- Structure-activity relationship study of NPP1 inhibitors based on uracil-N1-(methoxy)ethyl-β-phosphate scaffold. [Journal Article]Eur J Med Chem 2019; 184:111754EJ
- Overexpression of ecto-nucleotide pyrophosphatase-1 (NPP1) is associated with diseases such as calcium pyrophosphate dihydrate deposition disease, calcific aortic valve disease, and type 2 diabetes. In this context, NPP1 inhibitors are potential drug candidates for the treatment of these diseases. The present study focuses on the analysis of the structure-activity relationship of NPP1 inhibitors …
Overexpression of ecto-nucleotide pyrophosphatase-1 (NPP1) is associated with diseases such as calcium pyrophosphate dihydrate deposition disease, calcific aortic valve disease, and type 2 diabetes. In this context, NPP1 inhibitors are potential drug candidates for the treatment of these diseases. The present study focuses on the analysis of the structure-activity relationship of NPP1 inhibitors based on acyclic uracil-nucleotides. For this purpose, we synthesized acyclic uridine-monophosphate analogs, 10-11, uridine-diphosphate analogs, 12-14, and uridine-Pα,α-dithio-triphosphate analogs, 15-17. We evaluated their inhibitory activity and selectivity towards NPP1, -3, NTPDase1, -2, -3, and -8, and P2Y2,4,6 receptors. Analogs 16 and 17 were the most selective and potent NPP1 inhibitors (Ki 0.94 and 0.73 μM, respectively) among the tested molecules. Analogs 10-17 had only minute effect on uracil-nucleotide responding P2Y2,4,6 receptors. Analog 17 (100 μM) displayed 96% inhibition of NPPase activity in osteoarthritic human chondrocytes. Analogs 14-17 displayed weak inhibitory effect on alkaline phosphatase activity at equimolar concentrations in human chondrocytes. All tested analogs showed no toxicity at human chondrocytes. We concluded that ribose-ring to chain transformation, as well as the type of the nucleobase, are parameters of minor significance to NPP1 inhibition, whereas the major parameter is Pα-dithio-substitution. In addition, the length of the phosphate chain also significantly affects inhibition. Overall, the experimental results were well reproduced by molecular docking. A correlation was observed between the activities of the compounds and the number of H-bonds and salt bridges formed between the inhibitors and NPP1 binding site residues. Uracil-N1-(methoxy)ethyl-β-Pα,α-dithio, Pβ,γ-methylene tri-phosphate, 17, was identified as the most potent, selective, and non-toxic NPP1 inhibitor among the tested analogs, and may be used as a lead structure for further drug development.
- LncRNA-MALAT1 promotes tumorogenesis of infantile hemangioma by competitively binding miR-424 to stimulate MEKK3/NF-κB pathway. [Journal Article]Life Sci 2019; :116946LS
- CONCLUSIONS: MALAT1 promoted the IH progression through inhibiting miR-424 to activate MEKK3-mediated IKK/NF-κB pathway, suggesting that MALAT1, miR-424 and MEKK3 could be used as potential targets to improve IH treatment efficiency.
- A platform for screening abiotic/biotic interactions using indicator displacement assays. [Journal Article]Langmuir 2019L
- This paper describes novel adaptations of optically sectioned planar format assays to screen compounds for their affinities to materials surfaces. The novel platform, which we name Optical sectioned Indicator Displacement Assays (O-IDA), makes use of displaceable dyes in a format adaptable to high-throughput multi-well plate technologies. We describe two approaches; in the first the dye exhibits …
This paper describes novel adaptations of optically sectioned planar format assays to screen compounds for their affinities to materials surfaces. The novel platform, which we name Optical sectioned Indicator Displacement Assays (O-IDA), makes use of displaceable dyes in a format adaptable to high-throughput multi-well plate technologies. We describe two approaches; in the first the dye exhibits fluorescence in both the surface-bound and unbound state. In the second, fluorescence is lost upon displacement of the dye from the surface. Half maximal inhibitory concentration (IC50), binding affinity (Ki), and binding free energy (Gads) values can be extracted from the raw data. Representative biomolecules were tested for interactions with silica in aqueous environment and ZnO (0001)-Zn and (10-10) facets in a non-aqueous environment. We provide the first experimental values for both the binding of small molecules to silica and the facet-dependent ZnO binding affinity of key amino acids associated with ZnO-specific oligopeptides. The specific data will be invaluable to those studying interactions at interfaces both experimentally and computationally. O-IDA provides a general framework for the high-throughput screening of molecules binding to materials surfaces, which has important applications in drug delivery, (bio-) catalysis, biosensing and biomaterials engineering.
- Utility of YWHAE fluorescent in-situ hybridisation in mesenchymal tumors of uterus- An initial experience from tertiary oncology centre in India. [Journal Article]Indian J Cancer 2019 Oct-Dec; 56(4):335-340IJ
- CONCLUSIONS: HGESSs are defined by the presence of YWHAE rearrangement. These tumors present at higher stage and have poorer prognosis. They may not respond to hormonal therapy and may be treated with chemotherapy. Cyclin D1 though not specific remains a sensitive tool to triage endometrial stromal sarcomas for this FISH study.
- Risk factors for post-operative complications after sentinel lymph node biopsy for cutaneous melanoma: Results from a large cohort study. [Journal Article]J Plast Reconstr Aesthet Surg 2019JP
- CONCLUSIONS: Complications after SLN biopsy affect 12.3% of patients. Our results suggest that patients with diabetes, who had inguinal SLN biopsy and who were male have increased risk, and this might warrant more intense post-operative surveillance.
- [Effect of P53 Expression on Prognosis of Patients with Double Expressor Lymphoma]. [Journal Article]Zhongguo Shi Yan Xue Ye Xue Za Zhi 2019; 27(5):1504-1514ZS
- CONCLUSIONS: P53 and MYC expressions have a synergistically negative prognostic effect in DLBCL patients. P53 expression augments the negative prognostic effect of MYC+/BCL2+ double expression. Patients with MYC+/P53+ co-expression have a worse prognosis in comparison with the patients with MYC+/BCL2+ double expression.
- Altered Functional Brain Networks in Patients with Traumatic Anosmia: Resting-State Functional MRI Based on Graph Theoretical Analysis. [Journal Article]Korean J Radiol 2019; 20(11):1536-1545KJ
- CONCLUSIONS: Traumatic anosmia increased the inter-network connectivity observed with rs-fMRI in the olfactory and global brain functional networks. rs-fMRI parameters may serve as potential biomarkers for traumatic anosmia by revealing a more widespread functional damage than previously expected.
- Design, synthesis and biological evaluation of oxygenated chalcones as potent and selective MAO-B inhibitors. [Journal Article]Bioorg Chem 2019; 93:103335BC
- The present study documents the synthesis of oxygenated chalcone (O1-O26) derivatives and their abilities to inhibit monoamine oxidases. All 26 derivatives examined showed potent inhibitory activity against MAO-B. Compound O23 showed the greatest inhibitory activity against MAO-B with an IC50 value of 0.0021 µM, followed by compounds O10 and O17 (IC50 = 0.0030 and 0.0034 µM, respectively). In add…
The present study documents the synthesis of oxygenated chalcone (O1-O26) derivatives and their abilities to inhibit monoamine oxidases. All 26 derivatives examined showed potent inhibitory activity against MAO-B. Compound O23 showed the greatest inhibitory activity against MAO-B with an IC50 value of 0.0021 µM, followed by compounds O10 and O17 (IC50 = 0.0030 and 0.0034 µM, respectively). In addition, most of the derivatives potently inhibited MAO-A and O6 was the most potent inhibitor with an IC50 value of 0.029 µM, followed by O3, O4, O9, and O2 (IC50 = 0.035, 0.053, 0.072, and 0.082 µM, respectively). O23 had a high selectivity index (SI) value for MAO-B of 138.1, and O20 (IC50 value for MAO-B = 0.010 µM) had an extremely high SI of >4000. In dialysis experiments, inhibitions of MAO-A and MAO-B by O6 and O23, respectively, were recovered to their respective reversible reference levels, demonstrating both are reversible inhibitors. Kinetic studies revealed that O6 and O23 competitively inhibited MAO-A and MAO-B, respectively, with respective Ki values of 0.016 ± 0.0007 and 0.00050 ± 0.00003 µM. Lead compound are also non-toxic at 200 µg/mL in normal rat spleen cells. Molecular docking simulations and subsequent Molecular Mechanics/Generalized Born Surface Area calculations provided a rationale that explained experimental data.
- Predicting Prostate Cancer Death with Different Pretreatment Risk Stratification Tools: A Head-to-head Comparison in a Nationwide Cohort Study. [Journal Article]Eur Urol 2019EU
- CONCLUSIONS: A total of 139 515 men were included in the main analysis, of whom 15 961 died from prostate cancer during follow-up. The C-index at 10 yr of follow-up ranged from 0.73 (95% confidence interval [CI]: 0.72-0.73) to 0.81 (95% CI: 0.80-0.81) across the compared tools. The MSKCC nomogram (C-index: 0.81, 95% CI: 0.80-0.81), CAPRA score (C-index: 0.80, 95% CI: 0.79-0.81), and CPG system (C-index: 0.78, 95% CI: 0.78-0.79) performed the best. The order of performance between the tools remained in analyses stratified by primary treatment and year of diagnosis. The predicted cumulative incidences were close to the observed ones, with some underestimation at 5 yr. It is a limitation that the study was conducted solely in a Swedish setting (ie, case mix).The MSKCC nomogram, CAPRA score, and CPG risk grouping system performed better in discriminating prostate cancer death than the D'Amico and D'Amico-derived systems (NICE, GUROC, EAU, AUA, and NCCN). Use of these tools may improve clinical decision making.
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- [Ekbom syndrome or delusional parasitosis: Three cases in Ouagadougou (Burkina Faso)]. [Journal Article]Ann Dermatol Venereol 2019AD
- CONCLUSIONS: These three cases of delusional parasitism observed in Ouagadougou, Burkina Faso, confirm the main clinical characteristics of Ekbom syndrome and underline the role of emotional and financial isolation, as well as pre-existing psychological difficulties, as potential triggers for this syndrome.