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Synthetic transcriptional factor

Milsee Mol, Dipali Kosey, Ramanamurthy Boppana, Shailza Singh
With the advent of synthetic biology in medicine many synthetic or engineered proteins have made their way to therapeutics and diagnostics. In this paper, the downstream gene network of CD14-TNF-EGFR pathway in leishmaniasis, a tropical disease, is reconstructed. Network analysis showed that NFkB links the signaling and gene network, used as a point of intervention through a synthetic circuit embedded within the negative autoregulatory feedback loop. A chimeric protein kinase C (PKC) is incorporated in the synthetic circuit, under the transcriptional regulation of Lac repressor and IPTG, as an inducer...
February 22, 2018: Scientific Reports
Carlotta Granchi, Filippo Minutolo
SIRT1 is a nicotinamide adenosine dinucleotide (NAD+)-dependent deacetylase, which removes acetyl groups from many target proteins, such as histone proteins, transcription factors and cofactors. SIRT1-catalyzed deacetylation of these factors modulates the activity of downstream proteins, thus influencing many biological processes. SIRT1 is involved in the regulation of metabolism, inflammation, and tumor growth. The activity of this enzyme is related to the beneficial health effects of calorie restriction, such as lifespan extension and, in particular, the activation of SIRT1 has a positive impact on the cardiovascular system...
February 13, 2018: Current Medicinal Chemistry
Vladimir S Shavva, Denis A Mogilenko, Ekaterina V Nekrasova, Andrey S Trulioff, Igor V Kudriavtsev, Ekaterina E Larionova, Anna V Babina, Ella B Dizhe, Boris V Missyul, Sergey V Orlov
Apolipoprotein A-I (ApoA-I) is the main structural and functional protein component of high-density lipoprotein. ApoA-I has been shown to regulate lipid metabolism and inflammation in macrophages. Recently, we found the moderate expression of endogenous apoA-I in human monocytes and macrophages and showed that pro-inflammatory cytokine tumor necrosis factor α (TNFα) increases apoA-I mRNA and stimulates ApoA-I protein secretion by human monocytes and macrophages. Here, we present data about molecular mechanisms responsible for the TNFα-mediated activation of apoA-I gene in human monocytes and macrophages...
February 13, 2018: Molecular and Cellular Biochemistry
Kosei Yamauchi, Tohru Mitsunaga
In a previous study, we found that both synthetic 3-O-methylquercetin (3MQ) and 3,4',7-O-trimethylquercetin (34'7TMQ) increased extracellular melanin content. 34'7TMQ increased the activity of melanogenic enzymes by stimulating the p38 pathway and the expression of microphthalmia-associated transcription factor (MITF). In contrast, 3MQ increased the activity of melanogenic enzymes without the involvement of MITF, which suggests that 3MQ inhibits the degradation of melanogenic enzymes. In the present study, we investigated the effects of 3MQ and 34'7TMQ on melanogenesis in normal human melanocytes and using a commercial three-dimensional (3D) skin model system...
February 13, 2018: Journal of Natural Medicines
Christina L Wysoczynski-Horita, Michelle E Boursier, Ryan Hill, Kirk Hansen, Helen E Blackwell, Mair E A Churchill
Pseudomonas aeruginosa is an opportunistic pathogen that uses the process of quorum sensing (QS) to coordinate the expression of many virulence genes. During quorum sensing, N-acyl-homoserine lactone (AHL) signaling molecules regulate the activity of three LuxR-type transcription factors, LasR, RhlR, and QscR. To better understand P. aeruginosa QS signal reception, we examined the mechanism underlying the response of QscR to synthetic agonists and antagonists using biophysical and structural approaches. The structure of QscR bound to a synthetic agonist reveals a novel mode of ligand binding supporting a general mechanism for agonist activity...
February 13, 2018: Molecular Microbiology
Susan E Scanlon, Denise C Hegan, Parker L Sulkowski, Peter M Glazer
The von Hippel-Lindau ( VHL ) tumor suppressor gene is inactivated in the vast majority of human clear cell renal carcinomas. The pathogenesis of VHL loss is currently best understood to occur through stabilization of the hypoxia-inducible factors, activation of hypoxia-induced signaling pathways, and transcriptional reprogramming towards a pro-angiogenic and pro-growth state. However, hypoxia also drives other pro-tumorigenic processes, including the development of genomic instability via down-regulation of DNA repair gene expression...
January 12, 2018: Oncotarget
Tie-Feng Song, Li-Wen Huang, Ying Yuan, Hui-Qin Wang, Hong-Peng He, Wen-Jian Ma, Li-Hong Huo, Hao Zhou, Nan Wang, Tong-Cun Zhang
Vascular smooth muscle cells (VSMCs), switching from a differentiated to a proliferative phenotype, contribute to various vascular diseases. However, the role of long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 MALAT1 in the phenotype switching of VSMCs remains unclear. Here, we report that the knockdown of MALAT1 promotes the transformation of smooth muscle cells from a proliferative phenotype to a differentiated phenotype. MALAT1 knockdown inhibited cellular proliferation and migration, leading to significant cell cycle arrest in the G2 phase...
January 12, 2018: Oncotarget
Stefan J Tekel, Daniel A Vargas, Lusheng Song, Joshua LaBear, Michael R Caplan, Karmella A Haynes
Fusion proteins that specifically interact with biochemical marks on chromosomes represent a new class of synthetic transcriptional regulators that decode cell state information rather than DNA sequences. In multicellular organisms, information relevant to cell state, tissue identity, and oncogenesis is often encoded as biochemical modifications of histones, which are bound to DNA in eukaryotic nuclei and regulate gene expression states. We have previously reported the development and validation of the "Polycomb-based transcription factor" (PcTF), a fusion protein that recognizes histone modifications through a protein-protein interaction between its polycomb chromodomain (PCD) motif and trimethylated lysine 27 of histone H3 (H3K27me3) at genomic sites...
February 12, 2018: ACS Synthetic Biology
I Y H Martinez, A P C Santos, M P Bottino, R E Orlandi, G Santos, L M S Simões, J C Souza, A M G Díaza, M Binelli, J N S Sales
The growth profiles of the future dominant follicle (DF) and subordinate follicle (SF) and the gene expression of the granulosa cells during luteolysis induction in Bos indicus cows were evaluated. Forty cows were synchronized with a progesterone and estradiol based protocol. After synchronization, cows with a corpus luteum (CL) were evaluated by ultrasonography every 12 h, beginning at eight days post ovulation. Cows identified with a follicle of at least 6.0 mm in diameter in the second wave were split into two groups (BD-before follicular deviation and AD-after follicular deviation...
February 2, 2018: Theriogenology
Ruomeng Qiu, Yonghui Wang
The recent success of PD-1/PD-L1 antibodies for advanced cancer treatment has led to the conclusion that activating the immune system can be employed to fight cancer. These results also encourage the development of small molecule immuno-modulators for cancer immunotherapy. RORγt is a key transcription factor mediating Th17 cell differentiation and IL-17 production, which is able to activate CD8+ T cells and elicit antitumor efficacy. Since RORγt agonists have been shown to increase basal activity of RORγt and promote Th17 cell differentiation, development of RORγt agonists could provide a unique approach to cancer immunotherapy...
February 7, 2018: Journal of Medicinal Chemistry
María I Fonseca, Melisa A Molina, Daniana Winnik, María V Busi, Julia I Fariña, Laura L Villalba, Pedro D Zapata
AIMS: Isolate and characterize a laccase-encoding gene (lac I) of Phlebia brevispora BAFC 633, as well as cloning and expressing cDNA of lac I in Pichia pastoris. And to obtain a purified and characterized recombinant laccase to analyze the biotechnological application potential. METHODS AND RESULTS: lac I was cloned and sequenced, it contains 2447 pb obtained by PCR and long-distance inverse PCR. Upstream of the structural region of the laccase gene, response elements such as metals, antioxidants, copper, nitrogen and heat-shock were found...
February 6, 2018: Journal of Applied Microbiology
Hongxing Liao, Zhixiong Zhong, Zhanliang Liu, Liangping Li, Zemin Ling, Xuenong Zou
The aim of the present study was to investigate the potential of bone mesenchymal stem cells (BMSCs) treated with a combination of vascular endothelial growth factor (VEGF) and bone morphogenetic protein-6 (BMP-6) genes for the treatment of avascular necrosis of the femoral head (ANFH). Rat BMSCs were isolated and purified using a density gradient centrifugation method. The purity and characteristics of the BMSCs were detected by cell surface antigens identification using flow cytometry. The experimental groups were administered with one of the following adeno-associated virus (AAV) vector constructs: AAV-green fluorescent protein (AAV-GFP), AAV-BMP-6, AAV-VEGF or AAV-VEGF-BMP-6...
January 2018: Experimental and Therapeutic Medicine
Jiangang Liu, Zhongjie Liu, Xiaohui Hu, Yuan Zhang, Shiming Zhang
During the development of postoperative vascular restenosis, the aberrant proliferation of vascular smooth muscle cells (VSMCs) is a critical event resulting in intimal hyperplasia. Inflammatory responses involving the activation of nuclear factor (NF)‑κB are among the major molecular processes underlying restenosis. The present study aimed to investigate the roles of NF‑κB in VSMC proliferation and restenosis following vascular anastomosis, as well as to evaluate the potential of synthetic E‑selectin to downregulate NF‑κB and thus inhibit vascular hyperplasia...
February 1, 2018: Molecular Medicine Reports
Shin Hyuk Kang, Suk Yoon Jang, Jeong Hyun Ryou, Woo Seob Kim, Han Koo Kim, Tae Hui Bae, Mi Kyung Kim
BACKGROUND: In the field of plastic surgery, capsular contracture after silicone breast implant surgery is a major clinical problem. This experimental study confirms that the synthetic tryptophan metabolite N-(3',4'-dimethoxycinnamonyl) anthranilic acid (Tranilast) reduces capsule formation and prevents capsular contracture. METHODS: Eighteen New Zealand white rabbits were divided into 2 groups. In the experimental group, implants were inserted into each rabbit, and oral synthetic tryptophan metabolite was administered daily at a dose of 5 mg/kg in 10 mL of saline...
January 31, 2018: Annals of Plastic Surgery
Evan A Heiderscheit, Asuka Eguchi, Mackenzie C Spurgat, Aseem Z Ansari
Transcription factors (TFs) reprogram cell states by exerting control over gene regulatory networks and the epigenetic landscape of a cell. Artificial transcription factors (ATFs) are designer regulatory proteins comprised of modular units that can be customized to overcome challenges faced by natural TFs in establishing and maintaining desired cell states. Decades of research on DNA-binding proteins and synthetic molecules has provided a molecular toolkit for ATF design and the construction of genome-scale libraries of ATFs capable of phenotypic manipulation and reprogramming of cell states...
February 1, 2018: FEBS Letters
Andrew K D Younger, Peter Y Su, Andrea J Shepard, Shreya V Udani, Thaddeus R Cybulski, Keith E J Tyo, Joshua N Leonard
Naturally evolved metabolite-responsive biosensors enable applications in metabolic engineering, ranging from screening large genetic libraries to dynamically regulating biosynthetic pathways. However, there are many metabolites for which a natural biosensor does not exist. To address this need, we developed a general method for converting metabolite-binding proteins into metabolite-responsive transcription factors-Biosensor Engineering by Random Domain Insertion (BERDI). This approach takes advantage of an in vitro transposon insertion reaction to generate all possible insertions of a DNA-binding domain into a metabolite-binding protein, followed by fluorescence activated cell sorting to isolate functional biosensors...
January 29, 2018: Protein Engineering, Design & Selection: PEDS
Ulla Dolde, Vandasue Rodrigues, Daniel Straub, Kaushal Bhati, Sukwon Choi, Seong Wook Yang, Stephan Wenkel
MicroProteins are small, single-domain proteins that can regulate multi-domain proteins by sequestering them into novel, often non-productive complexes. In the past years, several microProteins have been identified in plants and animals, most of which negatively regulate transcription factors. Novel microProtein candidates that potentially target a wide range of different protein classes, were recently identified in a computational approach. Here, we identify and classify all Arabidopsis microProteins and developed a synthetic microProtein approach to target specific protein classes, such as hydrolases, receptors and lyases in a proof-of-concept approach...
January 30, 2018: Plant Physiology
Zhipeng Wang, Davit A Potoyan, Peter G Wolynes
BACKGROUND: Transfection of NF κB synthetic decoy Oligodeoxynucleotides (ODNs) has been proposed as a promising therapeutic strategy for a variety of diseases arising from constitutive activation of the eukaryotic transcription factor NF κB. The decoy approach faces some limitations under physiological conditions notably nuclease-induced degradation. RESULTS: In this work, we show how a systems pharmacology model of NF κB regulatory networks displaying oscillatory temporal dynamics, can be used to predict quantitatively the dependence of therapeutic efficacy of NF κB synthetic decoy ODNs on dose, unbinding kinetic rates and nuclease-induced degradation rates...
January 30, 2018: BMC Systems Biology
Courtney A Waugh, Augustine Arukwe, Veerle L B Jaspers
Polychlorinated biphenyls (PCBs), and similar environmental contaminants, have been linked to virus outbreaks and increased viral induced mortality since the 1970s. Yet the mechanisms behind this increased susceptibility remain elusive. It has recently been illustrated that the innate immune viral detection system is tightly regulated by small non-coding RNAs, including microRNAs (miRNAs). For virus infections miRNA-155 expression is an important host response against infection, and deregulation of this miRNA is closely associated with adverse outcomes...
January 30, 2018: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
Laura C Bohorquez, Katarina Surdova, Martijs J Jonker, Leendert W Hamoen
The DNA binding protein WhiA is conserved in Gram-positive bacteria, and is also present in the genetically simple, cell wall-lacking, mycoplasmas. The protein shows homology to eukaryotic homing endonucleases but lacks nuclease activity. WhiA was first characterized in streptomycetes, where it regulates expression of key differentiation genes, including the cell division gene ftsZ essential for sporulation. For Bacillus subtilis it was shown that WhiA is essential when certain cell division genes are deleted...
January 29, 2018: Journal of Bacteriology
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