Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 39
Filtrar
1.
Braz. j. biol ; 83: e249125, 2023. tab, graf
Artigo em Inglês | LILACS-Express | MEDLINE, LILACSEXPRESS | ID: biblio-1339338

RESUMO

Abstract COVID-19 is reported as an extremely contagious disease with common symptoms of fever, dry cough, sore throat, and tiredness. The published literature on incidence and gender-wise prevalence of COVID-19 is scarce in Pakistan. Therefore, the present study was designed to compare the distribution, incubation period and mortality rate of COVID-19 among the male and female population of district Attock. The data were collected between 01 April 2020 and 07 December 2020 from the population of district Attock, Pakistan. A total of 22,962 individuals were screened and 843 were found positive for RT-qPCR for SARS-CoV-2. The confirmed positive cases were monitored carefully. Among the positive cases, the incidence of COVID-19 was 61.7% among males and 38.2% among females. The average recovery period of males was 18.89±7.75 days and females were 19±8.40 days from SARS-CoV-2. The overall mortality rate was 8.06%. The death rate of male patients was significantly higher (P<0.05) compared to female patients. Also, the mortality rate was higher (P<0.05) in male patients of 40-60 years of age compared to female patients of the same age group. Moreover, the mortality rate significantly increased (P<0.05) with the increase of age irrespective of gender. In conclusion, the incidence and mortality rate of COVID-19 is higher in males compared to the female population. Moreover, irrespective of gender the mortality rate was significantly lower among patients aged <40 years.


Resumo Covid-19 é relatada como uma doença extremamente contagiosa com sintomas comuns de febre, tosse seca, dor de garganta e cansaço. A literatura publicada sobre incidência e prevalência de Covid-19 com base no gênero é escassa no Paquistão. Portanto, o presente estudo teve como objetivo comparar a distribuição, o período de incubação e a taxa de mortalidade de Covid-19 entre a população masculina e feminina do distrito de Attock. Os dados foram coletados entre 1 de abril de 2020 e 7 de dezembro de 2020 da população do distrito de Attock, Paquistão. Um total de 22.962 indivíduos foi selecionado, e 843 foram considerados positivos para RT-qPCR para SARS-CoV-2. Os casos positivos confirmados foram monitorados cuidadosamente. Entre os casos positivos, a incidência de Covid-19 foi de 61,7% no sexo masculino e 38,2% no feminino. O período médio de recuperação dos homens foi de 18,89 ± 7,75 dias e das mulheres 19 ± 8,40 dias do SARS-CoV-2. A mortalidade geral foi de 8,06%. A taxa de mortalidade de pacientes do sexo masculino foi significativamente maior (P < 0,05) em comparação com pacientes do sexo feminino. Além disso, a taxa de mortalidade foi maior (P < 0,05) em pacientes do sexo masculino com 40-60 anos de idade em comparação com pacientes do sexo feminino da mesma faixa etária. Além disso, a taxa de mortalidade aumentou significativamente (P < 0,05) com o aumento da idade, independentemente do sexo. Em conclusão, a incidência e a taxa de mortalidade de Covid-19 são maiores no sexo masculino em comparação com a população feminina. E também, independentemente do sexo, a taxa de mortalidade foi significativamente menor entre os pacientes com idade < 40 anos.

2.
Braz. j. biol ; 82: e243633, 2022. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1249273

RESUMO

Abstract Snow trout (Schizothorax plagiostomus) is an economically important freshwater fish, mostly found in northern areas of water reservoirs of Pakistan. The current study was conducted in River Swat to analyze the bioaccumulation of heavy metals (Pb, Cr, Ni, and Zn) in tissues of Schizothorax plagiostomus. Tissues were extracted and dissolved in perchloric acid (HClO4) and nitric acid (HNO3) along with hotplate. The heavy metals, zinc (Zn), lead (Pb), chromium (Cr), and Nickel (Ni) were determined using Perkin Elmer 2380 atomic absorption spectrophotometer. Results shows great variation in the content of the metal related to tissue type and sampling sites. A high concentration of bioaccumulation was reported at Charbagh, whereas lowest at Odigram: Charbagh>Landakai>Odigram. In the same way, Cr was the most accumulated heavy metal followed by lead, nickel, and Zinc:


Resumo A truta das neves (Schizothorax plagiostomus) é um peixe de água doce economicamente importante, encontrado principalmente nas áreas ao norte de reservatórios de água do Paquistão. O presente estudo foi realizado em River Swat para analisar a bioacumulação de metais pesados (Pb, Cr, Ni e Zn) em tecidos de Schizothorax plagiostomus. Os tecidos foram extraídos e dissolvidos em ácido perclórico (HClO4) e ácido nítrico (HNO3) com placa de aquecimento. Os metais pesados zinco (Zn), chumbo (Pb), cromo (Cr) e níquel (Ni) foram determinados usando espectrofotômetro de absorção atômica Perkin Elmer 2380. Os resultados mostram grande variação no conteúdo do metal relacionado ao tipo de tecido e locais de amostragem. Uma alta concentração de bioacumulação foi relatada em Charbagh, enquanto a mais baixa, em Odigram: Charbagh > Landakai > Odigram. Da mesma forma, Cr foi o metal pesado mais acumulado, seguido por Pb, Ni e Zn.

3.
Braz J Biol ; 83: e249125, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34669800

RESUMO

COVID-19 is reported as an extremely contagious disease with common symptoms of fever, dry cough, sore throat, and tiredness. The published literature on incidence and gender-wise prevalence of COVID-19 is scarce in Pakistan. Therefore, the present study was designed to compare the distribution, incubation period and mortality rate of COVID-19 among the male and female population of district Attock. The data were collected between 01 April 2020 and 07 December 2020 from the population of district Attock, Pakistan. A total of 22,962 individuals were screened and 843 were found positive for RT-qPCR for SARS-CoV-2. The confirmed positive cases were monitored carefully. Among the positive cases, the incidence of COVID-19 was 61.7% among males and 38.2% among females. The average recovery period of males was 18.89±7.75 days and females were 19±8.40 days from SARS-CoV-2. The overall mortality rate was 8.06%. The death rate of male patients was significantly higher (P<0.05) compared to female patients. Also, the mortality rate was higher (P<0.05) in male patients of 40-60 years of age compared to female patients of the same age group. Moreover, the mortality rate significantly increased (P<0.05) with the increase of age irrespective of gender. In conclusion, the incidence and mortality rate of COVID-19 is higher in males compared to the female population. Moreover, irrespective of gender the mortality rate was significantly lower among patients aged <40 years.


Assuntos
COVID-19 , Feminino , Humanos , Incidência , Masculino , Paquistão/epidemiologia , Reação em Cadeia da Polimerase em Tempo Real , SARS-CoV-2
4.
Braz J Biol ; 83: e246904, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34706025

RESUMO

Hyperhydricity is a serious physiological disorder and affects In vitro propagation of many plants and as well of Salvia santolinifolia. The donor material to initiate the in vitro culture was the callus taken from the in vitro shoots produced on Murashig and Skoogs (MS) medium at 4.0 mg/l BA. This callus formed numerous hyperhydric shoots on culturing upon the medium of the same composition. The aim was to systematically evaluate the effect of cytokinins (Benzyladnine (BA) and N6-(-2-isopentenyl) adenine (2iP), culture vessels magnitude, medium solidification, source of nitrogen and calcium chloride for the alleviation of hyperhydricity. In the tissue cultures of S. santolinifolia BA and 2iP induced severe hyperhydricity, when other factors i.e. culture vessels magnitude and a suitable concentration of agar, ammonium nitrate (NH4NO3), potassium nitrate (KNO3) & calcium chloride (CaCl2.2H2O) were not optimized. After 30 days' culture, we observed 83.82% hyperhydric shoots at increased level (1.5 mg/l 2iP) and 81.59% at decreased levels (1.0 mg/l 2iP). On the other hand, hyperhydricity percentage at decreased (0.4%) and at increased (0.8%) levels of agar were 72.37% and 39.08%, respectively. MS medium modification with NH4NO3 (412 mg/l), KNO3 (475 mg/l) and CaCl2.2H2O (880 mg/l) was found the best medium to reduced hyperhydricity (23.6%).


Assuntos
Salvia , Meios de Cultura , Brotos de Planta
5.
Braz J Biol ; 82: e243633, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34076166

RESUMO

Snow trout (Schizothorax plagiostomus) is an economically important freshwater fish, mostly found in northern areas of water reservoirs of Pakistan. The current study was conducted in River Swat to analyze the bioaccumulation of heavy metals (Pb, Cr, Ni, and Zn) in tissues of Schizothorax plagiostomus. Tissues were extracted and dissolved in perchloric acid (HClO4) and nitric acid (HNO3) along with hotplate. The heavy metals, zinc (Zn), lead (Pb), chromium (Cr), and Nickel (Ni) were determined using Perkin Elmer 2380 atomic absorption spectrophotometer. Results shows great variation in the content of the metal related to tissue type and sampling sites. A high concentration of bioaccumulation was reported at Charbagh, whereas lowest at Odigram: Charbagh>Landakai>Odigram. In the same way, Cr was the most accumulated heavy metal followed by lead, nickel, and Zinc.


Assuntos
Cyprinidae , Metais Pesados , Poluentes Químicos da Água , Animais , Bioacumulação , Monitoramento Ambiental , Metais Pesados/análise , Paquistão , Rios , Poluentes Químicos da Água/análise
6.
J Transl Med ; 19(1): 16, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407615

RESUMO

BACKGROUND: Cutaneous wounds in patients with diabetes exhibit impaired healing due to physiological impediments and conventional care options are severely limited. Multipotent stromal cells (MSCs) have been touted as a powerful new therapy for diabetic tissue repair owing to their trophic activity and low immunogenicity. However, variations in sources and access are limiting factors for broader adaptation and study of MSC-based therapies. Amniotic fluid presents a relatively unexplored source of MSCs and one with wide availability. Here, we investigate the potential of amniotic fluid-derived multipotent stromal cells (AFMSCs) to restore molecular integrity to diabetic wounds, amend pathology and promote wound healing. METHOD: We obtained third trimester amniotic fluid from term cesarean delivery and isolated and expanded MSCs in vitro. We then generated 10 mm wounds in Leprdb/db diabetic mouse skin, and splinted them open to allow for humanized wound modeling. Immediately after wounding, we applied AFMSCs topically to the sites of injuries on diabetic mice, while media application only, defined as vehicle, served as controls. Post-treatment, we compared healing time and molecular and cellular events of AFMSC-treated, vehicle-treated, untreated diabetic, and non-diabetic wounds. A priori statistical analyses measures determined significance of the data. RESULT: Average time to wound closure was approximately 19 days in AFMSC-treated diabetic wounds. This was significantly lower than the vehicle-treated diabetic wounds, which required on average 27.5 days to heal (p < 0.01), and most similar to time of closure in wild type untreated wounds (an average of around 18 days). In addition, AFMSC treatment induced changes in the profiles of macrophage polarizing cytokines, resulting in a change in macrophage composition in the diabetic wound bed. We found no evidence of AFMSC engraftment or biotherapy induced immune response. CONCLUSION: Treatment of diabetic wounds using amniotic fluid-derived MSCs encourages cutaneous tissue repair through affecting inflammatory cell behavior in the wound site. Since vehicle-treated diabetic wounds did not demonstrate accelerated healing, we determined that AFMSCs were therapeutic through their paracrine activities. Future studies should be aimed towards validating our observations through further examination of the paracrine potential of AFMSCs. In addition, investigations concerning safety and efficacy of this therapy in clinical trials should be pursued.


Assuntos
Líquido Amniótico , Diabetes Mellitus Experimental , Animais , Diabetes Mellitus Experimental/terapia , Feminino , Humanos , Macrófagos , Camundongos , Gravidez , Pele , Células Estromais , Cicatrização
7.
Sci Data ; 7(1): 111, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245972

RESUMO

High-resolution soil moisture (SM) information is essential to many regional applications in hydrological and climate sciences. Many global estimates of surface SM are provided by satellite sensors, but at coarse spatial resolutions (lower than 25 km), which are not suitable for regional hydrologic and agriculture applications. Here we present a 16 years (2000-2015) high-resolution spatially and temporally consistent surface soil moisture reanalysis (ESSMRA) dataset (3 km, daily) over Europe from a land surface data assimilation system. Coarse-resolution satellite derived soil moisture data were assimilated into the community land model (CLM3.5) using an ensemble Kalman filter scheme, producing a 3 km daily soil moisture reanalysis dataset. Validation against 112 in-situ soil moisture observations over Europe shows that ESSMRA captures the daily, inter-annual, intra-seasonal patterns well with RMSE varying from 0.04 to 0.06 m3m-3 and correlation values above 0.5 over 70% of stations. The dataset presented here provides long-term daily surface soil moisture at a high spatiotemporal resolution and will be beneficial for many hydrological applications over regional and continental scales.

8.
Cureus ; 12(2): e6878, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32190441

RESUMO

Diabetic people are at risk of developing acute complications when exposed to stress. Surgery brings a stressful period when the patient is exposed not only to surgical stress but also the effects of medications used during that particular period. The patient's comorbidities can influence the perioperative management of diabetes. Poorly controlled diabetes can complicate the hospital course. The literature was searched through PubMed and the articles of the last 5 years, from 2014 to 2019, were looked into. The studies available as a free text, in the English language and related to humans, were included. Inclusion criteria also included adults with type 2 diabetes undergoing surgery. The perioperative management of diabetes is a challenging one. Apart from the diabetes control; comorbidities, general health, intake, and interaction of medications both anti-diabetic and non-diabetic, type and duration of surgery, are some of the factors that influence the outcome of the surgery. With a variety of options available to manage diabetes currently, it is important to have a good insight into their effects to prevent complications to occur and ensure safe discharge from the hospital. The good control of diabetes is essential in bringing favorable outcomes. The perioperative management of diabetes should be individualized. Oral anti-hyperglycemic medications, other than sulfonylureas and SGLT2 inhibitors, provide a reasonable alternative to insulin and can be continued safely perioperatively depending upon the type of surgery and the patient is expected to resume oral intake soon postoperatively.

9.
Cureus ; 12(2): e7007, 2020 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-32206471

RESUMO

Vitamin K antagonists are being used in the last five decades as an effective anticoagulant. However, for the past few years, new oral anticoagulants (NOACs) have been introduced as newer anticoagulant agents, which are gradually replacing the previously used vitamin K antagonist. Yet, these agents have not fully replaced the use of warfarin and heparin. NOACs have few advantages over the vitamin K antagonist as they act on a specific factor of coagulation cascade rather than inhibiting the whole vitamin K synthesis. In this article, all the data has been searched electronically on PubMed and PRISMA guidelines were not followed. Instead, we used MOOSE statements and the data searched on PubMed was from articles published in the last five years. A total of 12,269 patients were observed;,out of which 64.19% had active cancer and 35.80% was observed as a control group comprised of both male or female participants. Approximately 61.14% were using NOACs, 42.83% were on warfarin, and 2.72% were on low-molecular-weight heparin (LMWH). The NOACs used in different patients were in the following percentages; edoxaban (6.81%), apixaban (5.28%), dabigatran (10.09%), and rivaroxaban (10.02%). The use of NOACs has been increasing day by day but these agents have not completely replaced the warfarin or heparin, because of some demerits associated with the use of warfarin and some conditions where these drugs should be avoided. All NOACs have either hepatic or renal clearance so the hepatic activity and creatinine clearance rate must be monitored before the start of NOACs. The drug interaction between anticancer drugs and NOACs is still not fully reported. The effects of NOACs in AF and VTE are therapeutically effective, but in oncology patients several other co-factors are also involved with the use of NOACs due to which, it is either contraindicated or in some cases dose adjustment is required. However, very little information has been collected and more investigation must be done in this perspective.

10.
Antiviral Res ; 162: 151-162, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30625344

RESUMO

The heat-shock protein 70 (Hsp70) inhibitor, VER-155008 (VER), was explored as a potential antiviral agent for two RNA viruses important to fish aquaculture, viral hemorrhagic septicemia virus (VHSV) and infectious pancreatic necrosis virus (IPNV). Studies were done at a temperature of 14 °C, and with cell lines commonly used to propagate these viruses. These were respectively EPC from fathead minnow for VHSV and CHSE-214 from Chinook salmon embryo for IPNV. Additionally, both viruses were studied with the Atlantic salmon heart endothelial cell line ASHe. For both VHSV and IPNV, 25 µM VER impeded replication. This was evidenced by delays in the development of cytopathic effect (CPE) and the expression of viral proteins, N for VHSV and VP2 for IPNV, and by less production of viral RNA and of viral titre. As VER inhibits the activity of Hsp70 family members, these results suggest that VHSV and IPNV utilize one or more Hsp70s in their life cycles. Yet neither virus induced Hsp70. Surprisingly VER alone induced Hsp70, but whether this induction modulated VER's antiviral effects is unknown. Exploring this apparent paradox in the future should improve the usefulness of VER as an antiviral agent.


Assuntos
Células Endoteliais/efeitos dos fármacos , Peixes/virologia , Proteínas de Choque Térmico HSP70/genética , Nucleosídeos de Purina/farmacologia , Vírus de RNA/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Técnicas de Cultura de Células , Linhagem Celular , Cyprinidae , Células Endoteliais/virologia , Doenças dos Peixes/tratamento farmacológico , Doenças dos Peixes/virologia , Vírus de RNA/fisiologia , RNA Viral , Salmão
11.
Nat Neurosci ; 21(8): 1126-1136, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30038276

RESUMO

Risk variants for schizophrenia affect more than 100 genomic loci, yet cell- and tissue-specific roles underlying disease liability remain poorly characterized. We have generated for two cortical areas implicated in psychosis, the dorsolateral prefrontal cortex and anterior cingulate cortex, 157 reference maps from neuronal, neuron-depleted and bulk tissue chromatin for two histone marks associated with active promoters and enhancers, H3-trimethyl-Lys4 (H3K4me3) and H3-acetyl-Lys27 (H3K27ac). Differences between neuronal and neuron-depleted chromatin states were the major axis of variation in histone modification profiles, followed by substantial variability across subjects and cortical areas. Thousands of significant histone quantitative trait loci were identified in neuronal and neuron-depleted samples. Risk variants for schizophrenia, depressive symptoms and neuroticism were significantly over-represented in neuronal H3K4me3 and H3K27ac landscapes. Our Resource, sponsored by PsychENCODE and CommonMind, highlights the critical role of cell-type-specific signatures at regulatory and disease-associated noncoding sequences in the human frontal lobe.


Assuntos
Epigênese Genética/genética , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Histonas/genética , Esquizofrenia/genética , Esquizofrenia/metabolismo , Doença de Alzheimer/genética , Mapeamento Encefálico , Cromatina/genética , Depressão/genética , Depressão/patologia , Escolaridade , Predisposição Genética para Doença/genética , Variação Genética , Estudo de Associação Genômica Ampla , Giro do Cíngulo/patologia , Humanos , Transtornos Neuróticos/genética , Transtornos Neuróticos/patologia , Córtex Pré-Frontal/patologia , Risco
12.
Prog Mol Biol Transl Sci ; 157: 21-40, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29933951

RESUMO

Chromosomal conformations, including promoter-enhancer loops, provide a critical regulatory layer for the transcriptional machinery. Therefore, schizophrenia, a common psychiatric disorder associated with broad changes in neuronal gene expression in prefrontal cortex and other brain regions implicated in psychosis, could be associated with alterations in higher-order chromatin. Here, we review early studies on spatial genome organization in the schizophrenia postmortem brain and discuss how integrative approaches using cell culture and animal model systems could gain deeper insight into the potential roles of higher-order chromatin for the neurobiology of and novel treatment avenues for common psychiatric disease.


Assuntos
Cromossomos/química , Epigenômica , Conformação de Ácido Nucleico , Esquizofrenia/genética , Animais , Modelos Animais de Doenças , Humanos , Sistema Nervoso/embriologia
13.
J Virol Methods ; 253: 31-37, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29288073

RESUMO

RNAlater is a commonly used transport and storage solution for samples collected for fish health investigations, particularly those potentially involving viruses. However, the infectivity of fish viruses after storage in RNAlater have not been determined. Nevertheless, knowledge of pathogen infectivity of preserved samples is crucial for ensuring safe transport and storage protocols. Therefore, the infectivity of three fish RNA viruses in RNAlater was examined at four temperatures: -80 °C, 4 °C, room temperature (RT, approximately 22 °C) and 37 °C. The viruses were viral hemorrhagic septicemia virus (VHSV), infectious pancreatic necrosis virus (IPNV) and chum salmon reovirus (CSV). Overall, three consistent outcomes were observed. First, all three viruses remained infectious in RNAlater at RT or lower. High log titres of these viruses remained over 30 d of storage in either RNAlater or PBS. Second, RNAlater delayed the thermal inactivation of these viruses when compared to PBS at 37 °C. For VHSV, the titre remained high in RNAlater after one day of incubation at 37 °C, but was inactivated to below threshold in PBS over the same period. For IPNV, the titre remained high in RNAlater after 30 d of incubation at 37 °C, but was inactivated to below threshold in PBS over the same period. For CSV, the titre was slightly higher in RNAlater than PBS at 37 °C over 7 d, and by day 30, only samples stored in RNAlater proved infectious at titres above the detection threshold. Third, RNAlater delayed the inactivation of these viruses when they were stored together with head kidney homogenates. For VHSV, infectious virus was recovered from samples stored at 4 °C in RNAlater by day 7 of incubation, whereas it was inactivated to below threshold in PBS over the same period. For both IPNV and CSV, infectious virus was recovered from samples stored at 37 °C in RNAlater for 7 d, but not so in PBS. In summary, fish viruses can remain infectious and are even temporarily protected from inactivation while in RNAlater. This makes RNAlater a potentially useful solution for the transport of fish viruses. At the same time, precautionary measures must be taken when transporting potentially infectious samples in RNAlater.


Assuntos
Doenças dos Peixes/virologia , Peixes/virologia , Viabilidade Microbiana , Soluções , Manejo de Espécimes , Fenômenos Fisiológicos Virais , Sulfato de Amônio , Animais , Linhagem Celular , Células Cultivadas , Temperatura Alta
14.
Leukemia ; 32(4): 1016-1022, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29249817

RESUMO

Systemic mastocytosis (SM) is a mast cell (MC) neoplasm with complex pathology and a variable clinical course. In aggressive SM (ASM) and MC leukemia (MCL), responses to conventional drugs are poor and the prognosis is dismal. R763 is a multi-kinase inhibitor that blocks the activity of Aurora-kinase-A/B, ABL1, AKT and FLT3. We examined the effects of R763 on proliferation and survival of neoplastic MC. R763 produced dose-dependent inhibition of proliferation in the human MC lines HMC-1.1 (IC50 5-50 nM), HMC-1.2 (IC50 1-10 nM), ROSAKIT WT (IC50 1-10 nM), ROSAKIT D816V (IC50 50-500 nM) and MCPV-1.1 (IC50 100-1000 nM). Moreover, R763 induced growth inhibition in primary neoplastic MC in patients with ASM and MCL. Growth-inhibitory effects of R763 were accompanied by signs of apoptosis and a G2/M cell cycle arrest. R763 also inhibited phosphorylation of KIT, BTK, AKT and STAT5 in neoplastic MC. The most sensitive target appeared to be STAT5. In fact, tyrosine phosphorylation of STAT5 was inhibited by R763 at 10 nM. At this low concentration, R763 produced synergistic growth-inhibitory effects on neoplastic MC when combined with midostaurin or dasatinib. Together, R763 is a novel promising multi-kinase inhibitor that blocks STAT5 activation and thereby overrides drug-resistance in neoplastic MC.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT5/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dasatinibe/farmacologia , Cães , Sinergismo Farmacológico , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Leucemia de Mastócitos/tratamento farmacológico , Leucemia de Mastócitos/metabolismo , Masculino , Mastócitos/metabolismo , Mastocitose Sistêmica/tratamento farmacológico , Mastocitose Sistêmica/metabolismo , Pessoa de Meia-Idade , Norbornanos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Pirimidinas/farmacologia , Estaurosporina/análogos & derivados , Estaurosporina/farmacologia , Adulto Jovem
15.
Am J Med Genet B Neuropsychiatr Genet ; 174(6): 631-640, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28699694

RESUMO

Large-scale consortia including the Psychiatric Genomics Consortium, the Common Minds Consortium, BrainSeq and PsychENCODE, and many other studies taken together provide increasingly detailed insights into the genetic and epigenetic risk architectures of schizophrenia (SCZ) and offer vast amounts of molecular information, but with largely unexplored therapeutic potential. Here we discuss how epigenomic studies in human brain could guide animal work to test the impact of disease-associated alterations in chromatin structure and function on cognition and behavior. For example, transcription factors such as MYOCYTE-SPECIFIC ENHANCER FACTOR 2C (MEF2C), or multiple regulators of the open chromatin mark, methyl-histone H3-lysine 4, are associated with the genetic risk architectures of common psychiatric disease and alterations in chromatin structure and function in diseased brain tissue. Importantly, these molecules also affect cognition and behavior in genetically engineered mice, including virus-mediated expression changes in prefrontal cortex (PFC) and other key nodes in the circuitry underlying psychosis. Therefore, preclinical and small laboratory animal work could target genomic sequences affected by chromatin alterations in SCZ. To this end, in vivo editing of enhancer and other regulatory non-coding DNA by RNA-guided nucleases including CRISPR-Cas, and designer transcription factors, could be expected to deliver pipelines for novel therapeutic approaches aimed at improving cognitive dysfunction and other core symptoms of SCZ.


Assuntos
Epigenômica , Esquizofrenia/genética , Animais , Camundongos
16.
Nat Genet ; 49(8): 1239-1250, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28671686

RESUMO

We report locus-specific disintegration of megabase-scale chromosomal conformations in brain after neuronal ablation of Setdb1 (also known as Kmt1e; encodes a histone H3 lysine 9 methyltransferase), including a large topologically associated 1.2-Mb domain conserved in humans and mice that encompasses >70 genes at the clustered protocadherin locus (hereafter referred to as cPcdh). The cPcdh topologically associated domain (TADcPcdh) in neurons from mutant mice showed abnormal accumulation of the transcriptional regulator and three-dimensional (3D) genome organizer CTCF at cryptic binding sites, in conjunction with DNA cytosine hypomethylation, histone hyperacetylation and upregulated expression. Genes encoding stochastically expressed protocadherins were transcribed by increased numbers of cortical neurons, indicating relaxation of single-cell constraint. SETDB1-dependent loop formations bypassed 0.2-1 Mb of linear genome and radiated from the TADcPcdh fringes toward cis-regulatory sequences within the cPcdh locus, counterbalanced shorter-range facilitative promoter-enhancer contacts and carried loop-bound polymorphisms that were associated with genetic risk for schizophrenia. We show that the SETDB1 repressor complex, which involves multiple KRAB zinc finger proteins, shields neuronal genomes from excess CTCF binding and is critically required for structural maintenance of TADcPcdh.


Assuntos
Cromatina/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Neurônios/metabolismo , Animais , Fator de Ligação a CCCTC , Caderinas/genética , Linhagem Celular , Metilação de DNA , Epigênese Genética , Feminino , Regulação da Expressão Gênica , Histona-Lisina N-Metiltransferase/genética , Humanos , Masculino , Camundongos , Mutação , Conformação de Ácido Nucleico , Ligação Proteica , Domínios Proteicos , Proteínas Repressoras/metabolismo
17.
Clin Sci (Lond) ; 131(15): 1941-1953, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28620011

RESUMO

DNA damage is an important contributor to endothelial dysfunction and age-related vascular disease. Recently, we demonstrated in a DNA repair-deficient, prematurely aging mouse model (Ercc1Δ/- mice) that dietary restriction (DR) strongly increases life- and health span, including ameliorating endothelial dysfunction, by preserving genomic integrity. In this mouse mutant displaying prominent accelerated, age-dependent endothelial dysfunction we investigated the signaling pathways involved in improved endothelium-mediated vasodilation by DR, and explore the potential role of the renin-angiotensin system (RAS). Ercc1Δ/- mice showed increased blood pressure and decreased aortic relaxations to acetylcholine (ACh) in organ bath experiments. Nitric oxide (NO) signaling and phospho-Ser1177-eNOS were compromised in Ercc1Δ/- DR improved relaxations by increasing prostaglandin-mediated responses. Increase of cyclo-oxygenase 2 and decrease of phosphodiesterase 4B were identified as potential mechanisms. DR also prevented loss of NO signaling in vascular smooth muscle cells and normalized angiotensin II (Ang II) vasoconstrictions, which were increased in Ercc1Δ/- mice. Ercc1Δ/- mutants showed a loss of Ang II type 2 receptor-mediated counter-regulation of Ang II type 1 receptor-induced vasoconstrictions. Chronic losartan treatment effectively decreased blood pressure, but did not improve endothelium-dependent relaxations. This result might relate to the aging-associated loss of treatment efficacy of RAS blockade with respect to endothelial function improvement. In summary, DR effectively prevents endothelium-dependent vasodilator dysfunction by augmenting prostaglandin-mediated responses, whereas chronic Ang II type 1 receptor blockade is ineffective.


Assuntos
Envelhecimento/metabolismo , Dano ao DNA , Receptor Tipo 1 de Angiotensina/metabolismo , Doenças Vasculares/dietoterapia , Envelhecimento/genética , Angiotensina II/metabolismo , Animais , Pressão Sanguínea , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dieta , Endonucleases/genética , Endonucleases/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Óxido Nítrico/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Doenças Vasculares/genética , Doenças Vasculares/metabolismo , Doenças Vasculares/fisiopatologia , Vasodilatação
18.
Environ Res ; 156: 697-704, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28477580

RESUMO

PURPOSE: To evaluate potential damages of chronic environmentally relevant low-dose/dose-rate high-LET irradiation from a naturally occurring alpha-emitting radionuclide (radium-226, 226Ra) on a human colorectal carcinoma HCT116 p53+/+ cell line. METHODS: Clonogenic survival assays and mitochondrial membrane potential (MMP) measurement with a sensitive fluorescent MMP probe JC-1 were performed in HCT116 p53+/+ cells chronically exposure to low doses/dose rates of 226Ra with high-LET. Comparisons were made with the human non-transformed keratinocyte HaCaT cell line and acute low-dose direct low-LET gamma radiation. RESULTS AND CONCLUSION: The chronic low-dose/dose-rate alpha radiation (CLD/DRAR) did not reduce the clonogenic survival of HCT116 p53+/+ cells over the period of 70 days of exposure. Only one significant reduction in the HCT116 p53+/+ cells' clonogenic survival was when cells were grown with 10,000mBq/mL 226Ra for 40 days and progeny cells were clonogenically assessed in the presence of 10,000mBq/mL 226Ra. The cumulative doses that cells received during this period ranged from 0.05 to 46.2mGy. The mitochondrial membrane potential (MMP) dropped initially in both HCT116 p53+/+ and HaCaT cells in response to CLD/DRAR. The MMP in HCT116 p53+/+ cells recovered more quickly at all dose points than and that in HaCaT cells until the end of the exposure period. The highest dose rate of 0.66mGy/day depolarized the HaCaT's mitochondria more consistently during the exposure period. The faster recovery status of the MMP in HCT116 p53+/+ cells than that in HaCaT cells was also observed after exposure to acute low-dose gamma rays. Overall, it was found that CLD/DRAR had little impact on the MMP of human colorectal cancer and keratinocyte cell lines.


Assuntos
Rádio (Elemento)/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos da radiação , Neoplasias Colorretais , Raios gama/efeitos adversos , Células HCT116 , Humanos , Queratinócitos/efeitos da radiação , Potencial da Membrana Mitocondrial/efeitos da radiação
19.
Hypertension ; 69(6): 1136-1144, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28396529

RESUMO

Because of the presence of the blood-brain barrier, brain renin-angiotensin system activity should depend on local (pro)renin synthesis. Indeed, an intracellular form of renin has been described in the brain, but whether it displays angiotensin (Ang) I-generating activity (AGA) is unknown. Here, we quantified brain (pro)renin, before and after buffer perfusion of the brain, in wild-type mice, renin knockout mice, deoxycorticosterone acetate salt-treated mice, and Ang II-infused mice. Brain regions were homogenized and incubated with excess angiotensinogen to detect AGA, before and after prorenin activation, using a renin inhibitor to correct for nonrenin-mediated AGA. Renin-dependent AGA was readily detectable in brain regions, the highest AGA being present in brain stem (>thalamus=cerebellum=striatum=midbrain>hippocampus=cortex). Brain AGA increased marginally after prorenin activation, suggesting that brain prorenin is low. Buffer perfusion reduced AGA in all brain areas by >60%. Plasma renin (per mL) was 40× to 800× higher than brain renin (per gram). Renin was undetectable in plasma and brain of renin knockout mice. Deoxycorticosterone acetate salt and Ang II suppressed plasma renin and brain renin in parallel, without upregulating brain prorenin. Finally, Ang I was undetectable in brains of spontaneously hypertensive rats, while their brain/plasma Ang II concentration ratio decreased by 80% after Ang II type 1 receptor blockade. In conclusion, brain renin levels (per gram) correspond with the amount of renin present in 1 to 20 µL of plasma. Brain renin disappears after buffer perfusion and varies in association with plasma renin. This indicates that brain renin represents trapped plasma renin. Brain Ang II represents Ang II taken up from blood rather than locally synthesized Ang II.


Assuntos
Amidas/farmacologia , Angiotensina II/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/metabolismo , Fumaratos/farmacologia , Hipertensão/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensinogênio/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Acetato de Desoxicorticosterona/farmacologia , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Valores de Referência
20.
Environ Res ; 156: 297-305, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28376375

RESUMO

PURPOSE: The clonogenic property and radiobiological responses of a fish brain endothelial cell line, eelB, derived from the American eel were studied. METHODS: Clonogenic assays were performed to determine the plating efficiency of the eelB cells and to evaluate the clonogenic survival fractions after direct irradiation to low-dose low-LET gamma radiation or receiving irradiated cell conditioned medium in the bystander effect experiments. RESULT: eelB had the second highest plating efficiency ever reported to date for fish cell lines. Large eelB macroscopic colonies could be formed in a short period of time and were easy to identify and count. Unlike with other fish clonogenic cell lines, which had a relatively slow proliferation profile, clonogenic assays with the eelB cells could be completed as early as 12 days in culture. After direct irradiation with gamma rays at low doses ranging from 0.1Gy to 5Gy, the dose-clonogenic survival curve of the eelB cell line showed a linear trend and did not develop a shoulder region. A classical radio-adaptive response was not induced with the clonogenic survival endpoint when the priming dose (0.1 or 0.5Gy) was delivered 6h before the challenge dose (3 or 5Gy). However, a radio-adaptive response was observed in progeny cells that survived 5Gy and developed lethal mutations. eelB appeared to lack the ability to produce damaging radiation-induced bystander signals on both eelB and HaCaT recipient cells. CONCLUSION: eelB cell line could be a very useful cell model in the study of radiation impacts on the aquatic health.


Assuntos
Anguilla , Encéfalo/efeitos da radiação , Células Endoteliais/efeitos da radiação , Raios gama/efeitos adversos , Animais , Efeito Espectador , Linhagem Celular , Relação Dose-Resposta à Radiação , Instabilidade Genômica/efeitos da radiação , Mutação/efeitos da radiação
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...