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Binod Kumar, Dipanjan Dutta, Jawed Iqbal, Mairaj Ahmed Ansari, Arunava Roy, Leela Chikoti, Gina Pisano, Mohanan Valiya Veettil, Bala Chandran
Kaposi's sarcoma-associated herpesvirus (KSHV) binding to the endothelial cell surface heparan sulfate is followed by sequential interactions with α3β1, αVβ3 and αVβ5 integrins and Ephrin A2 receptor tyrosine kinase (EphA2R). These interactions activate host cell pre-existing FAK, Src, PI3-K and RhoGTPase signaling cascades, c-Cbl mediated ubiquitination of receptors, recruitment of CIB1, p130Cas and Crk adaptor molecules, and membrane bleb formation leading to lipid raft dependent macropinocytosis of KSHV into human microvascular dermal endothelial (HMVEC-d) cells...
October 2016: PLoS Pathogens
Liming Yu, Chongxi Fan, Zhi Li, Jian Zhang, Xiaodong Xue, Yinli Xu, Guolong Zhao, Yang Yang, Huishan Wang
Stress hyperglycemia is commonly observed in patients suffering from ischemic heart disease. It not only worsens cardiovascular prognosis but also attenuates the efficacies of various cardioprotective agents. This study aimed to investigate the protective effect of melatonin against myocardial ischemia-reperfusion (MI/R) injury in acute hyperglycemic state with a focus on Notch1/Hes1/Akt signaling and intracellular thioredoxin (Trx) system. Sprague-Dawley rats were subjected to MI/R surgery and high glucose (HG, 500 g/L) infusion (4 ml/kg/h) to induce temporary hyperglycemia...
October 18, 2016: Journal of Pineal Research
Mohammad Shahidullah, Amritlal Mandala, Nicholas A Delamere
Insulin has been shown to elicit changes of Na,K-ATPase activity in various tissues. Na,K-ATPase in the nonpigmented ciliary epithelium (NPE) plays a role in aqueous humor secretion and changes of Na,K-ATPase activity impact the driving force. Because we detect a change of NPE Na,K-ATPase activity in response to insulin, studies were carried out to examine the response mechanism. Ouabain-sensitive rubidium (Rb) uptake by cultured NPE cells, measured as a functional index of Na,K-ATPase-mediated inward potassium transport, was found to increase in cells exposed for 5 min to insulin...
October 17, 2016: Journal of Cellular Physiology
Amrita Ahluwalia, Michael K Jones, Tomasz Brzozowski, Andrzej S Tarnawski
Angiogenesis is critical for the healing of gastric mucosal injury and is considered to be primarily regulated by vascular endothelial growth factor (VEGF), the fundamental pro-angiogenic factor. The role of nerve growth factor (NGF) in gastric angiogenesis is unknown. We examined: the expression of NGF and its TrkA receptor in endothelial cells (ECs) isolated from gastric mucosa of rats (GMECs); the effect of NGF treatment on in vitro angiogenesis in GMECs; and, the mechanisms underlying NGF's pro-angiogenic actions...
October 13, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Arif U Hasan, Koji Ohmori, Takeshi Hashimoto, Kazuyo Kamitori, Fuminori Yamaguchi, Kumi Konishi, Takahisa Noma, Junsuke Igarashi, Tetsuo Yamashita, Katsuya Hirano, Masaaki Tokuda, Tetsuo Minamino, Akira Nishiyama, Masakazu Kohno
Deterioration of adipocyte function due to increased oxidative stress predisposes patients to metabolic disorders in advanced age. However, the roles of tumor suppressors in such conditions remain largely unknown. Therefore, we aimed to address their dynamics in aged adipocytes using a long-term culture model. We compared 3T3-L1 adipocytes at 17-19 days (long-term) with those at 8-10 days (short-term) after initiation of adipogenic induction for mimicking 'aged' and 'young' adipocytes, respectively. H2O2 release and dihydroethidium (DHE) staining was increased, while superoxide dismutase (SOD) activity was reduced in long-term cultured adipocytes, which is suggestive of enhanced oxidative stress in this group...
October 12, 2016: Biogerontology
Claudia Manzoni, Adamantios Mamais, Dorien A Roosen, Sybille Dihanich, Marc P M Soutar, Helene Plun-Favreau, Rina Bandopadhyay, John Hardy, Sharon A Tooze, Mark R Cookson, Patrick A Lewis
Leucine rich repeat kinase 2 is a complex enzyme with both kinase and GTPase activities, closely linked to the pathogenesis of several human disorders including Parkinson's disease, Crohn's disease, leprosy and cancer. LRRK2 has been implicated in numerous cellular processes; however its physiological function remains unclear. Recent reports suggest that LRRK2 can act to regulate the cellular catabolic process of macroautophagy, although the precise mechanism whereby this occurs has not been identified. To investigate the signalling events through which LRRK2 acts to influence macroautophagy, the mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) and Beclin-1/phosphatidylinositol 3-kinase (PI3K) pathways were evaluated in astrocytic cell models in the presence and absence of LRRK2 kinase inhibitors...
October 12, 2016: Scientific Reports
Xu Liu, Dongxiao Wang, Runqing Zhao, Xianzhe Dong, Yuan Hu, Ping Liu
As two natural oligosaccharide esters, 3,6'-Disinapoyl sucrose (DISS) and tenuifolisideA (TFSA) are originating from the root of Polygala tenuifolia Willd, a traditional Chinese medicine used in treatment of mental disorders. Previous reports have shown that both of them possess in vitro neuroprotective effects by stimulating different upstream pathways related with cyclic AMP-responsive element-binding protein (CREB). In the present study, we investigated the additive neuroprotective effects of DISS and TFSA on Glu-induced damage of SY5Y cells and purposed the possible underlying mechanism...
2016: Frontiers in Pharmacology
Vandana Sharma, Rajaram Purushotham, Rupinder Kaur
The phosphoinositide 3-kinase (PI3K), which phosphorylates phosphatidylinositol and produces PI3P, has been implicated in protein trafficking, intracellular survival and virulence in the pathogenic yeast Candida glabrata Here, we demonstrate PI3-kinase (CgVps34) to be essential for maintenance of cellular iron homeostasis. We examine how CgVps34 regulates the fundamental process of iron acquisition, and underscore its function in vesicular trafficking as a central determinant. RNA-sequencing analysis revealed iron homeostasis genes to be differentially expressed upon CgVps34 disruption...
October 11, 2016: Journal of Biological Chemistry
Wen-Juan Huang, Wei-Wei Chen, Xia Zhang
Central nervous system-based cancers have a much higher mortality rate with the 2016 estimates at 6.4 for incidence and 4.3 for deaths per 100,000 individuals. Grade IV astrocytomas, known as glioblastomas are highly aggressive and show a high proliferation index, diffused infiltration, angiogenesis, microvascular proliferation and pleomorphic vessels, resistance to apoptosis, and pseudopalisading necrosis. Extensive hypoxic regions in glioblastomas contribute to the highly malignant phenotype of these tumors...
October 2016: Oncology Letters
Gaoyong Liao, Bing Gao, Yingnv Gao, Xuegan Yang, Xiaodong Cheng, Yu Ou
Pancreatic adenocarcinoma (PDA) is one of the most lethal human malignancies, and unresponsive to current chemotherapies. Here we investigate the therapeutic potential of phycocyanin as an anti-PDA agent in vivo and in vitro. Phycocyanin, a natural product purified from Spirulina, effectively inhibits the pancreatic cancer cell proliferation in vitro and xenograft tumor growth in vivo. Phycocyanin induces G2/M cell cycle arrest, apoptotic and autophagic cell death in PANC-1 cells. Inhibition of autophagy by targeting Beclin 1 using siRNA significantly suppresses cell growth inhibition and death induced by phycocyanin, whereas inhibition of both autophagy and apoptosis rescues phycocyanin-mediated cell death...
October 3, 2016: Scientific Reports
Ahmed T A Boraei, Mohamed S Gomaa, El Sayed H El Ashry, Axel Duerkop
Three sets of substituted indolyl-triazoles were synthesized by the alkylation of 1,2-dihydro-5-(1H-indol-2-yl)-1,2,4-triazole-3-thione with different alkyl halides. The use of pyridine restricted the alkylation to sulfur. Whereas, upon using K2CO3, the alkylation exceeded sulfur to one of the remaining triazole nitrogens. The assignment of which nitrogen is alkylated besides sulfur is made for the first time using X-ray analysis of single crystals and 2D NMR which indicated that S-, 2-N-isomers will be preferably formed over the S-, 1-N-isomers...
September 15, 2016: European Journal of Medicinal Chemistry
Randall J Cohrs, Hussain Badani, Nicholas L Baird, Teresa M White, Bridget Sanford, Don Gilden
Varicella zoster virus (VZV), a human neurotropic alphaherpesvirus, becomes latent after primary infection and reactivates to produce zoster. To study VZV latency and reactivation, human trigeminal ganglia removed within 24 h after death were mechanically dissociated, randomly distributed into six-well tissue culture plates and incubated with reagents to inactivate nerve growth factor (NGF) or phosphoinositide 3-kinase (PI3-kinase) pathways. At 5 days, VZV DNA increased in control and PI3-kinase inhibitor-treated cultures to the same extent, but was significantly more abundant in anti-NGF-treated cultures (p = 0...
September 28, 2016: Journal of Neurovirology
Ming-Shuo Chen, Hyosung Kim, Léonard Jagot-Lacoussiere, Patrice Maurel
Axo-glial interactions are critical for myelination and the domain organization of myelinated fibers. Cell adhesion molecules belonging to the Cadm family, and in particular Cadm3 (axonal) and its heterophilic binding partner Cadm4 (Schwann cell), mediate these interactions along the internode. Using targeted shRNA-mediated knockdown, we show that the removal of axonal Cadm3 promotes Schwann cell myelination in the in vitro DRG neuron/Schwann cell myelinating system. Conversely, over-expressing Cadm3 on the surface of DRG neuron axons results in an almost complete inability by Schwann cells to form myelin segments...
September 23, 2016: Glia
Marco Falasca, Justin R Hamilton, Maria Selvadurai, Krithika Sundaram, Aleksandra Adamska, Philip E Thompson
The phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases central to regulating a wide range of important intracellular processes. Despite the vast knowledge around class I PI3Ks, the class II PI3Ks have been neglected, seemingly only due to the chronology of their discovery. Here we focus on the cellular functions of the three class II PI3K isoforms, PI3KC2α, PI3KC2β, and PI3KC2γ, in different cell systems and underline the emerging importance of these enzymes in different physiological and pathological contexts...
October 21, 2016: Journal of Medicinal Chemistry
Yu Kou, Lei Li, Hong Li, Yuhui Tan, Bin Li, Kun Wang, Biaoyan Du
Berberine is a natural compound extracted from Coptidis rhizoma, and accumulating proof has shown its potent anti-tumor properties with diverse action on melanoma cells, including inhibiting cancer viability, blocking cell cycle and migration. However, the mechanisms of berberine have not been fully clarified. In this study, we identified that berberine reduced the migration and invasion capacities of B16 cells, and notably altered pluripotency of epithelial to mesenchymal transition associated factors. We found that berberine also downregulation the expression level of p-PI3K, p-AKT and retinoic acid receptor α (RARα) and upregulation the expression level of retinoic acid receptor β and γ (RARβ and RARγ)...
October 14, 2016: Biochemical and Biophysical Research Communications
Sophie Lepannetier, Nadège Zanou, Xavier Yerna, Noémie Emeriau, Inès Dufour, Julien Masquelier, Giulio Muccioli, Nicolas Tajeddine, Philippe Gailly
TRP channels are involved in the control of a broad range of cellular functions such as cell proliferation and motility. We investigated the gating mechanism of TRPC1 channel and its role in U251 glioblastoma cells migration in response to chemotaxis by platelet-derived growth factor (PDGF). PDGF induced an influx of Ca(2+) that was partially inhibited after pretreatment of the cells with SKI-II, a specific inhibitor of sphingosine kinase producing sphingosine-1-P (S1P). S1P by itself also induced an entry of Ca(2+)...
September 9, 2016: Cell Calcium
Yan Yang, Jiangong Ren, Yuzhen Tong, Xuejian Hu, Qingguo Lv, Nanwei Tong
Lipoapoptosis plays an important role in the pathogenesis of type 2 diabetes. Peroxisome proliferator-activated receptor delta (PPARdelta), a vital regulator of glucose and lipid metabolism, may reduce fatty acid-induced pancreatic β cell lipotoxicity in diabetes. However, the detailed molecular mechanisms underlying this process are not fully understood. In this study, we investigated the effect of activation of PPARdelta on palmitate-induced β cell apoptosis, and we explored the potential mechanism of the antiapoptotic effect...
September 8, 2016: Lipids
Juan Miguel Cejalvo, J Alejandro Pérez-Fidalgo, Gloria Ribas, Octavio Burgués, Cristina Mongort, Elisa Alonso, Maider Ibarrola-Villava, Begoña Bermejo, María Teresa Martínez, Andrés Cervantes, Ana Lluch
BACKGROUND: There is increasing interest in the molecular profiling of tumour tissues in order to investigate alternative breast cancer (BC) therapies. However, the impact of genomic screening for druggable mutations with targeted gene panel sequencing (TGPS) in routine practice remains controversial. METHODS: This is a retrospective analysis of data from a genomic screening programme at our institution, in which we performed simplified TGPS for mutations in PIK3CA, AKT1, KRAS, NRAS, and BRAF in order to select patients for targeted therapy clinical trials...
November 2016: Breast Cancer Research and Treatment
Yaqi Zhang, Si Zhang, Zhongren Ding
P2Y12 receptor is a 342 amino acid Gi-coupled receptor predominantly expressed on platelets. P2Y12 receptor is physiologically activated by ADP and inhibits adenyl cyclase (AC) to decrease cyclic AMP (cAMP) level, resulting in platelet aggregation. It also activates PI3 kinase (PI3K) pathway leading to fibrinogen receptor activation, and may protect platelets from apoptosis. Abnormalities of P2Y12 receptor include congenital deficiencies or high activity in diseases like diabetes mellitus (DM) and chronic kidney disease (CKD), exposing such patients to a prothrombotic condition...
September 15, 2016: Advances in Experimental Medicine and Biology
Rajani Kanteti, Jacob J Riehm, Immanuel Dhanasingh, Frances E Lennon, Tamara Mirzapoiazova, Bolot Mambetsariev, Hedy L Kindler, Ravi Salgia
Malignant pleural mesothelioma (MPM) is an aggressive cancer that is commonly associated with prior asbestos exposure. Receptor tyrosine kinases (RTKs) such as MET and its downstream target PI3K are overexpressed and activated in a majority of MPMs. Here, we studied the combinatorial therapeutic efficacy of the MET/ALK inhibitor crizotinib, with either a pan-class I PI3K inhibitor, BKM120, or with a PI3K/mTOR dual inhibitor, GDC-0980, in mesothelioma. Cell viability results showed that MPM cells were highly sensitive to crizotinib, BKM120 and GDC-0980 when used individually and their combination was more effective in suppressing growth...
2016: Scientific Reports
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