/the-natural-component-isolated-from-enterolobium-contortisiliquum-impairs-brain-tumors-and-affects-their-interactions-with-mesenchymal-stem-cells
#20
Camila Ramalho Bonturi, Helena Motaln, Mariana Cristina Cabral Silva, Bruno Ramos Salu, Marlon Vilela de Brito, Luciana de Andrade Luz Costa, Heron Fernandes Vieira Torquato, Natália Neto Dos Santos Nunes, Edgar Julian Paredes-Gamero, Tamara Lah Turnšek, Maria Luiza Vilela Oliva
Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor with an overall patient survival of about 16 months. Thus, natural compounds with anti-cancer properties are gaining attention as possible alternatives for GBM treatment. Studies in various cancer models have shown the anti-cancer effects of the Enterolobium contortisiliquum Trypsin Inhibitor (EcTI). Here, we investigated the outcomes of EcTI on U87 cells, mesenchymal stem cells (MSC), and their direct cocultures (U87/MSC). MSC are present in tumor stroma and represent a potential drug delivery vehicle as the result of their tumor tropism...
July 11, 2017: Oncology Research
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