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1.
Nanomedicine ; : 102363, 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33545405

RESUMO

RNA interference molecules have tremendous potential for cancer therapy but are limited by insufficient potency after i.v. administration. We previously found that Chol-DsiRNA Polyplexes formed between cholesterol-modified dicer-substrate siRNA (Chol-DsiRNA) and the cationic diblock copolymer PLL[30]-PEG[5 K] greatly increase the activity of Chol-DsiRNA against a stably expressed reporter mRNA in primary murine syngeneic breast tumors after daily i.v. dosing. Here, we provide a more thorough preliminary preclinical study of Chol-DsiRNA Polyplexes against the therapeutically relevant target protein, STAT3. We found that Chol-DsiSTAT3 Polyplexes greatly increase plasma exposure, distribution, potency, and therapeutic activity of Chol-DsiSTAT3 in primary murine syngeneic 4 T1 breast tumors after i.v. administration. Furthermore, inactive Chol-DsiCTRL Polyplexes are well tolerated by healthy female BALB/c mice after chronic i.v. administration at 50mg Chol-DsiCTRL/kg over 28days. Thus, Chol-DsiRNA Polyplexes may be a good candidate for Phase I clinical trials to improve the treatment of breast cancer and other solid tumors.

2.
J Environ Manage ; 284: 111985, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33581496

RESUMO

The ecological sustainability of rivers is in question due to severe pollution and lack of stringent regulations. Long term (1990-2016) water quality data of five stations namely Haridwar, Bareilly, Kanpur, Prayagraj and Varanasi of Upper Ganga river, India was considered for analysis using fuzzy analytical process (FAHP) based water quality index (WQI) to assess surface water quality. The value of water physical, biological and chemical parameters of temporal resolution (monthly, seasonal and yearly) indicate that value of electrical conductivity (EC), total dissolved solids (TDS), biological oxygen demand (BOD), chemical oxygen demand (COD), total alkalinity (Mg CaCO3), total hardness (Mg CaCO3), calcium (Ca), magnesium (Mg), sodium (Na), chlorine (Cl) and bicarbonate (HCO3) were observed very high compared to recommended value of Bureau of Indian Standards (BIS) and World Health Organization (WHO) at Kanpur, Prayagraj and Varanasi stations. However, low value of parameters is observed at Haridwar and Bareilly stations. Also, the high deviation was observed in water quality parameters during 1990-2010 whereas the deviation of parameters is decreased in 2011-2016. It is observed from the piper diagram that magnesium and bicarbonate at Haridwar, sodium, potassium and bicarbonate in Bareilly, Kanpur, Prayagraj and Varanasi stations are dominant during monthly and seasonal periods. The fuzzy based WQI value indicate that water quality is excellent to poor at Haridwar, while poor to unsuitable in Bareilly, Kanpur, Prayagraj and Varanasi during monthly and seasonal periods. The water quality ranges from poor to unsuitable during the 1990-2010 period and good to very poor during the 2011-2016 period at Bareilly, Kanpur, Prayagraj and Varanasi stations. Whereas very good to good during 1990-2010 and excellent to good during 2011-2016 at Haridwar. It was also determined that water quality parameters (Ca, Na+K, SO4, Hardness, Cl and Mg) and WQI values were increased with length of the stream. It indicates that drain discharge, urban growth, urban functions, ecological footprints and crop area increment were key sources of pollution.

3.
Abdom Radiol (NY) ; 2021 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-33388810

RESUMO

In this review, we will discuss the imaging findings of common as well as uncommon lower genitourinary tract infections. For both clinicians and radiologists, it is imperative to understand etiopathogenesis, epidemiological information, clinical presentation, imaging findings and management options of such conditions. Knowledge of salient imaging features of these infections is of utmost importance because prompt recognition enables appropriate management.

4.
Bioelectrochemistry ; 138: 107733, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33429154

RESUMO

An ultrasensitive, electrochemical biosensor has been fabricated by utilizing molybdenum disulfide (MoS2) grafted reduced graphene oxide (MoS2@rGO) nanohybrid as a sensing platform. Biomolecular-assisted synthetic method was adopted to synthesize MoS2@rGO nanohybrid, where L-cys was used to reduce GO. The MoS2@rGO nanohybrid exhibits improved electrochemical performance when it has been electrophoretically deposited onto the indium tin oxide (ITO) coated glass substrate. Further, epithelialcell adhesion moleculeantibodies (anti-EpCAM) specific to cancer biomarker has been covalently immobilized on the MoS2@rGO/ITO electrodes for label-free detection of EpCAM. Electrochemical results confirm that anti-EpCAM/MoS2@rGO/ITO based biosensor can detect EpCAM in the concentration range of 0.001-20 ng mL-1 with a detection limit of 44.22 fg mL-1 (S/N = 3). The biosensor's excellent analytical performance has been attributed to the efficient immobilization of EpCAM antibodies on the MoS2@rGO surface, which results in high specificity for EpCAM antigen. The fabricated biosensor showed good selectivity, reproducibility, and stability. The successful detection of EpCAM antigen in spiked samples (human saliva, serum and urine) makes this platform an alternative method for early screening of cancer biomarker.

5.
Clin Imaging ; 74: 123-130, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33485116

RESUMO

BACKGROUND: Assessment of visual-coronary artery calcification on non-cardiac gated CT in COVID-19 patients could provide an objective approach to rapidly identify and triage clinically severe patients for early hospital admission to avert worse prognosis. PURPOSE: To ascertain the role of semi-quantitative scoring in visual-coronary artery calcification score (V-CACS) for predicting the clinical severity and outcome in patients with COVID-19. MATERIALS AND METHODS: With institutional review board approval this study included 67 COVID-19 confirmed patients who underwent non-cardiac gated CT chest in an inpatient setting. Two blinded radiologist (Radiologist-1 &2) assessed the V-CACS, CT Chest severity score (CT-SS). The clinical data including the requirement for oxygen support, assisted ventilation, ICU admission and outcome was assessed, and patients were clinically subdivided depending on clinical severity. Logistic regression analyses were performed to identify independent predictors. ROC curves analysis is performed for the assessment of performance and Pearson correlation were performed to looks for the associations. RESULTS: V-CACS cut off value of 3 (82.67% sensitivity and 54.55% specificity; AUC 0.75) and CT-SS with a cut off value of 21.5 (95.7% sensitivity and 63.6% specificity; AUC 0.87) are independent predictors for clinical severity and also the need for ICU admission or assisted ventilation. The pooling of both CT-SS and V-CACS (82.67% sensitivity and 86.4% specificity; AUC 0.92) are more reliable in terms of predicting the primary outcome of COVID-19 patients. On regression analysis, V-CACS and CT-SS are individual independent predictors of clinical severity in COVID-19 (Odds ratio, 1.72; 95% CI, 0.99-2.98; p = 0.05 and Odds ratio, 1.22; 95% CI, 1.08-1.39; p = 0.001 respectively). The area under the curve (AUC) for pooled V-CACS and CT-SS was 0.96 (95% CI 0.84-0.98) which correctly predicted 82.1% cases. CONCLUSION: Logistic regression model using pooled Visual-Coronary artery calcification score and CT Chest severity score in non-cardiac gated CT can predict clinical severity and outcome in patients with COVID-19.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33316791

RESUMO

Understanding the effect of surface to bulk coupling on topological surface states is important for harnessing the topological insulators for low dissipation electronics and quantum technologies. Here we investigate this effect on a low bulk carrier density Bi2Te3 single crystal using magnetoresistance, Hall resistivity, and Shubnikov-de Haas oscillations. Our results show the presence of high mobility surface bands and low mobility bulk bands. The surface states exhibit ambipolar transport without any gating. The mobility of surface states strongly depend on the nature of band bending, the upward band bending with holes as surface charge carrier exhibit large mobility while the downward band bending with electrons as surface charge carriers exhibit low surface mobility. The large mobility of surface Dirac holes is related to low surface defect density and small cyclotron mass. We also observe large magnetoresistance ~285% due to multichannel quantum coherent transport in the bulk.

7.
Bioorg Chem ; 104: 104326, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33142431

RESUMO

SARS-CoV-2 (COVID-19) epidemic has created an unprecedented medical and economic crisis all over the world. SARS-CoV-2 is found to have more contagious character as compared to MERS-CoV and is spreading in a very fast manner all around the globe. It has affected over 31 million people all over the world till date. This virus shares around 80% of genome similarity with SARS-CoV. In this perspective, we have explored three major targets namely; SARS-CoV-2 spike (S) protein, RNA dependent RNA polymerase, and 3CL or Mpro Protease for the inhibition of SARS-CoV-2. These targets have attracted attention of the medicinal chemists working on computer-aided drug design in developing new small molecules that might inhibit these targets for combating COVID-19 disease. Moreover, we have compared the similarity of these target proteins with earlier reported coronavirus (SARS-CoV). We have observed that both the coronaviruses share around 80% similarity in their amino acid sequence. The key amino acid interactions which can play a crucial role in designing new small molecule inhibitors against COVID-19 have been reported in this perspective. Authors believe that this study will help the medicinal chemists to understand the key amino acids essential for interactions at the active site of target proteins in SARS-CoV-2, based on their similarity with earlier reported viruses. In this review, we have also described the lead molecules under various clinical trials for their efficacy against COVID-19.

8.
Mater Sci Eng C Mater Biol Appl ; 116: 111138, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32806311

RESUMO

In the present study, the combined effect of addition of varying concentrations (10-30 vol%) of biocompatible piezoelectric Na0.5K0.5NbO3 (NKN) as well as electrostatic and dynamic pulsed electrical treatment on antibacterial and cellular response of 1393 bioactive glass (1393 BG) has been examined. The phase analyses of the sintered (at 800 °C for 30 min) samples revealed the formation of 1393 BG - NKN composites without any appearance of secondary phases. The addition of 10-30 vol% NKN significantly improved the mechanical behaviour of 1393 BG like, hardness (1.7 to 2 times), fracture toughness (1.3 to 2.6 times), compressive (2.3 to 8 times) and flexural strengths (2 to 3.5 times) than monolithic 1393 BG. The piezoelectric NKN is observed to induce the antibacterial activity in 1393 BG - (10- 30 vol%) NKN composites, while Staphylococcus aureus (S. aureus, gram positive) and Escherichia coli (E. coli, gram negative) bacterial cells were exposed to unpolarized and polarized (20 kV, 500°C for 30 min) sample surfaces. The antibacterial response was examined using disc diffusion, nitro blue tetrazolium (NBT) and MTT assays. The statistical analyses revealed the significant reduction in the viability of bacterial cells on polarized 1393 BG - (10- 30 vol%) NKN composite samples. In addition, the combined effect of electrostatic and dynamic pulsed electrical stimulation (1 V/cm, 500 µs pulses) on the cellular response of 1393 BG and 1393 BG - 30 vol% NKN composites has been analysed with MG-63 osteoblast-like cells. The cell proliferation was observed to increase significantly for the dynamic pulsed electric field treated negatively charged surfaces.

9.
Eur J Med Chem ; 200: 112438, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32485533

RESUMO

Most of the anti-inflammatory drugs in clinical practice are becoming outdated owing to their potential side and adverse effects. These are found to be highly unsafe for long term use. Thus, since last few years, new anti-inflammatory agents are being developed and number of them are in advanced stages of clinical trials. Heterocyclic molecules have gained great attention of chemists due to their similarity to different biological precursors. In the current review, we have highlighted the recent developments (2015 onwards) in designing and synthesis of various heterocyclic anti-inflammatory molecules along with detailed SAR studies. The principal objective of this review is to provide a profound overview of the recently explored heterocyclic anti-inflammatory agents belonging to various classes such as pyrazole, pyrimidine, benzimidazole, indole, and other related heterocyclic compounds. In addition, an enlarged view on potential interactions of synthetic preparations with target inflammatory enzymes or cytokines has been provided. We have also enlisted lead compounds undergoing different clinical trials against inflammation. The elementary aim of this review is to provide restructured knowledge regarding heterocyclic molecules which will be valuable for the scientists working in the field of anti-inflammatory chemistry. The authors believe that lead compounds mentioned in the report will help to design and develop novel anti-inflammatory drug molecules targeting various factors involved in the progression of inflammation.

10.
Abdom Radiol (NY) ; 2020 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-32572513

RESUMO

PURPOSE: Testicular stromal tumors are uncommon, although mostly benign. The purpose of this study is to assess the role of multi-parametric MRI in differentiating benign testicular stromal tumors from malignant testicular neoplasms (non-stromal and stromal). METHODS: A single-center retrospective study comparing benign stromal tumors (STs) to malignant testicular neoplasms (MTNs) was conducted. MR imaging assessment included tumor size, T2- and T1-weighted signal intensity, T2- and T1-weighted texture pattern, diffusion restriction, presence of hemorrhage and/or necrosis, and measurement of apparent diffusion coefficient and dynamic contrast enhancement (DCE). Inter-observer agreement was assessed using Cohen's kappa and Bland-Altman and data were compared using independent t-tests or χ2. Receiver operating characteristic curve analysis was used to test models incorporating various imaging features. RESULTS: Radical orchiectomy and histopathology revealed 20 testicular neoplasms: seven STs (35%) and thirteen MTNs (65%). MTNs were significantly larger in size than STs (5.1 ± 2.36 cm vs. 1.27 ± 0.56 cm; p-value < 0.001). STs demonstrated more hypointense T2W signal (85.7% vs. 46.2%; p-value < 0.09), less T2W heterogeneous texture (14.3% vs. 61.5%; p-value < 0.04), and less diffusion restriction (16.7% vs. 83.3%; p-value < 0.01) in comparison to MTNs. STs demonstrated mainly homogenous post-contrast enhancement pattern (71.4% vs. 7.7%; p-value < 0.004), while MTNs showed primarily heterogeneous enhancement pattern (77% vs. 14.3%; p-value < 0.02). STs revealed greater corrected venous phase enhancement (STs: 0.59 ± 0.29; MTNs: 0.25 ± 0.25; p-value < 0.03). STs showed higher ADC values, though the difference was not statistically significant (p-value < 0.25). A model combining T2W, DWI, and DCE features showed the best overall diagnostic accuracy with area under ROC curve of 0.99 and confidence interval ranging from 0.94 to 1. CONCLUSION: Multi-parametric MRI can potentially differentiate benign stromal tumors from malignant testicular neoplasms, which can help to avoid radical orchiectomy. However, future studies using larger sample sizes are needed to validate our results.

11.
Plant Physiol Biochem ; 154: 171-183, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32563041

RESUMO

Nitrogen (N) is an important nutrient for plant growth. However, its excess application leads to environmental damage. Hence, improving nitrogen use efficiency (NUE) of plant is one of the plausible options to solve the problems. Aim of this study was to identify candidate genes involved in enhancing NUE in potato cv. Kufri Gaurav (N efficient). Plants were grown in aeroponic with two contrasting N regimes (low N: 0.75 mM, and high N: 7.5 mM). Higher NUE in Kufri Gaurav was observed in low N based on the parameters like NUE, NUpE (N uptake efficiency), NUtE (N utilization efficiency) and AgNUE (agronomic NUE). Further, global gene expression profiles in root, leaf and stolon tissues were analyzed by RNA-sequencing using Ion Proton™ System. Quality data (≥Q20) of 2.04-2.73 Gb per sample were mapped with the potato genome. Statistically significant (P ≤ 0.05) differentially expressed genes (DEGs) were identified such as 176 (up-regulated) and 30 (down-regulated) in leaves, 39 (up-regulated) and 105 (down-regulated) in roots, and 81 (up-regulated) and 694 (down-regulated) in stolons. The gene ontology (GO) terms like metabolic process, cellular process and catalytic activity were predominant. Our RT-qPCR analysis confirmed the gene expression profiles of RNA-seq. Overall, we identified candidate genes associated with improving NUE such as superoxide dismutase, GDSL esterase lipase, probable phosphatase 2C, high affinity nitrate transporters, sugar transporter, proline rich proteins, transcription factors (VQ motif, SPX domain, bHLH) etc. Our findings suggest that these candidate genes probably play crucial roles in enhancing NUE in potato.

12.
J Phys Condens Matter ; 32(36): 365703, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32369785

RESUMO

A comprehensive magnetotransport study including resistivity (ρ xx ), isothermal magnetoresistance, Hall resistivity (ρ xy ) and magnetization have been carried out at different temperatures on the Co2TiAl Heusler alloy. Co2TiAl alloy shows a paramagnetic to ferromagnetic (FM) transition below the Curie temperature (T C) ∼ 125 K. In the FM region, resistivity and magnetoresistance reveal a spin flip electron-magnon scattering and the Hall resistivity unveils the anomalous Hall resistivity. Scaling of anomalous Hall resistivity with resistivity establishes the extrinsic scattering process responsible for the anomalous Hall resistivity; however skew scattering is the dominant mechanism compared to the side-jump contribution. A one to one correspondence between magnetoresistance and side-jump contribution to anomalous Hall resistivity verifies the electron-magnon scattering being the source of side-jump contribution to the anomalous Hall resistivity.

13.
Mikrochim Acta ; 187(5): 275, 2020 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-32306099

RESUMO

An electrochemical immunosensor has been fabricated for the early determination of epithelial cell adhesion molecules (EpCAM, tumor biomarker) antigen using reduced graphene oxide (rGO) modified with nanostructured titanium dioxide (TiO2). The hydrothermally synthesized rGO@TiO2 nanocomposite has been electrophoretically deposited on indium tin oxide (ITO) coated glass substrate, and the deposition was confirmed using various spectroscopic, microscopic, and electrochemical techniques. The fabricated rGO@TiO2/ITO electrode shows improved electron transfer kinetics with an electron transfer rate constant of 1.93 × 10-7 cm·s-1. Furthermore, the rGO@TiO2/ITO electrodes were used for the covalent immobilization of monoclonal EpCAM antibodies. Electrochemical determination of the EpCAM cancer biomarker is achieved using differential pulse voltammetry by scanning the potential from - 0.4 to 0.8 V with an amplitude of 50 mV. The rGO@TiO2-based biosensor shows high sensitivity (3.24 µA·mL·ng-1·cm-2), wide detection range (0.01 ng·mL-1 to 60 ng·mL-1), and low detection limit (0.0065 ng·mL-1, S/N = 3). The fabricated biosensor is highly stable and regenerable and has been successfully applied to the determination of EpCAM in spiked human serum samples. Graphical abstract.


Assuntos
Biomarcadores Tumorais/sangue , Técnicas Biossensoriais , Técnicas Eletroquímicas , Molécula de Adesão da Célula Epitelial/sangue , Grafite/química , Nanoestruturas/química , Titânio/química , Humanos , Oxirredução , Tamanho da Partícula , Propriedades de Superfície
14.
Curr Drug Targets ; 21(9): 864-891, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32156235

RESUMO

Heterocyclic compounds play a significant role in various biological processes of the human body and many of them are in clinical use due to their diverse, chemical and biological properties. Among these, indole is one of the most promising pharmacologically active molecules. Due to its chemical reactivity, indole has been willingly modified to obtain a variety of new lead molecules, which has been successfully utilized to obtained novel drug candidates for the treatment of different pharmacological diseases. Indole-based compounds such as vincristine (anticancer), reserpine (antihypertensive), amedalin (antidepressant) and many more describe the medicinal and pharmacological importance of the indole in uplifting human life. In this review, we compiled various reports on indole derivatives and their biological significance, including antifungal, antiprotozoal, antiplatelet, anti- Alzheimer's, anti-Parkinson's, antioxidant and anticancer potential from 2015 onwards. In addition, structure-activity relationship studies of the different derivatives have been included. We have also discussed novel synthetic strategies developed during this period for the synthesis of different indole derivatives. We believe that this review article will provide comprehensive knowledge about the medicinal importance of indoles and will help in the design and synthesis of novel indole-based molecules with high potency and efficacy.

15.
Luminescence ; 35(6): 913-923, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32198843

RESUMO

In this study, we prepared carbon dots (CDs) from wheat bran via hydrothermal treatment at 180°C for 3 h. The prepared CDs showed blue-green fluorescence under UV light. The fluorescence emission study of the CDs revealed that they showed maximum fluorescence emission at 500 nm. The prepared CDs showed a high quantum yield of 33.23%. Solvent-dependent fluorescence emission analysis of the CDs was performed to study the variation in fluorescence emission characteristics with solvent polarity. The prepared CDs were conjugated with amoxicillin (AMX) to explore its potential for use as a drug delivery agent for AMX. The drug release profile of the CD-AMX conjugates was analyzed at different pH (5.0, 6.8 and 7.2) to study drug release kinetics. CD-AMX conjugates showed notable bacterial inhibition against Gram-positive (S. aureus) and Gram-negative (E. coli) strains with minimal cytotoxic effects, indicating its potential as a promising antibacterial drug delivery system.

16.
Anal Chem ; 92(8): 5676-5681, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32191451

RESUMO

The α-chymotrypsin-based cleavage reaction is necessary for manufacturing peptides using rDNA technology with tandem repeats. The current work showcases application of process analytical technology (PAT) tools for monitoring and control of this reaction, using recombinant Lethal Toxin Neutralizing Factor (rLTNF) as a case study. At-line Fourier Transform infrared spectroscopy (ATR-FTIR) combined with attenuated total internal reflectance sampling accessory was exploited to monitor the reaction. PLS spectral calibration models were created for real-time quantification of concentrations of rLTNF concatemer and urea in the reaction mixture. An end-to-end PAT monitoring and control strategy was developed to address potential deviations and ensure that targets for yield, purity, and impurity profile are met for each batch. The impact of various deviations of process parameters outside the operating space, such as deviations in the reaction buffer, concentration of concatemer in the IBs, enzyme loading relative to protein concentration, and reaction time with late quenching were investigated. Variation in impurity profile over time in the case of late reaction quenching was determined through HPLC and mass spectrometry. It has been demonstrated how process signatures from the PAT tools across various batches and campaigns can be analyzed to facilitate real-time process monitoring and control.

17.
J Biomol Struct Dyn ; 38(9): 2533-2545, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31232189

RESUMO

N-methyl-D-aspartate receptors (NMDARs), a class of ligand-gated ion channels, are involved in non-selective cation transport across the membrane. These are contained in glutamatergic synapse and produce excitatory effects leading to synaptic plasticity and memory function. GluN1-GluN2B, a subtype of NMDAR(s), has significant role in neurodegeneration, amyloid ß (Aß) induced synaptic dysfunction and loss. Thus, targeting and inhibiting GluN1-GluN2B may be effective in the management of neurodegenerative diseases including Alzheimer's disease. In the present study, ligand and structure-based approaches were tried to identify the inhibitors. The pharmacophore, developed from co-crystallised ifenprodil, afforded virtual hits, which were further subjected through drug likeliness and PAINS filters to remove interfering compounds. Further comprehensive docking studies, free energy calculations and ADMET studies resulted in two virtual leads. The leads, ZINC257261614 and ZINC95977857 displayed good docking scores of -12.90 and -12.20 Kcal/mol and free binding energies of -60.83 and -61.83 Kcal/mol, respectively. The compounds were having acceptable predicted ADMET profiles and were subjected to molecular dynamic (MD) studies. The MD simulation produced stable complexes of these ligands with GluN1-GluN2B subunit having protein and ligand RMSD in acceptable limit. AbbreviationsADAlzheimer's diseaseADMEAbsorption distribution metabolism and excretionATDAmino terminal domainBBBBlood-brain barrierCNSCentral nervous systemCREBcAMP response element binding proteinCTDCarboxy-terminal domainGluGlutamateGMQEGlobal model quality estimationHTVSHigh throughput virtual screeningHIAHuman intestinal absorptionLGALamarckian genetic algorithmMDMolecular dynamicsMM-GBSAMolecular mechanics, the Generalised Born model for Solvent AccessibilityNMDARN-methyl-D-aspartate receptorsPAINSPan assay interference compoundsRMSDRoot-mean square deviationRMSFRoot-mean-square fluctuationSMARTSSMILES arbitrary target specificationSPstandard precisionXPextra precisionCommunicated by Ramaswamy H. Sarma.

18.
ACS Biomater Sci Eng ; 6(5): 3055-3069, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33463258

RESUMO

Besides the excellent osteoconductivity and biocompatibility of 45S5 bioglass (BG), poor mechanical and electrical properties as well as susceptibility toward bacterial adhesion limit its widespread clinical applications. In this context, the present study investigates the effect of addition of piezoelectric sodium potassium niobate (Na0.5K0.5NbO3; NKN) on mechanical, dielectric, and antibacterial response of BG. BG-xNKN (x = 0, 10, 20, and 30 vol%) composites were synthesized at 800 °C for 30 min. The phase analyses using spectral techniques revealed the formation of the composite without any reaction between BG and piezoelectric ceramic NKN. The dielectric and electrical measurements were performed over a wide range of temperature (30-500 °C) and frequency (1 Hz-1 MHz) which suggests that space charge and dipolar polarizations are the dominant polarization mechanisms. The complex impedance analyses suggest that the average activation energies for grain and grain boundary resistances for BG-xNKN (x = 10, 20, and 30 vol%) composites are 0.59, 0.87, 0.94 and 0.76, 0.93, 1.06 eV, respectively. The issue of bacterial infection has been addressed by electrical polarization of the developed composite samples, at 20 kV for 30 min. Statistical analyses reveal that the viability of Gram-positive (S. aureus) and Gram-negative (E. coli) bacterial cells has been reduced significantly on positively and negatively charged BG-NKN composite samples, respectively. The qualitative analyses using the Kirby-Bauer test supports the above findings. Nitro blue tetrazolium and lipid peroxide assays were performed to understand the mechanism of such antibacterial response, which suggested that the combined effect of NKN addition and polarization significantly enhances the superoxide production, which kills the bacterial cells. Overall, incorporation of NKN in BG enhances the mechanical, electrical, and dielectric properties as well as improves the antibacterial response of polarized BG-xNKN composites.

19.
Future Med Chem ; 11(24): 3161-3178, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31838895

RESUMO

Aim: A breakthrough in modern medicine, in terms of treatment of Alzheimer's disease, is yet to be seen, as the scene is currently plagued with numerous clinical trial failures. Here, we are exploring multifunctional hybrid sulfonamides for their anti-Alzheimer activity due to the complex nature of the disease. Results & methodology: Compound 41 showed significant inhibition of MMP-2 (IC50: 18.24 ± 1.62 nM), AChE (IC50: 4.28 ± 0.15 µM) and BuChE (IC50: 1.32 ± 0.02 µM). It also exhibited a metal-chelating property, as validated by an in vitro metal-induced Aß aggregation assay using confocal fluorescence imaging. Whereas, MTT and DPPH assays revealed it to be nontoxic and neuroprotective with substantial antioxidant property. Conclusion: The present study puts forth potent yet nontoxic lead molecules, which foray into the field of multitargeted agents for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Quelantes/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Sulfonamidas/uso terapêutico , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Butirilcolinesterase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Quelantes/química , Quelantes/farmacocinética , Chlorocebus aethiops , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacocinética , Simulação por Computador , Modelos Animais de Doenças , Humanos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/química , Inibidores de Metaloproteinases de Matriz/farmacocinética , Aprendizagem em Labirinto/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Wistar , Sulfonamidas/química , Sulfonamidas/farmacocinética , Células Vero
20.
Eur J Med Chem ; 182: 111613, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31437780

RESUMO

Alzheimer's disease (AD) is associated with multifactorial neuropathological conditions, which include cholinergic deficit, amyloid-beta plaques formation, loss of neuronal plasticity and neuronal death. Treating such multifactorial conditions with a single target directed approach is considered to be inadequate. Accordingly, multi-target directed ligand (MTDL) strategy has been evolved as an auspicious approach for the treatment of AD. In light of that, a library of 2-substituted benzo[d]oxazol-5-amine derivatives (29-39; 86-107) was designed using the scaffold hopping guided MTDLs strategy, synthesized and evaluated through various in-vitro and in-vivo biological studies. The optimal compound 92 exhibited potent inhibitory activities against AChE (IC50 = 0.052 ±â€¯0.010 µM), BuChE (IC50 = 1.085 ±â€¯0.035 µM), and significant amyloid-beta aggregation (20 µM) inhibition. The compound possessed better blood-brain barrier permeability (Pe = 10.80 ±â€¯0.055 × 10-6 cm s-1) in PAMPA assay and neuro protective properties (40 µM) on SH-SY5Y neuroblastoma cell lines. Furthermore, in-vivo behavioural studies were performed on Y-maze test (scopolamine-induced amnesia model) and Morris water maze test (Aß1-42 induced ICV rat model). The compound 92, at a dose of 10 mg/kg oral administration, demonstrated a substantial improvement of the cognitive and special memory impairment. In summary, both in-vitro and in-vivo investigations evidenced that compound 92 was a potential lead for the discovery of safe and effective disease-modifying agents for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminas/farmacologia , Inibidores da Colinesterase/farmacologia , Descoberta de Drogas , Fármacos Neuroprotetores/farmacologia , Oxazóis/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Aminas/síntese química , Aminas/química , Amnésia/induzido quimicamente , Amnésia/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Enguias , Feminino , Cavalos , Humanos , Ligantes , Masculino , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Oxazóis/síntese química , Oxazóis/química , Ratos , Ratos Wistar , Escopolamina , Relação Estrutura-Atividade
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