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Atul Bhardwaj

Bio: Atul Bhardwaj is an academic researcher from University of Alberta. The author has contributed to research in topics: Medicine & Positron emission tomography. The author has an hindex of 14, co-authored 31 publications receiving 4313 citations. Previous affiliations of Atul Bhardwaj include Guru Nanak Dev University & Cross Cancer Institute.

Papers
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Journal ArticleDOI
TL;DR: In situ click chemistry is used to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity, significantly higher than that of widely used selective cyclooxygenase-2 inhibitors.
Abstract: Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isozyme can judiciously select most appropriate chemical building blocks from a pool of chemicals to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chemistry, we describe the discovery of two highly potent and selective cyclooxygenase-2 isozyme inhibitors. The in vivo anti-inflammatory activity of these two novel small molecules is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors. Traditional inflammation and pain relief drugs target both cyclooxygenase 1 and 2 (COX-1 and COX-2), causing severe side effects. Here, the authors use in situ click chemistry to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity.

6,061 citations

Journal ArticleDOI
TL;DR: Seven compounds from the category of di- and triaryl substituted THPs exhibited average GI(50) over all the human tumor cell lines in the range 1.6-3.2 microM and showed in vitro therapeutic indices of 8-17.
Abstract: Rationally designed tetrahydropyrans (THPs) carrying one, two, or three aryl rings and other substituents were synthesized by the allylation of β-hydroxy ketones followed by iodocyclization. It has been observed that compounds with one aryl ring on THP are moderate inhibitors of cyclooxygenase-1 (COX-1) (IC50 = 0.3 μM) and cyclooxygenase-2 (IC50 = 0.17 μM) with poor selectivity index (SI = 2−3) for COX-2. The presence of two aryl rings enhanced their inhibitory activities for COX-2 (IC50 = 0.9−5.5 nM). Selectivity for COX-2 over COX-1 also increased (SI = 50−1900), while triaryl substituted THPs, along with high inhibition (IC50 = 0.57−4.0 nM), also exhibited excellent selectivity for COX-2 over COX-1 (SI = 3200−44000). Similar to the experimental results of increased COX-2 inhibition and selectivity with the increase in the size of the molecule, their docking in the active sites of COX-1 and COX-2 also showed same trend. Seven compounds from the category of di- and triaryl substituted THPs exhibited aver...

40 citations

Journal ArticleDOI
TL;DR: 1-Benzoyl-3-[(4-trifluoromethylphenylimino)methyl]indole (20) emerged as the most potent (COX-1 IC(50) >100 μM; COX-2 IC( 50)=0.32 μM) and selective (SI >312) COX -2 inhibitor.

38 citations

Journal ArticleDOI
TL;DR: A celecoxib-rhodamine B conjugate that exhibited moderate COX-2 potency and selectivity and having the best fluorescence emission emerged as the most promising biomarker for fluorescence imaging using a colon cancer cell line that over-expresses the COx-2 isozyme.

36 citations

Journal ArticleDOI
TL;DR: A group of cyclooxygenase‐2 (COX‐2)‐specific fluorescent cancer biomarkers were synthesized by linking the anti‐inflammatory drugs ibuprofen, (S)‐naproxen, and celecoxib to the 7‐nitrobenzofurazan (NBD) fluorophore to identify an impending COx‐2‐specific biomarker for the fluorescence imaging of cancer.
Abstract: A group of cyclooxygenase-2 (COX-2)-specific fluorescent cancer biomarkers were synthesized by linking the anti-inflammatory drugs ibuprofen, (S)-naproxen, and celecoxib to the 7nitrobenzofurazan (NBD) fluorophore In vitro COX-1/COX-2 inhibition studies indicated that all of these fluorescent conjugates are COX-2 inhibitors (IC50 range: 019–230 mm) with an appreciable COX-2 selectivity index (SI 43–444) In this study the celecoxib–NBD conjugate N-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethyl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide (14), which displayed the highest COX-2 inhibitory potency and selectivity (COX-2 IC50 = 019 mm ;S I= 4436), was identified as an impending COX-2-specific biomarker for the fluorescence imaging of cancer using a COX-2-expressing human colon cancer cell line

35 citations


Cited by
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Journal ArticleDOI
TL;DR: In situ click chemistry is used to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity, significantly higher than that of widely used selective cyclooxygenase-2 inhibitors.
Abstract: Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isozyme can judiciously select most appropriate chemical building blocks from a pool of chemicals to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chemistry, we describe the discovery of two highly potent and selective cyclooxygenase-2 isozyme inhibitors. The in vivo anti-inflammatory activity of these two novel small molecules is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors. Traditional inflammation and pain relief drugs target both cyclooxygenase 1 and 2 (COX-1 and COX-2), causing severe side effects. Here, the authors use in situ click chemistry to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity.

6,061 citations

Posted ContentDOI
02 Nov 2018-bioRxiv
TL;DR: This work presents a strategy for comprehensive integration of single cell data, including the assembly of harmonized references, and the transfer of information across datasets, and demonstrates how anchoring can harmonize in-situ gene expression and scRNA-seq datasets.
Abstract: Single cell transcriptomics (scRNA-seq) has transformed our ability to discover and annotate cell types and states, but deep biological understanding requires more than a taxonomic listing of clusters. As new methods arise to measure distinct cellular modalities, including high-dimensional immunophenotypes, chromatin accessibility, and spatial positioning, a key analytical challenge is to integrate these datasets into a harmonized atlas that can be used to better understand cellular identity and function. Here, we develop a computational strategy to "anchor" diverse datasets together, enabling us to integrate and compare single cell measurements not only across scRNA-seq technologies, but different modalities as well. After demonstrating substantial improvement over existing methods for data integration, we anchor scRNA-seq experiments with scATAC-seq datasets to explore chromatin differences in closely related interneuron subsets, and project single cell protein measurements onto a human bone marrow atlas to annotate and characterize lymphocyte populations. Lastly, we demonstrate how anchoring can harmonize in-situ gene expression and scRNA-seq datasets, allowing for the transcriptome-wide imputation of spatial gene expression patterns, and the identification of spatial relationships between mapped cell types in the visual cortex. Our work presents a strategy for comprehensive integration of single cell data, including the assembly of harmonized references, and the transfer of information across datasets. Availability: Installation instructions, documentation, and tutorials are available at: https://www.satijalab.org/seurat

2,037 citations

Journal ArticleDOI
TL;DR: Cell Hashing is introduced, where oligo-tagged antibodies against ubiquitously expressed surface proteins uniquely label cells from distinct samples, which can be subsequently pooled and can robustly identify cross-sample multiplets.
Abstract: Despite rapid developments in single cell sequencing, sample-specific batch effects, detection of cell multiplets, and experimental costs remain outstanding challenges. Here, we introduce Cell Hashing, where oligo-tagged antibodies against ubiquitously expressed surface proteins uniquely label cells from distinct samples, which can be subsequently pooled. By sequencing these tags alongside the cellular transcriptome, we can assign each cell to its original sample, robustly identify cross-sample multiplets, and “super-load” commercial droplet-based systems for significant cost reduction. We validate our approach using a complementary genetic approach and demonstrate how hashing can generalize the benefits of single cell multiplexing to diverse samples and experimental designs.

608 citations

Journal ArticleDOI
01 Mar 2018-Small
TL;DR: A two-step intercalation mechanism that Zn ions first insert into the layers and then the tunnels of MnO2 framework is proved by in situ X-ray diffraction, galvanostatic intermittent titration technique, andX-ray photoelectron spectroscopy characterizations.
Abstract: The development of manganese dioxide as the cathode for aqueous Zn-ion battery (ZIB) is limited by the rapid capacity fading and material dissolution. Here, a highly reversible aqueous ZIB using graphene scroll-coated α-MnO2 as the cathode is proposed. The graphene scroll is uniformly coated on the MnO2 nanowire with an average width of 5 nm, which increases the electrical conductivity of the MnO2 nanowire and relieves the dissolution of the cathode material during cycling. An energy density of 406.6 Wh kg-1 (382.2 mA h g-1 ) at 0.3 A g-1 can be reached, which is the highest specific energy value among all the cathode materials for aqueous Zn-ion battery so far, and good long-term cycling stability with 94% capacity retention after 3000 cycles at 3 A g-1 are achieved. Meanwhile, a two-step intercalation mechanism that Zn ions first insert into the layers and then the tunnels of MnO2 framework is proved by in situ X-ray diffraction, galvanostatic intermittent titration technique, and X-ray photoelectron spectroscopy characterizations. The graphene scroll-coated metallic oxide strategy can also bring intensive interests for other energy storage systems.

569 citations

Journal ArticleDOI
TL;DR: In this article, the authors summarized the widely accepted pathways of photocatalytic CO2 reduction reactions and analyzed the important factors affecting product selectivity, mainly including light-excitation attributes, band structure of photocATalysts, separation of photogenerated charge carriers, adsorption/activation of reactants, surface active sites of catalytic reaction, and adaption/desorption of intermediates.

569 citations