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1.
Nat Commun ; 12(1): 654, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510174

RESUMO

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Debilidade Muscular/genética , Sarcopenia/genética , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Estudos de Coortes , Europa (Continente) , Feminino , Fator 5 de Diferenciação de Crescimento/genética , Cadeias alfa de HLA-DQ/genética , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular/genética , Força Muscular/fisiologia , Debilidade Muscular/fisiopatologia , Polimorfismo de Nucleotídeo Único , Sarcopenia/fisiopatologia
2.
Kidney Int ; 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33137338

RESUMO

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

3.
Pain Res Manag ; 2020: 3939757, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32676135

RESUMO

Aim: Orofacial chronic neuropathic pain commonly occurs following trigeminal nerve injuries. We investigated whether swimming exercise can reduce trigeminal neuropathic pain through improving antioxidant capacity. Materials and Methods: Twenty-eight Wistar rats of either sex and 180-220 grams were divided into 4 groups as sham, neuropathy, neuropathy + single bout exercise, and neuropathy + 2 weeks of exercise. Trigeminal neuropathy was carried out through chronic constriction injury (CCI) of infraorbital nerve. Protocols of exercise were included a single bout session (45 minutes) and a 2-week (45 minutes/day/6 days a week) swimming exercise. Mechanical allodynia was detected using Von Frey filaments. The activity of the serum antioxidant enzymes glutathione peroxidase and superoxides dismutase was assayed using ELISA kits. Results: We found that CCI significantly reduced facial pain threshold in both sexes (P < 0.05). Both swimming exercise protocols significantly reduced mechanical allodynia in female rats compared to the sham group; however, only 2 weeks of exercise were significantly effective in male rats. The activity of antioxidant enzyme glutathione peroxidase significantly (P < 0.05) decreased following CCI in female rats against that in the sham group and 2-week exercise significantly (P < 0.05) increased it toward the control level. The levels of glutathione peroxidase in male rats and superoxidase dismutase in both sexes were not significantly different compared to their sham groups. Conclusion: Swimming exercise alleviates trigeminal neuropathic pain in both sexes. Oxidative stress as a possible mechanism was involved in the effect of exercise on female rat trigeminal neuropathy.


Assuntos
Condicionamento Físico Animal/métodos , Caracteres Sexuais , Neuralgia do Trigêmeo , Animais , Modelos Animais de Doenças , Feminino , Hiperalgesia , Masculino , Estresse Oxidativo/fisiologia , Limiar da Dor/fisiologia , Ratos , Ratos Wistar , Neuralgia do Trigêmeo/metabolismo
4.
Nat Commun ; 11(1): 163, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919418

RESUMO

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.


Assuntos
Fibrilação Atrial/genética , Cardiomiopatias/genética , Doença da Artéria Coronariana/genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Função Ventricular Esquerda/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Cardiomiopatias/patologia , Proteínas de Transporte/genética , Estudos de Casos e Controles , Inibidor de Quinase Dependente de Ciclina p21/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Proteínas dos Microfilamentos/genética , Proteínas Musculares/genética , Fatores de Risco
5.
Int J Nanomedicine ; 14: 6901-6915, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564860

RESUMO

Background: Smart materials capable of responding to external stimuli are noteworthy candidates in designing drug delivery systems. In many of the recent research, temperature and pH have been recognized as the main stimulating factors in designing systems for anti-cancer drugs delivery systems. Purpose: In this study, thermo and pH-responsive character of a nano-carrier drug delivery platform based on lysine modified poly (vinylcaprolactam) hydrogel conjugated with doxorubicin was assessed. Methods: Poly (vinylcaprolactam) cross-linked with poly (ethyleneglycol) diacrylate was prepared via RAFT polymerization, and the prepared structure was linked with lysine through ring-opening. The anti-cancer drug doxorubicin, was linked to lysine moiety of the prepared structure via Schiff-base reaction. The prepared platform was characterized by 1HNMR and FT-IR, while molecular weight characterization was performed by size exclusion chromatography. The temperature-responsive activity was evaluated using differential scanning calorimetry and dynamic light scattering. In vitro release pattern in simulated physiologic pH at 37°C was compared with acidic pH attributed to tumor site and elevated temperature. The anticancer efficiency of the drug-conjugated structure was evaluated in breast cancer cell line MCF-7 in 24 and 48 h, and cell uptake assay was performed on the same cell line. Conclusion: According to the results, well-structure defined smart pH and temperature responsive nano-hydrogel was prepared. The enhanced release rates are observed at acidic pH and elevated temperature. We have concluded that the doxorubicin-conjugated nanoparticle results in higher cellular uptakes and more cytotoxicity.


Assuntos
Caprolactama/análogos & derivados , Sistemas de Liberação de Medicamentos , Hidrogéis/química , Lisina/química , Nanopartículas/química , Polímeros/química , Temperatura , Caprolactama/síntese química , Caprolactama/química , Morte Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Hidrogéis/síntese química , Concentração de Íons de Hidrogênio , Células MCF-7 , Peso Molecular , Nanopartículas/ultraestrutura , Transição de Fase , Polímeros/síntese química , Espectroscopia de Prótons por Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier , Testes de Toxicidade
6.
Nat Genet ; 51(10): 1459-1474, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31578528

RESUMO

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.


Assuntos
Doenças Cardiovasculares/sangue , Marcadores Genéticos , Gota/sangue , Doenças Metabólicas/sangue , Polimorfismo de Nucleotídeo Único , Transdução de Sinais , Ácido Úrico/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Estudos de Coortes , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Gota/epidemiologia , Gota/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , Rim/metabolismo , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/genética , Proteínas de Neoplasias/genética , Especificidade de Órgãos
7.
Nat Commun ; 10(1): 4130, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511532

RESUMO

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.


Assuntos
Albuminúria/genética , Mapeamento Cromossômico , Estudo de Associação Genômica Ampla , Metanálise como Assunto , Animais , Creatinina/urina , Diabetes Mellitus/genética , Diabetes Mellitus/urina , Drosophila melanogaster/genética , Regulação da Expressão Gênica , Loci Gênicos , Predisposição Genética para Doença , Humanos , Fenômica , Fatores de Risco
8.
Nat Genet ; 51(6): 957-972, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31152163

RESUMO

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Locos de Características Quantitativas , Característica Quantitativa Herdável , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Humanos , Padrões de Herança , Testes de Função Renal , Fenótipo , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/urina , Uromodulina/urina
9.
Nat Commun ; 9(1): 4228, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30315176

RESUMO

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10-56) and SLC2A9 (p = 4.5 × 10-7). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10-3). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.


Assuntos
Exoma/genética , Ácido Úrico/sangue , Predisposição Genética para Doença , Proteínas Facilitadoras de Transporte de Glucose/química , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Humanos , Testes de Função Renal , Metanálise como Assunto , Transportadores de Ânions Orgânicos/química , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/química , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Estrutura Secundária de Proteína
10.
Nanomedicine ; 13(2): 745-753, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27793790

RESUMO

Mesoporous silica nanoparticles having structure of MCM-41 category with amine and EDTA functional groups in the pores were prepared using a co-condensation reaction. The synthetic steps eventuated in the mesoporous silica nanoparticles with spherical sizes lower than 50nm supposed to have high surface area. The nanoparticles' structure and functionality were characterized by FTIR spectroscopy and CHN analysis and the topography were examined by SEM and TEM and hydrodynamic sizes were demonstrated by DLS. The crystallinity and mesoporous pattern were figured out by XRD technique. Then the efficiency of these materials was tested in vitro and in vivo in adsorbing ferrous sulfate which is a supplement normally prescribed in treating iron deficiency and its overdose is potentially lethal, especially in young children. In vivo experiments illustrated that both nanoparticles could efficiently be administrated as an antidote agent against iron overdose, but EDTA-MSN nanoparticles were superior to NH2-MSN nanoparticles.


Assuntos
Antídotos , Ácido Edético , Ferro/envenenamento , Nanopartículas , Animais , Humanos , Camundongos , Porosidade , Dióxido de Silício
11.
Int J Pharm ; 504(1-2): 110-6, 2016 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-26994523

RESUMO

In this work, novel hydroxyl-modified magnetite nanocarriers are introduced as efficient host for methotrexate conjugation. The modification was based on the Micheal type addition reaction between tris(hydroxymethyl) aminomethane and acrylamidopropyl functionalized, silica-coated magnetite nanoparticle. The chemical structure characterization was carried out by FT-IR and the organic content was determined by CHN analysis. The topography was studied by SEM, TEM, AFM. DLS was performed to show particles' mean diameter. Furthermore, the magnetite properties of modified particles were evaluated by VSM and the crystallinity was proved by XRD. To illustrate the efficiency of the modified particles, the anti-cancer drug methotrexate was conjugated to hydroxyl groups through estric bond formation. The controlled release activity of established nanoparticles was evaluated in simulated cellular fluid. Later, the anti-cancer behavior of drug conjugated nanoparticles was evaluated in vitro in MCF-7 cell line which showed enhanced toxicity after 48 h. Conclusively, the modified nanoparticles have remarked as powerful carrier to be applied as an anti-cancer agent.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Hidróxidos/administração & dosagem , Nanopartículas de Magnetita/administração & dosagem , Metotrexato/administração & dosagem , Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Portadores de Fármacos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Hidróxidos/química , Células MCF-7 , Nanopartículas de Magnetita/química , Metotrexato/química , Dióxido de Silício/administração & dosagem , Dióxido de Silício/química
12.
Artigo em Inglês | MEDLINE | ID: mdl-25280162

RESUMO

Methyl-tert-butyl ether (MTBE) is widely used as an antiknock additive for increasing octane number of gasoline. Recently, the in vivo studies demonstrated that MTBE has genotoxic potential and able to form adducts with DNA. In the work, the interactions of MTBE with calf thymus DNA (ct-DNA) and the Na(+) form of G-quadruplex DNA (wtTel22) were studied by using of head space-solid phase microextraction technique coupled to gas chromatography. The binding equilibrium constants were measured through the equilibriums of a four phase system. In addition, the MTBE Henry's law constants for two different buffers in the temperature range of 283-303K were measured. Thermodynamic studies revealed that the complexation of MTBE to both DNAs is enthalpy favored and entropy disfavored. The thermodynamic results revealed that MTBE may have interaction with ct-DNA via the minor groove of DNA. Also, MTBE may be complexed into the basket of G-quadruplex structure. In addition, the low difference in the binding constants of MTBE for both different DNA targets may confirm that MTBE is poorly selective for different conformations of DNA.


Assuntos
Cromatografia Gasosa/métodos , DNA/metabolismo , Quadruplex G , Éteres Metílicos/metabolismo , Telômero/química , Animais , Bovinos , Dicroísmo Circular , DNA/química , Humanos , Éteres Metílicos/química , Termodinâmica
13.
Toxicol In Vitro ; 27(2): 641-50, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23153512

RESUMO

In this work we proposed a model for in vitro interaction of fenitrothion (FEN) with calf thymus-DNA by combination of multispectroscopic and two dimensional molecular modeling (ONIOM) methods. The circular dichroism results showed that FEN changes the conformation of B-DNA and caused some changes to C-DNA form. The FT-IR results confirmed a partial intercalation between FEN and edges of all base pairs. The competitive fluorescence, using methylene blue as fluorescence probe, in the presence of increasing amounts of FEN, revealed that FEN is able to release the non-intercalated methylene blue from the DNA. The weak chemical shift and peak broadening of (1)H NMR spectrum of FEN in the presence of DNA confirmed a non-intercalation mode. The (31)P NMR showed that FEN interacts more with DNA via its -NO2 moiety. The ONIOM, based on the hybridization of QM/MM (DFT, 6.31++G (d,p)/UFF) methodology, was also performed by Gaussian 2003 package. The results revealed that the interaction is base sequence dependent, and FEN interacts more with AT base sequences.


Assuntos
DNA/química , Fenitrotion/química , Inseticidas/química , Modelos Químicos , Modelos Moleculares , Dicroísmo Circular , Fluorescência , Espectroscopia de Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier
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