Project

Carcinogenicity induced by environmental carcinogens

Goal: Implementation of computational methods to elucidate the mechanism of carcinogenicity induced by environmental carcinogens into the cellular system.

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Qazi Mohammad Sajid Jamal
added a research item
Nanotechnology, a science dealing with particles at nano scale, is currently used in many fields including environmental management and medicine for welfare of human being. The economic development and quality of life have been improved through nanotechnology. The Polycyclic aromatic hydrocarbons (PAHs) and other toxicants have higher affinity to scaveng by nanopartilces. The structural properties and surface chemistry of nanoparticles are the players, further, extremely high surface area to volume ratio results in multiple enhancement of many beneficial properties. Hence, we have followed a methodology to compare the binding efficiency of nanoparticles and cigarette smoke carcinogens with selected enzymes involved in DNA repair pathways. The molecular interactions have been accomplished using PatchDock server and interestingly got significant interacting results for our hypothesis. PatchDock results showed nanoparticles could be able to trap cigarette smoke carcinogens efficiently in the cellular system. The highest obtained binding efficiency between 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) versus Single wall carbon nanotube (SWcNT) is 2632 score in contrast with NNK versus Human MDC1 BRCT T2067D in complex (PDB ID: 3K05) shows 2454 score, which means NNK could interact with SWcNT more efficiently than 3K05. Another part of the study shows that the highest binding efficiency 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) versus SWcNT = 2746 score and NNAL versus Titanium dioxide (TiO2) Rutile = 2110 score in contract with NNAL versus Human Thymine DNA Glycosylase(PDB ID: 2RBA) shows 1696 score. It is also signified that NNAL interact with SWcNT and TiO2 rutile more efficiently than 2RBA. The results clearly signifying that SWcNT/TiO2 are binding with NNK/NNAL more efficiently than biomolecules.
Anupam Dhasmana
added a research item
Nanotechnology is a promptly growing field in this century, and it have been extensively used in several solicitations. Reactive oxygen species (ROS) generation is one of the important mechanism of action of nanoparticles. The excess ROS generation can induce oxidative stress, so the cells are unable to sustain the normal biological redox-regulated tasks. The high oxidative stress and ROS formation condition, damage the biological macromolecules, cell signaling pathways and finally leads to cell death or cancer initiation. The objective of the present study is to reveal the effects of TiO2 nanoparticle on co-culture system. The cell viability, oxidative stress and apoptosis were evaluated in monolayer and co-culture 3T3-L1 cells after the exposure of TiO2. Our results indicated that TiO2 significantly induces the reactive oxygen species (ROS), lipid peroxidation and decrease in the level of glutathione. Additionally, real-time PCR data analysis shown an increased in the expression of p53, Bax, caspase-9, caspase-3 and decreased the level of Bcl-2, by this means specifying that apoptosis induced by TiO2 NPs occurs via the caspase-dependent pathway. This study analytically shows that oxidative stress is the fundamental mechanism by which TiO2 causes apoptosis in a co-culture system even at very low concentrations. In the future, the use of such nanoparticles should be cautiously scrutinized.
Mohtashim Lohani
added a research item
Epidemiological and experimental studies have suggested an enhancement of asbestos-induced bronchogenic carcinoma by cigarette smoke. Further, our recent experimental and epidemiological studies have indicated that besides smoking, several other compounds including kerosene soot may accelerate disease processes in asbestos-exposed animals as well as in the humans. Incomplete combustion of kerosene oil generates large volumes of soot, which contains various polycyclic aromatic hydrocarbons and aliphatic compounds. As reported earlier, exposure to kerosene soot is known to cause biochemical and pathological changes in the pulmonary tissue, which may cause cardiopulmonary disorders. In this study we investigated genotoxic effects caused by kerosene soot and chrysotile asbestos as well as co-exposure of kerosene soot and chrysotile using Syrian hamster embryo fibroblasts (SHE). The micronucleus assay revealed a significant increase of induced micronuclei (MN), (P</=0.05) in SHE cells after treatment with kerosene soot (0.5-1.0 microg/cm(2)) for 66 h (36 MN/1000 cells). Combined treatment with chrysotile and soot induced up to 110 MN/1000 cells (chrysotile alone: 80 MN/1000 cells; concentrations: 1 microg/cm(2), exposure times: 66 h). Kinetochore staining revealed mainly clastogenic effects in all cases (soot: 21.3% CRMN(+); chrysotile: 27%; soot+chrysotile: 27.6%; control: 20.8%). This is the first study showing that kerosene soot is not only genotoxic but it can also elevate the genotoxic potential of chrysotile asbestos. This information may be of importance for workers occupationally exposed to asbestos and domestically exposed to kerosene soot.
Qazi Mohammad Sajid Jamal
added 2 research items
Nanotechnology has a global socioeconomic significance. On the brighter side, Nanoparticles (NPs) offer extraordinary technical competencies which allow them to perform enormously novel developments in science and industries. Whereas, on the darker side, just the same novel qualities of nanoparticles can concurrently evoke undesired features, which sometimes lead to adverse and harmful interactions with exposed organisms. Workers involved in manufacturing and handling of NPs in all countries face new hazards from these nanomaterials. The occupational safety and health associations have taken schemes to spot the gaps between awareness and practices. These international agencies formulate the guidelines for handling nano materials and fix their occupational exposure limits. In this chapter authors discussed the source and role of NPs in different areas, NPs induced toxicity, their interaction with different biomolecules, as well as the safety and handling guidelines of NPs in occupational and laboratory areas.
We have performed the interaction analysis of cigarette smoke carcinogens with the enzymes involved in DNA repair mechanisms. Cigarette smoke’s derivatives like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are well known carcinogens. The binding efficiency of carcinogens with enzymes obtained from docking methods were ranging from +36.96 to −7.47 kcal/mol. Binding efficiency was characterized for the enzymes sharing equivalent or better interaction as compared to positive control. Also we have analyzed the interaction pattern of NNK and NNAL with DNA. The present study suggests that NNK and NNAL may alter the DNA repair machinery that could initiate the progression of tumor leading to cancer. Computational method explores the toxicological characteristics of these enzymes and also opening an opportunity for researchers.
Qazi Mohammad Sajid Jamal
added 9 research items
Polycyclic aromatic hydrocarbons (PAH), like Benzo[alpha]Pyrene (BaP) are known to cause a number of toxic manifestations including lung cancer. As Titanium dioxide Nanoparticles (TiO2 NPs) have recently been shown to adsorb a number of PAHs from soil and water, we investigated whether TiO2 NPs could provide protection against the BaP induced toxicity in biological system. A549 cells when co-exposed with BaP (25 µM, 50 µM and 75 µM) along with 0.1 µg/ml,0.5 µg/ml and 1 µg/ml of TiO2 NPs, showed significant reduction in the toxic effects of BaP, as measured by Micronucleus Assay, MTT Assay and ROS Assay. In order to explore the mechanism of protection by TiO2 NP against BaP, we performed in silico studies. BaP and other PAHs are known to enter the cell via aromatic hydrocarbon receptor (AHR). TiO2 NP showed a much higher docking score with AHR (12074) as compared to the docking score of BaP with AHR (4600). This indicates a preferential binding of TiO2 NP with the AHR, in case if both the TiO2 NP and BaP are present. Further, we have done the docking of BaP with the TiO2 NP bound AHR-complex (score 4710), and observed that BaP showed strong adsorption on TiO2 NP itself, and not at its original binding site (at AHR). TiO2 NPs thereby prevent the entry of BaP in to the cell via AHR and hence protect cells against the deleterious effects induced by BaP.
TiO 2 showed Human exposure to PAHs is almost inevitable. They are produced during the combustion processes of organic materials during industrial and other human activities, like processing of coal and crude oil, vehicle traffic and cigarette smoking. A number of PAHs like Benzo[alpha]Pyrene are known to cause lung cancer. We investigated, if nanoparticles could somehow provide protection against the BaP induced toxicity. In this study we evaluated the protective potential of UF-TiO 2 against BaP induced toxicity by Wet lab and in silico experiments. BaP enters in the cell via Aromatic Hydrocarbon Receptor (AHR) and induces the cyto-genotoxicity. 0.1µg/ml,0.5µg/ml and 1µg/ml of UFTiO 2 when co-exposed with BaP (12 µg/ml) in A549 cells, showed significant reduction in the toxic effects of BaP, as measured by MTT Assay and ROS Assay. TiO2 showed a much higher in silico docking score with AHR (score 9920) as compared to the docking score of BaP with AHR (score 4078). The results of the study clearly indicated the toxic potential of the BaP as evident by ROS assay and MTT assay in A-549, a lung carcinoma cell line. The toxicity induced by BaP was found to reduce substantially when UF-TiO 2 was co-exposed along with BaP. The results of in silico docking fetch the insight of the mechanism how protection is provided by UF-TiO 2 against BaP induced toxicity. BaP and other PAHs are known to enter the cell via Aromatic Hydrocarbon Receptor. We observed that UF-TiO 2 binds to AHR with much more efficiency than the BaP does. This indicates a preferential binding of UF-TiO 2 with the AHR, in case if both the UF-TiO 2 and BaP are present, blocking the entry of BaP in the cell and hence protecting the cell against BaP induced toxicity.
Cell cycle is maintained almost all the times and is controlled by various regulatory proteins and their complexes (Cdk+Cyclin) in different phases of interphase (G1, S and G2) and mitosis of cell cycle. A number of mechanisms have been proposed for the initiation and progression of carcinogenesis by abruption in cell cycle process. One of the important features of cancer/carcinogenesis is functional loss of these cell cycle regulatory proteins particularly in CDKs and cyclins. We hypothesize that there is a direct involvement of these cell cycle regulatory proteins not only at the genetic level but also proteins level, during the initiation of carcinogenesis. Therefore, it becomes significant to determine inconsistency in the functioning of regulatory proteins due to interaction with carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Hence, we investigated the interaction efficiency of NNK, against cell cycle regulatory proteins. We found a different value of ΔG (free energy of binding) among the studied proteins ranging between -3.29 to -7.25 kcal/mol was observed. To validate the results, we considered Human Oxy-Hemoglobin at 1.25 Å Resolution, [PDB_ID:1HHO] as a +ve control, (binding energy -6.06 kcal/mol). Finally, the CDK8 (PDB_ID:3RGF) and CDK2 (PDB_ID:3DDP) regulatory proteins showing significantly strong molecular interaction with NNK -7.25 kcal/mol, -6.19 kcal/mol respectively were analyzed in details. In this study we predicted that CDK8 protein fails to form functional complex with its complementary partner cyclin C in presence of NNK. Consequently, inconsistency of functioning in regulatory proteins might lead to the abruption in cell cycle progression; contribute to the loss of cell cycle control and subsequently increasing the possibility of carcinogenesis.
Qazi Mohammad Sajid Jamal
added a research item
Cigarette smoke derivatives like NNK (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone) and NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol) are well-known carcinogens. We analyzed the interaction of enzymes involved in the NER (nucleotide excision repair) pathway with ligands (NNK and NNAL). Binding was characterized for the enzymes sharing equivalent or better interaction as compared to +Ve control. The highest obtained docking energy between NNK and enzymes RAD23A, CCNH, CDK7, and CETN2 were -7.13 kcal/mol, -7.27 kcal/mol, -8.05 kcal/mol and -7.58 kcal/mol respectively. Similarly the highest obtained docking energy between NNAL and enzymes RAD23A, CCNH, CDK7, and CETN2 were -7.46 kcal/mol, -7.94 kcal/mol, -7.83 kcal/mol and -7.67 kcal/mol respectively. In order to find out the effect of NNK and NNAL on enzymes involved in the NER pathway applying protein-protein interaction and protein-complex (i.e. enzymes docked with NNK/ NNAL) interaction analysis. It was found that carcinogens are well capable to reduce the normal functioning of genes like RAD23A (HR23A), CCNH, CDK7 and CETN2. In silico analysis indicated loss of functions of these genes and their corresponding enzymes, which possibly might be a cause for alteration of DNA repair pathways leading to damage buildup and finally contributing to cancer formation.
Qazi Mohammad Sajid Jamal
added a project goal
Implementation of computational methods to elucidate the mechanism of carcinogenicity induced by environmental carcinogens into the cellular system.