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1.
Int J Pharm ; 569: 118590, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31381988

RESUMO

Synthetic polymers, especially those with biocompatible and biodegradable characteristics, may offer effective alternatives for the treatment of severe wounds and burn injuries. Ideally, the scaffold material should induce as little pain as possible, enable quick healing, and direct the growth of defect-free epidermal cells. The best material with this multifunctionality, such as self-healing dressings, should be hydrophilic and have uninterrupted and direct contact with the damaged tissue. In addition, the ideal biomaterial should have some antibacterial properties. In this study, a novel technique was used to fabricate composite electrospun wound-dressing nanofibers composed of polyurethane encasing lavender oil and silver (Ag) nanoparticles (NPs). After electrospinning, the fabricated nanofibers were identified using various techniques, including scanning electron microscopy (SEM) and transmission electron microscopy (TEM). An abundance of Ag NPs in the fibers decreased the diameter of the fibers while increased concentration of the lavender oil increased the diameter. Fourier transform infrared (FTIR) and X-ray diffraction (XRD) studies showed the presence of the lavender oil and Ag NPs in the fiber dressings. The Ag NPs and lavender oil improved the hydrophilicity of the nanofibers and ensured the proliferation of chicken embryo fibroblasts cultured in-vitro on these fiber dressings. The antibacterial efficiency of the nanofiber dressings was investigated using E. coli and S. aureus, which yielded zones of inhibition of 16.2 ±â€¯0.8 and 5.9 ±â€¯0.5 mm, respectively, indicating excellent bactericidal properties of the dressings. The composite nanofiber dressings have great potential to be used as multifunctional wound dressings; offering protection against external agents as well as promoting the regeneration of new tissue.

2.
Molecules ; 24(5)2019 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-30832429

RESUMO

DiNap [(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one], an analog of a natural product (the chalcone flavokawain), was synthesized and characterized in this study. Porcine reproductive and respiratory syndrome virus (PRRSV) is the most challenging threat to the swine industry worldwide. Currently, commercially available vaccines are ineffective for controlling porcine reproductive and respiratory syndrome (PRRS) in pigs. Therefore, a pharmacological intervention may represent an alternative control measure for PRRSV infection. Hence, the present study evaluated the effects of DiNap on the replication of VR2332 (a prototype strain of type 2 PRRSV). Initially, in vitro antiviral assays against VR2332 were performed in MARC-145 cells and porcine alveolar macrophages (PAMs). Following this, a pilot study was conducted in a pig model to demonstrate the effects of DiNap following VR2332 infection. DiNap inhibited VR2332 replication in both cell lines in a dose-dependent manner, and viral growth was completely suppressed at concentrations ≥0.06 mM, without significant cytotoxicity. Consistent with these findings, in the pig study, DiNap also reduced viral loads in the serum and lungs and enhanced the weight gain of pigs following VR2332 infection, as indicated by comparison of the DiNap-treated groups to the untreated control (NC) group. In addition, DiNap-treated pigs had fewer gross and microscopic lesions in their lungs than NC pigs. Notably, virus transmission was also delayed by approximately 1 week in uninfected contact pigs within the same group after treatment with DiNap. Taken together, these results suggest that DiNap has potential anti-PRRSV activity and could be useful as a prophylactic or post-exposure treatment drug to control PRRSV infection in pigs.


Assuntos
Produtos Biológicos/química , Flavonoides/química , Síndrome Respiratória e Reprodutiva Suína/tratamento farmacológico , Replicação Viral/efeitos dos fármacos , Animais , Produtos Biológicos/administração & dosagem , Produtos Biológicos/síntese química , Chalcona/administração & dosagem , Chalcona/síntese química , Chalcona/química , Flavonoides/administração & dosagem , Flavonoides/síntese química , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Macrófagos Alveolares/efeitos dos fármacos , Projetos Piloto , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína , Suínos/virologia , Carga Viral
3.
Poult Sci ; 98(5): 2008-2013, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30597054

RESUMO

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a primary avian pathogen responsible for severe intestinal pathology in younger chickens and economic losses to poultry industry. Furthermore, S. Typhimurium is also able to cause infection in humans, characterized by acute gastrointestinal disease. A study was conducted to investigate antibody response and expression kinetics of interferon gamma (IFNγ), interleukin (IL-12, and IL-18) genes in broiler chicken at 0, 1, 3, 5, 7, 9, 11, 13, and 15 D post infection following experimental infection of S. Typhimurium. Immunological studies showed higher titres of IgG and IgM in the infected group as compared to the age-matched un-infected control group. The Real-Time PCR-based gene expression analysis revealed significant increase of IFNγ, IL-12, and IL-18 mRNA levels in the infected group as compared to their respective controls (P < 0.05). The present study shall help in understanding the immune responses in birds, thus allowing development of more effective vaccines and vaccination strategies.


Assuntos
Galinhas , Doenças das Aves Domésticas/genética , Doenças das Aves Domésticas/imunologia , Salmonelose Animal/genética , Salmonelose Animal/imunologia , Salmonella typhimurium/fisiologia , Animais , Anticorpos Antibacterianos/sangue , Formação de Anticorpos , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Expressão Gênica , Perfilação da Expressão Gênica/veterinária , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Interleucina-18/genética , Interleucina-18/metabolismo , Doenças das Aves Domésticas/microbiologia , RNA Mensageiro/genética , Salmonelose Animal/microbiologia
4.
BMC Vet Res ; 14(1): 380, 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30509265

RESUMO

BACKGROUND: Currently, an in vitro immunogenicity screening system for the immunological assessment of potential porcine reproductive and respiratory syndrome virus (PRRSV) vaccine candidates is highly desired. Thus, in the present study, two genetically divergent PRRSVs were characterized in vitro and in vivo to identify an in vitro system and immunological markers that predict the host immune response. Porcine alveolar macrophages (PAMs) and peripheral blood mononuclear cells (PBMCs) collected from PRRSV-negative pigs were used for in vitro immunological evaluation, and the response of these cells to VR2332c or JA142c were compared with those elicited in pigs challenged with the same viruses. RESULTS: Compared with VR2332c or mock infection, JA142c induced increased levels of type I interferons and pro-inflammatory cytokines (TNF-α, IL-1α/ß, IL-6, IL-8, and IL-12) in PAMs, and these elevated levels were comparable to the cytokine induction observed in PRRSV-challenged pigs. Furthermore, significantly greater numbers of activated CD4+ T cells, type I helper T cells, cytotoxic T cells and total IFN-γ+ cells were observed in JA142c-challenged pigs than in VR2332c- or mock-challenged pigs. CONCLUSIONS: Based on these results, the innate immune response patterns (particularly IFN-α, TNF-α and IL-12) to specific PRRSV strains in PAMs might reflect those elicited by the same viruses in pigs.

5.
J Cell Biochem ; 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30390320

RESUMO

Follicle-stimulating hormone-follicle-stimulating hormone receptor (FSH-FSHR) interaction is one of the most thoroughly studied signaling pathways primarily because of being implicated in sexual reproduction in mammals by way of maintaining gonadal function and sexual fertility. Despite material advances in understanding the role of point mutations, their mechanistic basis in FSH-FSHR signaling is still confined to mystically altered behavior of sTYS335 (sulfated tyrosine) yet lacking a substantial theory. To understand the structural basis of receptor modulation, we choose two behaviorally contradicting mutations, namely S128Y (activating) and D224Y (inactivating), found in FSH receptor responsible for ovarian hyperstimulation syndrome and ovarian dysgenesis, respectively. Using short-term molecular dynamics simulations, the atomic scale investigations reveal that the binding pattern of sTYS with FSH and movement of the thumb region of FSHR show distinct contrasting patterns in the two mutants, which supposedly could be a critical factor for differential FSHR behavior in activating and inactivating mutations.

6.
J Family Med Prim Care ; 7(2): 309-314, 2018 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30090769

RESUMO

Modern medicine is given overarching importance to tackle disease in the human body than environmental determinants. Although, most of the literature confirms that the determinants of disease are there in the environment. Yet in the modern times what is being emphasized is highly limited and reductionist approach of curing ailments in the human body only, which is one of the desired interventions but is full of other side effects and risks leading to iatrogenic reactions. Most of the literature establishes that modern medicine is one of the major threats to the world health. Besides treating disease at the clinical level, rational, and well-thoughtout changes in the overall environment can positively impact the nature, extent, and distribution of disease.

7.
BMC Vet Res ; 14(1): 180, 2018 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-29884179

RESUMO

BACKGROUND: Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) is a zoonotic pathogen responsible for severe intestinal pathology in young chickens. Natural resistance-associated macrophage protein (NRAMP) family has been shown to be associated with resistance to intracellular pathogens, including Salmonella Typhimurium. The role of NRAMP proteins in macrophage defence against microbial infection has been ascribed to changes in the metal-ion concentrations inside the bacteria-containing phagosomes. The present study was conducted to investigate tissue-specific (liver, spleen and caecum) expression kinetics of NRAMP gene family (NRAMP1 and NRAMP2) in broilers from day 0 to day 15 after Salmonella Typhimurium challenge concomitant to clinical, blood biochemical and immunological parameters survey. RESULTS: Clinical symptoms appeared 4 days post-infection (dpi) in infected birds. Symptoms like progressive weakness, anorexia, diarrhoea and lowering of the head were seen in infected birds one-week post-infection. On postmortem examination, liver showed congestion, haemorrhage and necrotic foci on the surface, while as the spleen, lungs and intestines revealed congestion and haemorrhages. Histopathological alterations were principally found in liver comprising of necrosis, reticular endothelial hyperplasia along with mononuclear cell and heterophilic infiltration. Red Blood Cell (RBC) count, Haemoglobin (Hb) and Packed Cell Volume (PCV) decreased significantly (P < 0.05) in blood while heterophil counts increased up to 7 days post-infection. Serum glucose, aspartate transaminase (AST) and alanine transaminase (ALT) enzymes concentrations increased significantly throughout the study. A gradual increase of specific humoral IgG response confirmed Salmonella infection. Meanwhile, expression of NRAMP1 and NRAMP2 genes was differentially regulated after infection in tissues such as liver, spleen and caecum known to be the target of Salmonella Typhimurium replication in the chicken. CONCLUSION: Thus the specific roles of NRAMP1 and NRAMP2 genes in Salmonella Typhimurium induced disease may be supposed from their differential expression according to tissues and timing after per os infection. However, these roles remain to be analyzed related to the severity of the disease which can be estimated by blood biochemistry and immunological parameters.


Assuntos
Proteínas de Transporte de Cátions/metabolismo , Galinhas , Doenças das Aves Domésticas/metabolismo , Salmonelose Animal/metabolismo , Salmonella typhimurium , Animais , Proteínas de Transporte de Cátions/genética , Regulação da Expressão Gênica , Doenças das Aves Domésticas/microbiologia , Salmonelose Animal/microbiologia
8.
Vet World ; 10(11): 1361-1366, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29263600

RESUMO

Since centuries, the traits for production and disease resistance are being targeted while improving the genetic merit of domestic animals, using conventional breeding programs such as inbreeding, outbreeding, or introduction of marker-assisted selection. The arrival of new scientific concepts, such as cloning and genome engineering, has added a new and promising research dimension to the existing animal breeding programs. Development of genome editing technologies such as transcription activator-like effector nuclease, zinc finger nuclease, and clustered regularly interspaced short palindromic repeats systems begun a fresh era of genome editing, through which any change in the genome, including specific DNA sequence or indels, can be made with unprecedented precision and specificity. Furthermore, it offers an opportunity of intensification in the frequency of desirable alleles in an animal population through gene-edited individuals more rapidly than conventional breeding. The specific research is evolving swiftly with a focus on improvement of economically important animal species or their traits all of which form an important subject of this review. It also discusses the hurdles to commercialization of these techniques despite several patent applications owing to the ambiguous legal status of genome-editing methods on account of their disputed classification. Nonetheless, barring ethical concerns gene-editing entailing economically important genes offers a tremendous potential for breeding animals with desirable traits.

9.
Viruses ; 8(8)2016 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-27556483

RESUMO

One of the major hurdles to porcine reproductive and respiratory syndrome (PRRS) vaccinology is the limited or no cross-protection conferred by current vaccines. To overcome this challenge, a PRRS chimeric virus (CV) was constructed using an FL12-based cDNA infectious clone in which open reading frames (ORFs) 3-4 and ORFs 5-6 were replaced with the two Korean field isolates K08-1054 and K07-2273,respectively. This virus was evaluated as a vaccine candidate to provide simultaneous protection against two genetically distinct PRRS virus (PRRSV) strains. Thirty PRRS-negative three-week-old pigs were divided into five groups and vaccinated with CV, K08-1054, K07-2273, VR-2332, or a mock inoculum. At 25 days post-vaccination (dpv), the pigs in each group were divided further into two groups and challenged with either K08-1054 or K07-2273. All of the pigs were observed until 42 dpv and were euthanized for pathological evaluation. Overall, the CV-vaccinated group exhibited higher levels of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin-12 (IL-12) expression and of serum virus-neutralizing antibodies compared with the other groups after vaccination and also demonstrated better protection levels against both viruses compared with the challenge control group. Based on these results, it was concluded that CV might be an effective vaccine model that can confer a broader range of cross-protection to various PRRSV strains.


Assuntos
Proteção Cruzada , Síndrome Respiratória e Reprodutiva Suína/prevenção & controle , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Citocinas/metabolismo , Leucócitos Mononucleares/imunologia , Síndrome Respiratória e Reprodutiva Suína/imunologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , Recombinação Genética , Suínos , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/genética
10.
J Virol ; 90(9): 4454-4468, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26889041

RESUMO

UNLABELLED: In a previous study, ribavirin-resistant porcine reproductive and respiratory syndrome virus (PRRSV) mutants (RVRp13 and RVRp22) were selected, and their resistance against random mutation was shown in cultured cells. In the present study, these ribavirin-resistant mutants were evaluated in terms of their genetic and phenotypic stability during three pig-to-pig passages in comparison with modified live virus (MLV) (Ingelvac PRRS MLV). Pigs challenged with RVRp22 had significantly lower (P< 0.05) viral loads in sera and tissues than pigs challenged with MLV or RVRp13 at the first passage, and the attenuated replication of RVRp22 was maintained until the third passage. Viral loads in sera and tissues dramatically increased in pigs challenged with MLV or RVRp13 during the second passage. Consistently, all five sequences associated with the attenuation of virulent PRRSV in RVRp13 and MLV quickly reverted to wild-type sequences during the passages, but two attenuation sequences were maintained in RVRp22 even after the third passage. In addition, RVRp22 showed a significantly lower (P< 0.001) mutation frequency in nsp2, which is one of the most variable regions in the PRRSV genome, than MLV. Nine unique mutations were found in open reading frames (ORFs) 1a, 2, and 6 in the RVRp22 genome based on full-length sequence comparisons with RVRp13, VR2332 (the parental virus of RVRp13 and RVRp22), and MLV. Based on these results, it was concluded that RVRp22 showed attenuated replication in pigs; further, because of the high genetic stability of RVRp22, its attenuated phenotype was stable even after three sequential passages in pigs. IMPORTANCE: PRRSV is a rapidly evolving RNA virus. MLV vaccines are widely used to control PRRS; however, there have been serious concerns regarding the use of MLV as a vaccine virus due to the rapid reversion to virulence during replication in pigs. As previously reported, ribavirin is an effective antiviral drug against many RNA viruses. Ribavirin-resistant mutants reemerged by escaping lethal mutagenesis when the treatment concentration was sublethal, and those mutants were genetically more stable than parental viruses. In a previous study, two ribavirin-resistant PRRSV mutants (RVRp13 and RVRp22) were selected, and their higher genetic stability was shown in vitro Consequently, in the present study, both of the ribavirin-resistant mutants were evaluated in terms of their genetic and phenotypic stability in vivo RVRp22 was found to exhibit higher genetic and phenotypic stability than MLV, and nine unique mutations were identified in the RVRp22 genome based on a full-length sequence comparison with the RVRp13, VR2332, and MLV genomes.


Assuntos
Antivirais/farmacologia , Farmacorresistência Viral , Fenótipo , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/efeitos dos fármacos , Ribavirina/farmacologia , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Linhagem Celular , Genoma Viral , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Testes de Sensibilidade Microbiana , Mutação , Taxa de Mutação , Fases de Leitura Aberta , Síndrome Respiratória e Reprodutiva Suína/patologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia , Suínos , Carga Viral , Viremia , Virulência/genética , Replicação Viral/efeitos dos fármacos
11.
Vet Microbiol ; 182: 187-95, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26711047

RESUMO

Porcine reproductive and respiratory syndrome (PRRS) is the most economically important disease to the swine industry, and effective prevention strategy for this disease is still required. Guanylate-binding protein 1 (GBP1) and myxovirus resistance protein 1 (Mx1) are two important proteins belonging to the GTPase superfamily that have been previously described to show antiviral effects. CD163 is considered the most important receptor for PRRSV attachment and internalization. Therefore, the aim of the present study was to evaluate the effects of these genes on host resistance against PRRSV infection in conjunction with the host immune response following PRRSV challenge. The results showed that pigs with AG genotype for the GBP1 exon2 exhibited a significantly higher average daily weight gain (ADWG) and lower average viremia than AA or GG genotype. Furthermore, pigs harbouring the AG genotype for the GBP1 gene presented greater CD4(+)CD25(+) and CD8(+)CD25(+) T cell populations at 4 and 18 days post challenge (dpc), respectively, as compared with other genotypes whereas pigs with CC genotype for the CD163 gene displayed significantly higher nucleocapsid-specific antibody titers at 11dpc. However, pigs with a single 11-bp deletion or insertion in the Mx1 gene did not show significant differences in either weight gain or viremia. Based on these results, we concluded that GBP1 is most significantly associated with resistance against PRRSV infection and efficient T cell activation in pigs.


Assuntos
Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Proteínas de Ligação ao GTP/genética , Interações Hospedeiro-Patógeno/genética , Proteínas de Resistência a Myxovirus/genética , Síndrome Respiratória e Reprodutiva Suína/genética , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Receptores de Superfície Celular/genética , Animais , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Proteínas de Ligação ao GTP/imunologia , Genótipo , Interações Hospedeiro-Patógeno/imunologia , Ativação Linfocitária , Proteínas de Resistência a Myxovirus/imunologia , Polimorfismo Genético , Síndrome Respiratória e Reprodutiva Suína/imunologia , Receptores de Superfície Celular/imunologia , Suínos , Linfócitos T/imunologia , Viremia/genética , Viremia/imunologia , Ganho de Peso
12.
PLoS One ; 10(5): e0127741, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26011121

RESUMO

O6-methylguanine-DNA methyltransferase (MGMT) is one of the major DNA repair protein that counteracts the alkalyting agent-induced DNA damage by replacing O6-methylguanine (mutagenic lesion) back to guanine, eventually suppressing the mismatch errors and double strand crosslinks. Exonic alterations in the form of nucleotide polymorphism may result in altered protein structure that in turn can lead to the loss of function. In the present study, we focused on the population feared for high exposure to alkylating agents owing to their typical and specialized dietary habits. To this end, gastric cancer patients pooled out from the population were selected for the mutational screening of a specific error prone region of MGMT gene. We found that nearly 40% of the studied neoplastic samples harbored missense mutation at codon151 resulting into Serine to Isoleucine variation. This variation resulted in bringing about the structural disorder, subsequently ensuing into a major stoichiometric variance in recognition domain, substrate binding and selectivity loop of the active site of the MGMT protein, as observed under virtual microscope of molecular dynamics simulation (MDS). The atomic insight into MGMT protein by computational approach showed a significant change in the intra molecular hydrogen bond pattern, thus leading to the observed structural anomalies. To further examine the mutational implications on regulatory plugs of MGMT that holds the protein in a DNA-Binding position, a MDS based analysis was carried out on, all known physically interacting amino acids essentially clustered into groups based on their position and function. The results generated by physical-functional clustering of protein indicated that the identified mutation in the vicinity of the active site of MGMT protein causes the local and global destabilization of a protein by either eliminating the stabilizing salt bridges in cluster C3, C4, and C5 or by locally destabilizing the "protein stabilizing hing" mapped on C3-C4 cluster, preceding the active site.


Assuntos
O(6)-Metilguanina-DNA Metiltransferase/química , Neoplasias Gástricas/enzimologia , Éxons/genética , Humanos , Ligações de Hidrogênio , Modelos Moleculares , Dados de Sequência Molecular , Proteínas Mutantes/química , Estrutura Terciária de Proteína , Termodinâmica
13.
BMC Vet Res ; 11: 21, 2015 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-25890207

RESUMO

BACKGROUND: Although modified live virus (MLV) vaccines are commonly used for porcine reproductive and respiratory syndrome virus (PRRSV) control, there have been safety concerns due to the quick reversion of MLV to virulence during replication in pigs. Previous studies have demonstrated that mutant viruses emerged from lethal mutagenesis driven by antiviral mutagens and that those viruses had higher genetic stability compared to their parental strains because they acquired resistance to random mutation. Thus, this strategy was explored to stabilize the PRRSV genome in the current study. RESULTS: Four antiviral mutagens (ribavirin, 5-fluorouracil, 5-azacytidine, and amiloride) were evaluated for their antiviral effects against VR2332, a prototype of type 2 PRRSV. Among the mutagens, ribavirin and 5-fluorouracil had significant antiviral effects against VR2332. Consequently, VR2332 was serially passaged in MARC-145 cells in the presence of ribavirin at several concentrations to facilitate the emergence of ribavirin-resistant mutants. Two ribavirin-resistant mutants, RVRp13 and RVRp22, emerged from serial passages in the presence of 0.1 and 0.2 mM ribavirin, respectively. The genetic stability of these resistant mutants was evaluated in MARC-145 cells and compared with VR2332. As expected, the ribavirin-resistant mutants exhibited higher genetic stability compared to their parental virus. CONCLUSIONS: In summary, ribavirin and 5-fluorouracil effectively suppressed PRRSV replication in MARC-145 cells. However, ribavirin-resistant mutants emerged when treated with low concentrations (≤0.2 mM) of ribavirin, and those mutants were genetically more stable during serial passages in cell culture.


Assuntos
Antivirais/farmacologia , Mutagênese/efeitos dos fármacos , Vírus da Síndrome Respiratória e Reprodutiva Suína/efeitos dos fármacos , Ribavirina/farmacologia , Replicação Viral/efeitos dos fármacos , Amilorida/farmacologia , Animais , Azacitidina/farmacologia , Linhagem Celular , Cercopithecus aethiops , Fluoruracila/farmacologia , Genoma Viral/efeitos dos fármacos , Mutagênicos/farmacologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia
14.
Appl Biochem Biotechnol ; 170(1): 164-75, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23483409

RESUMO

The epimutational event, i.e., ectopic methylation in tumor suppressor genes, can lead to gene silencing, thus promoting prognosis of cancer. The progression of DNA methylation is a cycle of demethylation, de novo methylation, and maintenance methylation. The enzyme responsible for maintenance of methylation status is DNA methyltransferase 1 (DNMT1), the continuous activity of which is required to maintain the pattern of epimutation; thus, its inhibition is a promising strategy for the treatment of cancer. To the best of our knowledge, this study is the first to focus on the recently developed crystal structure of the catalytic site of DNMT1. Here in this study, we have used the crystal structure for the development of non-nucleoside DNMT1 inhibitors using virtual screening (VS), absorption, distribution, metabolism, elimination/toxicology analysis, and molecular docking studies. In this study, VS was carried out on 48,531 natural products to create a subset of lead-like natural products. Three of them were found to form hydrogen bonds with the catalytic site of the DNMT1 (Cys 1226). Thus, this study adumbrates potential lead compounds for treatment of epimutation.


Assuntos
Antineoplásicos/química , Produtos Biológicos/química , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Desenho de Drogas , Inibidores Enzimáticos/química , Domínio Catalítico , Projeto Auxiliado por Computador , Cristalografia por Raios X , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/química , Metilação de DNA , Epigênese Genética , Inativação Gênica , Humanos , Ligações de Hidrogênio , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico
15.
Asian Pac J Cancer Prev ; 13(3): 1077-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22631641

RESUMO

The Kashmiri population is culturally distinct with special dietary features owing to the temperate climatic conditions of Kashmir valley. This has habituated the population to preserve food in smoked, pickled and sundried forms which include considerable amounts of N-nitroso compounds (NOCs). These are known to cause cytotoxicity, DNA damage, mutation, unscheduled DNA synthesis and DNA methylation. All of these changes at molecular level are known to contribute to the pathogenesis of cancer. One of the prominent NOCs found in Kashmiri food is N-Nitrosodimethylamine (NDMA). Here we review the occurrence of NDMA in sundried foods, dried fish, kehwa, traditional pickle, Brassica oleracia and tobbaco. We also discuss its possible role in the high prevalence of gastrointestinal cancers in Kashmir.


Assuntos
Dieta , Dimetilnitrosamina/efeitos adversos , Dimetilnitrosamina/análise , Análise de Alimentos , Conservantes de Alimentos/efeitos adversos , Conservantes de Alimentos/análise , Neoplasias Gastrointestinais/epidemiologia , Conservação de Alimentos , Neoplasias Gastrointestinais/etiologia , Humanos , Incidência , Índia/epidemiologia , Fatores de Risco
16.
Asian Pac J Cancer Prev ; 13(1): 181-6, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22502664

RESUMO

The aim of this study was to evaluate the methylation status of three important cancer related genes viz. p16, E-cadherin and hMLH1 promoters and to associate the findings with specific dietary habits in Kashmiris, a culturally distinct population in India, with gastric cancer. The study subjects were divided into three age groups viz. 0-30 yrs (1st), 31-60 yrs (2nd) and 61-90 yrs (3rd). A highly significant association between the intake of local hot salted tea in 2nd (p=0.001) and 3rd (p=0.009) age groups was observed with the promoter hypermethylation of E cadherin. Again a highly significant association between the aberrant methylation of hMLH1 (p=0.000) and p16 (p=0.000) promoters and the intake of local hot salted tea was observed in the 2nd age group of gastric cancer patients. The intake of sun-dried food was also significantly associated with the promoter hypermethylation of E cadherin (p=0.003) and p16 (p=0.015) genes in 3rd age group. The results of the present study suggest a close association between the aberrant methylation of p16, E-cadherin and hMLH1 promoters and the intake of local hot salted tea and sun-dried foods in Kashmiri population.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Caderinas/genética , Metilação de DNA , Alimentos em Conserva , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Regiões Promotoras Genéticas/genética , Neoplasias Gástricas/genética , Chá , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Ilhas de CpG/genética , Inibidor p16 de Quinase Dependente de Ciclina , DNA de Neoplasias/genética , Feminino , Temperatura Alta , Humanos , Índia/epidemiologia , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Reação em Cadeia da Polimerase , Prognóstico , Neoplasias Gástricas/epidemiologia , Luz Solar , Adulto Jovem
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