scholarly journals 3-(5-Nitrofuran-2-yl)prop-2-en-1-one Derivatives, with Potent Antituberculosis Activity, Inhibit A Novel Therapeutic Target, Arylamine N-acetyltransferase, in Mycobacteria

Antibiotics ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 368
Author(s):  
Neha Agre ◽  
Nilesh Tawari ◽  
Arundhati Maitra ◽  
Antima Gupta ◽  
Tulika Munshi ◽  
...  
Keyword(s):  
Cell Lines ◽  
Therapeutic Target ◽  
Therapeutic Index ◽  
Multidrug Resistant ◽  
Mycobacterium Tuberculosis H37rv ◽  
Mammalian Cell Lines ◽  
Low Cytotoxicity ◽  
Inhibitory Potential ◽  
Novel Target

In this study, the inhibitory potential of 3-(5-nitrofuran-2-yl)prop-2-en-1-one derivatives was evaluated against a panel of bacteria, as well as mammalian cell lines to determine their therapeutic index. In addition, we investigated the mechanism of antibiotic action of the derivatives to identify their therapeutic target. We discovered compound 2 to be an extremely potent inhibitor of Mycobacterium tuberculosis H37Rv growth (MIC: 0.031 mg/L) in vitro, performing better than the currently used first-line antituberculosis drugs such as isoniazid, rifampicin, ethambutol, and pretomanid in vitro. Furthermore, compound 3 was equipotent to pretomanid against a multidrug-resistant M. tuberculosis clinical isolate. The derivatives were selective and bactericidal towards slow-growing mycobacteria. They showed low cytotoxicity towards murine RAW 264.7 and human THP-1 cell lines, with high selectivity indices. Compound 1 effectively eliminated the intracellular mycobacteria in a mycobacteria-infected macrophage model. The derivatives were assessed for their potential to inhibit mycobacterial arylamine N-acetyltransferase (NAT) and were identified as good inhibitors of recombinant mycobacterial NAT, a novel target essential for the intracellular survival of M. tuberculosis. This study provided hits for designing new potent and selective antituberculosis leads, having mycobacterial NAT inhibition as their possible endogenous mechanisms of action.

Construction of lux-based promoter-reporter platforms in Mycobacterium bovis BCG for screening of drug repurposing small-molecule compounds as new anti-tuberculosis drugs

2021 ◽  
Author(s):  
Li Zhu ◽  
Annie Wing-tung Lee ◽  
Kelvin Ka-Lok WU ◽  
Peng GAO ◽  
Kingsley King-Gee Tam ◽  
...  
Keyword(s):  
Small Molecule ◽  
Drug Repurposing ◽  
Virulence Gene ◽  
Multidrug Resistant ◽  
Rapid Screening ◽  
Human Macrophage ◽  
Tuberculosis Complex ◽  
Low Cytotoxicity ◽  
Screening Platform

The emergence of multidrug-resistant strains and hyper-virulent strains of Mycobacterium tuberculosis are big therapeutic challenges for tuberculosis (TB) control. Repurposing bioactive small-molecule compounds has recently become a new therapeutic approach against TB. This study aimed to construct a rapid screening system to identify novel anti-TB agents from a library of small-molecule compounds. In this study, a total of 320 small-molecule compounds were used to screen for their ability to suppress the expression of a key virulence gene, phoP, of M. tuberculosis complex using luminescence (lux)-based promoter-reporter platforms. The minimum inhibitory and bactericidal concentrations on drug-resistant M. tuberculosis and cytotoxicity to human macrophage were determined. RNA-sequencing (RNA-seq) was conducted to determine the drug mechanisms of the selected compounds as novel antibiotics or anti-virulent agents against the M. tuberculosis complex. Six compounds displayed bactericidal activity against M. bovis BCG, in which Ebselen demonstrated the lowest cytotoxicity to macrophage and was considered as a potential antibiotic for TB. Another ten compounds did not inhibit the in vitro growth of the M. tuberculosis complex but down-regulated the expression of phoP specifically. Of them, ST-193 and ST-193 (hydrochloride) showed low cytotoxicity and could dysregulate the entire phoP-associated gene network, and thus identified as potential anti-virulence agents for M. tuberculosis. This study provides a rapid screening platform coupled with a systematic validation and eventually suggested one potential antibiotic and two anti-virulence agents for M. tuberculosis infections.

scholarly journals Global Genomic Analysis of Newly Diagnosed t(4 ;14) Multiple Myeloma Reveals a Specific Mutational Spectrum and Identifies PKD2 As a Potential Therapeutic Target

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4462-4462
Author(s):  
Xiu Ly Song ◽  
Raphaël Szalat ◽  
Alexis Talbot ◽  
HaiVu Nguyen ◽  
Mehmet K. Samur ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Plasma Cells ◽  
Genomic Analysis ◽  
Sequencing Analysis ◽  
Newly Diagnosed ◽  
Potential Therapeutic Target ◽  
Mutational Landscape

Abstract In Multiple Myeloma (MM), the t(4;14) translocation is associated with a poor outcome. However, beside this translocation, the genetic events which determine the adverse evolution of the disease and the resistance to treatments remain elusive. In this study we performed whole exome or RNA sequencing analysis of samples from 65 newly diagnosed t(4;14) MM. We found that NRAS, KRAS, MAPK and FGFR3 are frequently mutated (12%, 9%, 13.8%, and 20% respectively). Overall, the FGFR3/RAS/BRAF/MAPK genes were mutated in 36 cases (54%). There was a negative correlation between mutations in FGFR3 and those occurring in NRAS, KRAS and BRAF as expected from the mutually exclusive occurrence of mutations in these genes. In addition to alterations in TP53 and DIS3, we found marked elevated frequency of mutations in PRKD2 (10.7%), ATM/ATR (10.7%) and MYCBP2 (7.6%), reduced frequency in FAM46C (1.5%) and no mutation in TRAF3 and CCND1. Mutations in ATM/ATR were strongly associated with the MB4-2 breakpoint (Bp) (p = 1.62 10-4) and significantly correlated with mutations affecting genes coding for members of the MAPK family. We observed a positive correlation between non-silent mutations in PRKD2 and the MB4-1 or MB4-3 Bp (p = 1.3 10-2). Of note, PRKD2 mutations are exclusively found in 3 t(4;14) MM cell lines and among the 84 MM sequenced by Bolli et al. (1), none of the non t(4;14) patient were mutated in PRKD2, indicating that this genetic lesion is associated with t(4;14) MM. In the NCI-H929 t(4;14) MM cell line, which is mutated for PRKD2, encoding the PKD2 serine/threonine kinase, we observed elevated levels of phosphorylated PKD2. Furthermore, inhibition of PKD, decreased PKD2 phosphorylation and triggered reduced proliferation and apoptosis of MM cell lines and fresh plasma cells from patients in vitro. These results define a specific mutational landscape for t(4;14) MM and identify PKD2 as a potential therapeutic target in MM patients. Altogether, these results define a specific mutational landscape for t(4;14) MM and identify PKD2 as a potential therapeutic target in MM patients. Reference 1. Bolli, N., Avet-Loiseau, H., Wedge, D.C., Van Loo, P., Alexandrov, L.B., Martincorena, I., Dawson, K.J., Iorio, F., Nik-Zainal, S., Bignell, G.R., et al. (2014). Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun 5, 2997. Disclosures Munshi: Janssen: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Oncopep: Patents & Royalties.

scholarly journals Highly Crystalline WO3 Nanoparticles Are Nontoxic to Stem Cells and Cancer Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
B. Han ◽  
A. L. Popov ◽  
T. O. Shekunova ◽  
D. A. Kozlov ◽  
O. S. Ivanova ◽  
...  
Keyword(s):  
Stem Cells ◽  
Tungsten Oxide ◽  
Cell Lines ◽  
Colloidal Solutions ◽  
Sedimentation Stability ◽  
Ultrasonic Assisted ◽  
Low Cytotoxicity ◽  
Theranostic Applications

Tungsten oxide sol, containing highly crystalline nanoparticles of orthorhombic WO3 and having good sedimentation stability, was synthesized using a facile, ultrasonic-assisted technique. An additional steric stabilizer, dextran, was proposed to enhance the stability of WO3 nanoparticles in biological media and to reduce their in vivo toxicity. The cytotoxicity of dextran-stabilized and nonstabilized WO3 sols was studied in vitro using dental pulp stem (DPS) cell lines and breast cancer (MCF-7) cell lines. Both tungsten oxide sols demonstrated low cytotoxicity and low genotoxicity for both stem cells and malignant cells and only slightly reduced their metabolic activity in the concentration range studied (from 0.2 to 200 μg/ml). The data obtained support possible theranostic applications of tungsten oxide colloidal solutions.

scholarly journals In VitroandIn VivoAntimalarial Evaluations of Myrtle Extract, a Plant Traditionally Used for Treatment of Parasitic Disorders

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Farzaneh Naghibi ◽  
Somayeh Esmaeili ◽  
Noor Rain Abdullah ◽  
Mehdi Nateghpour ◽  
Mahdieh Taghvai ◽  
...  
Keyword(s):  
Cell Lines ◽  
Mammalian Cell ◽  
Methanolic Extract ◽  
Cytotoxic Activities ◽  
Traditional Use ◽  
Aerial Parts ◽  
Mammalian Cell Lines ◽  
Phytochemical Investigation

Based on the collected ethnobotanical data from the Traditional Medicine and Materia Medica Research Center (TMRC), Iran,Myrtus communisL. (myrtle) was selected for the assessment ofin vitroandin vivoantimalarial and cytotoxic activities. Methanolic extract of myrtle was prepared from the aerial parts and assessed for antiplasmodial activity, using the parasite lactate dehydrogenase (pLDH) assay against chloroquine-resistant (K1) and chloroquine-sensitive (3D7) strains ofPlasmodium falciparum. The 4-day suppressive test was employed to determine the parasitemia suppression of the myrtle extract againstP. berghei  in vivo. The IC50values of myrtle extract were 35.44 µg/ml against K1 and 0.87 µg/ml against 3D7. Myrtle extract showed a significant suppression of parasitaemia (84.8 ± 1.1% at 10 mg/kg/day) in mice infected withP. bergheiafter 4 days of treatment. Cytotoxic activity was carried out against mammalian cell lines using methyl thiazol tetrazolium (MTT) assay. No cytotoxic effect on mammalian cell lines up to 100 µg/mL was shown. The results support the traditional use of myrtle in malaria. Phytochemical investigation and understanding the mechanism of action would be in our upcoming project.

scholarly journals The Molecular Pharmacology of Pateamine A

2021 ◽  
Author(s):  
◽  
James Henry Matthews
Keyword(s):  
Protein Synthesis ◽  
Cell Lines ◽  
Mammalian Cell ◽  
Mode Of Action ◽  
Protein Synthesis Inhibitors ◽  
Primary Target ◽  
Dead Box ◽  
Mammalian Cell Lines ◽  
Pateamine A

<p>Pateamine A is a cytotoxic terpenoid isolated from the marine sponge Mycale hentscheli that induces apoptosis in mammalian cell lines and is growth inhibitory to yeasts and fungi, yet shows no inhibitory action in prokaryotes. The targets of pateamine in mammalian cell lines were isolated and identified using a combination of affinity chromatography and mass spectrometry, putative targets included the DEAD-Box helicase eIF4A family of proteins, β-tubulin and actin. In vitro assessment of tubulin and actin polymerization showed pateamine was able to affect them only at high micromolar concentrations, whereas the effect on eIF4A in vitro was shown by others to occur at nanomolar concentrations. Additionally, pateamine was shown to inhibit cap-dependent protein synthesis in vivo, suggesting eIF4A as a primary target. The generation of a pateamine resistance-conferring mutation in the yeast eIF4A encoding gene TIF1, suggested further that eIF4A is a primary target in both mammalian and yeast cells, and allows the speculation of the position of the binding site for pateamine on the N-terminal lobe of eIF4A and the proposal of potential covalent interaction between this drug and its target. Given the size of the DEAD-Box helicase family, all of which share considerable homology with the eIF4As, FAL1 especially which is essential for rRNA maturation, a chemogenomic screen was performed in an attempt to establish the breadth of functional interactions of pateamine. The results of hierarchical clustering of these screen results suggest that pateamine has a mode-of-action distinct from other compounds screened previously, despite its effect on protein synthesis it failed to cluster with any other protein synthesis inhibitors regardless of their separate mechanisms, though, as a class, protein synthesis inhibitors were not found to form a discrete cluster in any of the variations of cluster analysis performed. Functional analysis, by GO term enrichment, of the genes whose deletions are hypersensitive to pateamine indicates that deletions of genes involved in numerous aspects of RNA metabolism affect pateamine sensitivity, however clear results regarding the involvement of FAL1 or any other non-eIF4A target in pateamine’s mode-of-action were not found.</p>

scholarly journals Circ-ZFR Promotes Progression of Bladder Cancer by Upregulating WNT5A Via Sponging miR-545 and miR-1270

2021 ◽  
Vol 10 ◽  
Author(s):  
Liping Luo ◽  
Pingping Miao ◽  
Yao Ming ◽  
Jie Tao ◽  
Hongchun Shen
Keyword(s):  
Bladder Cancer ◽  
Cell Lines ◽  
Pearson Correlation ◽  
Survival Rates ◽  
Circular Rna ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Novel Target

BackgroundBladder cancer is one of the most common cancers all over the world. CircZFR is a circular RNA and has been implicated in tumor generation and invasion. However, the exact role of circZFR in the development of bladder cancer (BCa) remains unknown. This study aimed to investigate the function of circZFR in BCa, and further to probe into the association between circ-ZFR, miR-545/miR-1270 and WNT5A.MethodsThe expression of circZFR in BCa was quantified by qRT-PCR and was positively correlated with the prognosis of BCa patients. Next, the stable knockdown of circZFR BCa cell lines was established and the resulting capacities of proliferation, migration and invasion were measured. The association of circZFR with miR-1270/miR-545 was predicted by circinteractome prediction, and was confirmed by luciferase assay as well as RNA pull down assay. Furthermore, miRNA inhibitors, WNT5A overexpression and Pearson correlation analysis were used to examine the relationship between circZFR, miR-1270/miR-545 and WNT5A.ResultsThe expression of CircZFR was up-regulated both in BCa tissues and in BCa cell lines, and was positively correlated with patient survival rates. Blocking of circZFR’s expression by RNA inhibitors suppressed the proliferation, migration and invasion of BCa cells both in vitro and in vivo. On the other hand, overexpression of target miRNA supported that circZFR directly interact with miR-545 and miR-1270. Moreover, we demonstrated that circZFR promotes the progression of BCa by upregulating WNT5A’s expression via sponging miR-545 and miR-1270.ConclusionsCircZFR promotes the proliferation, migration and invasion of BCa cells by upregulating WNT5A signaling pathway via sponging miR-545 and miR-1270. These results provide new insights into the molecular mechanism of circZFR in BCa progression, and more important, a novel target for BCa clinical treatment.

scholarly journals Evaluating Cytotoxic Potential of the Fruit and the Leaf Extracts of Sambucus ebulus (L.) on MCF7 and AGs Cell Lines

2021 ◽  
Vol 9 (1) ◽  
pp. 11-20
Author(s):  
Farzaneh Rasouli Asl ◽  
◽  
Ali Barzegar ◽  
Mohammad Ali Ebrahimzadeh ◽  
◽  
...  
Keyword(s):  
Cell Lines ◽  
Cytotoxic Activities ◽  
Cancer Therapies ◽  
Leaf Extracts ◽  
Ags Cells ◽  
Sambucus Ebulus ◽  
Ic50 Values ◽  
Low Cytotoxicity ◽  
Inhibitory Potential ◽  
Mcf 7

Background: Breast and stomach cancers are the most common malignancies in Iranian females and males, respectively. Enriching with phytochemicals that have antioxidant and cytotoxic activities, extracts from dwarf elder (Sambucus ebulus L.) holds promises to be used for alternative medication. Materials and Methods: We investigated the cytotoxic and antiproliferative activities of the leaf and the fruit ethyl-acetate (EA), as well as the methanolic (MeOH) extracts of dwarf elder upon treatment of the MCF-7 and AGS cells. Twenty-seven concentration series ranging from 10 to 2000 μg/mL were administered to the cells, and their growth inhibitory potential was assessed using MTT assay. The potential anticancer compounds of the extracts were quantified applying an improved highperformance liquid chromatography (HPLC). Results: All extracts showed positive dose-dependent cytotoxic activities on both cell lines. The EA extracts demonstrated more cytotoxicity compared to those of the MeOH ones (P<0.0001). The leaf EA extract showed IC50 values of 65 and 50 μg/mL, while those of the fruit were estimated as 58 and 50 μg/mL on the MCF-7 and AGS cells, respectively. The AGS cell line showed more susceptibility to all extracts tested compared to the MCF-7. MeOH extracts caused only a maximum of ~20% reduction in cell viability at 2000 μg/mL concentration. According to the HPLC analysis, leaf extracts contained phenolic compounds, including p- coumaric acid (0.10 mg per g powder), rutin (0.07 mg per g powder), and quercetin (0.02 mg per g powder). Conclusion: EA extract of the fruit shows the highest cytotoxicity: reducing 35.3% viability of the AGS cells with 10 μg/mL concentration. It can be considered a potential chemopreventive agent for cancer therapies. However, MeOH extracts with far low cytotoxicity or non-cytotoxic at some concentrations would be an appropriate candidate for preventing tumor growth without affecting neighboring normal cells.

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