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1.
BMC Infect Dis ; 24(1): 495, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750422

RESUMO

BACKGROUND: In November 2019, the world faced a pandemic called SARS-CoV-2, which became a major threat to humans and continues to be. To overcome this, many plants were explored to find a cure. METHODS: Therefore, this research was planned to screen out the active constituents from Artemisia annua that can work against the viral main protease Mpro as this non-structural protein is responsible for the cleavage of replicating enzymes of the virus. Twenty-five biocompounds belonging to different classes namely alpha-pinene, beta-pinene, carvone, myrtenol, quinic acid, caffeic acid, quercetin, rutin, apigenin, chrysoplenetin, arteannunin b, artemisinin, scopoletin, scoparone, artemisinic acid, deoxyartemisnin, artemetin, casticin, sitogluside, beta-sitosterol, dihydroartemisinin, scopolin, artemether, artemotil, artesunate were selected. Virtual screening of these ligands was carried out against drug target Mpro by CB dock. RESULTS: Quercetin, rutin, casticin, chrysoplenetin, apigenin, artemetin, artesunate, sopolin and sito-gluside were found as hit compounds. Further, ADMET screening was conducted which represented Chrysoplenetin as a lead compound. Azithromycin was used as a standard drug. The interactions were studied by PyMol and visualized in LigPlot. Furthermore, the RMSD graph shows fluctuations at various points at the start of simulation in Top1 (Azithromycin) complex system due to structural changes in the helix-coil-helix and beta-turn-beta changes at specific points resulting in increased RMSD with a time frame of 50 ns. But this change remains stable after the extension of simulation time intervals till 100 ns. On other side, the Top2 complex system remains highly stable throughout the time scale. No such structural dynamics were observed bu the ligand attached to the active site residues binds strongly. CONCLUSION: This study facilitates researchers to develop and discover more effective and specific therapeutic agents against SARS-CoV-2 and other viral infections. Finally, chrysoplenetin was identified as a more potent drug candidate to act against the viral main protease, which in the future can be helpful.


Assuntos
Artemisia annua , Proteases 3C de Coronavírus , Simulação de Acoplamento Molecular , SARS-CoV-2 , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Artemisia annua/química , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Humanos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Tratamento Farmacológico da COVID-19 , Antivirais/farmacologia , Antivirais/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Simulação por Computador , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , COVID-19/virologia , Simulação de Dinâmica Molecular
2.
Mamm Genome ; 34(4): 632-643, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37668737

RESUMO

Dyslipidemia is a major risk factor for the development of coronary artery disease (CAD). Understanding the genetic determinants of dyslipidemia can provide valuable information on the pathogenesis of CAD and aid in the development of early detection strategies. In this study, we used a Global Screening Array (GSA) to elucidate the genetic factors associated with dyslipidemia and their potential role in the prediction of CAD. We conducted a GSA-based association study in 265 subjects to identify the genetic loci associated with dyslipidemia traits using Multiple Linear Regression (MLR) and Logistic Regression (LR), Classification and Regression Tree (CART), and Manhattan plots. We identified an association between dyslipidemia and variants identified in genes such as JCAD, GLIS3, CD38, FN1, CELSR2, MTNR1B, GIPR, DYM, APOB, APOE, ADCY5. The MLR models explained 62%, 71%, and 81% of the variability in HDL, LDL, and triglycerides, respectively. The Area Under the Curve (AUC) values in the LR models of HDL, LDL, and triglycerides were 1.00, 0.94, and 0.95, respectively. CART models identified novel gene-gene interactions influencing the risk for dyslipidemia. To conclude, we have identified the association of 12 SNVs with dyslipidemia and demonstrated their clinical utility in four different models such as MLR, LR, CART, and Manhattan plots. The identified genetic variants and associated pathways shed light on the underlying biology of dyslipidemia and offer potential avenues for precision medicine strategies in the management of CAD.


Assuntos
Doença da Artéria Coronariana , Dislipidemias , Humanos , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/genética , Fatores de Risco , Triglicerídeos , Dislipidemias/diagnóstico , Dislipidemias/genética
3.
Epidemiol Infect ; 151: e127, 2023 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-37293986

RESUMO

Evolutionary studies on Dengue virus (DENV) in endemic regions are necessary since naturally occurring mutations may lead to genotypic variations or shifts in serotypes, which may lead to future outbreaks. Our study comprehends the evolutionary dynamics of DENV, using phylogenetic, molecular clock, skyline plots, network, selection pressure, and entropy analyses based on partial CprM gene sequences. We have collected 250 samples, 161 in 2017 and 89 in 2018. Details for the 2017 samples were published in our previous article and that of 2018 are presented in this study. Further evolutionary analysis was carried out using 800 sequences, which incorporate the study and global sequences from GenBank: DENV-1 (n = 240), DENV-3 (n = 374), and DENV-4 (n = 186), identified during 1944-2020, 1956-2020, and 1956-2021, respectively. Genotypes V, III, and I were identified as the predominant genotypes of the DENV-1, DENV-3, and DENV-4 serotypes, respectively. The rate of nucleotide substitution was found highest in DENV-3 (7.90 × 10-4 s/s/y), followed by DENV-4 (6.23 × 10-4 s/s/y) and DENV-1 (5.99 × 10-4 s/s/y). The Bayesian skyline plots of the Indian strains revealed dissimilar patterns amongst the population size of the three serotypes. Network analyses showed the presence of different clusters within the prevalent genotypes. The data presented in this study will assist in supplementing the measures for vaccine development against DENV.


Assuntos
Vírus da Dengue , Dengue , Humanos , Vírus da Dengue/genética , Sorogrupo , Dengue/epidemiologia , Filogenia , Teorema de Bayes , Genótipo
4.
Int J Mol Sci ; 23(4)2022 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-35216066

RESUMO

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in children and infants. To date, there is no effective vaccine available against RSV. Heparan sulfate is a type of glycosaminoglycan that aids in the attachment of the RSV to the host cell membrane via the G protein. In the present study, the effect of amino acid substitution on the structure and stability of the ectodomain G protein was studied. Further, it was investigated whether mutation (K117A) in the CX3C motif of G protein alters the binding with heparan sulfate. The point mutation significantly affects the conformational stability of the G protein. The mutant protein showed a low binding affinity with heparan sulfate as compared to the wild-type G protein, as determined by fluorescence quenching, isothermal titration calorimetry (ITC), and molecular docking studies. The low binding affinity and decreased stability suggested that this mutation may play an important role in prevention of attachment of virion to the host cell receptors. Collectively, this investigation suggests that mutation in the CX3C motif of G protein may likely improve the efficacy and safety of the RSV vaccine.


Assuntos
Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Heparitina Sulfato/metabolismo , Mutação/genética , Substituição de Aminoácidos/genética , Calorimetria/métodos , Linhagem Celular , Humanos , Simulação de Acoplamento Molecular/métodos , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Infecções por Vírus Respiratório Sincicial/metabolismo , Vírus Sincicial Respiratório Humano/metabolismo , Análise Espectral/métodos , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo , Vírion/genética , Replicação Viral/genética
5.
J Gene Med ; 23(1): e3289, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33105068

RESUMO

BACKGROUND: The present study aimed to delineate the pharmacologically relevant dihydropyrimidine dehydrogenase (DPYD) variants in the Indian population. METHODS: We screened 2000 Indian subjects for DPYD variants using the Infinium Global Screening Array (GSA) (Illumina Inc., San Diego, CA, USA). RESULTS: The GSA analysis identified seven coding, two intronic and three synonymous DPYD variants. Level 1A alleles (rs75017182, rs3918290, P633Qfs*5 and D949V) were found to be rare (minor allele frequency: 1.889%), whereas Level 3 alleles were observed to be predominant (C29R: 24.91%, I543V: 9.047%, M166V: 8.993% and V732I: 8.44%). In silico predictions revealed that all Level 1A alleles were deleterious, whereas three (M166V, S534N and V732I) of seven Level 3 alleles were damaging. CUPSAT analysis revealed that two Level 1A (P633Qfs*, D949V) and three Level 3 (I543V, V732I and S534N) variants were thermolabile. The pooled Indian data showed that V732I, S534N and rs3918290 variants were associated with 5-FU/capecitabine toxicity, whereas C29R, I543V and M166V variants exhibited the null association. A comparison of our data with other population data from the 'Allele Frequency Aggregator' (https://www.ncbi.nlm.nih.gov/snp/docs/gsr/alfa/) database showed similarities with the South Asian data. CONCLUSIONS: We have identified four Level 1A (non-functional/dysfunctional) and seven Level 3 variants in the DPYD gene. The pooled Indian data revealed the association of V732I, S534N and rs3918290 variants with 5-FU/capecitabine toxicity. Clustering analysis revealed the similarities in the DPYD profiles of the Indian and South Asian populations.


Assuntos
Di-Hidrouracila Desidrogenase (NADP)/genética , Variação Genética , Genética Populacional , Farmacogenética/métodos , Alelos , Fluoruracila/farmacologia , Frequência do Gene , Genótipo , Humanos , Índia
6.
Ann Pharmacother ; 55(12): 1429-1438, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33749319

RESUMO

BACKGROUND: Methotrexate (MTX) is an antirheumatic drug, transported by reduced folate carrier-1 (RFC1). The most common RFC1 gene variant, c.80 A>G (rs1051266) is ambiguously linked to adverse effects of MTX therapy in some rheumatoid arthritis (RA) patients. OBJECTIVE: The purpose of meta-analysis was to summarize all major published studies on c.80 A>G SNP to clarify this ambiguity in MTX therapy. METHODS: A total of 18 studies representing 3592 RA patients comprising 699 men and 2893 women were included. Both fixed and random effect models were applied to study the data. RESULTS: The RFC1 80A-allele showed null association with MTX-mediated toxicity in both fixed (odds ratio [OR] = 0.91; 95% CI = 0.80-1.03) and random effects (OR = 0.89; 95% CI: 0.71-1.11) models. Because heterogeneity was observed in this association (P = 0.0006), data were segregated based on use of folate therapy. In 7 studies (n = 1191) where folate was used along with MTX, RFC1 AA patients showed reduced risk for MTX-mediated toxicity (OR = 0.67; 95% CI: 0.50-0.89; P = 0.0006). The RFC1 80A-allele was found to increase the efficacy of MTX therapy by 1.53-fold (95% CI: 1.24-1.88), whereas the 80AA-genotype increased the efficacy by 1.85-fold (95% CI: 1.41-2.42). No publication bias was observed in these associations. CONCLUSION AND RELEVANCE: RFC1 c.80 A>G is an important pharmacogenetic determinant of MTX therapy in RA. The RFC1 80A-allele robustly increased therapeutic efficacy and safety when folate was used along with MTX. Findings are relevant to decision-making in the clinical use of MTX as a treatment for RA patients harboring the RFC1 gene variant.


Assuntos
Antirreumáticos , Artrite Reumatoide , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Feminino , Genótipo , Humanos , Masculino , Metotrexato/efeitos adversos , Polimorfismo Genético
7.
Molecules ; 26(23)2021 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-34885979

RESUMO

The global burden of disease caused by a respiratory syncytial virus (RSV) is becoming more widely recognized in young children and adults. Heparan sulfate helps in attaching the virion through G protein with the host cell membrane. In this study, we examined the structural changes of ectodomain G protein (edG) in a wide pH range. The absorbance results revealed that protein maintains its tertiary structure at physiological and highly acidic and alkaline pH. However, visible aggregation of protein was observed in mild acidic pH. The intrinsic fluorescence study shows no significant change in the λmax except at pH 12.0. The ANS fluorescence of edG at pH 2.0 and 3.0 forms an acid-induced molten globule-like state. The denaturation transition curve monitored by fluorescence spectroscopy revealed that urea and GdmCl induced denaturation native (N) ↔ denatured (D) state follows a two-state process. The fluorescence quenching, molecular docking, and 50 ns simulation measurements suggested that heparan sulfate showed excellent binding affinity to edG. Our binding study provides a preliminary insight into the interaction of edG to the host cell membrane via heparan sulfate. This binding can be inhibited using experimental approaches at the molecular level leading to the prevention of effective host-pathogen interaction.


Assuntos
Domínio Catalítico , Heparitina Sulfato/metabolismo , Interações Hospedeiro-Patógeno , Simulação de Acoplamento Molecular/métodos , Vírus Sincicial Respiratório Humano/metabolismo , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/metabolismo , Membrana Celular/metabolismo , Humanos , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Agregados Proteicos , Agregação Patológica de Proteínas/metabolismo , Desnaturação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Espectrometria de Fluorescência/métodos , Ureia/farmacologia
8.
Molecules ; 26(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068693

RESUMO

The intracellular environment is overcrowded with a range of molecules (small and large), all of which influence protein conformation. As a result, understanding how proteins fold and stay functional in such crowded conditions is essential. Several in vitro experiments have looked into the effects of macromolecular crowding on different proteins. However, there are hardly any reports regarding small molecular crowders used alone and in mixtures to observe their effects on the structure and stability of the proteins, which mimics of the cellular conditions. Here we investigate the effect of different mixtures of crowders, ethylene glycol (EG) and its polymer polyethylene glycol (PEG 400 Da) on the structural and thermal stability of myoglobin (Mb). Our results show that monomer (EG) has no significant effect on the structure of Mb, while the polymer disrupts its structure and decreases its stability. Conversely, the additive effect of crowders showed structural refolding of the protein to some extent. Moreover, the calorimetric binding studies of the protein showed very weak interactions with the mixture of crowders. Usually, we can assume that soft interactions induce structural perturbations while exclusion volume effects stabilize the protein structure; therefore, we hypothesize that under in vivo crowded conditions, both phenomena occur and maintain the stability and function of proteins.


Assuntos
Substâncias Macromoleculares/química , Mioglobina/química , Redobramento de Proteína , Temperatura , Animais , Difusão Dinâmica da Luz , Etilenoglicol/química , Fluorescência , Guanidina/farmacologia , Cavalos , Hidrodinâmica , Simulação de Acoplamento Molecular , Polietilenoglicóis/química , Conformação Proteica , Desnaturação Proteica/efeitos dos fármacos , Redobramento de Proteína/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos
9.
Indian J Clin Biochem ; 35(1): 121-126, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32071505

RESUMO

The rationale of the current study was to assess the prevalence of 25-hydroxyvitamin D (25-OHD) deficiency and hyperparathyroidism in South Indian population and to explore interrelationships of 25-OHD, Ca, P towards parathyroid hormone (PTH) production using adaptive neuro-fuzzy inference system (ANFIS). A total of 407 subjects (228 men 179 women) with the mean age 56.8 ± 14.1 were tested for these parameters. In view of the skewed distribution of biochemical variables, data segregation was performed in tertiles and this data was trained to generate fuzzy interference system based on subclusters. The optimized model had 358 nodes and followed 44 fuzzy rules for prediction. This ANFIS model demonstrates that the deficiency of 25-OHD and Calcium triggers PTH production. PTH elevation is significant when Phosphorus is in the highest tertile. The associations observed by this model were consistent with the Kendall-Tau correlation matrix, which revealed inverse associations of Ca with P; and Ca with PTH and positive associations of P with PTH, and Ca with 25-OHD. Furthermore, the association statistics of the machine learning algorithm were also consistent, which suggested that depletion of Ca below 8.245 mg/dl was shown to elevate PTH levels greater than 167 pg/ml when P > 4.66. Subnormal depletion in 25-OHD (9.3-16.2 ng/ml) is associated with subnormal elevation in PTH (47-73.6 pg/ml). To conclude, ANFIS and machine learning algorithm are in agreement with each other in stating that 25-OHD deficiency triggers lower calcium levels, lower calcium and higher phosphorus trigger PTH production.

10.
BMC Med Genet ; 20(1): 193, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31822280

RESUMO

BACKGROUND: The deficiency of vitamin D receptor (VDR) or its ligand, vitamin D3, is linked to the development of renal diseases. The TaqI (rs731236) and ApaI (rs7975232) polymorphisms of VDR gene are widely studied for their association with renal disease risk. However, studies have largely been ambiguous. METHODS: Meta-analysis was carried out to clarify the association of TaqI (2777 cases and 3522 controls) and ApaI (2440 cases and 3279 controls) polymorphisms with nephrolithiasis (NL), diabetic nephropathy (DN) and end stage renal disease (ESRD). RESULTS: The VDR TaqI C-allele under allele contrast was significantly associated with ESRD in both fixed effect and random effect models, and ApaI C-allele with ESRD only under fixed effect model. Cochrane Q-test showed no evidence of heterogeneity for TaqI polymorphism and a significant heterogeneity for Apa I polymorphism. No publication bias was observed for both the polymorphisms. CONCLUSIONS: The present meta-analysis identifies TaqI and ApaI polymorphisms of VDR gene as risk factors for renal diseases.


Assuntos
Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo , Nefropatias Diabéticas/genética , Falência Renal Crônica/genética , Nefrolitíase/genética , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/genética , Estudos de Casos e Controles , Humanos , Receptores de Calcitriol/metabolismo
11.
Toxicol Mech Methods ; 29(3): 211-218, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30480468

RESUMO

Incense smoke is reported to increase cardiovascular disease (CVD) risk in exposed individuals. However, the mechanism underlying the toxic effect of incense smoke on cardiovascular system is unclear. To test this, we chronically exposed male albino rats to two different types of Arabian incense smoke and studied their effects on oxidative stress, inflammation, and endothelial function. Rats exposed to either of incense smoke showed a significant increase in malondialdehyde (MDA) and a significant decline in superoxide dismutase (SOD) and reduced glutathione (GSH). Endothelial functional marker, nitric oxide (NO) was significantly decreased while endothelin-1 was significantly increased in rats exposed to both the incense types. Incense smoke exposure also led to a significant increase in chemokines and inflammatory mediators including monocyte chemoattractant protein-1 (MCP-1), granulocyte-macrophage-colony stimulating factor (GM-CSF), regulated on activation normal T cell expressed and secreted (RANTES), interleukin-4 (IL-4), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α). Besides, incense smoke-exposed rats demonstrated a significant increase in the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecules-1 (VCAM-1), and E-selectin. Importantly, cessation of incense smoke exposure for 30 days led to a significant reversal in the levels of all the studied markers. Collectively, this study describes oxidative stress, endothelial dysfunction, and inflammation as possible underlying mechanisms in the toxic effects of incense smoke on increased CVD risk in exposed individuals. Findings also underscore that avoiding incense smoke exposure may have beneficial health effects.


Assuntos
Aorta Abdominal/efeitos dos fármacos , Citocinas/sangue , Endotélio Vascular/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Fumaça/efeitos adversos , Animais , Aorta Abdominal/imunologia , Aorta Abdominal/metabolismo , Biomarcadores/sangue , Moléculas de Adesão Celular/genética , Endotelina-1/metabolismo , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Masculino , Óxido Nítrico/metabolismo , Estresse Oxidativo/imunologia , Ratos Wistar
12.
Mol Biol Rep ; 45(5): 901-910, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29995270

RESUMO

In view of high mortality associated with coronary artery disease (CAD), development of an early predicting tool will be beneficial in reducing the burden of the disease. The database comprising demographic, conventional, folate/xenobiotic genetic risk factors of 648 subjects (364 cases of CAD and 284 healthy controls) was used as the basis to develop CAD risk and percentage stenosis prediction models using ensemble machine learning algorithms (EMLA), multifactor dimensionality reduction (MDR) and recursive partitioning (RP). The EMLA model showed better performance than other models in disease (89.3%) and stenosis prediction (82.5%). This model depicted hypertension and alcohol intake as the key predictors of CAD risk followed by cSHMT C1420T, GCPII C1561T, diabetes, GSTT1, CYP1A1 m2, TYMs 5'-UTR 28 bp tandem repeat and MTRR A66G. MDR and RP models are in agreement in projecting increasing age, hypertension and cSHMTC1420T as the key determinants interacting in modulating CAD risk. Receiver operating characteristic curves exhibited clinical utility of the developed models in the following order: EMLA (C = 0.96) > RP (C = 0.83) > MDR (C = 0.80). The stenosis prediction model showed that xenobiotic pathway genetic variants i.e. CYP1A1 m2 and GSTT1 are the key determinants of percentage of stenosis. Diabetes, diet, alcohol intake, hypertension and MTRR A66G are the other determinants of stenosis. These eleven variables contribute towards 82.5% stenosis. To conclude, the EMLA model exhibited higher predictability both in terms of disease prediction and stenosis prediction. This can be attributed to higher number of iterations in EMLA model that can increase the prediction accuracy.


Assuntos
Doença da Artéria Coronariana/genética , Previsões/métodos , Redução Dimensional com Múltiplos Fatores/métodos , Adulto , Idoso , Algoritmos , Estudos de Casos e Controles , Doença da Artéria Coronariana/mortalidade , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Epistasia Genética/genética , Feminino , Ácido Fólico/metabolismo , Predisposição Genética para Doença/genética , Glicina Hidroximetiltransferase/genética , Glicina Hidroximetiltransferase/metabolismo , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Xenobióticos/metabolismo
13.
Exp Dermatol ; 26(10): 955-957, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28191671

RESUMO

The expression of filaggrin in differentiated keratinocytes and the association of filaggrin mutations with ichthyosis vulgaris and atopic dermatitis suggest that this prototypical member of the S100 fused-type protein (SFTP) family plays a key role in the epidermal barrier to the environment. Here, we report that SFTP genes are present not only in amniotes but also in amphibians. Four SFTPs are expressed in the skin of the frog Xenopus laevis. The results of this study indicate that filaggrin has evolved from an ancestral SFTP that may have contributed to skin modifications during the evolutionary transition to terrestrial life.


Assuntos
Evolução Molecular , Proteínas de Filamentos Intermediários/química , Proteínas de Filamentos Intermediários/genética , Proteínas S100/química , Proteínas S100/genética , Animais , Proteínas Filagrinas , Genômica , Humanos , Filogenia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de Proteína , Xenopus laevis
14.
J Theor Biol ; 406: 137-42, 2016 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-27430729

RESUMO

To develop a potential inhibitor for glutamate carboxypeptidase II (GCPII) effective against all the eight common genetic variants reported, PyMOL molecular visualization system was used to generate models of variants using the crystal structure of GCPII i.e. 2OOT as a template. High-throughput virtual screening of 29 compounds revealed differential efficacy across the eight genetic variants (pIC50: 4.70 to 10.22). Pharmacophore analysis and quantitative structure-activity relationship (QSAR) studies revealed a urea-based N-acetyl aspartyl glutamate (NAAG) analogue as more potent inhibitor, which was effective across all the genetic variants of GCPII as evidenced by glide scores (-4.32 to -7.08) and protein-ligand interaction plots (13 interactions in wild GCPII). This molecule satisfied Lipinski rule of five and rule of three for drug-likeliness. Being a NAAG-analogue, this molecule might confer neuroprotection by inhibiting glutamatergic neurotransmission mediated by N-acetylated alpha-linked acidic dipeptidase (NAALADase), a splice variant of GCPII.


Assuntos
Simulação por Computador , Glutamato Carboxipeptidase II/antagonistas & inibidores , Neuroproteção/efeitos dos fármacos , Inibidores de Proteases/análise , Inibidores de Proteases/farmacologia , Variação Genética , Glutamato Carboxipeptidase II/química , Ligantes , Modelos Moleculares , Inibidores de Proteases/química , Relação Quantitativa Estrutura-Atividade
15.
Inhal Toxicol ; 28(8): 364-73, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27180632

RESUMO

CONTEXT: Previous studies, including ours, have shown adverse effects of incense smoke on human health. However, the effect of incense smoke on kidney function and structure remains unknown. OBJECTIVE: To evaluate possible adverse effects of incense smoke on kidney function and architecture in albino rats after chronic exposure to Arabian incense. MATERIALS AND METHODS: Emission characteristics including particle size distribution, volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs) were determined by gravimetric and GCMS analyses. Kidney functional markers, oxidative stress and inflammatory markers were measured by standard or ELISA based procedures. Ultrastructural changes in kidney were examined by transmission electron microscope (TEM) and the gene expression of xenobiotic metabolizing enzymes including cytochrome P-450-1A1 (CYP1A1) and CYP1A2 were studied by real time PCR. RESULTS: Rats exposed to incense smoke demonstrated a significant increase in serum creatinine, uric acid, blood urea nitrogen (BUN), tissue malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α) and interleukin-4 (IL-4) levels and a significant decline in tissue reduced glutathione (GSH) and catalase activity. Incense smoke exposed rats also displayed marked ultrastructural changes in kidney tissue. Further, a significant increase in tissue gene expression of both CYP1A1 and CYP1A2 was noted in exposed rats. DISCUSSION: Changes to kidney functional markers and architecture appear to be mediated through augmented oxidative stress and inflammation. CONCLUSION: Long-term exposure to incense smoke may have deleterious effects on kidney function and architecture. Though, inhalation is the rout of exposure, findings of this study underscore that incense smoke may also have an effect on non-pulmonary tissues.


Assuntos
Rim/efeitos dos fármacos , Fumaça/efeitos adversos , Animais , Nitrogênio da Ureia Sanguínea , Catalase/metabolismo , Creatinina/sangue , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/genética , Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Interleucina-4/metabolismo , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Masculino , Malondialdeído/metabolismo , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo , Ácido Úrico/sangue
17.
Mol Cell Biochem ; 392(1-2): 273-80, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24676543

RESUMO

Obesity, genetic polymorphisms of xenobiotic metabolic pathway, hypermethylation of tumor suppressor genes, and hypomethylation of proapoptotic genes are known to be independent risk factors for breast cancer. The objective of this study is to evaluate the combined effect of these environmental, genetic, and epigenetic risk factors on the susceptibility to breast cancer. PCR-RFLP and multiplex PCR were used for the genetic analysis of six variants of xenobiotic metabolic pathway. Methylation-specific PCR was used for the epigenetic analysis of four genetic loci. Multifactor dimensionality reduction analysis revealed a significant interaction between the body mass index (BMI) and catechol-O-methyl transferase H108L variant alone or in combination with cytochrome P450 (CYP) 1A1m1 variant. Women with "Luminal A" breast cancer phenotype had higher BMI compared to other phenotypes and healthy controls. There was no association between the BMI and tumor grade. The post-menopausal obese women exhibited lower glutathione levels. BMI showed a positive association with the methylation of extracellular superoxide dismutase (r = 0.21, p < 0.05), Ras-association (RalGDS/AF-6) domain family member 1 (RASSF1A) (r = 0.31, p < 0.001), and breast cancer type 1 susceptibility protein (r = 0.19, p < 0.05); and inverse association with methylation of BNIP3 (r = -0.48, p < 0.0001). To conclude based on these results, obesity increases the breast cancer susceptibility by two possible mechanisms: (i) by interacting with xenobiotic genetic polymorphisms in inducing increased oxidative DNA damage and (ii) by altering the methylome of several tumor suppressor genes.


Assuntos
Neoplasias da Mama/genética , Ilhas de CpG , Metilação de DNA , Genes Supressores de Tumor , Obesidade/genética , Xenobióticos/metabolismo , Adulto , Sequência de Bases , Neoplasias da Mama/complicações , Primers do DNA , Feminino , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Obesidade/complicações , Reação em Cadeia da Polimerase
18.
Mol Cell Biochem ; 391(1-2): 127-36, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24557852

RESUMO

Incense smoke is increasingly being recognized as a potential environmental contaminant and is linked to malignant and non-malignant respiratory diseases. The detoxification of environmental contaminants including polycyclic aromatic hydrocarbons (PAHs) involves the induction of cytochrome P-450 family enzymes (CYPs) by PAHs. However, the detoxification of PAHs also results in the generation of reactive and unstable intermediary metabolites which are implicated in the oxidative stress, DNA damage, and inflammation. It is unclear whether CYPs are similarly induced by incense smoke, which incidentally contains substantial amounts of PAHs. Here, we examined the impact of long-term incense smoke exposure on the induction of CYPs in male Wister Albino rats. Incense smoke exposure significantly induced the expression of CYP1A1, CYP1A2, and CYP1B1 mRNAs in both lung and liver tissues. The extent of CYP1A1 and CYP1B1 induction was significantly higher in the liver compared to that in the lung, while that of CYP1A2 was greater in the lung than in liver. Incense smoke exposure also increased malondialdehyde and reduced glutathione levels in lung and liver tissues, and the catalase activity in the liver tissues to significant levels. Furthermore incense smoke exposure led to a marked increase in TNF-α and IL-4 levels. The data demonstrate for the first time the capacity of incense smoke to induce CYP1 family enzymes in the target and non-target tissues. Induction of CYPs increased oxidative stress and inflammation appear to be intimately linked to promote the carcinogenesis and health complications in people chronically exposed to incense smoke.


Assuntos
Citocromo P-450 CYP1A1/biossíntese , Citocromo P-450 CYP1A2/biossíntese , Citocromo P-450 CYP1B1/biossíntese , Inflamação/enzimologia , Fígado/enzimologia , Pulmão/enzimologia , Estresse Oxidativo , Fumaça/efeitos adversos , Animais , Biomarcadores/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Exposição Ambiental/efeitos adversos , Indução Enzimática , Inflamação/patologia , Interleucina-4/metabolismo , Fígado/patologia , Pulmão/patologia , Masculino , Especificidade de Órgãos/genética , Estresse Oxidativo/genética , Perfumes/efeitos adversos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
19.
Plants (Basel) ; 13(2)2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38256812

RESUMO

Hyperspectral imaging (HSI) is a promising tool in chlorophyll quantification, providing a non-invasive method to collect important information for effective crop management. HSI contributes to food security solutions by optimising crop yields. In this study, we presented a custom HSI system specifically designed to provide a quantitative analysis of leaf chlorophyll content (LCC). To ensure precise estimation, significant wavelengths were identified using optimal-band analysis. Our research was centred on two sets of 120 leaf samples sourced from Thailand's unique Chaew Khing rice variant. The samples were subjected to (i) an analytical LCC assessment and (ii) HSI imaging for spectral reflectance data capture. A linear regression comparison of these datasets revealed that the green (575 ± 2 nm) and near-infrared (788 ± 2 nm) bands were the most outstanding performers. Notably, the green normalised difference vegetation index (GNDVI) was the most reliable during cross-validation (R2=0.78 and RMSE = 2.4 µg∙cm-2), outperforming other examined vegetable indices (VIs), such as the simple ratio (RED/GREEN) and the chlorophyll index. The potential development of a streamlined sensor dependent only on these two wavelengths is a significant outcome of identifying these two optimal bands. This innovation can be seamlessly integrated into farming landscapes or attached to UAVs, allowing real-time monitoring and rapid, targeted N management interventions.

20.
Biochim Biophys Acta ; 2012 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-22659376

RESUMO

This article has been withdrawn at the request of the editors. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

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