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Activator protein 1

Antonia Lanni, Maria Moreno, Fernando Goglia
The hypermetabolic effects of thyroid hormones (THs), the major endocrine regulators of metabolic rate, are widely recognized. Although, the cellular mechanisms underlying these effects have been extensively investigated, much has yet to be learned about how TH regulates diverse cellular functions. THs have a profound impact on mitochondria, the organelles responsible for the majority of cellular energy production, and several studies have been devoted to understand the respective importance of the nuclear and mitochondrial pathways for organelle activity...
September 15, 2016: Comprehensive Physiology
Virginia G Perdomo, Juan P Rigalli, Marcelo G Luquita, José M Pellegrino, María Laura Ruiz, Viviana A Catania
The effect of benznidazole (BZL) on the expression and activity of P-glycoprotein (P-gp, ABCB1) and multidrug resistance-associated protein 2 (MRP2, ABCC2), the two major transporters of endogenous and exogenous compounds, was evaluated in differentiated THP-1 cells. BZL induced P-gp and MRP2 proteins in a concentration-dependent manner. The increase in mRNA levels of both transporters suggests transcriptional regulation. P-gp and MRP2 activities correlated with increased protein levels. BZL intracellular accumulation was significantly lower in BZL-pre-treated cells than in control cells...
October 24, 2016: Memórias do Instituto Oswaldo Cruz
Yukihide Koyama, Tomio Andoh, Yoshinori Kamiya, Tomoyuki Miyazaki, Koichi Maruyama, Takayuki Kariya, Takahisa Goto
Gamma-aminobutyric acid (GABA) has been shown to induce excitation on immature neurons due to increased expression of Na+-K+-2Cl- co-transporter isoform 1 (NKCC1), and the transition of GABAergic signaling from excitatory to inhibitory occurs before birth in the rat spinal cord and spreads rostrally according to the developmental changes in cation-chloride co-transporter expression. We previously showed that midazolam activates the hippocampal CA3 area and induces less sedation in neonatal rats compared with adolescent rats in an NKCC1-dependent manner...
2016: PloS One
Xingyue Ji, Jinhua Chen, Guang-Hui Zheng, Meng-Hao Huang, Lei Zhang, Jie Jin, Hong Yi, Jian-Dong Jiang, Zong-Gen Peng, Zhuo-Rong Li
There still remains a need to develop new anti-HCV agents with distinct mechanism of action (MOA) due to the occurrence of resistance to direct-acting antiviral agents (DAAs). Cajanine, a stilbenic component isolated from Cajanus cajan L., was identified as a potent HCV inhibitor by phenotypic screening in this work (EC50 = 3.17±0.75 μM). The intensive structure optimization provided significant insights into the structure-activity relationships. Furthermore, the MOA study revealed that cajanine inhibited HCV replications via down-regulating a cellular protein chondroitin sulfate N-acetylgalactosaminyltransferase 1...
October 26, 2016: Journal of Medicinal Chemistry
Travis S Hughes, Jinsai Shang, Richard Brust, Ian Mitchelle S de Vera, Jakob Fuhrmann, Claudia Ruiz, Michael D Cameron, Theodore M Kamenecka, Douglas J Kojetin
In a previous study, a co-crystal structure of PPARγ bound to 2-chloro-N-(3-chloro-4-((5-chlorobenzo[d]thiazol-2-yl)thio)phenyl)-4-(trifluoromethyl)benzenesulfonamide (1, T2384) revealed two orthosteric pocket binding modes attributed to a concentration-dependent biochemical activity profile. However, 1 also bound an alternate/allosteric site that could alternatively account for the profile. Here, we show ligand aggregation afflicts the activity profile of 1 in biochemical assays. However, ligand-observed fluorine (19F) and protein-observed NMR confirms 1 binds PPARγ with two orthosteric binding modes and an allosteric site...
October 26, 2016: Journal of Medicinal Chemistry
Caijuan Wang, Hiroshi Yamamoto, Fumika Narumiya, Yuri Nakajima Munekage, Giovanni Finazzi, Ildiko Szabo, Toshiharu Shikanai
KEA3 is a thylakoid membrane localized K(+) /H(+) antiporter and regulates photosynthesis by modulating two components of proton motive force (pmf), the proton gradient (∆pH) and the electric potential (∆ψ). We identified a mutant allele of KEA3, disturbed proton gradient regulation (dpgr) based on its reduced non-photochemical quenching (NPQ) in artificial (CO2 -free with low O2 ) air. This phenotype was enhanced in the mutant backgrounds of PSI cyclic electron transport (pgr5 and crr2-1). In ambient air, reduced NPQ was observed during induction of photosynthesis in dpgr, the phenotype that was enhanced after overnight dark adaptation...
October 26, 2016: Plant Journal: for Cell and Molecular Biology
Binh Thanh Nguyen, Min Park, Jae-Chul Pyun, Young Sook Yoo, Min-Jung Kang
An assay for protein kinase C delta (PKCδ) activity based on the quantification of a synthetic substrate using capillary electrophoresis with laser-induced fluorescence detection was developed. The peptides labeled with fluorescein isothiocyanate F-ERK (where ERK is extracellular signal-regulated kinase) and the phosphorylated form, P-F-ERK, were utilized for the method development and validation. The migration time of F-ERK and P-F-ERK were 6.3 ± 0.1 and 8.7 ± 0.2 min, respectively. LOD and LOQ values of F-ERK were 2 and 6 ng/mL and those of P-F-ERK were 4 and 12 ng/mL...
October 26, 2016: Electrophoresis
Laura M Tanner, Johanna Kurko, Maaria Tringham, Heikki Aho, Juha Mykkänen, Kirsti Näntö-Salonen, Harri Niinikoski, Heikki Lukkarinen
Pulmonary alveolar proteinosis (PAP) is a potentially fatal complication of lysinuric protein intolerance (LPI), an inherited disorder of cationic amino acid transport. The patients often present with mild respiratory symptoms, which may rapidly progress to acute respiratory failure responding poorly to conventional treatment with steroids and bronchoalveolar lavations (BALs). The pathogenesis of PAP in LPI is still largely unclear. In previous studies, we have shown disturbances in the function and activity of alveolar macrophages of these patients, suggesting that increasing the activity and the number of macrophages by recombinant human GM-CSF (rhuGM-CSF) might be beneficial in this patient group...
October 26, 2016: JIMD Reports
Kit Man Wong, Lindsey N Micel, Heather M Selby, Aik Choon Tan, Todd M Pitts, Stacey M Bagby, Anna Spreafico, Peter J Klauck, Stephen J Blakemore, Peter F Smith, Alice McDonald, Allison Berger, John J Tentler, S Gail Eckhardt
Background The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma. Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, respectively, to identify sensitive/resistant models...
October 25, 2016: Investigational New Drugs
Yang Chen, Lei Wang, Ashley L Pitzer, Xiang Li, Pin-Lan Li, Yang Zhang
: Recent studies indicate that inflammasomes serve as intracellular machinery to initiate classical cytokine-mediated inflammatory responses and play a crucial role in the pathogenesis of cardiovascular diseases. However, whether or not the activation of endothelial inflammasomes directly causes cell dysfunction or tissue injury without recruitment of inflammatory cells is unknown. We explored the role of endothelial cell inflammasome activation in mediating tight junction disruption, a hallmark event of endothelial barrier dysfunction leading to endothelial hyperpermeability in diabetes...
October 25, 2016: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Yong Huang, Jinxiu Huang, Renli Qi, Qi Wang, Yongjiang Wu, Jing Wang
MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate growth, development, and programmed death of cells. A newly-published study has shown that miRNA-23a could regulate 3T3-L1 adipocyte differentiation. Here, we identified miRNA-23a as a negative regulator of 3T3-L1 adipocyte differentiation again. Over-expression of miRNA-23a inhibited differentiation and decreased lipogenesis as well as down-regulated mRNA and protein expression of both peroxisome proliferator-activated receptor (PPAR) γ and fatty acid binding protein (FABP) 4, whereas knock down of miRNA-23a showed the opposite effects on differentiation as well as increasing the number of apoptotic cells...
October 24, 2016: Genes
Haijun Liu, Shencun Fang, Wei Wang, Yusi Cheng, Yingming Zhang, Hong Liao, Honghong Yao, Jie Chao
BACKGROUND: Silicosis is characterized by accumulation of fibroblasts and excessive deposition of extracellular matrix. Monocyte chemotactic protein-1-induced protein 1 (MCPIP1) plays a critical role in fibrosis induced by SiO2. However, the details of the downstream events of MCPIP1 activity in pulmonary fibrosis remain unclear. To elucidate the role of MCPIP1-induced autophagy in SiO2-induced fibrosis, both the upstream molecular mechanisms and the functional effects of SiO2 on cell apoptosis, proliferation and migration were investigated...
October 25, 2016: Particle and Fibre Toxicology
Ximena Corso-Díaz, Charles N de Leeuw, Vivian Alonso, Diana Melchers, Bibiana K Y Wong, René Houtman, Elizabeth M Simpson
BACKGROUND: NR2E1 (Tlx) is an orphan nuclear receptor that regulates the maintenance and self-renewal of neural stem cells, and promotes tumourigenesis. Nr2e1-null mice exhibit reduced cortical and limbic structures and pronounced retinal dystrophy. NR2E1 functions mainly as a repressor of gene transcription in association with the co-repressors atrophin-1, LSD1, HDAC and BCL11A. Recent evidence suggests that NR2E1 also acts as an activator of gene transcription. However, co-activator complexes that interact with NR2E1 have not yet been identified...
October 26, 2016: BMC Genomics
Christian Brinkmann, Benedikt Schulte-Körne, Marijke Grau, Sinja Obels, Roman Kemmerling, Thorsten Schiffer, Wilhelm Bloch, Klara Brixius
BACKGROUND: Increases in the amount of inducible nitric oxide synthase (iNOS) protein and abnormal production of nitric oxide (NO) in skeletal muscle have been suggested to be associated with peripheral insulin resistance in patients with type 2 diabetes mellitus (T2DM). This pilot study analyzed whether a 3-month endurance training can affect iNOS protein and NO metabolite levels in the vastus lateralis muscle of insulin-independent T2DM men, thereby affecting the patients` glycemic control...
October 26, 2016: Metabolic Syndrome and related Disorders
Saswat Mohapatra, Abhijit Saha, Prasenjit Mondal, Batakrishna Jana, Subhajit Ghosh, Atanu Biswas, Surajit Ghosh
Microtubule dynamics play a crucial role in cancer cell division. Various drugs are developed to target microtubule. Although a few of them show potential in treatment of cancer, but success rate is limited due to their poor bioavailability and lack of specificity. Thus, development of highly bioavailable and target specific anticancer drug is extremely necessary. To address these key issues, here, a combination of approaches such as development of a dodecapeptide-docetaxel nanoassembly targeted to tubulin and MUC1 (mucin 1, cell surface associated glycoprotein) targeting oligonucleotide aptamer conjugated liposome for delivering peptide-docetaxel nanoassembly into the breast cancer cell have been demonstrated...
October 26, 2016: Advanced Healthcare Materials
Peter Garred, Ninette Genster, Katrine Pilely, Rafael Bayarri-Olmos, Anne Rosbjerg, Ying Jie Ma, Mikkel-Ole Skjoedt
Mannose-binding lectin (MBL), collectin-10, collectin-11, and the ficolins (ficolin-1, ficolin-2, and ficolin-3) are soluble pattern recognition molecules in the lectin complement pathway. These proteins act as mediators of host defense and participate in maintenance of tissue homeostasis. They bind to conserved pathogen-specific structures and altered self-antigens and form complexes with the pentraxins to modulate innate immune functions. All molecules exhibit distinct expression in different tissue compartments, but all are found to a varying degree in the circulation...
November 2016: Immunological Reviews
Ryan Pekson, Vladimir Poltoratsky, Samir Gorasiya, Sruthi Sundaram, Charles R Ashby, Ivana Vancurova, Sandra E Reznik
Previously, we have shown that N,N-dimethylacetamide (DMA) prevents inflammation-induced preterm birth in a murine model, inhibits LPS-induced increases in placental pro-inflammatory cytokines and up-regulates the anti-inflammatory cytokine Interleukin-10 (IL-10). However, DMA's mechanism of action remains to be elucidated. In the current study we investigate how DMA produces its anti-inflammatory effect. Using in vitro and ex vivo models, we show that DMA suppresses secretion of pro-inflammatory cytokines in lipopolysaccharide (LPS)-induced RAW 264...
October 24, 2016: Molecular Medicine
Vincent Kuek, Zhifan Yang, Shek Man Chim, Sipin Zhu, Huazi Xu, Siu To Chow, Jennifer Tickner, Vicki Rosen, Wendy Erber, Xiucheng Li, Qin An, Yu Qian, Jiake Xu
Angiogenesis plays an important role in bone development and remodeling and is mediated by a plethora of potential angiogenic factors. However, data regarding specific angiogenic factors that are secreted within the bone microenvironment to regulate osteoporosis is lacking. Here, we report that Nephronectin (NPNT), a member of the epidermal growth factor (EGF) repeat superfamily proteins and a homologue of EGFL6, is expressed in osteoblasts. Intriguingly, the gene expression of NPNT is reduced in the bone of C57BL/6J ovariectomised mice and in osteoporosis patients...
October 26, 2016: Scientific Reports
Michael Christensen, Jonas B Jensen, Steen Jakobsen, Niels Jessen, Jørgen Frøkiær, Bruce E Kemp, Allison L Marciszyn, Hui Li, Núria M Pastor-Soler, Kenneth R Hallows, Rikke Nørregaard
The type-2 diabetes drug metformin has proven to have protective effects in several renal disease models. Here, we investigated the protective effects in a 3-day unilateral ureteral obstruction (3dUUO) mouse model. Compared with controls, ureteral obstructed animals displayed increased tubular damage and inflammation. Metformin treatment attenuated inflammation, increased the anti-oxidative response and decreased tubular damage. Hepatic metformin uptake depends on the expression of organic cation transporters (OCTs)...
October 26, 2016: Scientific Reports
Anna Pérez-Bosque, Lluïsa Miró, Concepció Amat, Javier Polo, Miquel Moretó
Spray-dried preparations from porcine and bovine plasma can alleviate mucosal inflammation in experimental models and improve symptoms in patients with enteropathy. In rodents, dietary supplementation with porcine spray-dried plasma (SDP) attenuates intestinal inflammation and improves the epithelial barrier function during intestinal inflammation induced by Staphylococcus aureus enterotoxin B (SEB). The aim of this study was to discern the molecular mechanisms involved in the anti-inflammatory effects of SDP...
October 22, 2016: Nutrients
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