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1.
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
2.
Microb Pathog ; 130: 1-9, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30825502

RESUMO

Interferon-γ (IFN-γ) plays a crucial role in immunological responses against Mycobacterium tuberculosis (M.tb) infection. The polymorphism at +874 A > T (rs2430561) influences the levels of IFN-γ, which may further influence the susceptibility to extrapulmonary tuberculosis (EPTB). This polymorphism has been investigated with respect to EPTB occurrence in different populations and provided contradictory and conflicting results. This study was performed to meta-statistically analyze the data and draw a more accurate conclusion regarding the association of IFN-γ +874 A > T gene polymorphism and EPTB susceptibility. A quantitative synthesis was executed for the pertinent studies retrieved from online web-databases viz. Google Scholar, PubMed/Medline and EMBASE. The pooled odds ratios (ORs) and confidence intervals (95% CIs) were estimated for all the genetic models by meta-analysis. A total of eight studies were retrieved which included 762 confirmed EPTB cases and 1341 controls. The meta-analysis results revealed reduced association of EPTB in allelic contrast (T vs. A: p = 0.001; OR = 0.668, 95% CI = 0.524 to 0.850), homozygous (TT vs. AA: p = 0.017; OR = 0.450, 95% CI = 0.234 to 0.868), heterozygous (AT vs. AA: p = 0.004; OR = 0.574, 95% CI = 0.395 to 0.835), dominant (TT + AT vs. AA: p = 0.003; OR = 0.536, 95% CI = 0.354 to 0.810) and recessive (TT vs. AA + AT: p = 0.039; OR = 0.662, 95% CI = 0.448 to 0.980) genetic models. Furthermore, re-sampling statistics also revealed reduced risk of EPTB in overall population and Asian subgroup. This meta-analysis concluded that IFN-γ +874 A > T gene polymorphism is meaningfully related with the reduced EPTB risk in overall and Asian population, and further necessitates larger studies to be conducted on this topic in other races.


Assuntos
Predisposição Genética para Doença , Interferon gama/genética , Mycobacterium tuberculosis/imunologia , Polimorfismo de Nucleotídeo Único , Tuberculose/genética , Humanos
3.
Curr Comput Aided Drug Des ; 15(3): 265-276, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30706824

RESUMO

INTRODUCTION: The regulation of apoptosis via compounds originated from marine organisms signifies a new wave in the field of drug discovery. Marine organisms produce potent compounds as they hold the phenomenal diversity in chemical structures. The main focus of drug development is anticancer therapy. METHODS: Expertise on manifold activities of compounds helps in the discovery of their derivatives for preclinical and clinical experiment that promotes improved activity of compounds for cancer patients. RESULTS: These marine derived compounds stimulate apoptosis in cancer cells by targeting Bcl-2 and Survivin, highlighting the fact that instantaneous targeting of these proteins by novel derivatives results in efficacious and selective killing of cancer cells. CONCLUSION: Our study reports the identification of Aplysin and Haterumaimide J as Bcl-2 inhibitors and Cortistatin A as an inhibitor of survivin protein, from a sequential virtual screening approach.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Organismos Aquáticos/química , Proteínas Proto-Oncogênicas c-bcl-2/química , Survivina/química , Survivina/farmacologia , Animais , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Survivina/síntese química
4.
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
5.
Infect Drug Resist ; 12: 185-210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30666135

RESUMO

Background: Mannose-binding lectin (MBL) or mannose-binding protein (MBP), encoded by MBL2 gene and secreted by the liver, activates complement system through lectin pathway in innate immunity against the host's infection. Conflictingly, a number of MBL2 variants, rs1800450 (A>B), rs1800451 (A>C), rs5030737 (A>D), rs7096206 (Y>X), rs11003125 (H>L), and rs7095891 (P>Q) allele, have been found to be associated with compromised serum levels and pulmonary tuberculosis (PTB) susceptibility. The present meta-analysis study was performed to evaluate the potential association of these MBL2 gene variants with PTB susceptibility. Materials and methods: A quantitative synthesis was performed on PubMed (Medline), EMBASE, and Google Scholar web database searches. A meta-analysis was performed to calculate the pooled odds ratios and 95% CIs for all the genetic models. Results: A total of 14 eligible studies were included to analyze their pooled data for associations between alleles, genotypes, and minor allele carriers. The statistical analysis revealed the significant reduced PTB risk with homozygous variant genotype of rs1800451 polymorphism (CC vs AA: P=0.043; OR =0.828, 95% CI =0.689-0.994). Contrary to this, the variant allele of rs5030737 polymorphism showed association with increased PTB risk (D vs A: P=0.026; OR =1.563, 95% CI =1.054-2.317). However, the other genetic models of rs1800450 (A>B), rs7096206 (Y>X), and rs11003125 (H>L) MBL2 gene polymorphisms did not divulge any association with PTB susceptibility. Conclusion: The current meta-analysis concludes that rs1800451 (A>C) and rs5030737 (A>D) polymorphisms of MBL2 gene play a significant role in PTB susceptibility. Further, well-designed epidemiological studies with larger sample size including consideration of environmental factors are warranted for the future.

6.
Pathol Oncol Res ; 25(3): 925-936, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29376201

RESUMO

The current study investigates the role of circulating free DNA (cfDNA) as a liquid biopsy in diagnosis gall bladder carcinoma (GBC) utilizing levels of long DNA fragments (ALU247) derived from tumor necrosis, short apoptotic fragments (ALU115) denoting total cfDNA and cfDNA integrity denoting ratio of ALU247 and ALU115. The global methylation status of cfDNA was also estimated with the hypothesis that these parameters provide a diagnostic distinction between cancer and non-cancer subjects, with higher or altered values favoring presence of malignancy. Study group included 60 cases of GBC and 36 controls including diseased controls (cholecystitis) and healthy subjects. Median levels of ALU115, ALU247 and cfDNA integrity were significantly different in GBC at 1790.88, 673.75, 0.4718 vs. controls at 840.73, 165.03, 0.1989 ng/ml respectively. Global DNA methylation was not significantly different between GBC at 0.679% and controls at 0.695%. The sensitivity and specificity of ALU 247 in discriminating GBC from controls was highest with a sensitivity, specificity and diagnostic accuracy of 80.0%, 86.1% and 82.2% respectively. Global DNA methylation showed lowest sensitivity of 55.0% and specificity of 50.0%. Clinico-pathological parameters showing significant association with cfDNA integrity, on ROC curve analysis, showed significant diagnostic discrimination of the tumor stage, lymphovascular invasion, disease stage and grade histology. This is a first time analysis of ALU115, ALU247 and cfDNA integrity in the diagnosis of GBC and confirms that the combination of ALU247 and cfDNA integrity provides good sensitivity, specificity and diagnostic accuracy in discriminating GBC from controls as well correlates with aggressive disease parameters.


Assuntos
Ácidos Nucleicos Livres/genética , Metilação de DNA/genética , DNA de Neoplasias/genética , Neoplasias da Vesícula Biliar/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Colecistite/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade , Adulto Jovem
7.
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
8.
Biosci Rep ; 39(1)2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30509962

RESUMO

Hepatotoxicity is a severe problem generally faced by tuberculosis (TB) patients. It is a well-known adverse reaction due to anti-TB drugs in TB patients undergoing long-term treatment. The studies published previously have explored the connection of N-acetyltransferase 2 (NAT2) gene polymorphisms with isoniazid-induced hepatotoxicity, but the results obtained were inconsistent and inconclusive. A comprehensive trial sequence meta-analysis was conducted employing 12 studies comprising 3613 controls and 933 confirmed TB cases using the databases namely, EMBASE, PubMed (Medline) and Google Scholar till December 2017. A significant association was observed with individuals carrying variant allele at position 481C>T (T vs. C: P = 0.001; OR = 1.278, 95% CI = 1.1100-1.484), at position 590G>A (A vs. G: P = 0.002; OR = 1.421, 95% CI = 1.137-1.776) and at position 857G>A (A vs. G: P = 0.0022; OR = 1.411, 95% CI = 1.052-1.894) to higher risk of hepatotoxicity vis-à-vis wild-type allele. Likewise, the other genetic models of NAT2 gene polymorphisms have also shown increased risk of hepatotoxicity. No evidence of publication bias was observed. These results suggest that genetic variants of NAT2 gene have significant role in isoniazid induced hepatotoxicity. Thus, NAT2 genotyping has the potential to improve the understanding of the drug-enzyme metabolic capacity and help in early predisposition of isoniazid-induced hepatotoxicity.


Assuntos
Antituberculosos/efeitos adversos , Arilamina N-Acetiltransferase/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Isoniazida/efeitos adversos , Polimorfismo de Nucleotídeo Único , Tuberculose Pulmonar/tratamento farmacológico , Alelos , Antituberculosos/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ensaios Clínicos como Assunto , Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença , Humanos , Isoniazida/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
9.
Biosci Rep ; 39(1)2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30509964

RESUMO

PURPOSE: Tumor necrosis factor-α (TNF-α), secreted by the activated macrophages, may participate in the onset and progression of colorectal cancer (CRC). The association of TNF-α -308 G>A (rs1800629) single-nucleotide polymorphism (SNP) with CRC risk has been investigated by many studies but the results are inconclusive. A trial sequential meta-analysis was performed for precise estimation of the relationship between TNF-α -308 G>A gene polymorphism with CRC risk. METHODS: Medline (PubMed), EMBASE (Excerpta-Medica) and Google Scholar were mined for relevant articles. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the significance of association. RESULTS: The pooled analysis indicated no risk associated with TNF-α -308 G>A SNP and overall CRC risk in five genetic comparison models, i.e. allelic (A vs. G: P = 0.524; OR = 1.074, 95% CI = 0.863-1.335), homozygous (AA vs. GG: P = 0.489; OR = 1.227, 95% CI = 0.688-2.188), heterozygous (AG vs. GG: P = 0.811; OR = 1.024, 95% CI = 0.843-1.244), dominant (AA+AG vs. GG: P = 0.630; OR = 1.055, 95% CI = 0.849-1.311) and recessive (AA vs. AG+GG: P = 0.549; OR = 1.181, 95% CI = 0.686-2.033). Subgroup analysis revealed that TNF-α -308 G>A SNP is associated with reduced risk of CRC in Asian ethnicity. The study showed no publication bias. CONCLUSIONS: No association of TNF-α -308 G>A SNP with overall CRC risk was found. This SNP is likely to be protective against CRC in Asian population when compared with Caucasian population. Larger prospective-epidemiological studies are warranted to elucidate the roles of TNF-α -308 G>A SNP in the etiology of CRC and to endorse the present findings.


Assuntos
Neoplasias Colorretais/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Fator de Necrose Tumoral alfa/genética , Grupo com Ancestrais do Continente Asiático , Ensaios Clínicos como Assunto , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/patologia , Grupo com Ancestrais do Continente Europeu , Expressão Gênica , Genótipo , Heterozigoto , Homozigoto , Humanos , Modelos Genéticos , Razão de Chances
10.
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
11.
Comput Biol Chem ; 77: 390-401, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30469054

RESUMO

The B-cell lymphoma-2 (Bcl-2) family proteins have been attributed to be the key regulators in programmed cell death and apoptosis with a prominent role in human cancer. Understanding the fundamental principles of cell survival and death have been the main cornerstone in cancer drug discovery for identification of novel anticancer agents. In this context the Bcl-2 family of anti-and pro-apoptotic proteins provide an excellent opportunity for development of anticancer agents, as blocking the Bcl-2 or Bcl-XL functionally promotes apoptosis in tumor cells and also sensitize them to chemo- and radiotherapies. The present study reports the identification of novel Aplysin analogs as BCL-2 inhibitors from a sequential virtual screening approach using drug-like, ADMET, docking, pharmacophore filters and molecular dynamics simulation. We identified promising Aplysin analogs that have a potential to be Bcl-2 inhibitors just like the standard drug Obatoclax. One of the compound analog 11 was identified to be a promising inhibitor of Bcl-2 in the docking, pharmacophore and simulation based models.The molecular modeling information provided here can be vital in designing of the novel Bcl-2 inhibitors.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Hidrocarbonetos Bromados/química , Hidrocarbonetos Bromados/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Apoptose/efeitos dos fármacos , Projeto Auxiliado por Computador , Desenho de Drogas , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
12.
Curr Genomics ; 19(5): 395-410, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30065615

RESUMO

Background: Genetic changes in p53 gene contribute to breast cancer susceptibility. Objective and Methods: A case-control study and a meta-analysis were performed to investigate the role of p53 codon72 SNP with breast cancer susceptibility in Indian women. Results: p53 heterozygous arginine variant was associated with decreased risk of breast cancer in total cohort. In meta-analysis, Allelic and GG vs. CC genetic comparison model were found to be associated with breast cancer risk. Moreover, recessive comparison model indicated a protective correlation with breast cancer occurrence. Conclusion: The findings of our case-control study and meta-analysis suggest a significant association between p53 Arg72Pro polymorphism and an increased risk of breast cancer in Indian population.

13.
Int J Health Sci (Qassim) ; 12(3): 3-9, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29896065

RESUMO

Objectives: The role of caveolin-1 (CAV1)(G>A, rs3807987) polymorphism is still dubious in cancer causation in Taiwanese population. The present study is an effort to assess the above relation for precise conclusion. Methods: EMBASE and PubMed (MEDLINE) databases were explored for the pertinent case-control studies reporting the connection of CAV1 G14713A polymorphism to the vulnerability to cancer. A cumulative analysis using meta-analytic approach was accomplished and pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated for all the polymorphs. Results: Overall, 2549 subjects and 3161 controls were analyzed from six selected studies. Our study showed no confirmation of noteworthy risk between CAV1 G14713A polymorphism and susceptibility to cancer in any of the polymorph, for instance, allele (A vs. G: P = 0.165; OR = 1.252, 95% CI = 0.911-1.721), homozygous (AA vs. GG: P = 0.252; OR = 1.328, 95% CI = 0.817-2.157), heterozygous (AG vs. GG: P = 0.091; OR = 1.356, 95% CI = 0.952-1.930), dominant (AA vs. GG + AG: P = 0.345; OR = 1.191, 95% CI = 0.829-1.709), and recessive (AA + AG vs. GG: P = 0.125; OR = 1.344, 95% CI = 0.921-1.961). Conclusions: We conclude that CAV1 G14713A polymorphism does not contribute as an independent predisposing risk factor for developing cancer in Taiwanese population.

14.
Microb Pathog ; 121: 293-302, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29857121

RESUMO

Quorum sensing (QS) is a complex bacterial intercellular communication system. It is mediated by molecules called auto-inducers (AIs) and allows coordinated responses to a variety of environmental signals by inducing alterations in gene expression. Communication through QS can tremendously stimulate the pathogenicity and virulence via multiple mechanisms in pathogenic bacteria. The present review explores the major types of multitudinous QS systems known in Gram-positive and Gram-negative bacteria and their roles in bacterial pathogenesis and drug resistance. Because bacterial resistance to antibiotics is increasingly becoming a significant clinical challenge to human health; alternate strategies to combat drug resistance are warranted. Targeting bacterial pathogenicity by interruptions in QS using natural QS inhibitors and synthetic quorum-quenching analogs are being increasingly considered for development of next generation antimicrobials. The review highlights the recent advancements in discovery of promising new QS modulators and their efficiency in controlling infections caused by multidrug-resistant bacterial pathogens.


Assuntos
Farmacorresistência Bacteriana Múltipla/genética , Percepção de Quorum/genética , Fatores de Virulência/genética , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/genética , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/genética , Humanos
15.
Microb Pathog ; 122: 1-6, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29870744

RESUMO

Efforts to develop preventatives against HIV infection through sexual route have identified, among many, algal lectins as the potent molecules for scaffolding HIV entry inhibition. Algal lectin scytovirin (SVN) from Scytonema varium, a cyanobacterium, has anti-HIV effects with the potential for use in sculpting HIV neutralization. We created a recombinant strain of human vaginal L. plantarum for extracellular expression of recombinant (r)SVN. The rSVN protein containing culture supernatant was analyzed for its binding with HIV-1 gp160, and for inhibiting infection with primary R5 and X4 HIV-1 strains in TZM-bl cells. The rSVN protein extant in recombinant L. plantarum culture supernatant binds to HIV-1 gp160 and reduces the HIV-induced cytopathic effect to nearly 56.67% and 86.47% in R5 and X4 HIV-1 infected TZM-bl cells, respectively. The fortified L. plantarum may be explored for its use as a live virucide in vaginal mucosa of high risk women to prevent HIV entry.


Assuntos
Antivirais/farmacologia , Proteínas de Bactérias/farmacologia , Proteínas de Transporte/farmacologia , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , Lactobacillus plantarum/metabolismo , Lectinas/farmacologia , Proteínas Recombinantes/farmacologia , Internalização do Vírus/efeitos dos fármacos , Antivirais/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Efeito Citopatogênico Viral , HIV-1/fisiologia , Humanos , Lactobacillus plantarum/genética , Lectinas/genética , Lectinas/metabolismo , Proteínas de Membrana , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
16.
Microb Pathog ; 120: 132-139, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29704668

RESUMO

BACKGROUND: Human Cytomegalovirus (CMV), because of its ability to extensively manipulate host immunity during active infection, has been suggested to be involved in autoimmunity. However, its influence on T-cells and cytokines in systemic autoimmune diseases like systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is indistinct. METHODS: We investigated the in-vitro response of T lymphocytes from SLE and SSc patients to CMV antigen. Functional activity of T lymphocytes was determined by estimating Th1 (IL-2 and IFN-γ) and Th2 (IL-4 and IL-10) cytokines. RESULTS: We observed that CMV antigen stimulation in-vitro resulted in significant increase in CD4:CD8 T-cell ratio in peripheral blood mononuclear cells (PBMCs) from SLE and SSc patients; response dominated by CD4+ than CD8+ memory T-cells. SSc T-cell response was differentiated by aberrant increase in CD4+CD25+ T-cells. CMV antigen caused elevation in IL-4 and IFN-γ production in both patient PBMCs, whereas IL-2 was also raised in SLE PBMCs. The development of large pool of memory T-cells and overproduction of IFN-γ may result in flare-up of autoimmunity in these patients. CONCLUSION: Our study provides an insight into the immunopathological potential of CMV-reactive immune cells to develop new potential strategies for targeted therapeutic intervention.


Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Citomegalovirus/patogenicidade , Adolescente , Adulto , Antígenos Virais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Criança , Citocinas/metabolismo , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-4/metabolismo , Leucócitos Mononucleares/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/virologia , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/virologia , Linfócitos T/metabolismo , Células Th1/imunologia , Células Th2/imunologia , Adulto Jovem
17.
J Cell Biochem ; 119(8): 6961-6973, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29693278

RESUMO

Human aldose reductase (hAR) is the key enzyme in sorbitol pathway of glucose utilization and is implicated in the etiology of secondary complications of diabetes, such as, cardiovascular complications, neuropathy, nephropathy, retinopathy, and cataract genesis. It reduces glucose to sorbitol in the presence of NADPH and the major cause of diabetes complications could be the change in the osmotic pressure due to the accumulation of sorbitol. An activated form of hAR (activated hAR or ahAR) poses a potential obstacle in the development of diabetes drugs as hAR-inhibitors are ineffective against ahAR. The therapeutic efficacy of such drugs is compromised when a large fraction of the enzyme (hAR) undergoes conversion to the activated ahAR form as has been observed in the diabetic tissues. In the present study, attempts have been made to employ systems biology strategies to identify the elementary nodes of human polyol metabolic pathway, responsible for normal metabolic states, followed by the identification of natural potent inhibitors of the activated form of hAR represented by the mutant C298S for possible antidiabetic applications. Quantum Mechanical Molecular Mechanical docking strategy was used to determine the probable inhibitors of ahAR. Rosmarinic acid was found as the most potent natural ahAR inhibitor and warrants for experimental validation in the near future.


Assuntos
Aldeído Redutase , Simulação por Computador , Diabetes Mellitus , Redes e Vias Metabólicas , Modelos Biológicos , Modelos Moleculares , Mutação , Aldeído Redutase/química , Aldeído Redutase/genética , Aldeído Redutase/metabolismo , Diabetes Mellitus/enzimologia , Diabetes Mellitus/genética , Humanos , NAD/química , NAD/genética , NAD/metabolismo
18.
Crit Rev Oncol Hematol ; 125: 84-88, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29650281

RESUMO

Metastatic melanoma is a least common form of cancer as it accounts only for 1% of all cancer cases. But, it is most deadly in nature and is haunting mankind for long emotionally as well as economically. The sites for the onset of the disease are pigment-producing cells of the skin, mucosa, eye etc. It has the potential to spread other sites like subcutaneous tissue, lymph nodes, lungs, liver, bone and brain. The United States Food & Drug Administration has approved various drug molecules from time to time. The molecules (Dabrafenib-BRAF inhibitor and Trametinib-MEK inhibitor) have proved their credentials alone and in combination as well. These molecules have demonstrated good results for various end points like median progression free survival, overall survival, objective response etc. The median progression free survival for patients using dabrafenib and trametinib were 5.1 and 4.8 months, respectively (administered singly). It has increased to 11.4 months in the combination treatment "dabrafenib + trametinib", which is approximately 104% and 138% greater than dabrafenib and trametinib treated groups alone. Similarly, the overall survival rate and objective response rate for the patients administered with "dabrafenib + trametinib" have been increased by 72% 64%, respectively. All these increments in these parameters were for a short period of time as the molecules were unable to withstand the pressure of resistance developed in the patients. So, the current review suggests the use of BRAF and MEK inhibitors as intermittent therapy along with heat shock protein 90 (HSP90) molecules.


Assuntos
Melanoma/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Terapias em Estudo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Humanos , Melanoma/genética , Melanoma/mortalidade , Melanoma/patologia , Mutação , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Terapias em Estudo/métodos , Terapias em Estudo/normas , Terapias em Estudo/tendências
19.
Oncotarget ; 9(5): 6572-6585, 2018 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-29464093

RESUMO

Genetic variant LMP7 (low molecular weight polypeptide 7) -145 C > A may influence the function of immune surveillance of an individual and lead to cancer development. Various studies have investigated the relevance of LMP7 -145 C > A gene polymorphism with cancer risk; but, their results are conflicting and inconsistent. To obtain a comprehensive conclusion, a meta-analysis was performed by including eight eligible published studies retrieved from PubMed (Medline), EMBASE and Google Scholar web search until December 2016. Individuals with AA genotype (AA vs CC: p = 0.001; OR = 2.602, 95% CI = 1.780 to 3.803) of LMP7 -145 C > A were found to have 2 folds higher risk of cancer than those with CC genotype. The recessive genetic model (AA vs AC + CC) also indicated that individuals with AA genotype have 2 folds higher cancer risk than AC and CC genotypes (p = 0.001; OR = 2.216, 95% CI = 1.525 to 3.221). Also, significant increased cancer risk was observed in Asians but not in Caucasians. No publication bias was observed during the analysis. Trial sequential analysis also strengthened our current findings. These results suggest that genetic variant LMP7-145 C > A has significant role in increasing cancer risk in overall and Asian population, and could be useful as a prognostic marker for early cancer predisposition.

20.
J Cell Biochem ; 119(3): 2832-2842, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29068470

RESUMO

The emergence of multi-drug resistant strains and co-occurrence of tuberculosis with HIV creates a major burden to the human health globally. Failure of primary antibacterial therapy necessitates the identification of new mycobacterial drugs. In this study, a comprehensive analysis involving bottom-up systems biology approach was applied wherein we have identified potential therapeutic targets of Mycobacterium tuberculosis infections. Our study prioritized M. tuberculosis therapeutic targets (aspartate-ß-semialdeyhde dehydrogenase [ASD], dihydrodipicolinate reductase and diaminopimelate decarboxylase) based on flux and elementary mode analysis using direct mathematical modeling of the relevant metabolic pathways. Molecular docking and simulation studies of the priority target (ie, ASD) revealed the therapeutic potential of the selected natural products (Huperzine A, Rosmarinic acid, and Curcumin) based ASD inhibitors. The study highlights the crucial role of systems biology in conjunction with molecular interaction (docking) for probing novel leads against an increasingly resistant pathogen, M. tuberculousis.


Assuntos
Antituberculosos/química , Aspartato-Semialdeído Desidrogenase , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/enzimologia , Aspartato-Semialdeído Desidrogenase/antagonistas & inibidores , Aspartato-Semialdeído Desidrogenase/química , Simulação por Computador , Tuberculose/tratamento farmacológico , Tuberculose/enzimologia
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