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The proposed neural network demonstrates that the guided contour features can significantly improve the performance of the segmentation task. Methamphetamine (METH) has been reported to induce endoplasmic reticulum (ER) stress and neuronal apoptosis in the central nervous system (CNS) during the development of addiction. Thioredoxin-1 (Trx-1) is a redox regulating protein and plays an important role in inhibiting apoptosis and protects neurons from cytotoxicity through ER and mitochondria-mediated pathways. Our previous study has been reported that Trx-1 protects mice from METH-induced rewarding effect. However, whether Trx-1 plays the role in resisting METH injury is still unclear. Here, we aim to investigate whether Trx-1 participates in the regulation of METH-induced CNS injury via ER stress and mitochondria-mediated pathways. Our study first repeated the contioned place preference expression induced by METH. Then we detected and found that METH increased the expression of N-methyl-d-asparate (NMDA) receptor subunit 2B (NR2B) and the level of glutamate (Glu) in the ventral tegmental area (VTA) and nucleus accumbens (NAc), while Trx-1 overexpression suppressed the increases. We further examined ER stress-related proteins and mitochondrial apoptosis pathway in the VTA and NAc, and found that METH increased the expressions of glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and Bax, as same time decreased the expressions of procaspase12, Bcl-2, and procaspase3, while Trx-1 overexpression blocked these changes. These results indicate that Trx-1 blocks METH-induced injury by suppressing ER stress and mitochondria-mediated apoptosis in the VTA and NAc via targeting glutamatergic system. The discovery of the TLRs family and more precisely its functions opened a variety of gates to modulate immunological host responses. TLRs 7/8 are located in the endosomal compartment and activate a specific signaling pathway in a MyD88-dependant manner. According to their involvement into various autoimmune, inflammatory and malignant diseases, researchers have designed diverse TLRs 7/8 ligands able to boost or block the inherent signal transduction. These modulators are often small synthetic compounds and most act as agonists and to a much lesser extent as antagonists. Some of them have reached preclinical and clinical trials, and only one has been approved by the FDA and EMA, imiquimod. The key to the success of these modulators probably lies in their combination with other therapies as recently demonstrated. We gather in this review more than 360 scientific publications, reviews and patents, relating the extensive work carried out by researchers on the design of TLRs 7/8 modulators, which are classified firstly by their biological activities (agonist or antagonist) and then by their chemical structures, which total syntheses are not discussed here. This review also reports about 90 clinical cases, thereby showing the biological interest of these modulators in multiple pathologies. Cytochrome P450 1B1 (CYP1B1) is a promising target for prevention and therapy of cancer, particularly those with drug resistance, stimulating cancer cell survival, and promoting cancer resistance. In view of the extreme complexity and high risk in drug discovery and development, a drug repurposing strategy was applied in the present study to find potential CYP1B1 inhibitors through structure-based virtual screening in the FDA database. Intriguingly, after a thorough assessment of docking scores, binding affinities, as well as binding modes, six compounds were highlighted for further verification. In fact, both carvedilol and indacaterol showed inhibitory activity towards human CYP1B1 with the IC50 of 1.11 μM and 59.52 μM, respectively, according to EROD assay; however, neither docking score nor the detailed binding mode of carvedilol in the hit pose dictated to be a superior CYP1B1 inhibitor to indacaterol, which called for the necessity to re-access the binding mode of carvedilol. Thus, the top two representative docking poses of carvedilol were re-assessed. Indeed, compared to the one hit in the virtual screening (due to a false positive Glide gscore), the other docking pose exhibited ideal performance in both molecular dynamics (MD) simulation, binding free energy, and density functional theory (DFT) calculation evaluations. This identification of the exact binding pose of carvedilol is not only essential for a better understanding of the mechanism underlying its activity, but also contributes to uncovering the structure-activity relationship of CYP1B1 inhibitors. Of note, carvedilol exhibited direct cytotoxicity against both human lung adenocarcinoma epithelial cell line A459 and its Taxol-resistant subline (A549/Taxol). In particular, it showed superior toxicity towards A549/Taxol cells that overexpressed CYP1B1, which further supported its potential to be an effective CYP1B1 inhibitor. Two new series of 1,3,4-oxadiazole benzenesulfonamide hybrids 3 and 4, having twenty novel compounds, have been designed and synthesized in order to assess their inhibition potential as CAIs against hCA I, II, IX, and XII. 'Tail approach' strategy has been used to design the aromatic sulfonamide scaffolds with carbonyl and amide linker. Excellent inhibitory activity against hCA I has been exhibited by compounds 3g and 4j, 3.5 magnitude of order better than reference drug AAZ (KI = 250 nM). Moreover, compound 4j (KI = 7.9 nM) effectively inhibited glaucoma-associated hCA II isoform as well as tumor-associated hCA IX isoform with KI = 16.3 nM. Further hCA XII was weakly inhibited by all the compounds with KI values ranging from 0.23 μM to 3.62 μM. Interestingly structure-activity relationship (SAR) study indicates that N-(3-nitrophenyl)-2-((5-(4-sulfamoylphenyl)-1,3,4-oxadiazol-2-yl)thio)acetamide (4j) is a potent compound to be investigated further for antiglaucoma and antitumor activity. The chemistry of the nature of different substitutions on the 1,3,4-oxadiazole bearing benzenesulfonamide substituted aromatic ring for potency and selectivity over one hCA isoform versus others is deliberated in the present study. In this context, the 1,3,4-oxadiazole motif can be a valuable tool worth developing for the procurement of novel and potent selective CAIs potentially useful for the management of a variety of diseases as chemotherapeutic agents. Microsomal epoxide hydrolase (mEH) hydrolyzes a wide range of epoxide containing molecules. Although involved in the metabolism of xenobiotics, recent studies associate mEH with the onset and development of certain disease conditions. This phenomenon is partially attributed to the significant role mEH plays in hydrolyzing endogenous lipid mediators, suggesting more complex and extensive physiological functions. In order to obtain pharmacological tools to further study the biology and therapeutic potential of this enzyme target, we describe the development of highly potent 2-alkylthio acetamide inhibitors of the human mEH with IC50 values in the low nanomolar range. These are around 2 orders of magnitude more potent than previously obtained primary amine, amide and urea-based mEH inhibitors. Experimental assay results and rationalization of binding through docking calculations of inhibitors to a mEH homology model indicate that an amide connected to an alkyl side chain and a benzyl-thio function as key pharmacophore units. Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death around the world. The current treatments of CRC exhibited high occurrence rate of side effects. Docetaxel (DTX), an important drug widely used in cancer chemotherapy, showed serious toxicity in CRC. Reducing toxicity of DTX could be a feasible and promising way to achieve the new indication of DTX for CRC. In this study, a series of MMP-7 activated octapeptide-DTX/4FDT prodrugs (6a-10a and 6b-10b) were designed and synthesized based on the features of MMP-7 which is highly expressed in CRC and could specially recognize octapeptides with specific sequences. Among them, 9a and 9b, both possessing an octapeptide Gly-Pro-Gln-Gly-Ile-Ala-Met-Gln moiety, were the most potent prodrugs. Compounds 9a and 9b were also tested their release rate in HCT116 cell culture fluids and tumor homogenate along with in vivo anti-CRC activity and systemic toxicity. Since 9a showed better anti-CRC activity and lower systemic toxicity than 9b in CRC tumor bearing mice, it was further evaluated for its acute toxicity, pharmacokinetics and tissue distribution in comparison with its parent drug DTX. These results revealed that 9a possessed good systemic stability, rapid release rate in CRC and reduced systemic toxicity, while retaining similar anti-CRC activity to its parent drug DTX. Thus, 9a, an MMP-7 polypeptide prodrug of DTX, has been identified as a promising candidate for the treatment of CRC. Activity concentration of 210Po in the edible muscle tissues of twelve sea-food species (the most common marine food consumed of population in Vietnam) were analyzed using the PIPS detectors ORTEC Alpha-Ensemble spectrometer. The 210Po activity concentration in studied samples was found to vary from 0.82 ± 0.47 to 70.3 ± 8.5 Bq/kg fresh weight. The highest activity concentration was recorded for the Blood cockle (Anadara granosa) and the lowest for Silver pomfret (Pampus argenteus). The annual committed effective dose (CED) of 210Po to humans (the local residents) due to ingestion of each studied species was calculated from 18.5 to 1586 μSv/y. The average annual committed effective dose value was reported 394 μSv/y, which is marginally higher than the average CED contributed from ingestion of food and water total in global background (290 μSv/y). Plants are known to remediate dyes, metals and emerging contaminants from wastewaters. Vetiveria zizanioides, a perennial bunchgrass showed removal of Remazol Red (RR, 100 mg/L) up to 93% within 40 h. Root and shoot tissues of V. zizanioides revealed induction in dye degrading enzymes viz. lignin peroxidase by 2.28 and 1.43, veratryl alcohol oxidase 2.72 and 1.60, laccase 6.15 and 3.55, and azo reductase 2.17 and 2.65-fold, respectively, during RR decolorization. Substantial increase was observed in the contents of chlorophyll a, chlorophyll b, and carotenoids in the plant leaves during treatment. Anatomical studies of roots, HPLC and GC-MS analysis of metabolites, and phytotoxicity assessment confirmed phytotransformation of RR into nontoxic metabolites. Floating phytobed with V. zizanioides treated textile wastewater (400 L) effectively and reduced ADMI, COD, BOD, TDS, and TSS by 74, 74, 81, 66 and 47%, respectively within 72 h. In-situ treatment of textile wastewater for 5 days in constructed furrows planted with semiaquatic plants, V. zizanioides, Ipomoea aquatica and its consortium-VI decreased ADMI by 68, 61 and 76%, COD by 75, 74 and 79%, BOD by 73, 71 and 84%, TDS by 77, 75 and 83%, and TSS by 34, 31 and 51%, respectively. https://www.selleckchem.com/products/ljh685.html This treatment was also useful to remove arsenic, cadmium, chromium and lead from wastewater. Overall observation suggests wise strategy to use this plantation in the furrows of high rate transpiration system and phytobeds in deep water for textile wastewater treatment.
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