scholarly journals Novel pyrano 1,3 oxazine based ligand inhibits the epigenetic reader hBRD2 in glioblastoma

2020 ◽  
Vol 477 (12) ◽  
pp. 2263-2279
Author(s):  
Prashant Deshmukh ◽  
Shruti Mathur ◽  
Gejo Gangadharan ◽  
Gopinatha Krishnappa ◽  
Nandakumar Dalavaikodihalli Nanjaiah ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Chemotherapeutic Agents ◽  
Significant Inhibition ◽  
High Recurrence Rate ◽  
The Novel ◽  
Binding Studies ◽  
Therapeutic Success ◽  
Oxazine Derivative ◽  
And Migration ◽  
Druggable Targets

Glioblastoma (GBM) is the most common primary brain malignancy, rarely amenable to treatment with a high recurrence rate. GBM are prone to develop resistance to the current repertoire of drugs, including the first-line chemotherapeutic agents with frequent recurrence, limiting therapeutic success. Recent clinical data has evidenced the BRD2 and BRD4 of the BET family proteins as the new druggable targets against GBM. In this relevance, we have discovered a compound (pyrano 1,3 oxazine derivative; NSC 328111; NS5) as an inhibitor of hBRD2 by the rational structure-based approach. The crystal structure of the complex, refined to 1.5 Å resolution, revealed that the NS5 ligand significantly binds to the N-terminal bromodomain (BD1) of BRD2 at the acetylated (Kac) histone binding site. The quantitative binding studies, by SPR and MST assay, indicate that NS5 binds to BD1 of BRD2 with a KD value of ∼1.3 µM. The cell-based assay, in the U87MG glioma cells, confirmed that the discovered compound NS5 significantly attenuated proliferation and migration. Furthermore, evaluation at the translational level established significant inhibition of BRD2 upon treatment with NS5. Hence, we propose that the novel lead compound NS5 has an inhibitory effect on BRD2 in glioblastoma.

scholarly journals Coumarin centered copper(ii) complex with appended-imidazole as cancer chemotherapeutic agents against lung cancer: molecular insight via DFT-based vibrational analysis

RSC Advances ◽  
2017 ◽  
Vol 7 (57) ◽  
pp. 36056-36071 ◽  
Author(s):  
Mohammad Usman ◽  
Mehvash Zaki ◽  
Rais Ahmad Khan ◽  
Ali Alsalme ◽  
Musheer Ahmad ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Structural Characterization ◽  
Copper Complex ◽  
Vibrational Analysis ◽  
Chemotherapeutic Agents ◽  
The Novel ◽  
Binding Studies ◽  
Dna Binding Studies

Synthesis and structural characterization of the novel copper complex, DFT based vibrational analysis, DNA binding studies. In vitro cytotoxicity against A549 cancer cell lines and estimation of GSH, ROS, LPO levels, have been reported.

scholarly journals Effects of Allium sativum Stem Extract on Growth and Migration in Melanoma Cells through Inhibition of VEGF, MMP-2, and MMP-9 Genes Expression

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 21
Author(s):  
Da-Hye Gam ◽  
Jae-Hyun Park ◽  
Jun-Hee Kim ◽  
Dong-Ho Beak ◽  
Jin-Woo Kim
Keyword(s):  
Matrix Metalloproteinases ◽  
High Performance ◽  
Allium Sativum ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Mrna Levels ◽  
Chromatography Analysis ◽  
Genes Expression ◽  
Stem Extract ◽  
And Migration

The present study investigated the effects of Allium sativum stem extract (ASE) on B16-F0 cell growth and metastasis. Evaluation of the effects of ASE on B16-F0 cells’ viability and migration showed that 0.5 mg/mL ASE inhibited B16-F0 cells’ growth by 30.2% and migration by 38.5%, which indicates that the ASE has anticancer and antimetastatic effects on B16-F0 cells. To study the anticancer and antimetastatic mechanism, mRNA levels of vascular endothelial growth factor (VEGF), matrix metalloproteinases-2 (MMP-2), and matrix metalloproteinases-9 (MMP-9) expressions were evaluated with reverse transcription polymerase chain reaction, and 0.25 and 0.5 mg/mL ASE was found to exert significant inhibition on mRNA expressions of VEGF, MMP-2, and MMP-9 in B16-F0 cells. Thus, ASE reduce extracellular matrix degradation through inhibitions of expression of MMP-2 and MMP-9, and also showed an angiogenesis inhibitory effect through reduction of VEGF expression. High-performance liquid chromatography analysis showed that among various polyphenols, gallic acid (2.1 mg/g) was a major compound of ASE. Overall, our results demonstrated that ASE inhibited the growth and migration of B16-F0 cells through downregulation of the VEGF, MMP-2, and MMP-9 genes expression, which indicates ASE could be applied for the prevention and treatment of melanoma.

A comparative study of the antibacterial activity of Quercus robur (Ethanolic extract) and Zinc oxide nanoparticles on Salmonella (In vitro)

2018 ◽  
Vol 9 (SPL1) ◽  
Author(s):  
Hams H. H. Alfattli ◽  
Ghufran Zuhair Jiber ◽  
Ghaidaa Gatea Abbass
Keyword(s):  
Zinc Oxide ◽  
Antibacterial Activity ◽  
Zinc Oxide Nanoparticles ◽  
Quercus Robur ◽  
Ethanolic Extract ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Oxide Nanoparticles ◽  
Inhibition Zones

This study which designed to evaluate the inhibitory effect of Ethanolic extract of (Quercusrobur) and Zinc oxide nanoparticles on the growth of one genus of enterobacteriacae (Salmonella). In vitro. For this purpose graduate concentrates for plant extract (50, 100, 200, 400 )mg/ml which prepared and compared with Zinc oxide nanoparticles of different concentration (2, 1, 0.5, 0.25) μg/ml,and examined. The result showed that the studied medicinal plant has antibacterial activity against this bacteria which used. The result showed that the plant has good activity in decrease the growth of this bacteria. The results of the study also showed that the nano-ZnO has very effective antibacterial action against the studied bacteria which was Salmonella,nanoparticles concentrations lead to increasing in the inhibition zones of tested bacterial growth. We also study the effect of three antibiotics Lomefloxacin (LOM), Ciprofloxacin (SIP) and Rifampin (RA) and the result showed,in a comparison within the tested bacteria,Salmonella had a significant inhibition increase in Lomefloxacin ; the ciprofloxacin showed effect on tested bacteria. However,Rifampin does not show any effect on tested bacteria.

scholarly journals Application of Furcellaran Nanocomposite Film as Packaging of Cheese

Polymers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1428
Author(s):  
Agnieszka Pluta-Kubica ◽  
Ewelina Jamróz ◽  
Gohar Khachatryan ◽  
Adam Florkiewicz ◽  
Pavel Kopel
Keyword(s):  
Silver Nanoparticles ◽  
Nanocomposite Film ◽  
Microbiological Quality ◽  
Inhibitory Effect ◽  
Quality Properties ◽  
In Situ Method ◽  
And Migration ◽  
Total Bacteria

There is a serious need to develop and test new biodegradable packaging which could at least partially replace petroleum-based materials. Therefore, the objective of this work was to examine the influence of the recently developed furcellaran nanocomposite film with silver nanoparticles (obtained by an in situ method) on the quality properties of two cheese varieties: a rennet-curd (gouda) and an acid-curd (quark) cheese. The water content, physicochemical properties, microbiological and organoleptic quality of cheese, and migration of silver nanoparticles were examined. Both the number of Lactococcus and total bacteria count did not differ during storage of gouda regardless of the packaging applied. The number of Lactococcus decreased in analogous quark samples. The use of the film slowed down and inhibited the growth of yeast in gouda and quark, respectively. An inhibitory effect of this film on mold count was also observed; however, only regarding gouda. The level of silver migration was found to be lower in quark than in gouda. The film improved the microbiological quality of cheeses during storage. Consequently, it is worth continuing research for the improvement of this film in order to enable its use in everyday life.

scholarly journals Inhibitory Effect of (2R)-4-(4-hydroxyphenyl)-2-butanol 2-O-β-d-apiofuranosyl-(1→6)-β-d-glucopyranoside on RANKL-Induced Osteoclast Differentiation and ROS Generation in Macrophages

2020 ◽  
Vol 22 (1) ◽  
pp. 222
Author(s):  
Eun-Nam Kim ◽  
Ga-Ram Kim ◽  
Jae Sik Yu ◽  
Ki Hyun Kim ◽  
Gil-Saeng Jeong
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Bone Disease ◽  
Osteoclast Differentiation ◽  
Inhibitory Effect ◽  
Bone Diseases ◽  
Ros Generation ◽  
Bone Homeostasis ◽  
Disease Treatment ◽  
And Migration

In bone homeostasis, bone loss due to excessive osteoclasts and inflammation or osteolysis in the bone formation process cause bone diseases such as osteoporosis. Suppressing the accompanying oxidative stress such as ROS in this process is an important treatment strategy for bone disease. Therefore, in this study, the effect of (2R)-4-(4-hydroxyphenyl)-2-butanol 2-O-β-d-apiofuranosyl-(1→6)-β-d-glucopyranoside (BAG), an arylbutanoid glycoside isolated from Betula platyphylla var. japonica was investigated in RANKL-induced RAW264.7 cells and LPS-stimulated MC3E3-T1 cells. BAG inhibited the activity of TRAP, an important marker of osteoclast differentiation and F-actin ring formation, which has osteospecific structure. In addition, the protein and gene levels were suppressed of integrin β3 and CCL4, which play an important role in the osteoclast-induced bone resorption and migration of osteoclasts, and inhibited the production of ROS and restored the expression of antioxidant enzymes such as SOD and CAT lost by RANKL. The inhibitory effect of BAG on osteoclast differentiation and ROS production appears to be due to the inhibition of MAPKs phosphorylation and NF-κβ translocation, which play a major role in osteoclast differentiation. In addition, BAG inhibited ROS generated by LPS and effectively restores the mineralization of lost osteoblasts, thereby showing the effect of bone formation in the inflammatory situation accompanying bone loss by excessive osteoclasts, suggesting its potential as a new natural product-derived bone disease treatment.

scholarly journals A novel radiolytic rotenone derivative, rotenoisin A, displays potent anticarcinogenic activity in breast cancer cells

2021 ◽  
Author(s):  
Dong-ho Bak ◽  
Seong Hee Kang ◽  
Chul-hong Park ◽  
Byung Yeoup Chung ◽  
Hyoung-Woo Bai
Keyword(s):  
Breast Cancer ◽  
Adverse Effects ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Parent Compound ◽  
Inhibitory Effect ◽  
Chemotherapeutic Agents ◽  
Epidermal Keratinocytes ◽  
Functional Changes ◽  
Structural Modifications

Abstract Chemotherapy for cancer treatment has therapeutic limitations, such as drug resistance, excessive toxic effects and undesirable adverse effects. Therefore, efforts to improve the safety and efficacy of chemotherapeutic agents are essential. Ionizing radiation can improve physiological and pharmacological properties by transforming structural modifications of the drug. In this study, in order to reduce the adverse effects of rotenone and increase anticancer activity, a new radiolytic rotenone derivative called rotenoisin A was generated through radiolytic transformation. Our findings showed that rotenoisin A inhibited the proliferation of breast cancer cells and increased the rate of apoptosis, whereas it had no inhibitory effect on primary epidermal keratinocytes compared with rotenone. Moreover, rotenoisin A-induced DNA damage by increasing reactive oxygen species (ROS) accumulation. It was also confirmed not only to alter the composition ratio of mitochondrial proteins, but also to result in structural and functional changes. The anticancer effect and molecular signalling mechanisms of rotenoisin A were consistent with those of rotenone, as previously reported. Our study suggests that radiolytic transformation of highly toxic compounds may be an alternative strategy for maintaining anticancer effects and reducing the toxicity of the parent compound.

scholarly journals Inhibitory Effect of a Glutamine Antagonist on Proliferation and Migration of VSMCs via Simultaneous Attenuation of Glycolysis and Oxidative Phosphorylation

2021 ◽  
Vol 22 (11) ◽  
pp. 5602
Author(s):  
Hyeon Young Park ◽  
Mi-Jin Kim ◽  
Seunghyeong Lee ◽  
Jonghwa Jin ◽  
Sungwoo Lee ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Metabolic Reprogramming ◽  
Neointima Formation ◽  
Artery Ligation ◽  
Carotid Artery Ligation ◽  
And Migration ◽  
Proliferation And Migration

Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of atherosclerosis and restenosis. Glycolysis and glutaminolysis are increased in rapidly proliferating VSMCs to support their increased energy requirements and biomass production. Thus, it is essential to develop new pharmacological tools that regulate metabolic reprogramming in VSMCs for treatment of atherosclerosis. The effects of 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, have been broadly investigated in highly proliferative cells; however, it is unclear whether DON inhibits proliferation of VSMCs and neointima formation. Here, we investigated the effects of DON on neointima formation in vivo as well as proliferation and migration of VSMCs in vitro. DON simultaneously inhibited FBS- or PDGF-stimulated glycolysis and glutaminolysis as well as mammalian target of rapamycin complex I activity in growth factor-stimulated VSMCs, and thereby suppressed their proliferation and migration. Furthermore, a DON-derived prodrug, named JHU-083, significantly attenuated carotid artery ligation-induced neointima formation in mice. Our results suggest that treatment with a glutamine antagonist is a promising approach to prevent progression of atherosclerosis and restenosis.

Effects of prostaglandins E1, E2, and F2alpha on the growth of leukaemia cells in culture

1976 ◽  
Vol 20 (1) ◽  
pp. 199-206
Author(s):  
T.J. Yang ◽  
J.B. Dale ◽  
R. Machanoff
Keyword(s):  
Tritiated Thymidine ◽  
Inhibitory Effect ◽  
Soft Agar ◽  
Significant Inhibition ◽  
Leucine Incorporation ◽  
Inhibitory Effects ◽  
Uridine Incorporation ◽  
Cells In Culture ◽  
Mouse Leukaemia

Prostaglandins E1, E2, and F2alpha (PGE1, PGE2, and PGF2alpha) were shown to inhibit the growth of mouse leukaemia lymphoblasts L5178Y in culture. The effects of PGE1 and PGE2 were greater than that of PGF2alpha. PGE1 and PGE2, at the concentration of 100 mug per ml showed significant inhibitory effects on the rates of incorporation of tritiated thymidine, uridine and leucine. At concentrations of 50 and 25 mug per ml, there was significant inhibition of thymidine and uridine incorporation, but not of leucine, PGF2alpha showed significant inhibition of thymidine and uridine incorporation but not leucine incorporation, in all 3 concentrations studied (100, 50, and 25 mug/ml). The ability of the cells to form colonies in soft agar was significantly inhibited by PGE1 and PGE2 at concentrations as low as 1–8 mug/ml. For F2alpha, however, a concentration as high as 56mug/ml was required to show inhibitory effect, but at 1–8 mug/ml it was found to be stimulatory.

Development of an integrated membrane process for water reclamation

2005 ◽  
Vol 51 (6-7) ◽  
pp. 455-463 ◽  
Author(s):  
C.H. Lew ◽  
J.Y. Hu ◽  
L.F. Song ◽  
L.Y. Lee ◽  
S.L. Ong ◽  
...  
Keyword(s):  
Retention Time ◽  
Unique Feature ◽  
Inhibitory Effect ◽  
Water Reclamation ◽  
The Novel ◽  
Membrane Process ◽  
Treatment Efficiency ◽  
Effluent Quality ◽  
Toc Removal ◽  
Ro Concentrate

An integrated membrane process (IMP) comprising a membrane bioreactor (MBR) and a reverse osmosis (RO) process was developed for water reclamation. Wastewater was treated by an MBR operated at a sludge retention time (SRT) of 20 days and a hydraulic retention time (HRT) of 5.5 h. The IMP had an overall recovery efficiency of 80%. A unique feature of the IMP was the recycling of a fraction of RO concentrate back to the MBR. Experimental results revealed that a portion of the slow- and hard-to-degrade organic constituents in the recycle stream could be degraded by an acclimated biomass leading to an improved MBR treatment efficiency. Although recycling concentrated constituents could impose an inhibitory effect on the biomass and suppress their respiratory activities, results obtained suggested that operating MBR (in the novel IMP) at an F/M ratio below 0.03 g TOC/g VSS.day could yield an effluent quality comparable to that achievable without concentrate recycling. It is noted in this study that the novel IMP could achieve an average overall TOC removal efficiency of 88.94% and it consistently produced product water usable for high value reuse applications.

scholarly journals Inhibition of Cytochrome P450 (CYP450) Isoforms by Isoniazid: Potent Inhibition of CYP2C19 and CYP3A

2001 ◽  
Vol 45 (2) ◽  
pp. 382-392 ◽  
Author(s):  
Zeruesenay Desta ◽  
Nadia V. Soukhova ◽  
David A. Flockhart
Keyword(s):  
Cytochrome P450 ◽  
Liver Microsomes ◽  
Cost Effective ◽  
Competitive Inhibitor ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Specific Substrate ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
The Mean

ABSTRACT Isoniazid (INH) remains the most safe and cost-effective drug for the treatment and prophylaxis of tuberculosis. The use of INH has increased over the past years, largely as a result of the coepidemic of human immunodeficiency virus infection. It is frequently given chronically to critically ill patients who are coprescribed multiple medications. The ability of INH to elevate the concentrations in plasma and/or toxicity of coadministered drugs, including those of narrow therapeutic range (e.g., phenytoin), has been documented in humans, but the mechanisms involved are not well understood. Using human liver microsomes (HLMs), we tested the inhibitory effect of INH on the activity of common drug-metabolizing human cytochrome P450 (CYP450) isoforms using isoform-specific substrate probe reactions. Incubation experiments were performed at a single concentration of each substrate probe at its Km value with a range of INH concentrations. CYP2C19 and CYP3A were inhibited potently by INH in a concentration-dependent manner. At 50 μM INH (∼6.86 μg/ml), the activities of these isoforms decreased by ∼40%. INH did not show significant inhibition (<10% at 50 μM) of other isoforms (CYP2C9, CYP1A2, and CYP2D6). To accurately estimate the inhibition constants (Ki values) for each isoform, four concentrations of INH were incubated across a range of five concentrations of specific substrate probes. The meanKi values (± standard deviation) for the inhibition of CYP2C19 by INH in HLMs and recombinant human CYP2C19 were 25.4 ± 6.2 and 13 ± 2.4 μM, respectively. INH showed potent noncompetitive inhibition of CYP3A (Ki = 51.8 ± 2.5 to 75.9 ± 7.8 μM, depending on the substrate used). INH was a weak noncompetitive inhibitor of CYP2E1 (Ki = 110 ± 33 μM) and a competitive inhibitor of CYP2D6 (Ki = 126 ± 23 μM), but the mean Ki values for the inhibition of CYP2C9 and CYP1A2 were above 500 μM. Inhibition of one or both CYP2C19 and CYP3A isoforms is the likely mechanism by which INH slows the elimination of coadministered drugs, including phenytoin, carbamazepine, diazepam, triazolam, and primidone. Slow acetylators of INH may be at greater risk for adverse drug interactions, as the degree of inhibition was concentration dependent. These data provide a rational basis for understanding drug interaction with INH and predict that other drugs metabolized by these two enzymes may also interact.

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