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1.
Sci Rep ; 9(1): 17980, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784542

RESUMO

The sesquiterpene lactones, Isodeoxyelephantopin (IDET) and Deoxyelephantopin (DET) are known to exhibit activities against some cancer types. The activities of these lactones against breast cancer and the molecular bases is not known. We examined the efficacy of lactones in breast cancer preclinical model. Although both lactones exhibited drug like properties, IDET was relatively effective in comparison to DET. IDET suppressed the proliferation of both invasive and non-invasive breast cancer cell lines. IDET also suppressed the colony formation and migration of breast cancer cells. The assays for Acridine Orange (AO)/Propidium Iodide (PI) staining, cell cycle distribution, phosphatidylserine externalization and DNA laddering suggested the apoptosis inducing potential of IDET. The treatment with IDET also induced an accumulation of cells in the sub-G1 and G2/M phases. The exposure of breast cancer cells to the lactone was associated with a depolarization in mitochondrial membrane potential, and cleavage of caspase and PARP. The lactone induced reactive oxygen species (ROS) generation in breast cancer cells. Further, the use of N-acetyl cysteine (NAC) suppressed IDET induced ROS generation and apoptosis. The NF-κB-p65 nuclear translocation induced by okadaic acid (OA) was suppressed by the sesquiterpene. IDET also suppressed the expression of NF-κB regulated tumorigenic proteins, and induced the expression of proapoptotic gene (Bax) in cancer cells. While the expression of oncogenic lncRNAs was suppressed, the tumor suppressor lncRNAs were induced by the sesquiterpene. Collectively, the modulation of multiple cell signaling molecules by IDET may contribute to its activities in breast cancer cells.

2.
Genes (Basel) ; 10(8)2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357510

RESUMO

Cancer is the second deadliest disease listed by the WHO. One of the major causes of cancer disease is tobacco and consumption possibly due to its main component, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). A plethora of studies have been conducted in the past aiming to decipher the association of NNK with other diseases. However, it is strongly linked with cancer development. Despite these studies, a clear molecular mechanism and the impact of NNK on various system-level networks is not known. In the present study, system biology tools were employed to understand the key regulatory mechanisms and the perturbations that will happen in the cellular processes due to NNK. To investigate the system level influence of the carcinogen, NNK rewired protein-protein interaction network (PPIN) was generated from 544 reported proteins drawn out from 1317 articles retrieved from PubMed. The noise was removed from PPIN by the method of modulation. Gene ontology (GO) enrichment was performed on the seed proteins extracted from various modules to find the most affected pathways by the genes/proteins. For the modulation, Molecular COmplex DEtection (MCODE) was used to generate 19 modules containing 115 seed proteins. Further, scrutiny of the targeted biomolecules was done by the graph theory and molecular docking. GO enrichment analysis revealed that mostly cell cycle regulatory proteins were affected by NNK.


Assuntos
Carcinogênese/genética , Carcinógenos/toxicidade , Nitrosaminas/toxicidade , Mapas de Interação de Proteínas , Carcinogênese/efeitos dos fármacos , Carcinógenos/farmacologia , Ontologia Genética , Humanos , Simulação de Acoplamento Molecular , Nitrosaminas/farmacologia , Ligação Proteica , Proteoma/genética , Proteoma/metabolismo , Biologia de Sistemas
3.
Asian Pac J Cancer Prev ; 20(1): 199-206, 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30678432

RESUMO

Breast cancer is the leading cause of death among women worldwide. It is a multi-factorial disease caused by genetic and environmental factors. Vitamin D has been hypothesized to lower the risk of breast cancer via the nuclear vitamin D receptor (VDR). Genetic variants of these vitamin D metabolizing genes may alter the bioavailability of vitamin D, and hence modulate the risk of breast cancer. Materials and Methods: The distribution of Fok1 VDR gene (rs2228570) polymorphism and its association with breast cancer was analysed in a case­control study based on 125 breast cancer patients and 125 healthy females from North Indian population, using PCR-RFLP. An In silico exploration of the probable mechanism of increased risk of breast cancer was performed to investigate the role of single nucleotide polymorphisms (SNPs) in cancer susceptibility. Results: The Fok1 ff genotype was significantly associated with an increased risk of breast cancer (p=0.001; χ2=13.09; OR=16.909; %95 CI=2.20 - 130.11). In silico analysis indicated that SNPs may lead to a loss in affinity of VDR to calcitriol, and may also cause the impairment of normal interaction of liganded VDR with its heterodimeric partner, the retinoid X receptor (RXR), at protein level, thereby affecting target gene transcription. Conclusion: Breast cancer risk and pathogenesis in females can be influenced by SNPs. SNPs in VDR may cause alterations in the major molecular actions of VDR, namely ligand binding, heterodimerization and transactivation. VDRE binding and co-activator recruitment by VDR appear to be functionally inseparable events that affect vitamin D-elicited gene transcription. This indicates that breast cancer risk and pathogenesis in females may be influenced by SNPs.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Calcitriol/genética , Grupo com Ancestrais do Continente Asiático/genética , Calcitriol/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Polimorfismo de Fragmento de Restrição/genética , Risco , Transcrição Genética/genética , Vitamina D/genética
4.
J Cell Biochem ; 120(1): 232-242, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30171725

RESUMO

The role of niacin's metabolite, nicotinamide adenine dinucleotide (NAD), in DNA repair via base-excision repair pathway is well documented. We evaluated if niacin deficiency results in genetic instability in normal human fetal lung fibroblasts (MRC-5), and further, does it leads to enhanced accumulation of cigarette smoke-induced genetic damage? MRC-5 cells were grown discretely in niacin-proficient/deficient media, and exposed to nicotine-derived nitrosamine ketone (NNK, a cigarette smoke carcinogen). Niacin deficiency abated the NAD polymerization, augmented the spontaneous induction of micronuclei (MN) and chromosomal aberrations (CA) and raised the expression of 10 genes and suppressed 12 genes involved in different biological functions. NNK exposure resulted in genetic damage as measured by the induction of MN and CA in cells grown in niacin-proficient medium, but the damage became practically marked when niacin-deficient cells were exposed to NNK. NNK exposure raised the expression of 16 genes and suppressed the expression of 56 genes in cells grown in niacin-proficient medium. NNK exposure to niacin-deficient cells raised the expression of eight genes including genes crucial in promoting cancer such as FGFR3 and DUSP1 and suppressed the expression of 33 genes, including genes crucial in preventing the onset and progression of cancer like RASSF2, JUP, and IL24, in comparison with the cells grown in niacin-proficient medium. Overall, niacin deficiency interferes with the DNA damage repair process induced by chemical carcinogens like NNK, and niacin-deficient population are at the higher risk of genetic instability caused by cigarette smoke carcinogen NNK.


Assuntos
Neoplasias/genética , Niacina/deficiência , Fumantes , Carcinógenos/farmacologia , Linhagem Celular , Aberrações Cromossômicas/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Pesquisa Fetal , Fibroblastos/fisiologia , Expressão Gênica , Humanos , Pulmão/citologia , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Testes para Micronúcleos , NAD/metabolismo , Nitrosaminas/farmacologia , Polimerização
5.
J BUON ; 23(5): 1514-1527, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30570880

RESUMO

PURPOSE: The linkage of human T-cell leukemia virus type 1 (HTLV-1) to fatal diseases is a well known fact for many years. However, there has been no significant progress in the field of the treatment that can lead to the development of a successful vaccine. Furthermore, there are no means of assessing the risk of disease and its prognosis in the infected people. METHODS: The current study has taken the cognizance of the importance of host's immune response in reducing the risk of infectious diseases to carry out immunoinformatics driven epitope screening strategy of vaccine candidates against HTLV-1. In this study, a genetic variability and HLA distribution analysis among the documented HTLV-1 genotypes I, II, III, IV, V & VI was performed to ensure the coverage of the vast majority of population, where vaccine would be employed. The meticulous screening of effective dominant immunogens was done with the help of ABCPred and Immune Epitope Database. RESULTS: The results showed that the identified epitopes might be protective immunogens with high conservancy and potential of inducing both protective neutralizing antibodies and T-cell responses. The peptides "PSQLPPTAPPLLPHSNLDHI", "PCPNLVAYSSYHATY", and "YHATYSLYLF", were 100% conserved among different isolates from far and wide separated countries, suggesting negligible antigenic drift in HTLV-1. CONCLUSIONS: Overall, the mentioned epitopes are soluble, non-toxic suitable candidates for the development of vaccine against HTLV-1 and warrant further investigation and experimental validation.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Antígenos HLA/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Sequência de Aminoácidos , Anticorpos Neutralizantes/imunologia , Epitopos/imunologia , Infecções por HTLV-I/imunologia , Infecções por HTLV-I/virologia , Humanos , Imunidade Humoral
6.
Biomed Pharmacother ; 108: 1435-1450, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30372846

RESUMO

INTRODUCTION: Pulmonary emphysema characterized by alveolar wall destruction is resultant of persistent chronic inflammation. All-trans retinoic acid (ATRA) has been reported to reverse elastase-induced emphysema in rats. However, the underlying molecular mechanisms are so far unknown. OBJECTIVE: To investigate the therapeutic potential effect of ATRA via the amelioration of the ERK/JAK-STAT pathways in the lungs of emphysematous rats. METHODS: In silico analysis was done to find the binding efficiency of ATRA with receptor and ligands of ERK & JAK-STAT pathway. Emphysema was induced by porcine pancreatic elastase in Sprague-Dawley rats and ATRA was supplemented as therapy. Lungs were harvested for histopathological, genomics and proteomics analysis. RESULTS AND DISCUSSION: In silico docking, analysis confirms that ATRA interferes with the normal binding of ligands (TNF-α, IL6ST) and receptors (TNFR1, IL6) of ERK/JAK-STAT pathways respectively. ATRA restored the histology, proteases/antiproteases balance, levels of inflammatory markers, antioxidants, expression of candidate genes of ERK and JAK-STAT pathways in the therapy group. CONCLUSION: ATRA ameliorates ERK/JAK-STAT pathway in emphysema condition, resulting in alveolar epithelium regeneration. Hence, ATRA may prove to be a potential drug in the treatment of emphysema.


Assuntos
Anti-Inflamatórios/farmacologia , Alvéolos Pulmonares/efeitos dos fármacos , Enfisema Pulmonar/tratamento farmacológico , Regeneração/efeitos dos fármacos , Tretinoína/farmacologia , Animais , Janus Quinases/fisiologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Elastase Pancreática/metabolismo , Elastase Pancreática/farmacologia , Alvéolos Pulmonares/fisiologia , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição STAT/fisiologia , Tretinoína/uso terapêutico , Fator de Necrose Tumoral alfa/análise
7.
Medchemcomm ; 9(7): 1213-1225, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30109010

RESUMO

ß-Carbolines have been assessed for osteoclastogenesis. However, their effect on osteoblasts during estrogen deficiency is still unclear. Here, a series of novel piperazine and tetrazole tag ß-carbolines have been synthesized and examined for osteoblast differentiation in vitro. In vitro data suggest that compound 8g is the most promising osteoblast differentiating agent that was evaluated for in vivo studies. Compound 8g promoted osteoblast mineralization, stimulated Runx2, BMP-2 and OCN expression levels, increased BrdU incorporation and inhibited generation of free radicals as well as nitric oxide. Since a piperazine group is involved in bone repair activity and ß-carboline in IκB kinase (IKK) inhibition, compound 8g inhibited tumor necrosis factor α (TNFα) directed IκBα phosphorylation, preventing nuclear translocation of NF-κB thereby alleviating osteoblast apoptosis. In vivo studies show that compound 8g was able to restore estrogen deficiency-induced bone loss in ovariectomized rats without any toxicity, thus signifying its potential in bone-protection chemotherapy under postmenopausal conditions.

8.
J Nanosci Nanotechnol ; 18(6): 3870-3879, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29442721

RESUMO

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.


Assuntos
Apoptose/efeitos dos fármacos , Nanopartículas Metálicas , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio , Titânio/química , Animais , Sobrevivência Celular , Camundongos , Titânio/farmacologia
9.
Microb Pathog ; 115: 343-352, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29197526

RESUMO

The immune signalling genes during the challenge of bovine macrophages with bacterial products derived from tuberculosis causing bacteria in cattle were investigated in the present study. An in-vitro cell culture model of bovine monocyte-derived macrophages were challenged to Mycobacterium bovis. Macrophages from healthy and already infected animals can both be fully activated during M. bovis infection. Analysis of mRNA abundance in peripheral blood mononuclear cells from M. bovis infected and non-infected cattle were performed as a controls. Cells of treatment were challenged after six days for six hours incubation at 37 °C, with 5% CO2, to total RNA was extracted then cDNA labelling, hybridization and scanning for microarray methods have been developed for microarray based immune related gene expression analysis. The differential expressions twenty genes (IL1, CCL3, CXCR4, TNF, TLR2, IL12, CSF3, CCR5, CCR3, MAPT, NFKB1, CCL4, IL6, IL2, IL23A, CCL20, IL8, CXCL8, TRIP10, CXCL2 and IL1B) implicated in M. bovis response were examined Agilent Bovine_GXP_8 × 60 K microarray platform. Cells of treatment were challenged after six days for six hours incubation then pathways analysis of Toll like receptor and Chemokine signalling pathway study of responsible genes in bovine tuberculosis. The PBMC from M. bovis infected cattle exhibit different transcriptional profiles compared with PBMC from healthy control animals in response to M. bovis antigen stimulation, providing evidence of a novel genes expression program due to M. bovis exposure. It will guide future studies, regarding the complex macrophage specific signalling pathways stimulated upon phagocytosis of M. bovis and role of signalling pathways in creating the host immune response to cattle tuberculosis.


Assuntos
Regulação da Expressão Gênica/imunologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Mycobacterium bovis/imunologia , Tuberculose Bovina/imunologia , Animais , Bovinos , Células Cultivadas , Macrófagos/microbiologia , Fagocitose/genética , RNA Mensageiro/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Tuberculose Bovina/microbiologia
10.
Ann Clin Lab Sci ; 47(4): 409-415, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28801366

RESUMO

GOALS: Fullerenes have tremendous potential for human biological studies which may further lead to their therapeutic applications. Hence, it has become necessary to explore the possibility of their interference with various important cellular processes. The current study was designed to explore how the presence of fullerenes can affect the binding of DNA with different enzymes and factors involved in transcription and translation process. METHODS: Various bioinformatics approaches and software programs were used to study the effect of fullerenes on the binding pattern of DNA with different enzymes and factors involved in transcription and translation process. RESULTS: Fullerenes of different molecular weights were interacted with various transcription enzymes and factors and no significant effects were observed on transcription machinery. On the contrary, the factors involved in translation process when docked with their functional partners in the presence/absence of fullerenes display reduced activity of eIF2, eIF4A, eIF4H, eIF4G, eIF4B, eIF5B, and eEF1 with fullerenes of different molecular weights. CONCLUSIONS: We conclude that these molecules mostly control the translation of a number of genes. The reduced expression of these factors may cause a number of clinical pathological conditions including neurodegenerative disorders like Alzheimer's, Parkinson's, and Huntington's diseases.


Assuntos
Fatores de Iniciação em Eucariotos/metabolismo , Fulerenos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Biossíntese de Proteínas , Mapas de Interação de Proteínas/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Simulação por Computador , Fatores de Iniciação em Eucariotos/química , Humanos , Conformação Proteica
11.
EXCLI J ; 16: 63-72, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28435428

RESUMO

Zika virus (ZIKV) is a mosquito-borne flavivirus distributed all over Africa, South America and Asia. The infection with the virus may cause acute febrile sickness that clinically resembles dengue fever, yet there is no vaccine, no satisfactory treatment, and no means of evaluating the risk of the disease or prognosis in the infected people. In the present study, the efficacy of the host's immune response in reducing the risk of infectious diseases was taken into account to carry out immuno-informatics driven epitope screening strategy of vaccine candidates against ZIKV. In this study, HLA distribution analysis was done to ensure the coverage of the vast majority of the population. Systematic screening of effective dominant immunogens was done with the help of Immune Epitope & ABCPred databases. The outcomes suggested that the predicted epitopes may be protective immunogens with highly conserved sequences and bear potential to induce both protective neutralizing antibodies, T & B cell responses. A total of 25 CD4+ and 16 CD8+ peptides were screened for T-cell mediated immunity. The predicted epitope "TGLDFSDLYYLTMNNKHWLV" was selected as a highly immunogenic epitope for humoral immunity. These peptides were further screened as non-toxic, immunogenic and non-mutated residues of envelop viral protein. The predicted epitope could work as suitable candidate(s) for peptide based vaccine development. Further, experimental validation of these epitopes is warranted to ensure the potential of B- and T-cells stimulation for their efficient use as vaccine candidates, and as diagnostic agents against ZIKV.

12.
J Microbiol Methods ; 136: 6-10, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28235560

RESUMO

Clostridium difficile is an enteric pathogen that causes approximately 20% to 30% of antibiotic-associated diarrhea. In recent years, there has been a substantial rise in the rate of C. difficile infections as well as the emergence of virulent and antibiotic resistant C. difficile strains. So, there is an urgent need for the identification of therapeutic potential targets and development of new drugs for the treatment and prevention of C. difficile infections. In the current study, we used a hybrid approach by combining sequence similarity-based approach and protein-protein interaction network topology-based approach to identify and characterize the potential drug targets of C. difficile. A total of 155 putative drug targets of C. difficile were identified and the metabolic pathway analysis of these putative drug targets using DAVID revealed that 46 of them are involved in 9 metabolic pathways. In-silico characterization of these proteins identified seven proteins involved in pathogen-specific peptidoglycan biosynthesis pathway. Three promising targets viz. homoserine dehydrogenase, aspartate-semialdehyde dehydrogenase and aspartokinase etc. were found to be involved in multiple enzymatic pathways of the pathogen. These 3 drug targets are of particular interest as they can be used for developing effective drugs against multi-drug resistant C. difficile strain 630 in the near future.


Assuntos
Proteínas de Bactérias/isolamento & purificação , Clostridium difficile/efeitos dos fármacos , Clostridium difficile/metabolismo , Biologia Computacional/métodos , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Resistência a Múltiplos Medicamentos , Proteoma/metabolismo , Antibacterianos/farmacologia , Aspartato Quinase , Aspartato-Semialdeído Desidrogenase/metabolismo , Proteínas de Bactérias/efeitos dos fármacos , Proteínas de Bactérias/metabolismo , Fenômenos Bioquímicos , Clostridium difficile/enzimologia , Clostridium difficile/genética , Enterocolite Pseudomembranosa/tratamento farmacológico , Genes Essenciais/genética , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/fisiologia , Modelos Biológicos , Peptidoglicano/biossíntese , Peptidoglicano/metabolismo , Domínios e Motivos de Interação entre Proteínas , Proteoma/genética
13.
Mol Neurobiol ; 54(5): 3633-3651, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27206429

RESUMO

Expression of various cytochrome P450s (CYPs) in mammalian brain cells is well documented. However, such studies are hampered in neural/glial cells of human origin due to nonavailability of human brain cells. To address this issue, we investigated the expression and inducibility of CYP2C8 and CYP3A4 and their responsiveness against cyclophosphamide (CPA) and organophosphorus pesticide monocrotophos (MCP), a known developmental neurotoxicant in human neural (SH-SY5Y) and glial (U373-MG) cell lines. CPA induced significant expression of CYP2C8 and CYP3A4 in both types of cells in a time-dependent manner. Neural cell line exhibited relatively higher constitutive and inducible expression of CYPs than the glial cell line. MCP exposure alone could not induce the significant expression of CYPs, whereas the cells preexposed to CPA showed a significant response to MCP. Similar to the case of CPA induced expressions, neural cells were found to be more vulnerable than glial cells. Our data indicate differential expressions of CYPs in cultured human neural and glial cell lines. The findings were synchronized with protein ligand docking studies, which showed a significant modulatory capacity of MCP by strong interaction with CYP regulators-CAR and PXR. Similarly, the known CYP inducer CPA has also shown significant high docking scores with the two studied CYP regulators. We also observed a significant induction in reactive oxygen species (ROS), lipid peroxides (LPO), micronucleus (MN), chromosomal aberration (CA), and reduction in reduced glutathione (GSH) and catalase following the exposure of MCP. Moreover, the expressions of apoptotic markers such as caspase-3, caspase-9, Bax, and p53 were significantly upregulated, whereas the levels of antiapoptotic marker, Bcl2, was downregulated after the exposure of MCP in both cell lines. These findings confirm the involvement of ROS-mediated oxidative stress, which subsequently triggers apoptosis pathways in both human neural (SH-SY5Y) and glial (U373-MG) cell lines following the exposure of MCP.


Assuntos
Encéfalo/enzimologia , Encéfalo/patologia , Citocromo P-450 CYP2C8/genética , Citocromo P-450 CYP3A/genética , Monocrotofós/toxicidade , Neurotoxinas/toxicidade , Xenobióticos/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Caspases/metabolismo , Catalase/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular , Ciclofosfamida/farmacologia , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP3A/metabolismo , Citocromos c/metabolismo , Indução Enzimática/efeitos dos fármacos , Humanos , Ligantes , Peroxidação de Lipídeos/efeitos dos fármacos , Testes para Micronúcleos , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Receptor de Pregnano X , Biossíntese de Proteínas/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/metabolismo , Transcrição Genética/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
14.
Biotechnol Appl Biochem ; 63(4): 497-513, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25913286

RESUMO

We examined the interaction of polycyclic hydrocarbons (PAHs) like benzo-α-pyrene (BaP), chrysene, and their metabolites 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene,9,10-oxide (BPDE) and chrysene 1,2-diol-3,4-epoxide-2 (CDE), with the enzymes involved in DNA repair. We investigated interaction of 120 enzymes with PAHs and screened out 40 probable targets among DNA repair enzymes, on the basis of higher binding energy than positive control. Out of which, 20 enzymes lose their function in the presence of BaP, chrysene, and their metabolites, which may fetter DNA repair pathways resulting in damage accumulation and finally leading to cancer formation. We propose the use of nanoparticles as a guardian against the PAH's induced toxicity. PAHs enter the cell via aryl hydrocarbon receptor (AHR). TiO2 NP showed a much higher docking score with AHR (12,074) as compared with BaP and chrysene with AHR (4,600 and 4,186, respectively), indicating a preferential binding of TiO2 NP with the AHR. Further, docking of BaP and chrysene with the TiO2 NP bound AHR complex revealed their strong adsorption on TiO2 NP itself, and not on their original binding site (at AHR). TiO2 NPs thereby prevent the entry of PAHs into the cell via AHR and hence protect cells against the deleterious effects induced by PAHs.


Assuntos
Benzopirenos/toxicidade , Crisenos/toxicidade , Biologia Computacional , Reparo do DNA/efeitos dos fármacos , Nanopartículas , Titânio/química , Titânio/farmacologia , Enzimas Reparadoras do DNA/química , Enzimas Reparadoras do DNA/metabolismo , Humanos , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Conformação Proteica , Titânio/metabolismo
16.
PLoS One ; 10(12): e0142818, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26624291

RESUMO

Of late, a consirable interest has grown in literature on early development of arsenicosis and untimely death in humans after exposure to iAs in drinking water in utero or during the childhood. The mechanism of this kind of intrauterine arsenic poisoning is not known; however it is often suggested to involve stem cells. We looked into this possibility by investigating in mice the influence of chronic in utero exposure to arsenical drinking water preliminarily on multipotent adult stem cell and progenitor cell counts at the beginning of neonatal age. We found that repeated intake of 42.5 or 85 ppm iAs in drinking water by pregnant BALB/c mice substantially changed the counts of EpASCs, the progenitor cells, and the differentiated cells in epidermis of their zero day old neonates. EpASCs counts decreased considerably and the differentiated/apoptosed cell counts increased extensively whereas the counts of progenitor cell displayed a biphasic effect. The observed trend of response was dose-dependent and statistically significant. These observations signified a disruption in stem cell homeostasis. The disorder was in parallel with changes in expression of biomarkers of stem cell and progenitor (TA) cell besides changes in expression of pro-inflammatory and antioxidant molecules namely Nrf2, NFkB, TNF-α, and GSH. The biological monitoring of exposure to iAs and the ensuing transplacental toxicity was verifiable correspondingly by the increase in iAs burden in hair, kidney, skin, liver of nulliparous female mice and the onset of chromosomal aberrations in neonate bone marrow cells. The combined intake of selenite and curcumin in utero was found to prevent the disruption of homeostasis and associated biochemical changes to a great extent. The mechanism of prevention seemed possibly to involve (a) curcumin and Keap-1 interaction, (b) consequent escalated de novo GSH biosynthesis, and (c) the resultant toxicant disposition. These observations are important with respect to the development of vulnerability to arsenicosis and other morbidities later in life after repeated in utero or postnatal exposure to iAs in drinking water that may occur speculatively through impairment of adult stem cell dependent innate tissue repair mechanism.


Assuntos
Células-Tronco Adultas/metabolismo , Intoxicação por Arsênico/tratamento farmacológico , Curcumina/farmacologia , Epiderme/patologia , Homeostase/efeitos dos fármacos , Troca Materno-Fetal , Selênio/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células-Tronco Adultas/efeitos dos fármacos , Células-Tronco Adultas/patologia , Animais , Intoxicação por Arsênico/metabolismo , Intoxicação por Arsênico/patologia , Curcumina/uso terapêutico , Proteínas do Citoesqueleto/metabolismo , Água Potável/química , Interações de Medicamentos , Feminino , Glutationa/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Selênio/uso terapêutico
17.
Asian Pac J Cancer Prev ; 16(13): 5311-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26225671

RESUMO

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.


Assuntos
Algoritmos , Proteínas de Ligação ao Cálcio/metabolismo , Carcinógenos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Ciclina H/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Nitrosaminas/metabolismo , Piridinas/metabolismo , Proteínas de Ligação ao Cálcio/química , Carcinógenos/química , Proteínas de Ciclo Celular/química , Cromatografia Líquida de Alta Pressão , Biologia Computacional/métodos , Ciclina H/química , Quinases Ciclina-Dependentes/química , Reparo do DNA , Enzimas Reparadoras do DNA/química , Proteínas de Ligação a DNA/química , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Nitrosaminas/química , Domínios e Motivos de Interação entre Proteínas , Piridinas/química , Fumar
18.
Bioinformation ; 11(3): 122-6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25987764

RESUMO

Fullerenes have attracted considerable attention due to their unique chemical structure and potential applications which has opened wide venues for possible human exposure to various fullerene types. Therefore, in depth knowledge of how fullerene may interfere with various cellular processes becomes quite imperative. The present study was designed to investigate how the presence of fullerene affect the binding of DNA with different enzymes involved in replication process. Different fullerenes were first docked with DNA and then binding scores of different enzymes was analyzed with fullerene docked DNA. C30, C40 & C50 once docked with DNA, reduced the binding score of primase, whereas no significant change in the binding score was observed with the helicase, ssb protein, dna pol δ, dna pol ε, ligase, DNA clamp, and topoisomerases. On the contrast, the binding score of RPA14 decreases in fluctuating manner while interacting with increasing molecular weight of fullerene bound single-stranded DNA complex. The study revealed the affect of fullerene family interacting with DNA on the binding pattern of enzymes involved in replication process. Study suggests that the presence of most of fullerenes may not affect the activity of these enzymes necessary for replication process whereas C30, C40 & C50 may disrupt the activity of primase, (strating point for DNA polymerase) its docking score decreases from 13820 to 10702.

19.
Pharmacogn Mag ; 11(Suppl 3): S365-74, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26929569

RESUMO

BACKGROUND: Cissus quadrangularis Linn. (CQ) commonly known as Hadjod (Family: Vitaceae) is usually distributed in India and Sri Lanka and contains several bioactive compounds responsible for various metabolic and physiologic effects. OBJECTIVE: In this study, the biological effects of CQ ethanolic extract were evaluated by in vitro and supported by in silico analysis on KB oral epidermoid cancer cell line. MATERIALS AND METHODS: Anti-cancer potential of ethanolic extract of CQ stem against KB oral epidermoid cancer cells was evaluated in terms of morphological analysis, nuclei staining, liberation of reactive oxygen species (ROS), cell cycle arrest, mitochondrial membrane potential (MMP) and p53 and Bcl-2 protein expression which reveal the induction of apoptosis along with supporting in silico analysis. RESULTS: Ethanolic extract of CQ stem contains various bioactive compounds responsible for cancer cell morphological alterations, liberation of ROS, G1 phase cell cycle arrest and decreased MMP along with up-regulation of p53 and down-regulation of Bcl-2. By employing in silico approach, we have also postulated that the CQ extract active constituents sequester Bcl-2 with higher affinity as compared to p53, which may be the reason for induction of growth arrest and apoptosis in KB cells. CONCLUSION: Our data indicate that the CQ extract has a remarkable apoptotic effect that suggests that it could be a viable treatment option for specific types of cancers. SUMMARY: Cissus quadrangularis stem ethanolic extract induces apoptosis and cell cycle arrest at G1 phaseIt liberates (ROS) and mitochondria mediated apoptosisIt upregulates p53 and down-regulates Bcl-2 protein expressionIn silico studies indicates that the active constituents of CQ binds Bcl-2 with higher affinity as compared to p53.

20.
Theor Biol Forum ; 108(1-2): 41-55, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27167909

RESUMO

Recently, the venues of exposure to nanoparticles have increased significantly owing to their increased deliberate production. In this study the interaction of fullerenes with DNA was analyzed along with various factors affecting this interaction like mol. wt. of fullerenes (C20 to C180), the form of DNA i.e., A, B and Z, and sequences of DNA, and was compared with the DNA binding of CNTs. Increase in the molecular weight of the fullerene showed increase in the binding score with A & B-form of DNA, but no regular affect was seen on binding with Z-form of DNA. Although the binding of all fullerenes was best with A form. While CNTs bind with all forms of DNA, but best scores were with B form, which were comparable with those of fullerene C80 and C84 with A form. The interaction of both fullerenes and CNTs were not affected by the sequence of DNA. The number of interacting base pairs increased from 1 base-pair to 4, as the molecular size of fullerene increases in all A & B-and Z form of DNA. Whereas CNTs interact with 5 bases in A and B form, and 3 bases in Z form. The groove where binding occurs depended on the form of DNA. Smaller (< C48) fullerenes bind in minor groove of B-DNA, and larger fullerenes bind in major groove. While in A form of DNA, fullerenes of all sizes bind in major groove. The binding was random and not size dependent in Z form of DNA. Whereas, CNTs bind to major groove of DNA in a parallel fashion in A and B form of DNA, and in minor groove attached perpendicularly in Z form.


Assuntos
DNA/química , Nanotubos de Carbono/química , Biologia Computacional
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