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https://www.readbyqxmd.com/read/28109128/population-pharmacokinetics-and-pharmacodynamics-of-benralizumab-in-healthy-volunteers-and-patients-with-asthma
#1
B Wang, L Yan, Z Yao, L K Roskos
Benralizumab is a humanized, afucosylated, anti-interleukin-5 receptor α, immunoglobulin G (IgG) 1 κ monoclonal antibody. We developed a population pharmacokinetic (PK)/pharmacodynamic (PD) model for benralizumab by analyzing PK and blood eosinophil count data from two healthy volunteer studies (N = 48) and four studies in patients with asthma (N = 152). Benralizumab PK was dose-proportional and adequately described by a two-compartment model with first-order elimination from the central compartment and first-order absorption from the subcutaneous dosing site...
January 21, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28109123/sodium-butyrate-protects-against-high-fat-diet-induced-cardiac-dysfunction-and-metabolic-disorders-in-type-ii-diabetic-mice
#2
Ling Zhang, Jianfeng Du, Naohiro Yano, Hao Wang, Yu Tina Zhao, Dubielecka-Szczerba Patricia, Shougang Zhuang, Eugene Y Chin, Gangjian Qin, Ting C Zhao
Histone deacetylases are recently identified to act as key regulators for cardiac pathophysiology and metabolic disorders. However, the function of histone deacetylase (HDAC) in controlling cardiac performance in type II diabetes and obesity remains unknown. Here we determine whether HDAC inhibition attenuates high fat diet (HFD)-induced cardiac dysfunction and improves metabolic features. Adult mice were fed with either HFD or standard chow food for 24 weeks. Starting at 12 weeks, mice were divided into four groups randomly, in which sodium butyrate (1%), a potent HDAC inhibitor, was provided to chow and HFD-fed mice in drinking water, respectively...
January 21, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28109078/3-phosphoinositide-dependent-protein-kinase-1-pdk-1-promotes-migration-and-invasion-in-gastric-cancer-cells-through-activating-the-nf-%C3%AE%C2%BAb-pathway
#3
Ning Wu, Changyu He, Bohui Zhu, Jinling Jiang, Yiwen Chen, Tao Ma
Gastric cancer (GC) is one of the most common cancers and the second leading cause of cancer deaths in the world. Manyfactors were reported involving the progression and development of GC. In this study, we aimed to investigate the correlation of 3-phosphoinositide dependent protein kinase 1 (PDK-1) with cell viability, cell migration, and cell invasion of GC. The expression of PDK-1 was measured in different GC cell lines. Thereafter, the expression of PDK-1 was interfered by small hairpin RNA (shRNA) and then incubated with or without the inhibitor of NF-κB pyrrolidine dithiocarbamate (PDTC)...
January 20, 2017: Oncology Research
https://www.readbyqxmd.com/read/28108614/osteopontin-and-protein-kinase-c-regulate-pdlim2-activation-and-stat1-ubiquitination-in-lps-treated-murine-macrophages
#4
Hongtao Guo, Zhiyong Mi, Dawn E Bowles, Syamal D Bhattacharya, Paul C Kuo
No abstract text is available yet for this article.
January 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28108582/identification-of-a-novel-protein-kinase-that-affects-the-chronological-lifespan-in-fission-yeast
#5
Tatsuhiro Kurauchi, Aya Hashizume, Yuki Imai, Kanako Hayashi, Satoshi Tsubouchi, Kunio Ihara, Hokuto Ohtsuka, Hirofumi Aiba
Chronological lifespan is defined by how long a cell can survive in a non-dividing state. In yeast, it is measured by viability after entry into the stationary phase. To understand the regulatory mechanisms of chronological lifespan in Schizosaccharomyces pombe, it is necessary to identify and characterize novel factors involved in the regulation of chronological lifespan. To this end, we have screened for a long-lived mutant and identified that novel gene nnk1(+) that encodes an essential protein kinase is the determinant of chronological lifespan...
January 2017: FEMS Microbiology Letters
https://www.readbyqxmd.com/read/28108554/genome-wide-analysis-of-lncrna-and-mrna-expression-during-differentiation-of-abdominal-preadipocytes-in-the-chicken
#6
Tao Zhang, Xiangqian Zhang, Kunpeng Han, Genxi Zhang, Jinyu Wang, Kaizhou Xie, Qian Xue
Long non-coding RNAs (lncRNAs) regulate adipogenesis and other processes associated with metabolic tissue development and function. However, little is known about the function and profile of lncRNAs during preadipocyte differentiation in the chicken (Gallus gallus). Herein, lncRNA and mRNA expression in preadipocytes at different stages of differentiation were analyzed using RNA sequencing. A total of 1,300,074,528 clean reads and 27,023 novel lncRNAs were obtained from 12 samples. The number of genes (1,336 lncRNAs and 1,759 mRNAs; 3,095 in total) differentially expressed across various stages declined as differentiation progressed...
January 20, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28108419/regulation-of-protein-kinase-c-related-kinase-prk-signalling-by-the-tp%C3%AE-and-tp%C3%AE-isoforms-of-the-human-thromboxane-a2-receptor-implications-for-thromboxane-and-androgen-dependent-neoplastic-and-epigenetic-responses-in-prostate-cancer
#7
Aine G O'Sullivan, Eamon P Mulvaney, B Therese Kinsella
The prostanoid thromboxane (TX) A2 and its T Prostanoid receptor (the TP) are increasingly implicated in prostate cancer (PCa). Mechanistically, we recently discovered that both TPα and TPβ form functional signalling complexes with members of the protein kinase C-related kinase (PRK) family, AGC- kinases essential for the epigenetic regulation of androgen receptor (AR)-dependent transcription and promising therapeutic targets for treatment of castrate-resistant prostate cancer (CRPC). Critically, similar to androgens, activation of the PRKs through the TXA2/TP signalling axis induces phosphorylation of histone H3 at Thr11 (H3Thr11), a marker of androgen-induced chromatin remodelling and transcriptional activation, raising the possibility that TXA2-TP signalling can mimic and/or enhance AR-induced cellular changes even in the absence of circulating androgens such as in CRPC...
January 17, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28108312/ctgf-promotes-osteosarcoma-angiogenesis-by-regulating-mr-543-angiopoietin-2-signaling
#8
Li-Hong Wang, Hsiao-Chi Tsai, Yu-Che Cheng, Chih-Yang Lin, Yuan-Li Huang, Chun-Hao Tsai, Guo-Hong Xu, Shih-Wei Wang, Yi-Chin Fong, Chih-Hsin Tang
Osteosarcoma is the most common primary solid tumor of bone. It has a high metastatic potential and occurs predominantly in adolescents and young adults. Angiopoietin 2 (Angpt2) is a key regulator in tumor angiogenesis, facilitating tumor growth and metastasis. Connective tissue growth factor (CTGF, also known as CCN2), is a cysteine-rich protein that has been reported to promote metastasis of osteosarcoma. However, the effect of CTGF on Angpt2 regulation and angiogenesis in human osteosarcoma remains largely unknown...
January 17, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28108289/negative-feedback-regulation-between-microrna-let-7g-and-lox-1-mediated-hypoxia-induced-pasmcs-proliferation
#9
Wei-Fang Zhang, Tian-Tian Zhu, You-Wen Xiong, Ai-Zhen Xiong, Xiao-Yue Ge, Chang-Ping Hu, Zheng Zhang
BACKGROUND: Pulmonary hypertension (PH) is a proliferative disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary artery smooth muscle cells (PASMCs). Our lately study demonstrated that let-7g inhibited hypoxia-induced proliferation of PASMCs via repressed c-myc-Bmi-1-p16 signaling pathway. However, the upstream of let-7g has not yet been fully defined. Previous studies have shown that LOX-1, a target of let-7g, could also regulate the expression of let-7g in human aortic endothelial cells...
January 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28108261/heterotrimeric-g-protein-g%C3%AE-s-subunit-attenuates-plekhg2-a-rho-family-specific-guanine-nucleotide-exchange-factor-by-direct-interaction
#10
Kazue Sugiyama, Kenji Tago, Sayumi Matsushita, Masashi Nishikawa, Katsuya Sato, Yoshinori Muto, Takahiro Nagase, Hiroshi Ueda
PLEKHG2 is a Gβγ-dependent guanine nucleotide exchange factor (GEF) for the small GTPases Rac and Cdc42, and has been shown to mediate signalling pathways such as actin cytoskeleton reorganization and serum response element (SRE)-dependent gene transcription. Here we show that the constitutively active mutant of the Gαs subunit significantly attenuated PLEKHG2-induced SRE-mediated gene transcription. Strikingly, we observed that the constitutive activation of endogenous Gαs by treatment with CTx caused a similar inhibitory effect on PLEKHG2-induced activation of SRE...
January 17, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28108151/a-functional-genetic-screen-identifies-the-phosphoinositide-3-kinase-pathway-as-a-determinant-of-resistance-to-fibroblast-growth-factor-receptor-inhibitors-in-fgfr-mutant-urothelial-cell-carcinoma
#11
Liqin Wang, Tonći Šuštić, Rodrigo Leite de Oliveira, Cor Lieftink, Pasi Halonen, Marieke van de Ven, Roderick L Beijersbergen, Michel M van den Heuvel, René Bernards, Michiel S van der Heijden
Activating mutations and translocations of the FGFR3 gene are commonly seen in urothelial cell carcinoma (UCC) of the bladder and urinary tract. Several fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical development and response rates appear promising for advanced UCC. A common problem with targeted therapeutics is intrinsic or acquired resistance of the cancer cells. To find potential drug targets that can act synergistically with FGFR inhibition, we performed a synthetic lethality screen for the FGFR inhibitor AZD4547 using a short hairpin RNA library targeting the human kinome in the UCC cell line RT112 (FGFR3-TACC3 translocation)...
January 17, 2017: European Urology
https://www.readbyqxmd.com/read/28107777/the-dc1-domain-protein-vacuoleless-gametophytes-is-essential-for-female-and-male-gametophyte-development-in-arabidopsis
#12
Sebastián D'Ippólito, Leonardo Agustín Arias, Claudia Anahí Casalongué, Gabriela Carolina Pagnussat, Diego Fernando Fiol
In this work we identified VACUOLELESS GAMETOPHYTES (VLG) as a DC1 domain containing protein present in the endomembrane system essential for both female and male gametophyte development. VLG was originally annotated as a gene coding for an unknown function protein containing DC1 domains. DC1 domains are cysteine and histidine -rich zinc finger domains found exclusively in the plant Kingdom that have been named based on its similarity with the C1 domain present in protein kinase C (PKC). In Arabidopsis, both male and female gametophytes are characterized by the formation of a big vacuole early in development, which is absent in vlg mutant plants...
January 20, 2017: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/28107700/comparative-pharmacokinetics-of-eight-major-bioactive-components-in-normal-and-bacterial-diarrhea-mini-pigs-after-oral-administration-of-gegen-qinlian-decoction
#13
Xiao Ling, Yuqiang Xiang, Qingfa Tang, Feilong Chen, Xiaomei Tan
Healthy animals are most widely used in current pharmacokinetic(PK) studies. However, neglecting the effects of specific diseases on drug absorption results in the PK parameters of those experiments not accurately reflecting in vivo drug concentration changes during treatment. In this study, an E. coli infective diarrheal minipig model was applied to explore the pharmacokinetics of Gegen Qinlian decoction (GQD). A simple and rapid ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed to determine the concentrations of the eight GQD components in minipig plasma after intragastric administration of GQD...
January 11, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28107516/liver-amp-activated-protein-kinase-is-unnecessary-for-gluconeogenesis-but-protects-energy-state-during-nutrient-deprivation
#14
Clinton M Hasenour, D Emerson Ridley, Freyja D James, Curtis C Hughey, E Patrick Donahue, Benoit Viollet, Marc Foretz, Jamey D Young, David H Wasserman
AMPK is an energy sensor that protects cellular energy state by attenuating anabolic and promoting catabolic processes. AMPK signaling is purported to regulate hepatic gluconeogenesis and substrate oxidation; coordination of these processes is vital during nutrient deprivation or pathogenic during overnutrition. Here we directly test hepatic AMPK function in regulating metabolic fluxes that converge to produce glucose and energy in vivo. Flux analysis was applied in mice with a liver-specific deletion of AMPK (L-KO) or floxed control littermates to assess rates of hepatic glucose producing and citric acid cycle (CAC) fluxes...
2017: PloS One
https://www.readbyqxmd.com/read/28107512/nonstructural-5a-protein-of-hepatitis-c-virus-interferes-with-toll-like-receptor-signaling-and-suppresses-the-interferon-response-in-mouse-liver
#15
Takeya Tsutsumi, Kazuya Okushin, Kenichiro Enooku, Hidetaka Fujinaga, Kyoji Moriya, Hiroshi Yotsuyanagi, Hideki Aizaki, Tetsuro Suzuki, Yoshiharu Matsuura, Kazuhiko Koike
The hepatitis C virus nonstructural protein NS5A is involved in resistance to the host immune response, as well as the viral lifecycle such as replication and maturation. Here, we established transgenic mice expressing NS5A protein in the liver and examined innate immune responses against lipopolysaccharide (LPS) in vivo. Intrahepatic gene expression levels of cytokines such as interleukin-6, tumor necrosis factor-α, and interferon-γ were significantly suppressed after LPS injection in the transgenic mouse liver...
2017: PloS One
https://www.readbyqxmd.com/read/28107427/serine-phosphorylation-of-slp76-is-dispensable-for-t-cell-development-but-modulates-helper-t-cell-function
#16
Victor H Navas, Céline Cuche, Andres Alcover, Vincenzo Di Bartolo
The adapter protein SLP76 is a key orchestrator of T cell receptor (TCR) signal transduction. We previously identified a negative feedback loop that modulates T cell activation, involving phosphorylation of Ser376 of SLP76 by the hematopoietic progenitor kinase 1 (HPK1). However, the physiological relevance of this regulatory mechanism was still unknown. To address this question, we generated a SLP76-S376A-expressing knock-in mouse strain and investigated the effects of Ser376 mutation on T cell development and function...
2017: PloS One
https://www.readbyqxmd.com/read/28107387/neuronal-cell-death-and-degeneration-through-increased-nitroxidative-stress-and-tau-phosphorylation-in-hiv-1-transgenic-rats
#17
Young-Eun Cho, Myoung-Hwa Lee, Byoung-Joon Song
The underlying mechanisms for increased neurodegeneration and neurocognitive deficits in HIV-infected people are unclear. Therefore, this study was aimed to investigate the mechanisms of increased neurodegeneration in 5-month old male HIV-1 Transgenic (Tg) rats compared to the age- and gender-matched wild-type (WT) by evaluating histological changes and biochemical parameters of the key proteins involved in the cell death signaling and apoptosis. Histological and immunohistochemical analyses revealed decreased neuronal cells with elevated astrogliosis in HIV-1 Tg rats compared to WT...
2017: PloS One
https://www.readbyqxmd.com/read/28107384/an-approach-to-elucidate-nbs1-function-in-dna-repair-using-frequent-nonsynonymous-polymorphism-in-wild-medaka-oryzias-latipes-populations
#18
Kento Igarashi, Junya Kobayashi, Takafumi Katsumura, Yusuke Urushihara, Kyohei Hida, Tomomi Watanabe-Asaka, Hiroki Oota, Shoji Oda, Hiroshi Mitani
Nbs1 is one of the genes responsible for Nijmegen breakage syndrome, which is marked with high radiosensitivity. In human NBS1 (hNBS1), Q185E polymorphism is known as the factor to cancer risks, although its DSB repair defect has not been addressed. Here we investigated the genetic variations in medaka (Oryzias latipes) wild populations, and found 40 nonsynonymous single nucleotide polymorphisms (SNPs) in medaka nbs1 (olnbs1) gene within 5 inbred strains. A mutation to histidine in Q170 residue in olNbs1, which corresponds to Q185 residue of hNBS1, was widely distributed in the closed colonies derived from the eastern Korean population of medaka...
2017: PloS One
https://www.readbyqxmd.com/read/28107201/homeodomain-interacting-protein-kinase-2-hipk2-a-promising-target-for-anti-cancer-therapies
#19
Yuanyuan Feng, Lihong Zhou, Xiaoting Sun, Qi Li
The HIPK2 (serine/threonine homeodomain-interacting protein kinase 2) is a "caretaker" gene, its inactivation increases tumorigenicity while its activation inhibits tumor growth. This report reviews the anti-tumorigenic mechanisms of HIPK2, which include promotion of apoptosis, inhibition of angiogenesis in hypoxia, prevention of tumor invasion/metastasis and attenuation of multidrug resistance in cancer. Additionally, we summarize conditions or factors that may increase HIPK2 activity.
January 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28106845/post-translational-modifications-of-the-tak1-tab-complex
#20
REVIEW
Yusuke Hirata, Miki Takahashi, Tohru Morishita, Takuya Noguchi, Atsushi Matsuzawa
Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family that is activated by growth factors and cytokines such as TGF-β, IL-1β, and TNF-α, and mediates a wide range of biological processes through activation of the nuclear factor-κB (NF-κB) and the mitogen-activated protein (MAP) kinase signaling pathways. It is well established that activation status of TAK1 is tightly regulated by forming a complex with its binding partners, TAK1-binding proteins (TAB1, TAB2, and TAB3)...
January 19, 2017: International Journal of Molecular Sciences
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