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Molecular targeting

Rag da Silva, C P Churchward, A V Karlyshev, O Eleftheriadou, A K Snabaitis, M R Longman, A Ryan, R Griffin
BACKGROUND AND PURPOSE: The level of cell surface expression of the meningococcal vaccine antigen, Factor H binding protein (FHbp) varies between and within strains and this limits the breadth of strains that can be targeted by FHbp-based vaccines. The molecular pathway dictating expression of FHbp at the cell surface, including its lipidation, sorting to the outer membrane and export, and the potential regulation of this pathway have not been investigated until now. This knowledge will aid our evaluation of FHbp vaccines...
October 26, 2016: British Journal of Pharmacology
Peter Sandner, Peter Berger, Christoph Zenzmaier
Fibrotic diseases cause high rates of morbidity and mortality, and their incidence increases with age. Despite intense research and development efforts, effective and well-tolerated antifibrotic treatments are scarce. Transforming growth factor-β signaling, which is widely considered the most important profibrotic factor, causes a pro-oxidant shift in redox homeostasis and a concomitant decrease in nitric oxide (NO) signaling. The NO/cyclic guanosine monophosphate (cGMP) signaling cascade plays a pivotal role in the regulation of cell and organ function in whole-body hemostasis...
October 27, 2016: Gerontology
Yiqing Pan, Yue Liu, Li Wang, Feng Xue, Yanqin Hu, Ran Hu, Chen Xu
Sertoli cells create a local tolerogenic microenvironment to maintain testicular immune privilege especially through the formation of a blood-testis barrier (BTB). However, the molecular mechanisms underlying the immune modulation function and BTB dynamics of Sertoli cells remained elusive. MAP phosphatase (MKP)-1 acts as a crucial negative regulator of the inflammatory response. Nevertheless, the role of MKP-1 in regulating Sertoli cells has not been elucidated. In this study, we have for the first time uncovered distinct cellular localization of MKP-1 in the cells at different stages of mouse testis, and the level of MKP-1 expression was significantly up-regulated by LPS-induced acute testis inflammation...
October 22, 2016: Oncotarget
Ju Hui Jeong, Yong Jin Oh, Yunmee Lho, Sun You Park, Kwang-Hyeon Liu, Eunyoung Ha, Young Ho Seo
The molecular chaperone Hsp90 plays an important role in cancer cell survival and proliferation by regulating the maturation and stabilization of numerous oncogenic proteins. Due to its potential to simultaneously disable multiple signaling pathways, Hsp90 has emerged as an attractive therapeutic target for cancer treatment. In this study, the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors are described. Among the synthetic compounds, 6,7-dihydrothieno [3,2-c]pyridin-5(4H)-yl amide 19 exhibits a remarkable binding affinity to the N-terminus of Hsp90 in a fluorescence polarization (FP) binding assay (IC50 = 50...
October 18, 2016: European Journal of Medicinal Chemistry
Timothy J Ritchie, Simon J F Macdonald
The impact of replacing a mono-substituted benzene (phenyl) ring with thirty three aromatic and nine aliphatic heterocycles on nine ADME-related screens (solubility, lipophilicity, permeability, protein binding CYP450 inhibition and metabolic clearance) was assessed using matched molecular pair analysis. The results indicate that the influence on the ADME profile can differ significantly depending on the ring identity and importantly on the individual regioisomers that are possible for some rings. This information enables the medicinal chemist to make an informed choice about which rings and regioisomers to employ as mono-substituted benzene replacements, based upon the knowledge of how such replacements are likely to influence ADME-related parameters, for example to target higher solubility whilst avoiding CYP450 liabilities...
October 15, 2016: European Journal of Medicinal Chemistry
Shanshan Li, Wenda Zhang, Yanwei Yang, Ting Ma, Jianpeng Guo, Shanshan Wang, Wenying Yu, Lingyi Kong
Constitutive activation of STAT3 has been found in a wide variety of cancers and demonstrated as a very attractive therapeutic target. Disrupting both acetylation and phosphorylation of STAT3 protein was hypothesized to greatly deactivate STAT3, therefore, treating cancers. To demonstrate the hypothesis, two series of novel resveratrol-caffeic acid hybrids were designed aiming to regulate both acetylation and phosphorylation of STAT3 protein, which is also the first report of the synthetic inhibitors simultaneously regulating two biological reactions of STAT3 to our knowledge...
October 15, 2016: European Journal of Medicinal Chemistry
Jocelyn P Wong, Jason R Todd, Martina A Finetti, Frank McCarthy, Malgorzata Broncel, Simon Vyse, Maciej T Luczynski, Stephen Crosier, Karen A Ryall, Kate Holmes, Leo S Payne, Frances Daley, Patty Wai, Andrew Jenks, Barbara Tanos, Aik-Choon Tan, Rachael C Natrajan, Daniel Williamson, Paul H Huang
Subunits of the SWI/SNF chromatin remodeling complex are mutated in a significant proportion of human cancers. Malignant rhabdoid tumors (MRTs) are lethal pediatric cancers characterized by a deficiency in the SWI/SNF subunit SMARCB1. Here, we employ an integrated molecular profiling and chemical biology approach to demonstrate that the receptor tyrosine kinases (RTKs) PDGFRα and FGFR1 are coactivated in MRT cells and that dual blockade of these receptors has synergistic efficacy. Inhibitor combinations targeting both receptors and the dual inhibitor ponatinib suppress the AKT and ERK1/2 pathways leading to apoptosis...
October 25, 2016: Cell Reports
Karla A Mark, Kathleen J Dumas, Dipa Bhaumik, Birgit Schilling, Sonnet Davis, Tal Ronnen Oron, Dylan J Sorensen, Mark Lucanic, Rachel B Brem, Simon Melov, Arvind Ramanathan, Bradford W Gibson, Gordon J Lithgow
Vitamin D has multiple roles, including the regulation of bone and calcium homeostasis. Deficiency of 25-hydroxyvitamin D, the major circulating form of vitamin D, is associated with an increased risk of age-related chronic diseases, including Alzheimer's disease, Parkinson's disease, cognitive impairment, and cancer. In this study, we utilized Caenorhabditis elegans to examine the mechanism by which vitamin D influences aging. We found that vitamin-D3-induced lifespan extension requires the stress response pathway genes skn-1, ire-1, and xbp-1...
October 25, 2016: Cell Reports
Georgios N Panagopoulos, Panayiotis D Megaloikonomos, Andreas F Mavrogenis
Peripheral nerve injury can have a potentially devastating impact on a patient's quality of life, resulting in severe disability with substantial social and personal cost. Refined microsurgical techniques, advances in peripheral nerve topography, and a better understanding of the pathophysiology and molecular basis of nerve injury have all led to a decisive leap forward in the field of translational neurophysiology. Nerve repair, nerve grafting, and nerve transfers have improved significantly with consistently better functional outcomes...
October 25, 2016: Orthopedics
Marc B Anglès d'Auriac
Avoiding complementarity between primers when designing a PCR assay constitutes a central rule strongly anchored in the mind of the molecular scientist. 3'-complementarity will extend the primers during PCR elongation using one another as template, consequently disabling further possible involvement in traditional target amplification. However, a 5'-complementarity will leave the primers unchanged during PCR cycles, albeit sequestered to one another, therefore also suppressing target amplification. We show that 5'-complementarity between primers may be exploited in a new PCR method called COMplementary-Primer-Asymmetric (COMPAS)-PCR, using asymmetric primer concentrations to achieve target PCR amplification...
2016: PloS One
Anders Lundgren, Björn Agnarsson, Ronald Zirbs, Vladimir P Zhdanov, Erik Reimhult, Fredrik Höök
Emerging biomedical applications such as molecular imaging and drug delivery often require directed binding of nanoparticles to cell-membrane receptors. The specific apparent affinity of such ligand-functionalized particles is size-dependent, an observation so far solely attributed to multivalent receptor-ligand interaction. We question the universality of this explanation by demonstrating that the binding kinetics also depends on weak, attractive colloidal-type interaction between nanoparticles and a lipid membrane...
October 26, 2016: ACS Nano
Huabing Wang, Lisa Lang, Derek Thomas Logan, Jens Danielsson, Mikael Oliveberg
Despite continuing interest in partly unfolded proteins as precursors for aggregation and adverse gain-of-function in human disease, there is yet little known about the local transitions of native structures that possibly lead to such intermediate states. To target this problem, we present here a protein-design strategy that allows real-time detection of rupture and swapping of complete secondary-structure elements in globular proteins: molecular events that have previously been inaccessible experimental analysis...
October 26, 2016: Journal of the American Chemical Society
Junhui Zhang, Dongxia Zhang, Tiantian Yan, Xupin Jiang, Can Zhang, Liping Zhao, Lingfei Li, Di Tang, Qiong Zhang, Jiezhi Jia, Jiaping Zhang, Yuesheng Huang
The migration of keratinocytes from wound margins plays a critical role in the re-epithelialization of skin wounds. Hypoxia occurs immediately after injury and acts as an early stimulus to initiate the healing processes. Although our previous studies have revealed that hypoxia promotes keratinocyte migration, the precise mechanisms involved remain unclear. Here, we found that BNIP3 expression was up-regulated in hypoxic keratinocytes, and BNIP3 silencing suppressed hypoxia-induced cell migration. Additionally, hypoxia activated the FAK pathway through up-regulation of BNIP3, while FAK inhibition attenuated hypoxic keratinocyte migration...
October 26, 2016: Experimental Dermatology
Cenk Daglioglu, Burcu Okutucu
PURPOSE: Resistance to chemotherapy is one of the major problems facing current cancer research. Enhancing tumor cell response to anticancer agents increases chemotherapeutic effectiveness. We have recently addressed this issue and reported on producing multifunctional nanoparticles (Fe3O4@SiO2(FITC)-FA/AICAR/DOX) aiming to overcome chemoresistance with synergetic effect of AICAR and DOX. In the present study, we demonstrated that these nanoparticles not only show enhanced cellular uptake and cytotoxic effect but can also show enhanced pro-apoptotic and anti-proliferative effects in five different tumor-derived cell lines (A549, HCT-116, HeLa, Jurkat and MIA PaCa-2)...
October 25, 2016: Pharmaceutical Research
Yannis M Paulus, Akrit Sodhi
Recent breakthroughs in our understanding of the molecular pathophysiology of retinal vascular disease have allowed us to specifically target pathological angiogenesis while minimizing damage to the neurosensory retina. This is perhaps best exemplified by the development of therapies targeting the potent angiogenic growth factor and vascular permeability mediator, vascular endothelial growth factor (VEGF). Anti-VEGF therapies, initially introduced for the treatment of choroidal neovascularization in patients with age-related macular degeneration, have also had a dramatic impact on the management of retinal vascular disease and are currently an indispensable component for the treatment of macular edema in patients with diabetic eye disease and retinal vein occlusions...
October 26, 2016: Handbook of Experimental Pharmacology
Cheng Ye, Duo Zhang, Lei Zhao, Yan Li, Xiaohan Yao, Hui Wang, Shengjie Zhang, Wei Liu, Hongchao Cao, Shuxian Yu, Yucheng Wang, Jingjing Jiang, Hui Wang, Xihua Li, Hao Ying
Skeletal muscle has a major role in locomotion and muscle disorders are associated with poor regenerative efficiency. Therefore, a deeper understanding of muscle regeneration is needed to provide a new insight for new therapies. CaMKK2 plays a role in the calcium/calmodulin-dependent kinase cascade; however, its role in skeletal muscle remains unknown. Here, we found that CaMKK2 expression levels were altered under physiological and pathological conditions including postnatal myogensis, freeze or cardiotoxin-induced muscle regeneration, and Duchenne muscular dystrophy...
October 24, 2016: International Journal of Molecular Sciences
Charanya Sampathkumar, Yuan-Ju Wu, Mayur Vadhvani, Thorsten Trimbuch, Britta Eickholt, Christian Rosenmund
Mutations in the MECP2 gene cause the neurodevelopmental disorder Rett syndrome (RTT). Previous studies have shown that altered MeCP2 levels result in aberrant neurite outgrowth and glutamatergic synapse formation. However, causal molecular mechanisms are not well understood since MeCP2 is known to regulate transcription of a wide range of target genes. Here, we describe a key role for a constitutive BDNF feed forward signaling pathway in regulating synaptic response, general growth and differentiation of glutamatergic neurons...
October 26, 2016: ELife
Tracy L Stockley, Amit M Oza, Hal K Berman, Natasha B Leighl, Jennifer J Knox, Frances A Shepherd, Eric X Chen, Monika K Krzyzanowska, Neesha Dhani, Anthony M Joshua, Ming-Sound Tsao, Stefano Serra, Blaise Clarke, Michael H Roehrl, Tong Zhang, Mahadeo A Sukhai, Nadia Califaretti, Mateya Trinkaus, Patricia Shaw, Theodorus van der Kwast, Lisa Wang, Carl Virtanen, Raymond H Kim, Albiruni R A Razak, Aaron R Hansen, Celeste Yu, Trevor J Pugh, Suzanne Kamel-Reid, Lillian L Siu, Philippe L Bedard
BACKGROUND: The clinical utility of molecular profiling of tumor tissue to guide treatment of patients with advanced solid tumors is unknown. Our objectives were to evaluate the frequency of genomic alterations, clinical "actionability" of somatic variants, enrollment in mutation-targeted or other clinical trials, and outcome of molecular profiling for advanced solid tumor patients at the Princess Margaret Cancer Centre (PM). METHODS: Patients with advanced solid tumors aged ≥18 years, good performance status, and archival tumor tissue available were prospectively consented...
October 25, 2016: Genome Medicine
Eun-Sang Cho, Jin-Mu Yi, Jong-Shik Park, You Jin Lee, Chae Jun Lim, Ok-Sun Bang, No Soo Kim
BACKGROUND: Oxaliplatin can induce peripheral neuropathy (OXIPN) as an adverse side effect in cancer patients. Until now, no effective preventive or therapeutic drug has been developed; therefore, the dose-limiting factor of OXIPN is still an obstacle in the use of oxaliplatin to treat cancer patients. In the present study, we report for the first time that the aqueous extract of Lithospermi radix (WLR) can attenuate the OXIPN in both in vitro and in vivo neuropathic models. METHODS: The protective effect of WLR on OXIPN was evaluated in vitro by quantifying nerve growth factor (NGF)-stimulated neurite outgrowth in PC12 cells treated with a combination of oxaliplatin and WLR...
October 26, 2016: BMC Complementary and Alternative Medicine
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
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