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1.
Curr Med Chem ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34514981

RESUMO

This article presents a simplified view of celecoxib as a potential inhibitor in the treatment of inflammatory diseases. The enzyme cyclooxygenase (COX) has, predominantly, two isoforms called cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). The former plays a constitutive role that is related to homeostatic effects in renal and platelets, while the latter is mainly responsible for induction of inflammatory effects. Since COX-2 plays an important role in the pathogenesis of inflammatory diseases, it has been signaled as a target for the planning of anti-inflammatory intermediates. Many inhibitors developed and planned for COX-2 inhibition have presented side effects to humans, mainly in the gastrointestinal and/or cardiovascular tract. Therefore, it is necessary to design new potential COX-2 inhibitors, which are relatively safe and without side effects. To this end, of the generation of non-steroidal anti-inflammatory drugs from "coxibs", celecoxib is the only potent selective COX-2 inhibitor that is still commercially available. Thus, the compound celecoxib became a commercial prototype inhibitor for the development of anti-inflammatory agents for COX-2 enzyme. In this review, we provide highlights where such inhibition should provide a structural basis for the design of promising new non-steroidal anti-inflammatory drugs (NSAIDs) which act as COX-2 inhibitors with lesser side effects on the human body.

2.
Neuromuscul Disord ; 31(6): 505-511, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33903021

RESUMO

Mutations in ganglioside-induced differentiation-associated-protein 1 (GDAP1) are associated with several subtypes of Charcot-Marie-Tooth (CMT) disease, including autosomal recessive and demyelinating (CMT4A); autosomal recessive and axonal (AR-CMT2K); autosomal dominant and axonal (CMT2K); and an intermediate and recessive form (CMTRIA). To date, at least 103 mutations in this gene have been described, but the relative frequency of GDAP1 mutations in the Brazilian CMT population is unknown. In this study, we investigated the frequency of GDAP1 mutations in a cohort of 100 unrelated Brazilian CMT patients. We identified five variants in unrelated axonal CMT patients, among which two were novel and probably pathogenic (N64S, P119T) one was novel and was classified as VUS (K207L) and two were known pathogenic variants (R125* and Q163*). The prevalence rate of GDAP1 among the axonal CMT cases was 7,14% (5/70), all of them of recessive inheritance, thus suggesting that the prevalence was higher than what is observed in most countries. All patients exhibited severe early-onset CMT that was rapidly progressive. Additionally, this study widens the mutational spectrum of GDAP1-related CMT through identification of two novel likely pathogenic variants.

3.
Sci Total Environ ; 768: 144899, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33736351

RESUMO

Tropical plant species are vulnerable to climate change and global warming. Since flowering is a critical factor for plant reproduction and seed-set, warming and elevated atmospheric carbon dioxide concentrations (eCO2) are crucial climate change factors that can affect plant reproductive dynamics and flowering related events in the tropics. Using a combined free-air CO2 enrichment and a free-air temperature-controlled enhancement system, we investigate how warming (+2 °C above ambient, eT) and elevated [CO2] (~600 ppm, eCO2) affect the phenological pattern, plant-insect interactions, and outcrossing rates in the tropical legume forage species Stylosanthes capitata Vogel (Fabaceae). In comparison to the control, a significantly greater number of flowers (NF) per plot (+62%) were observed in eT. Furthermore, in warmed plots flowers began opening approximately 1 h earlier (~09:05), with a canopy temperature of ~23 °C, than the control (~09:59) and eCO2 (~09:55) treatments. Flower closure occurred about 3 h later in eT (~11:57) and control (~13:13), with a canopy temperature of ~27 °C. These changes in flower phenology increased the availability of floral resources and attractiveness for pollinators such as Apis mellifera L. and visitors such as Paratrigona lineata L., with significant interactions between eT treatments and insect visitation per hour/day, especially between 09:00-10:40. In comparison to the control, the additive effects of combined eCO2 + eT enhanced the NF by 137%, while the number of A. mellifera floral visits per plot/week increased by 83% during the period of greatest flower production. Although we found no significant effect of treatments on mating system parameters, the overall mean multilocus outcrossing rate (tm = 0.53 ± 0.03) did confirm that S. capitata has a mixed mating system. The effects of elevated [CO2] and warming on plant-pollinator relationships observed here may have important implications for seed production of tropical forage species in future climate scenarios.


Assuntos
Dióxido de Carbono , Reprodução , Animais , Abelhas , Mudança Climática , Flores , Insetos , Polinização
4.
J Biomol Struct Dyn ; : 1-23, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33427075

RESUMO

Cyclooxygenase 2 (COX-2) is a well-established target for the design of anti-inflammatory intermediates. Celecoxib was selected as a template molecule to perform ligand-based virtual screening, i.e. to search for structures with similarity in shape and electrostatic potential, with a gradual increase in accuracy through the combined fitting of several steps using eight commercial databases. The molecules ZINC408709 and ZINC2090319 reproduced values within the limits established in an initial study of absorption and distribution in the body. No alert was fired for possible toxic groups when these molecules were subjected to toxicity prediction. Molecular docking results with these compounds showed a higher binding affinity in comparison to rofecoxib for the COX-2 target. Additionally, ZINC408709 and ZINC2090319 were predicted to be potentially biologically active. In in silico prediction of endocrine disruption potential, it was established that the molecule ZINC2090319 binds strongly to the target related to cardiovascular risk in a desirable way as a non-steroidal antagonist and ZINC408709 binds strongly to the target that is associated with the treatment of inflammatory pathologies and similar to celecoxib. Metabolites generated from these compounds are less likely to have side effects. Simulations were used to evaluate the interaction of compounds with COX-1 and COX-2 during 200 ns. Despite the differences, ZINC408709 molecule showed better stability for COX-2 during molecular dynamics simulation. In the calculations of free energy MM/PBSA, the molecule ZINC408709 ΔGbind value has a higher affinity to celecoxib and rofecoxib COX-2. This demonstrates that the selected substances can be considered as promising COX-2 inhibitors. Communicated by Ramaswamy H. Sarma.

5.
Chembiochem ; 22(6): 988-991, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33125805

RESUMO

It is possible to gain a deeper insight into the role of water in biology by using physicochemical variant molecules, such as deuterium oxide (D2 O); however, D2 O is toxic to multicellular organisms in high concentrations. By using a unique desiccation-rehydration process, we demonstrate that the anhydrobiotic nematode Panagrolaimus superbus is able to tolerate and proliferate in 99 % D2 O. Moreover, we analysed P. superbus' water-channel protein (aquaporin; AQP), which is associated with dehydration/rehydration, by comparing its primary structure and modelling its tertiary structure in silico. Our data evidence that P. superbus' AQP is an aquaglyceroporin, a class of water channel known to display a wider pore; this helps to explain the rapid and successful organismal influx of D2 O into this species. This is the first demonstration of an animal able to withstand high D2 O levels, thus paving a way for the investigation of the effects D2 O on higher levels of biological organization.

6.
J Biomol Struct Dyn ; 39(3): 1017-1028, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32028848

RESUMO

The objectives of this study were to extract and purify Bixin from the seeds of Bixa orellana and to evaluate its hypoglycemic activity in vivo, as well as, to conduct an in silico study of selectivity on peroxisome proliferator-activated receptors via molecular docking and molecular dynamics simulations. Oral administration of Bixin (10 mg/kg) significantly reduced their glucose level that was alloxan-induced diabetic rats. Bixin showed in silico selectivity on peroxisome proliferator-activated receptors (PPARs), particularly by the peroxisome proliferator-activated receptor gamma (PPARγ), which supports the hypoglycemic activity of Bixin. From the results obtained, it can be inferred that Bixin presents hypoglycemic characteristics, which was confirmed by the results obtained from the in vivo and in silico tests. Bixin may act by other pathways to control blood glucose and thus it is possible that it presents a different toxicity profile than troglitazone, rosiglitazone and pioglitazone. However, more studies on the activity and toxicity of Bixin are needed to evaluate for further clinical use. Communicated by Ramaswamy H. Sarma.


Assuntos
Diabetes Mellitus Experimental , Tiazolidinedionas , Aloxano , Animais , Carotenoides , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Simulação de Acoplamento Molecular , PPAR gama , Ratos
7.
Planta Med ; 87(1-02): 136-147, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33321518

RESUMO

Plants produce a high diversity of metabolites that can act as regulators of cholinergic dysfunction. Among plants, the potential of species of the genus Tabernaemontana to treat neurological disorders has been linked to iboga-type alkaloids that are biosynthesized by those species. In this context, precursor-directed biosynthesis approaches were carried out using T. catharinensis plantlets to achieve new-to-nature molecules as promising agents against Alzheimer's disease. Aerial parts of T. catharinensis, cultured in vitro, produced 7 unnatural alkaloids (5-fluoro-ibogamine, 5-fluoro-voachalotine, 5-fluoro-12-methoxy-Nb-methyl-voachalotine, 5-fluoro-isovoacangine, 5-fluoro-catharanthine, 5-fluoro-19-(S)-hydroxy-ibogamine, and 5-fluoro-coronaridine), while root extracts showed the presence of the same unnatural iboga-type alkaloids and 2 additional ones: 5-fluoro-voafinine and 5-fluoro-affinisine. Moreover, molecular docking approaches were carried out to evaluate the potential inhibition activity of T. catharinensis' natural and unnatural alkaloids against AChE and BChE enzymes. Fluorinated iboga alkaloids (5-fluoro-catharanthine, 5-fluoro-voachalotine, 5-fluoro-affinisine, 5-fluoro-isovoacangine, 5-fluoro-corinaridine) were more active than natural ones and controls against AchE, while 5-fluoro-19-(S)-hydroxy-ibogamine, 5-fluoro-catharanthine, 5-fluoro-isovoacangine, and 5-fluoro-corinaridine showed better activity than natural ones and controls against BChE. Our findings showed that precursor-directed biosynthesis strategies generated "new-to-nature" alkaloids that are promising Alzheimer's disease drug candidates. Furthermore, the isotopic experiments also allowed us to elucidate the initial steps of the biosynthetic pathway for iboga-type alkaloids, which are derived from the MEP and shikimate pathways.


Assuntos
Alcaloides , Doença de Alzheimer , Tabernaemontana , Doença de Alzheimer/tratamento farmacológico , Humanos , Alcaloides Indólicos , Simulação de Acoplamento Molecular
8.
Front Immunol ; 11: 575076, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240264

RESUMO

HLA-G is considered to be an immune checkpoint molecule, a function that is closely linked to the structure and dynamics of the different HLA-G isoforms. Unfortunately, little is known about the structure and dynamics of these isoforms. For instance, there are only seven crystal structures of HLA-G molecules, being all related to a single isoform, and in some cases lacking important residues associated to the interaction with leukocyte receptors. In addition, they lack information on the dynamics of both membrane-bound HLA-G forms, and soluble forms. We took advantage of in silico strategies to disclose the dynamic behavior of selected HLA-G forms, including the membrane-bound HLA-G1 molecule, soluble HLA-G1 dimer, and HLA-G5 isoform. Both the membrane-bound HLA-G1 molecule and the soluble HLA-G1 dimer were quite stable. Residues involved in the interaction with ILT2 and ILT4 receptors (α3 domain) were very close to the lipid bilayer in the complete HLA-G1 molecule, which might limit accessibility. On the other hand, these residues can be completely exposed in the soluble HLA-G1 dimer, due to the free rotation of the disulfide bridge (Cys42/Cys42). In fact, we speculate that this free rotation of each protomer (i.e., the chains composing the dimer) could enable alternative binding modes for ILT2/ILT4 receptors, which in turn could be associated with greater affinity of the soluble HLA-G1 dimer. Structural analysis of the HLA-G5 isoform demonstrated higher stability for the complex containing the peptide and coupled ß2-microglobulin, while structures lacking such domains were significantly unstable. This study reports for the first time structural conformations for the HLA-G5 isoform and the dynamic behavior of HLA-G1 molecules under simulated biological conditions. All modeled structures were made available through GitHub (https://github.com/KavrakiLab/), enabling their use as templates for modeling other alleles and isoforms, as well as for other computational analyses to investigate key molecular interactions.


Assuntos
Membrana Celular/metabolismo , Antígenos HLA-G/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Antígenos HLA-G/química , Antígenos HLA-G/genética , Humanos , Bicamadas Lipídicas , Domínios e Motivos de Interação entre Proteínas , Isoformas de Proteínas , Multimerização Proteica , Estabilidade Proteica , Relação Estrutura-Atividade
9.
Neurotox Res ; 38(3): 691-706, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32613603

RESUMO

Alzheimer's disease (AD) is the primary dementia-causing disease worldwide, involving a multifactorial combination of environmental, genetic, and epigenetic factors, with essential participation of age and sex. Biochemically, AD is characterized by the presence of abnormal deposition of beta amyloid peptide (Aß(1-42)), which in the brain is strongly correlated with oxidative stress, inflammation, DNA damage, and cholinergic impairment. The multiple mechanisms involved in its etiology create significant difficulty in producing an effective treatment. Neuroprotective properties of genistein and galantamine have been widely demonstrated through different mechanisms; however, it is unknown a possible synergistic neuroprotective effect against Aß(1-42). In order to understand how genistein and galantamine combinations regulate the mechanisms of neuroprotection, we conducted a set of bioassays in vitro to evaluate cell viability, clonogenic survival, cell death, and anti-genotoxicity. Through molecular docking and therapeutic viability assays, we analyzed the inhibitory activity exerted by genistein on three major protein targets (AChE, BChE, and NMDA) involved in AD. The results showed that genistein and galantamine afforded significant protection at higher concentrations; however, combinations of sub-effective concentrations of both compounds provided marked neuroprotection when they were combined. In silico approaches showed that genistein has higher scores than the positive controls and low toxicity levels; nevertheless, the therapeutic viability indicated that unlike galantamine, genistein cannot undergo the action by P glycoprotein (PGP) and probably may be unable to cross the blood-brain barrier. In conclusion, our results show that genistein and galantamine exert neuroprotective by decreasing genotoxicity and cell death. In silico analysis, suggest that genistein modulates positively the expression of AChE, BChE, and NMDA. In this context, a combination of two or more drugs could inspire an attractive therapeutic strategy.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Galantamina/farmacologia , Genisteína/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Humanos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/farmacologia
10.
J Mol Model ; 24(9): 225, 2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30088101

RESUMO

Receptor-interacting protein kinase 2 (RIPK2) plays an essential role in autoimmune response and is suggested as a target for inflammatory diseases. A pharmacophore model was built from a dataset with ponatinib (template) and 18 RIPK2 inhibitors selected from BindingDB database. The pharmacophore model validation was performed by multiple linear regression (MLR). The statistical quality of the model was evaluated by the correlation coefficient (R), squared correlation coefficient (R2), explanatory variance (adjusted R2), standard error of estimate (SEE), and variance ratio (F). The best pharmacophore model has one aromatic group (LEU24 residue interaction) and two hydrogen bonding acceptor groups (MET98 and TYR97 residues interaction), having a score of 24.739 with 14 aligned inhibitors, which were used in virtual screening via ZincPharmer server and the ZINC database (selected in function of the RMSD value). We determined theoretical values of biological activity (logRA) by MLR, pharmacokinetic and toxicology properties, and made molecular docking studies comparing binding affinity (kcal/mol) results with the most active compound of the study (ponatinib) and WEHI-345. Nine compounds from the ZINC database show satisfactory results, yielding among those selected, the compound ZINC01540228, as the most promising RIPK2 inhibitor. After binding free energy calculations, the following molecular dynamics simulations showed that the receptor protein's backbone remained stable after the introduction of ligands.


Assuntos
Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteína Serina-Treonina Quinase 2 de Interação com Receptor , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inflamação/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/antagonistas & inibidores , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/química , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo
11.
Front Immunol ; 9: 964, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867946

RESUMO

The function of medullary thymic epithelial cells (mTECs) is associated with thymocyte adhesion, which is crucial for the negative selection of autoreactive thymocytes in the thymus. This process represents the root of central tolerance of self-components and prevents the onset of autoimmune diseases. Since thymic epithelia correspond to an important target of donor T cells during the onset of chronic graft-vs-host-disease, mTEC-thymocyte adhesion may have implications for alloimmunity. The Aire and Fezf2 genes function as transcriptome controllers in mTECs. The central question of this study is whether there is a mutual relationship between mTEC-thymocyte adhesion and the control of the mTEC transcriptome and whether Aire is involved in this process. Here, we show that in vitro mTEC-thymocyte adhesion causes transcriptome changes in mTECs and upregulates the transcriptional expression of Aire and Fezf2, as well as cell adhesion-related genes such as Cd80 or Tcf7, among others. Crispr-Cas9-mediated Aire gene disruption demonstrated that this gene plays a role in the process of mTEC-thymocyte adhesion. Consistent with the nuclear localization signal (NLS) encoded by Aire exon 3, which was targeted, we demonstrate that Aire KO-/- mTECs impair AIRE protein localization in the nucleus. Consequently, the loss of function of Aire reduced the ability of these cells to adhere to thymocytes. Their transcriptomes differed from their wild-type Aire+/+ counterparts, even during thymocyte adhesion. A set of mRNA isoforms that encode proteins involved in cell adhesion were also modulated during this process. This demonstrates that both thymocyte interactions and Aire influence transcriptome profiling of mTEC cells.


Assuntos
Células Epiteliais/metabolismo , Timócitos/metabolismo , Timo/citologia , Fatores de Transcrição/genética , Transcriptoma , Animais , Adesão Celular , Diferenciação Celular/imunologia , Células Epiteliais/imunologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Timócitos/imunologia , Timo/imunologia , Ativação Transcricional
12.
J Ethnopharmacol ; 222: 107-120, 2018 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-29723629

RESUMO

ETHNOBOTANICAL RELEVANCE: The oil obtained from the fruits of Pterodon emarginatus Vog. (OPe) is used orally and topically, in traditional medicine for some purposes, such as acute and chronic inflammatory states as rheumatoid arthritis. MATERIALS AND METHODS: In this work, the anti-inflammatory activity of the OPe was demonstrated based on several animal models and presented an in silico study based on the 6α,7ß-dihydroxy-vouacapan-17ß-oic acid (DHVA) majority compound of the OPe to evaluate the interaction this compound, with cyclooxygenase-2 (COX-2) in 4COX (Mus musculus) and 5KIR (Homo sapiens) and molecular dynamics simulation. RESULTS: The OPe (498 mg/kg, p.o) significantly inhibited (p < 0.05, Student t-test) the primary and secondary reactions of arthritis by Freund's Complete Adjuvant (FCA) and in dermatitis induced by croton oil in mice, OPe inhibited peak of edema. In vascular permeability test in rats, the treatment with OPe was able to block the response to PGE2, serotonin, and bradykinin (p < 0.05, Student t-test). In the writhing test in mice, the OPe at doses of 498 and 980 mg/kg (p.o) produced inhibition of 73% and 92%, respectively, and was not significantly effective in the hot plate test. In the evaluation of the potency in relation to gastric injury (gastric ulcer induced by stress) and combined assay in the assessment of anti-inflammatory potency and gastric damage, it was observed that indomethacin (10 mg/kg, p.o.) inhibited carrageenan edema by 51% and produced a higher number of gastric lesions when compared to the group treated with OPe, where only areas of hyperemia were observed, without the occurrence of ulcerative lesion, and which inhibited the edema by 47%. In the in silico study, it was found that the DHVA is capable of binding to two organisms (4COX - Mus musculus and 5KIR - Homo sapiens), however, with higher binding affinity to the organism Homo sapiens. CONCLUSIONS: As expected, all tested ligands were capable of forming hydrogen interactions with residues at their respective binding sites, but the DHVA ligand was capable of creating slightly more hydrogen bonds when docked to either 4COX or 5KIR than the other tested ligands, thus demonstrating the participation of this compound in the anti-inflammatory and antialgic responses observed in the in vivo assays as a COX-2 inhibitor. Therefore, the results obtained support the traditional use of OPe for inflammatory and gastric problems.


Assuntos
Anti-Inflamatórios , Diterpenos , Fabaceae , Óleos Vegetais , Ácido Acético , Animais , Anti-Inflamatórios/análise , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Óleo de Cróton , Ciclo-Oxigenase 2/metabolismo , Dermatite de Contato/tratamento farmacológico , Diterpenos/análise , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Frutas , Humanos , Indometacina , Masculino , Camundongos , Simulação de Acoplamento Molecular , Dor/induzido quimicamente , Dor/tratamento farmacológico , Fitoterapia , Óleos Vegetais/análise , Óleos Vegetais/farmacologia , Óleos Vegetais/uso terapêutico , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico
13.
Int J Mol Sci ; 19(1)2018 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-29315236

RESUMO

Intrinsic disorder is very important in the biological function of several proteins, and is directly linked to their foldability during interaction with their targets. There is a close relationship between the intrinsically disordered proteins and the process of carcinogenesis involving viral pathogens. Among these pathogens, we have highlighted the human papillomavirus (HPV) in this study. HPV is currently among the most common sexually transmitted infections, besides being the cause of several types of cancer. HPVs are divided into two groups, called high- and low-risk, based on their oncogenic potential. The high-risk HPV E6 protein has been the target of much research, in seeking treatments against HPV, due to its direct involvement in the process of cell cycle control. To understand the role of intrinsic disorder of the viral proteins in the oncogenic potential of different HPV types, the structural characteristics of intrinsically disordered regions of high and low-risk HPV E6 proteins were analyzed. In silico analyses of primary sequences, prediction of tertiary structures, and analyses of molecular dynamics allowed the observation of the behavior of such disordered regions in these proteins, thereby proving a direct relationship of structural variation with the degree of oncogenicity of HPVs. The results obtained may contribute to the development of new therapies, targeting the E6 oncoprotein, for the treatment of HPV-associated diseases.


Assuntos
Proteínas Intrinsicamente Desordenadas/química , Proteínas Oncogênicas Virais/química , Papillomaviridae/metabolismo , Proteínas de Ligação a DNA/química , Bases de Dados Genéticas , Humanos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular , Estrutura Terciária de Proteína , Proteínas Repressoras/química , Eletricidade Estática
14.
Neurochem Res ; 42(10): 2826-2830, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28497342

RESUMO

Alzheimer's disease (AD) is a progressive condition, where dementia symptoms gradually worsen. Biochemically the disease is characterized by the presence of neuritic plaques, neurofibrillary tangles, in addition to cholinergic dysfunction in the central nervous system. The role of the cholinergic neurotransmission in AD is the basis of the widely accepted cholinergic hypothesis. Some of the most relevant therapies for the treatment of the disease are based on the acetylcholinesterase (AChE) inhibitor activity; however, these therapies are not effective to stop the disease progression, but only can temporarily slow down the worsening of dementia symptoms, and improve quality of life of patients and their caregivers. In recent years, plant alkaloids extracted from Amaryllidaceae family have received great attention due to the well-known anti cholinergic activity. In this context, the purpose of this study was to apply the docking molecular in sílico analysis aiming to examine the recombinant human AChE enzyme (rhAChE) inhibitory activity displayed by different alkaloids from Amaryllidaceae family. Overall, the present results support the idea that alkaloids reported in this research are capable of interacting with rhAChE-binding sites.


Assuntos
Acetilcolinesterase/metabolismo , Sítios de Ligação , Inibidores da Colinesterase/química , Simulação por Computador , Simulação de Acoplamento Molecular , Acetilcolinesterase/química , Alcaloides/farmacologia , Doença de Alzheimer/tratamento farmacológico , Amaryllidaceae/química , Sistema Nervoso Central/metabolismo , Inibidores da Colinesterase/farmacologia , Humanos , Simulação de Acoplamento Molecular/métodos , Ligação Proteica
15.
J. health inform ; 7(4)out.-dez. 2015. ilus
Artigo em Português | LILACS | ID: lil-768582

RESUMO

Objective: To develop a web-based system to store, recover, compare, and associate information obtained using high-throughput molecular genetic techniques regarding differentially expressed genes in patients with endometriosis. Methods: A web-based tool was developed using the Java programming and XHTML markup languages. Professionals and researchers in the contributed to the database by uploading research data from scientific articles in which screening techniques had been performed to determine differential gene expression in women with and without endometriosis. Results: a web-based system with the main functionalities of article registration and gene searching was developed. These functions allow the user to identify coincidences between the results reported in the registered articles regarding differential gene expression. Conclusion: The developed tool allows for the collection of principal data regarding dysregulated gene expression in endometriosis and highlights candidate genes for future studies to better understand the etiopathogenesis of this disease.


Objetivo: O presente trabalho apresenta o primeiro sistema em ambiente web capaz de armazenar, recuperar,comparar e relacionar informações sobre expressão gênica em larga escala em pacientes com endometriose. Métodos:A ferramenta foi desenvolvida em ambiente web utilizando-se a linguagem de programação Java e a linguagem demarcação XHTML. O banco de dados foi alimentado por profissionais e pesquisadores da área, utilizando dados de pesquisas relatadas em artigos científicos, nas quais foram realizadas técnicas de screening para expressão gênica diferencial em pacientes com e sem endometriose. Resultados: Entre as principais funcionalidades do sistema destacam-se o cadastro de artigos e busca de genes. Tais funções permitem que o usuário identifique coincidências entre os resultados de expressão gênica registrados nos artigos cadastrados no sistema. Conclusão: A ferramenta desenvolvida permite reunir os principais dados referentes às alterações de expressão gênica na endometriose,contribuindo para uma melhor compreensão da origem da doença.


Objetivo: En este trabajo se presenta el primer sistema capaz de almacenar, recuperar, comparar y relacionar en web, informaciones sobre expresión génica en gran escala en pacientes con endometriosis. Métodos: La herramienta se ha desarrollado en web utilizando el lenguaje de programación Java y el lenguaje XHTML. La base de datos fue generada por profesionales e investigadores, con datos de investigaciones publicadas en artículos científicos, en donde se efectuaron las técnicas para la detección de expresión diferencial de genes en pacientes con presencia y ausencia de endometriosis. Resultados: Entre las principales características del sistema se incluyen registros de artículos y búsqueda de genes. Estas funciones permiten que el usuario identifique similitudes entre los resultados de expresión de genes grabados en los artículos registrados en el sistema. Conclusión: Esta herramienta ha permitido reunir datos de variaciones de expresión génica en la endometriosis, lo que contribuye a una mejor comprensión del origen de esta enfermedad.


Assuntos
Humanos , Biologia Computacional , Endometriose , Expressão Gênica , Sistemas de Informação
17.
Transfusion ; 54(10): 2468-76, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24724911

RESUMO

BACKGROUND: The Diego blood group presents a major polymorphic site at Residue 854, causing a proline (Di(b) antigen) to leucine (Di(a) antigen) substitution. Di(a) alloimmunization has been observed among Asian and Native South American populations. Considering that Brazilians represent a genetically diverse population, and considering that we have observed a high incidence of Di(a) alloimmunization, we typed HLA-DRB1 alleles in these patients and performed in silico studies to investigate the possible associated mechanisms. STUDY DESIGN AND METHODS: We studied 212 alloimmunized patients, of whom 24 presented immunoglobulin G anti-Di(a) , 15 received Di(a+) red blood cells and were not immunized, and 1008 were healthy donors. HLA typing was performed using commercial kits. In silico analyses were performed using the TEPITOPEpan software to identify Diego-derived anchor peptide binding to HLA-DRB1 molecules. Residue alignment was performed using the IMGT/HLA for amino acid identity and homology analyses. RESULTS: HLA-DRB1*07:01 allele was overrepresented in Di(a) -alloimmunized patients compared to nonimmunized patients and to healthy donors. Two motifs were predicted to be potential epitopes for Di(a) alloimmunization, the WVVKSTLAS motif was predicted to bind several HLA-DR molecules, and the FVLILTVPL motif exhibited highest affinity for the HLA-DRB1*07:01 molecule. Pocket 4 of the DRB1*07:01 molecule contained specific residues not found in other HLA-DRB1 molecules, particularly those at Positions 13(Y), 74(Q), and 78(V). CONCLUSION: Individuals carrying the HLA-DRB1*07:01 allele present an increased risk for Di(a) alloimmunization. The identification of susceptible individuals and the knowledge of potential sensitization peptides are relevant approaches for transfusion care, diagnostic purposes, and desensitization therapies.


Assuntos
Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Isoantígenos/sangue , Isoantígenos/imunologia , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Brasil/epidemiologia , Criança , Eritrócitos/imunologia , Feminino , Humanos , Isoantígenos/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
J Mol Model ; 19(9): 4025-37, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23864166

RESUMO

Cervical cancer affects millions of women worldwide each year. Most cases of cervical cancer are caused by the sexually transmitted human papillomavirus (HPV). The approximately 40 HPV types that infect the cervix are designated high- or low-risk based on their potential to lead to high-grade lesions and cancer. The HPV E7 oncoprotein is directly involved in the onset of cervical cancer and associates with the pRb protein and other cellular targets that promote cell immortalization and carcinogenesis. This is the first description of the modeling and molecular dynamics analysis of complete three-dimensional structures of high-risk (HPV types 16 and 18), low-risk (HPV type 11), and HPV type 01 E7 proteins. The models were constructed by a hybrid approach using homology (MODELLER) and ab initio (Rosetta) modeling, and the protein dynamics were simulated for 50 ns under normal pressure and temperature (NPT) conditions. The intrinsic disorder of the E7 protein sequence was assessed in silico. Complete models of E7 were obtained despite the predicted intrinsic disorder of the N-termini from the high-risk HPV types. The N-terminal domains of all of the E7 proteins studied, even those from high-risk strains, exhibited secondary structure after modeling. Trajectory analysis of E7 proteins from HPV types 16 and 18 showed higher instability in their N-terminal domains than in those of HPV types 11 and 01; however, this variation did not affect the secondary structure during the simulation. ANCHOR analysis indicated that the CR1 and CR2 regions of HPV types 16 and 18 contain possible targets for future drug-discovery studies.


Assuntos
Proteínas Intrinsicamente Desordenadas/química , Modelos Moleculares , Proteínas E7 de Papillomavirus/química , Algoritmos , Sequência de Aminoácidos , Aminoácidos/química , Sítios de Ligação , Proteínas de Ligação a DNA/química , Humanos , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Proteínas Oncogênicas Virais/química , Ligação Proteica , Conformação Proteica , Alinhamento de Sequência
19.
Electron. j. biotechnol ; 14(1): 6-7, Jan. 2011. ilus, tab
Artigo em Inglês | LILACS | ID: lil-591924

RESUMO

Plant-antivenom is a computational Websystem about medicinal plants with anti-venom properties. The system consists of a database of these plants, including scientific publications on this subject and amino acid sequences of active principles from venomous animals. The system relates these data allowing their integration through different search applications. For the development of the system, the first surveys were conducted in scientific literature, allowing the creation of a publication database in a library for reading and user interaction. Then, classes of categories were created, allowing the use of tags and the organization of content. This database on medicinal plants has information such as family, species, isolated compounds, activity, inhibited animal venoms, among others. Provision is made for submission of new information by registered users, by the use of wiki tools. Content submitted is released in accordance to permission rules defined by the system. The database on biological venom protein amino acid sequences was structured from the essential information from National Center for Biotechnology Information (NCBI). Plant-antivenom's interface is simple, contributing to a fast and functional access to the system and the integration of different data registered on it. Plant-antivenom system is available on the Internet at http://gbi.fmrp.usp.br/plantantivenom.


Assuntos
Animais , Antídotos/isolamento & purificação , Antídotos/síntese química , Antídotos/uso terapêutico , Antivenenos/administração & dosagem , Antivenenos/biossíntese , Antivenenos/uso terapêutico , Bases de Dados de Ácidos Nucleicos , Peçonhas/efeitos adversos , Peçonhas/toxicidade , Internet , Extratos Vegetais
20.
Reprod Sci ; 17(11): 1016-23, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20940247

RESUMO

Endometriosis is a gynecologic disease characterized by the presence of endometrial tissue outside the uterine cavity. Although 15% of the female population in reproductive age is affected by endometriosis, its pathogenesis remains unclear. According to the most accepted pathogenesis hypothesis, endometrial fragments from the menstrual phase are transported through the uterine tubes to the peritoneal cavity, where they undergo implantation and growth, invading adjacent tissues. However, the establishment of the disease requires that endometrial cells present molecular characteristics favoring the onset and progression of ectopic implantation. In this investigation, we analyzed the differential gene expression profiles of peritoneal and ovarian endometriotic lesions compared to the endometrial tissue of nonaffected women using rapid subtraction hybridization (RaSH). In our study, this method was applied to samples of endometriotic lesions from affected women and to biopsies of endometrium of healthy women without endometriosis, where we could identify 126 deregulated genes. To evaluate the expression of genes found by RaSH method, we measured LOXL1, HTRA1, and SPARC genes by real-time polymerase chain reaction. Significant different expression was obtained for HTRA1 and LOXL1, upregulated in the ectopic endometrium, suggesting that these genes are involved in the physiopathology of endometriosis and may favor the viability of endometrial cells at ectopic sites.


Assuntos
Aminoácido Oxirredutases/metabolismo , Endometriose/metabolismo , Serina Endopeptidases/metabolismo , Regulação para Cima , Aminoácido Oxirredutases/genética , Endométrio/metabolismo , Feminino , Regulação da Expressão Gênica , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Doenças Ovarianas/metabolismo , Doenças Peritoneais/metabolismo , Serina Endopeptidases/genética
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