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1.
Chemosphere ; 240: 124898, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31557644

RESUMO

Urinary polycyclic aromatic hydrocarbon (PAH) metabolites, biomarkers of internal PAH exposure, are commonly used to explore the effects of PAH on human health. However, the correlation between environmental PAH exposure and the species or levels of urinary PAH metabolites remains unclear. We collected detailed information on PAH exposure sources, including cigarette smoking, cooking, traffic and diet habits via structured questionnaires, and determined 12 urinary monohydroxylated PAH metabolites (OH-PAHs) among 4092 participants from the Wuhan-Zhuhai cohort. Linear mixed models and generalized linear models were conducted to explore the associations of urinary metabolite levels with single or multiple PAH exposure sources. We also calculated the standardized regression coefficients to further compare the contributions of different sources to urinary OH-PAH levels. Our results showed that increasing levels of urinary 1-, 2-hydroxynaphthalene (1-, 2- OHNa) and 2-hydroxyfluorene (2-OHFlu) were significantly correlated with tobacco smoking (all P < 0.01). The concentrations of 1-, 2- OHNa and 9-hydroxyfluorene (9-OHFlu) were positively correlated with dietary intake (all P < 0.05). Individuals who spent a long time in traffic showed elevated levels of 9-OHFlu and 1-hydroxyphenanthrene (1-OHPh) compared with individuals who spent a short time in traffic (all P < 0.05). Self-cooking was associated only with elevated 1-hydroxypyrene (1-OHP) levels. Moreover, good kitchen ventilation resulted in significantly decreased urinary low-molecular-weight OH-PAH levels. These findings suggested that cigarette smoking, self-cooking, high dietary PAH intake and a long time spent in traffic were associated with increased levels of specific urinary PAH metabolites, and good kitchen ventilation effectively reduced the exposure to low-molecular-weight PAHs in self-cooking participants.


Assuntos
Exposição Ambiental/análise , Poluentes Ambientais/urina , Hidrocarbonetos Policíclicos Aromáticos/urina , Adulto , Biomarcadores/urina , China , Estudos de Coortes , Estudos Transversais , Exposição Ambiental/estatística & dados numéricos , Feminino , Fluorenos , Humanos , Estilo de Vida , Modelos Lineares , Pulmão/metabolismo , Masculino , Naftóis , Fenantrenos
2.
Mol Oncol ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31782885

RESUMO

Identification of new genetic pathways or molecular targets that sensitize cancer cells to chemotherapeutic drugs may improve the efficacy of current chemotherapy. Here, we report that downmodulation of UHRF1 (ubiquitin-like with PHD and RING finger domains 1) in retinoblastoma (RB) cells increases the sensitivity to histone deacetylase (HDAC) inhibitors, augmenting apoptotic cell death. We found that UHRF1 depletion downregulates two redox-responsive genes GSTA4 (glutathione S-transferase α4) and TXN2 (thioredoxin-2) in RB cells, and increases the basal level of intracellular oxidative stress. Antioxidant treatment significantly reduced both basal and HDAC inhibitor-induced DNA damage and apoptosis in UHRF1-depleted cells. Knockdown of GSTA4 or TXN2 sensitized RB cells to HDAC inhibitors, demonstrating that GSTA4 and TXN2 play key roles in redox homeostasis in RB cells and the susceptibility to HDAC inhibitor treatment upon UHRF1 depletion. In human primary RB, GSTA4 and TXN2 proteins were found to be mostly elevated along with high UHRF1 expression. In addition to augmentation of apoptosis in UHRF1-depleted RB cells, we also show that UHRF1 downmodulation derepresses the expression of photoreceptor-specific genes in RB cells in cooperation with a HDAC inhibitor MS-275 and promotes neuron-like differentiation. However, further investigation revealed that the enhanced growth-inhibitory effects of MS-275 in UHRF1-depleted cells were still mainly due to robust apoptosis induction rather than differentiation-mediated growth arrest. Consistent with our findings, UHRF1 depletion in RB cells increased the therapeutic efficacy of MS-275 in murine orthotopic xenografts. These results provide a novel basis for potential benefits of UHRF1 targeting for RB treatment.

3.
Artif Cells Nanomed Biotechnol ; 47(1): 3671-3676, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31496296

RESUMO

Accumulating studies showed that microRNAs are maintaining a variety of important biological processes but the underlying mechanism in proliferation and tumourigenicity is unclear. In this study we show that miR-342 expression in bone marrow and patients' sera of childhood acute myeloid leukemia (AML) was both significantly higher than those in the corresponding normal controls. Functional assays demonstrated that forced expression of miR-342 significantly suppresses AML cell proliferation and G1/S transition of leukemia cells. Mechanistically, bioinformatics prediction and luciferase reporter assay identified N-a-acetyltransferase 10 protein (Naa10p) as a direct molecular target of miR-342, Naa10p siRNA significantly repressed cell proliferation and increased cell apoptosis. In conclusion, our study confirmed that miR-342/Naa10p plays key roles in AML progression, providing insights into underlying mechanisms of AML pathogenesis and also a potential therapeutic target for this malignancy.

4.
J Neuroophthalmol ; 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31246675

RESUMO

PURPOSE: Clinical trials of gene therapy for Leber hereditary optic neuropathy (LHON) were conducted in 9 volunteers with the mitochondrial mutation, G11778A in ND4. The purpose of this study was to investigate whether multilocus mitochondrial mutations directly influence the efficacy of gene therapy for LHON. METHODS: Nine volunteers with LHON participated in a clinical trial with intravitreal injection of an adenoviral vector expressing wild-type ND4. Patients were subsequently divided into 2 groups: according to the differences in therapy efficacy and based on improvements in visual acuity. Full mitochondrial DNA sequences of the 2 groups of patients were generated and compared using PubMed, PolyPhen, and PROVEAN. Furthermore, the association between the detected mutations and clinical effects of gene therapy was analyzed. RESULTS: Best-corrected visual acuity (BCVA) significantly improved (≥0.3 log of minimum angle of resolution [logMAR]) in 7 patients 6 months after gene therapy, whereas there was no significant change in BCVA (<0.3 logMAR) of the remaining 2 patients. All 9 patients carried the G1178A mutation in addition to other nonsynonymous mutations. Among these mutations, some were predicted to be neutral and deleterious. Meanwhile, different mitochondrial mutations in the group in which treatment was ineffective, compared with those in responders, were at nucleotide positions 6569 (CO1; Patient 3), 9641 (CO3; Patient 3), and 4491 (ND2; Patient 5). CONCLUSIONS: Detection of the 3 primary mitochondrial mutations causing LHON is sufficient for screening before gene therapy; sequencing of the entire mitochondrial genome is unnecessary before treatment. Patients with LHON can respond to targeted gene therapy irrespective of additional multilocus mitochondrial mutations.

5.
Occup Med (Lond) ; 69(3): 182-188, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-30923828

RESUMO

BACKGROUND: Shift work is common in many industries. The potential association between shift work and ischaemic heart disease (IHD) remains controversial. AIMS: To conduct a systematic review and meta-analysis of epidemiological evidence and summarize the potential relationship between shift work and IHD. METHODS: We searched all relevant case-control and cohort studies that were published from January 1970 to October 2017 on PubMed, Web of Science and Embase. The random-effects model and the generalized least-squares trend model were, respectively, used to evaluate the pooled relative risk and dose-response relationship between shift work and IHD. Two different authors extracted data and assessed the quality of each study independently. RESULTS: Twenty-one articles with 31 independent results of 19 782 IHD cases in 320 002 participants were included. The pooled relative risk for the association between shift work and risk of IHD was 1.13 (95% CI 1.08-1.20, I2 = 53%, P < 0.001). Further evaluation of dose-response relationship indicated that each 1-year increase in shift work was associated with 0.9% (RR = 1.009; 95% CI 1.006-1.012) increase of the risk of IHD. CONCLUSIONS: This meta-analysis updated the evidence that shift work was associated with the risk of IHD and supported a positive dose-response relationship between the risk of IHD and increasing duration of shift work.

6.
Mol Med Rep ; 19(2): 1016-1023, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30569131

RESUMO

Hepatitis C virus (HCV) infection remains a major public health issue despite the introduction of several direct­acting antiviral agents (DAAs), with some 185 million individuals infected with HCV worldwide. There is an urgent need for an effective prophylactic HCV vaccine. In the present study, we constructed genetic vaccines based on novel recombinant adeno­associated viral (rAAV) vectors (AAV2/8 or AAV2/rh32.33) that express the envelope glycoprotein E2 from the HCV genotype 1b. Expression of HCV E2 protein in 293 cells was confirmed by western blot analysis. rAAV2/8.HCV E2 vaccine or rAAV2/rh32.33.HCV E2 vaccine was intramuscularly injected into C57BL/6 mice. HCV E2­specific antigen was produced, and long­lasting specific antibody responses remained detectable XVI weeks following immunization. In addition, the rAAV2/rh32.33 vaccine induced higher antigen­specific antibody levels than the rAAV2/8 vaccine or AAV plasmid. Moreover, both AAV vaccines induced neutralizing antibodies against HCV genotypes 1a and 1b. Finally, it is worth mentioning that neutralizing antibody levels directed against AAV2/rh32.33 were lower than those against AAV2/8 in both mouse and human serum. These results demonstrate that AAV vectors, especially the AAVrh32.33, have particularly favorable immunogenicity for development into an effective HCV vaccine.


Assuntos
Anticorpos Neutralizantes/biossíntese , Dependovirus/imunologia , Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/biossíntese , Hepatite C Crônica/prevenção & controle , Vacinas de DNA/imunologia , Proteínas do Envelope Viral/imunologia , Vacinas contra Hepatite Viral/imunologia , Adulto , Animais , Anticorpos Neutralizantes/sangue , Dependovirus/genética , Feminino , Vetores Genéticos/química , Vetores Genéticos/imunologia , Células HEK293 , Hepacivirus/genética , Anticorpos Anti-Hepatite C/sangue , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Humanos , Soros Imunes/química , Imunidade Humoral/efeitos dos fármacos , Imunização , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Vacinas de DNA/administração & dosagem , Vacinas de DNA/biossíntese , Vacinas de DNA/genética , Proteínas do Envelope Viral/administração & dosagem , Proteínas do Envelope Viral/biossíntese , Proteínas do Envelope Viral/genética , Vacinas contra Hepatite Viral/administração & dosagem , Vacinas contra Hepatite Viral/biossíntese , Vacinas contra Hepatite Viral/genética
7.
Occup Med (Lond) ; 69(8-9): 637-638, 2019 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-32058575
8.
Plant Physiol Biochem ; 127: 525-536, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29723824

RESUMO

A major constraint in producing lilies is gray mold caused by Botrytis elliptica and B. cinerea. WRKY transcription factors play important roles in plant immune responses. However, limited information is available about the WRKY gene family in lily plants. In this study, 23 LrWRKY genes with complete WRKY domains were identified from the Botrytis-resistant species Lilium regale. The putative WRKY genes were divided into seven subgroups (Group I, IIa-e, and III) according to their structural features. Sequence alignment revealed that LrWRKY proteins have a highly conserved WRKYGQK domain and a variant, the WRKYGKK domain, and these proteins generally contained similar motif compositions throughout the same subgroup. Functional annotation predicted they might be involved in biological processes related to abiotic and biotic stresses. A qRT-PCR analysis confirmed that expression of six LrWRKY genes in L. regale or the susceptible Asian hybrid 'Yale' was induced by B. cinerea infection. Among these genes, LrWRKY4, LrWRKY8 and LrWRKY10 were expressed at a higher level in L. regale than 'Yale', while the expression of LrWRKY6 and LrWRKY12 was lower in L. regale. Furthermore, LrWRKY4 and LrWRKY12 genes, which also respond to salicylic acid (SA) and methyl jasmonate (MeJA) treatments, were isolated from L. regale. Subcellular localization analysis determined that they were targeted to the nucleus. Constitutive expression of LrWRKY4 and LrWRKY12 in Arabidopsis resulted in plants that were more resistant to B. cinerea than wild-type plants. This resistance was coupled with the transcriptional changes of SA and JA-responsive genes. Overall, our study provides valuable information about the structural and functional characterization of LrWRKY genes that will not only deepen our understanding of the molecular mechanisms underlying the defense of lily against B. cinerea but also offer potential targets for cultivar improvement via biotechnology.


Assuntos
Botrytis , Resistência à Doença/fisiologia , Regulação da Expressão Gênica/fisiologia , Lilium/metabolismo , Doenças das Plantas/microbiologia , Proteínas de Plantas/biossíntese , Fatores de Transcrição/biossíntese , Lilium/genética , Lilium/microbiologia , Doenças das Plantas/genética , Proteínas de Plantas/genética , Fatores de Transcrição/genética
9.
J Trauma Acute Care Surg ; 85(1): 122-127, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29538237

RESUMO

BACKGROUND: Penetrating injuries to the extremity proximal to the elbow or knee are anatomic criteria for full trauma team activation (FFTA) by the American College of Surgeon's Committee on Trauma standards. This criterion lacks objective evidence-based support. Overtriage of trauma team activation may result in excessive costs and resource burden at trauma centers. We hypothesized that FFTA for penetrating injuries to the proximal extremities by anatomic criteria alone may lead to significant overtriage. METHODS: A 3-year retrospective review (2013-2015) was completed of all patients evaluated at an urban Level I trauma center with isolated penetrating extremity injuries. Data included the number of full and limited trauma team activations as well as criterion met, Injury Severity Score (ISS), injury, limb characteristics, and disposition. Overtriage was defined as FFTA for an ISS of 15 or less, with a goal rate less than 50%. RESULTS: We identified 6,335 total trauma team activations with 795 isolated penetrating extremity injuries. Of these injuries, 413 (51.9%) were injuries proximal to the joint. Within this subgroup, 71.2% of patients were discharged from the emergency department with a median ISS of 1 and no additional intervention. Only 5.3% of patients that did not meet additional FFTA criteria underwent immediate operative intervention. By comparison, 21% of FFTAs and 5.8% of limited trauma team activations underwent immediate operative intervention during the 3-year period. Of the 413 isolated penetrating proximal-extremity injuries, only one had an ISS of 15 or greater, resulting in a 99.7% overtriage rate. CONCLUSION: Penetrating injuries to the extremities are common in urban trauma centers. Full trauma team activation based on anatomic, rather than physiologic, criteria may lead to a significant overtriage rate. Further distinction in the level of trauma team activation may be made based on hard signs of neurovascular injury. LEVEL OF EVIDENCE: Epidemiological study, level III; Care Management, level IV.


Assuntos
Extremidades/lesões , Sobremedicalização/estatística & dados numéricos , Triagem/estatística & dados numéricos , Ferimentos Penetrantes/diagnóstico , Adulto , Feminino , Humanos , Escala de Gravidade do Ferimento , Masculino , Pessoa de Meia-Idade , Equipe de Assistência ao Paciente/estatística & dados numéricos , Sistema de Registros , Estudos Retrospectivos , Centros de Traumatologia , Adulto Jovem
10.
Cell Death Dis ; 9(2): 164, 2018 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-29415984

RESUMO

UHRF1 (ubiquitin-like with PHD and ring finger domains 1) is highly expressed in various human cancers including retinoblastoma, and associated with tumor-promoting effects such as inhibition of apoptosis and high proliferation. However, the molecular mechanisms underlying tumor-promoting functions of UHRF1 in retinoblastoma still remain elusive. Here, we show that stable knockdown of UHRF1 renders retinoblastoma cells sensitized to conventional chemotherapeutic drugs such as etoposide and camptothecin, resulting in enhanced DNA damage and apoptotic cell death. We found that UHRF1-depleted retinoblastoma cells can recognize DNA damages normally but have markedly low expression of XRCC4 (X-ray repair cross complementing 4) among the components of nonhomologous end-joining (NHEJ) repair complex. Conversely, overexpression of UHRF1 increased the XRCC4 expression and stable knockdown of XRCC4 sensitized retinoblastoma cells to etoposide treatment, suggesting that XRCC4 is a key mediator for the drug sensitivity upon UHRF1 depletion in retinoblastoma cells. Consistent with the findings, chromatin association of DNA ligase IV in response to acute DNA damage was found to be significantly reduced in UHRF1-depleted retinoblastoma cells and functional complementation for XRCC4 in UHRF1-depleted cells attenuated the drug sensitivity, demonstrating that XRCC4 downregulation in UHRF1-depleted cells impaired DNA repair and consequently induced robust apoptosis upon genotoxic drug treatment. In human primary retinoblastoma, high expression of UHRF1 and XRCC4 could be detected, and elevated XRCC4 expression correlated with reduced apoptosis markers, implying that UHRF1-mediated XRCC4 upregulation under pathophysiological conditions triggered by RB1 gene inactivation may confer protection against endogenous DNA damages that arise during retinoblastoma development. Taken together, these results present a new mechanistic insight into how UHRF1 mediates its tumor-promoting functions in retinoblastoma, and also provide a basis for UHRF1 targeting to improve the efficacy of current chemotherapy for retinoblastoma treatment.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas Estimuladoras de Ligação a CCAAT/deficiência , Proteínas de Ligação a DNA/genética , Regulação para Baixo/genética , Retinoblastoma/tratamento farmacológico , Retinoblastoma/genética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Linhagem Celular Tumoral , Dano ao DNA/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Retinoblastoma/patologia
11.
Plant Physiol Biochem ; 123: 392-399, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29304484

RESUMO

Gray mold disease, caused by the fungus Botrytis elliptica, is one of the major diseases affecting Lilium species, and it has become a limiting factor in the production of ornamental lilies. To support selecting and breeding Botrytis-resistant cultivars, a total of 50 Lilium cultivars belonging to seven hybrid types were evaluated using a detached leaf technique for resistance to B. elliptica. Through resistance evaluations, Oriental × Trumpet and Oriental hybrid cultivars were classified as resistant lines, while Asiatic and Trumpet hybrids were classified as susceptible lines. A highly resistant (HR) Oriental hybrid, 'Sorbonne', and a highly susceptible (HS) Asiatic hybrid, 'Tresor', were selected for further study of early host-parasite interactions. After infection, B. elliptica grew faster and more easily on the leaves of 'Tresor' than on those of 'Sorbonne' during initial infection; when 'Tresor' leaves were completely infected, only a few lesions were observed on 'Sorbonne' leaves. Biochemical differences between these two cultivars were found following inoculation with B. elliptica, as shown by studies of reactive oxygen species (ROS) and the enzymatic antioxidant system. Rapid accumulation of H2O2 and ·O2- to trigger a defense response was detected in HR 'Sorbonne'. Meanwhile, higher levels of antioxidant activity, including SOD, POD and CAT, were found in HR 'Sorbonne' than in HS 'Tresor' before 48 h post-inoculation, but antioxidant activity was reduced with subsequent infection progress. These large and timely increases in ROS and antioxidant activities could be the main contributors to the high resistance of the 'Sorbonne' cultivar.


Assuntos
Botrytis/metabolismo , Quimera , Resistência à Doença , Lilium , Doenças das Plantas/microbiologia , Antioxidantes/metabolismo , Quimera/metabolismo , Quimera/microbiologia , Peróxido de Hidrogênio/metabolismo , Lilium/metabolismo , Lilium/microbiologia , Oxirredutases/metabolismo , Proteínas de Plantas/metabolismo , Superóxidos/metabolismo
12.
Front Plant Sci ; 8: 753, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28572808

RESUMO

MicroRNAs, as master regulators of gene expression, have been widely identified and play crucial roles in plant-pathogen interactions. A fatal pathogen, Botrytis elliptica, causes the serious folia disease of lily, which reduces production because of the high susceptibility of most cultivated species. However, the miRNAs related to Botrytis infection of lily, and the miRNA-mediated gene regulatory networks providing resistance to B. elliptica in lily remain largely unexplored. To systematically dissect B. elliptica-responsive miRNAs and their target genes, three small RNA libraries were constructed from the leaves of Lilium regale, a promising Chinese wild Lilium species, which had been subjected to mock B. elliptica treatment or B. elliptica infection for 6 and 24 h. By high-throughput sequencing, 71 known miRNAs belonging to 47 conserved families and 24 novel miRNA were identified, of which 18 miRNAs were downreguleted and 13 were upregulated in response to B. elliptica. Moreover, based on the lily mRNA transcriptome, 22 targets for 9 known and 1 novel miRNAs were identified by the degradome sequencing approach. Most target genes for elliptica-responsive miRNAs were involved in metabolic processes, few encoding different transcription factors, including ELONGATION FACTOR 1 ALPHA (EF1a) and TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR 2 (TCP2). Furthermore, the expression patterns of a set of elliptica-responsive miRNAs and their targets were validated by quantitative real-time PCR. This study represents the first transcriptome-based analysis of miRNAs responsive to B. elliptica and their targets in lily. The results reveal the possible regulatory roles of miRNAs and their targets in B. elliptica interaction, which will extend our understanding of the mechanisms of this disease in lily.

13.
Oncotarget ; 8(24): 39497-39511, 2017 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-28467809

RESUMO

UHRF1 (ubiquitin-like with PHD and RING finger domains 1) is a critical regulator for DNA methylation, and its frequent overexpression in human cancers has been associated with tumor-promoting effects. However, whether the overexpressed UHRF1 contributes to the establishment and maintenance of tumor methylomes and whether this process can affect the tumorigenesis remain unclear. In this study, we show that UHRF1 is highly expressed in retinoblastoma, and genomes of human primary retinoblastoma and cell lines have differential DNA methylation patterns compared with those of normal retina, characterized by lower global methylation and higher promoter methylation of tumor suppressors. However, our genome-wide DNA methylation study uncovers that UHRF1 down-modulation in retinoblastoma cells exerts minor effects on the existing methylation patterns at both bulk genome and individual gene loci, suggesting that retinoblastoma methylome is primarily maintained by other mechanisms. Furthermore, using two murine retinoblastoma models, we found that high UHRF1 expression does not alter global methylation levels in both premalignant neonatal retina and retinoblastoma tumors, implying that DNA hypomethylation may not be an early mechanism driving retinoblastoma tumorigenesis unlike what has been proposed for other types of cancer. These results suggest that tumor-promoting functions of UHRF1 in retinoblastoma are largely independent of its role in DNA methylation.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Retinoblastoma/genética , Retinoblastoma/metabolismo , Transcriptoma , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Camundongos , Regiões Promotoras Genéticas
14.
Circ Heart Fail ; 10(2)2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28209764

RESUMO

BACKGROUND: Despite increased secondary cardiovascular events in patients with ischemic cardiomyopathy (ICM), the expression of innate cardiac protective molecules in the hearts of patients with ICM is incompletely characterized. Therefore, we used a nonbiased RNAseq approach to determine whether differences in cardiac protective molecules occur with ICM. METHODS AND RESULTS: RNAseq analysis of human control and ICM left ventricular samples demonstrated a significant decrease in KCNJ11 expression with ICM. KCNJ11 encodes the Kir6.2 subunit of the cardioprotective KATP channel. Using wild-type mice and kcnj11-deficient (kcnj11-null) mice, we examined the effect of kcnj11 expression on cardiac function during ischemia-reperfusion injury. Reactive oxygen species generation increased in kcnj11-null hearts above that found in wild-type mice hearts after ischemia-reperfusion injury. Continuous left ventricular pressure measurement during ischemia and reperfusion demonstrated a more compromised diastolic function in kcnj11-null compared with wild-type mice during reperfusion. Analysis of key calcium-regulating proteins revealed significant differences in kcnj11-null mice. Despite impaired relaxation, kcnj11-null hearts increased phospholamban Ser16 phosphorylation, a modification that results in the dissociation of phospholamban from sarcoendoplasmic reticulum Ca2+, thereby increasing sarcoendoplasmic reticulum Ca2+-mediated calcium reuptake. However, kcnj11-null mice also had increased 3-nitrotyrosine modification of the sarcoendoplasmic reticulum Ca2+-ATPase, a modification that irreversibly impairs sarcoendoplasmic reticulum Ca2+ function, thereby contributing to diastolic dysfunction. CONCLUSIONS: KCNJ11 expression is decreased in human ICM. Lack of kcnj11 expression increases peroxynitrite-mediated modification of the key calcium-handling protein sarcoendoplasmic reticulum Ca2+-ATPase after myocardial ischemia-reperfusion injury, contributing to impaired diastolic function. These data suggest a mechanism for ischemia-induced diastolic dysfunction in patients with ICM.


Assuntos
Cardiomiopatias/metabolismo , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo , Canais de Potássio Corretores do Fluxo de Internalização/deficiência , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Adulto , Animais , Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio , Proteínas de Ligação ao Cálcio/metabolismo , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Fenótipo , Canais de Potássio Corretores do Fluxo de Internalização/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda , Pressão Ventricular
15.
Medicine (Baltimore) ; 95(40): e5110, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27749593

RESUMO

Gene therapy may be a promising approach for the treatment of Leber hereditary optic neuropathy. The aim of this study was to evaluate patients with this condition who were recruited into an upcoming gene therapy clinical trial and to assess any changes in the detection parameters to provide support for the clinical trial. Sixteen patients with Leber hereditary optic neuropathy were evaluated using visual function tests 12 months before the initiation of gene therapy. Then, the results of visual acuity (VA), visual field (VF), RNFL (retinal nerve fiber layer) thickness, and Pattern-reversal Visual evoked potential (PR-VEP) were compared and analyzed. A total of 32 eyes of 16 patients were evaluated. Based on the best-corrected visual acuity (BCVA), 24 eyes were relatively stable compared with the baseline evaluation, and 8 eyes had significant changes, including 5 eyes that showed improvement and 3 eyes that showed impairment. In all eyes, the changes in the best-corrected visual acuity were significantly correlated with the changes in the visual field index (VFI), mean defect (MD), and P100 of the visual evoked potential. In the eyes with relatively stable BCVA and those with an obvious improvement in the BCVA, only the visual mean defect showed a significant change; the other indicators were not significantly different. Aside from the patients showing a tendency of spontaneous improvement, the others were in accordance with the requirement. The effects of Leber hereditary optical neuropathy (LHON) gene therapy should be evaluated primarily based on visual acuity. Additionally, visual field, neural fiber thickness, and electrophysiology should be considered in the evaluation.


Assuntos
Terapia Genética/métodos , Atrofia Óptica Hereditária de Leber/terapia , Retina/diagnóstico por imagem , Acuidade Visual , Adolescente , Adulto , Criança , Eletrorretinografia , Potenciais Evocados Visuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Óptica Hereditária de Leber/diagnóstico , Atrofia Óptica Hereditária de Leber/genética , Retina/fisiopatologia , Tomografia de Coerência Óptica , Campos Visuais , Adulto Jovem
16.
Springerplus ; 5(1): 843, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27386292

RESUMO

The objective of this study is to investigate the characteristics and the evolution of visual field damage caused by Leber's hereditary optic neuropathy (LHON) and to provide clinical data for the diagnosis of LHON. Parameters of visual field in 32 consecutive patients (49 eyes) with LHON who were confirmed by genetic diagnostic tests were retrospectively measured within 1 week, between three to six months, and at six months after onset. Visual field defects revealed central scotoma in 26 eyes (53.1 %), paracentral scotoma in 12 eyes (24.5 %), ceco-central defects in 6 eyes (12.2 %), blind spot enlargenment in 3 eyes (6.1 %), quadrantanopia in 2 eyes (4.1 %) within 1 week after onset. After 3 to 6 months, ceco-central defects were detected in 22 eyes (44.9 %), central isopter constriction in 10 eyes (20.4 %), hemianopia or quadrantanopia in 5 eyes (10.2 %), central scotoma in 4 eyes (8.2 %), and paracentral scotoma in 1 eye (2.0 %). After 6 months, central isopter constriction was observed in 18 eyes (36.7 %), diffuse defects in 21 eyes (42.9 %), ceco-central defects in 3 eyes (6.1 %), hemianopia or quadrantanopia in 5 eyes (10.2 %), and central scotoma in 2 eyes (4.1 %). LHON at different stages was characterized by different focal visual field defects: visual field defects in LHON patients within 1 week after onset were mostly central or paracentral scotoma, which was enlarged around the ceco-central defect, or connected to form a blind spot after 3-6 months. Diffuse and central isopter constriction defects were usually developed after 6 months. Damages firstly appeared in papillomacular bundle and gradually expanded outward. These characteristics of visual field defects reported in this study might provide a clinical basis for better diagnosis of LHON.

17.
EBioMedicine ; 10: 258-68, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27426279

RESUMO

Leber's hereditary optic neuropathy (LHON) is a disease that leads to blindness. Gene therapy has been investigated with some success, and could lead to important advancements in treating LHON. This was a prospective, open-label trial involving 9 LHON patients at Tongji Hospital, Wuhan, China, from August 2011 to December 2015. The purpose of this study was to evaluate the long-term outcomes of gene therapy for LHON. Nine LHON patients voluntarily received an intravitreal injection of rAAV2-ND4. Systemic examinations and visual function tests were performed during the 36-month follow-up period to determine the safety and efficacy of this gene therapy. Based on successful experiments in an animal model of LHON, 1 subject also received an rAAV2-ND4 injection in the second eye 12months after gene therapy was administered in the first eye. Recovery of visual acuity was defined as the primary outcome of this study. Changes in the visual field, visual evoked potential (VEP), optical coherence tomography findings, liver and kidney function, and antibodies against AAV2 were defined as secondary endpoints. Eight patients (Patients 2-9) received unilateral gene therapy and visual function improvement was observed in both treated eyes (Patients 4, 6, 7, and 8) and untreated eyes (Patients 2, 3, 4, 6 and 8). Visual regression fluctuations, defined as changes in visual acuity greater than or equal to 0.3 logMAR, were observed in Patients 2 and 9. Age at disease onset, disease duration, and the amount of remaining optic nerve fibers did not have a significant effect on the visual function improvement. The visual field and pattern reversal VEP also improved. The patient (Patient 1) who received gene therapy in both eyes had improved visual acuity in the injected eye after the first treatment. Unfortunately, visual acuity in this eye decreased 3months after he received gene therapy in the second eye. Animal experiments suggested that ND4 expression remains stable in the contralateral eye after intravitreal injections. No serious safety problem was observed in the 3-year follow-up of the 9 participants enrolled in this virus-based gene therapy. Meanwhile, our results support the use of intravitreal rAAV2-ND4 as an aggressive maneuver in our clinical trial. Further study in additional patients and in these 9 subjects is needed to better understand the effects of rAAV2-ND4 gene therapy on LHON and to increase the applications of this technique.


Assuntos
Terapia Genética , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/terapia , Adolescente , Adulto , Criança , Dependovirus/genética , Potenciais Evocados Visuais , Feminino , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , NADH Desidrogenase/genética , Atrofia Óptica Hereditária de Leber/diagnóstico , Tomografia de Coerência Óptica , Resultado do Tratamento , Acuidade Visual , Campos Visuais , Adulto Jovem
18.
Chin Med J (Engl) ; 129(11): 1291-7, 2016 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-27231165

RESUMO

BACKGROUND: The incidence of diabetic nephropathy (DN) increases year by year. However, clinical characteristics of DN patients on maintenance hemodialysis (MHD) were rarely reported in China. The purpose of this study was to examine the clinical characteristics of the DN patients on MHD in Anhui Province, Eastern China. METHODS: The clinical data of MHD patients in the hemodialysis centers of 26 hospitals in Anhui Province from January 1, 2014, to March 31, 2014, were examined. The differences between DN patients and non-DN patients were compared regarding vascular access, nutritional status, mineral and bone disorder, and other indexes. RESULTS: Among the selected 2768 adult MHD patients, 427 had DN. The incidence of hypertension, coronary heart disease, and cerebral thrombus in DN patients was 94.1%, 21.5%, and 15.0%, respectively, which were higher than those in non-DN patients (P < 0.001). Category of vascular access for hemodialysis in DN patients was arteriovenous fistula (AVF) (87.4% [373/427]) and tunneled cuffed catheter (TCC) (11.2% [48/427]). The percentage of AVF was significantly lower than that of non-DN patients (P < 0.001), and percentage of TCC was significantly higher than that of non-DN patients (P < 0.001). Hemoglobin achievement rate in DN patients was 32.0%. The incidence of hypoalbuminemia was 24.7%, significantly higher than that in non-DN patients (P < 0.001). The achievement rate of the target range in mineral values was 55.9% in corrected serum calcium level, 30.1% in serum phosphorus level, and 49.3% in intact parathyroid hormone (iPTH) level in DN patients. Compared with non-DN patients, the achievement rate of serum phosphorus was significantly higher in DN patients. CONCLUSIONS: DN patients on MHD in Anhui province exhibited different clinical characteristics compared to non-DN hemodialysis patients. They presented higher percentage in TCC use and cardiovascular complication, lower serum albumin and iPTH levels than those in non-DN patients.


Assuntos
Nefropatias Diabéticas/epidemiologia , Diálise Renal , Idoso , Cálcio/sangue , China , Doença das Coronárias/sangue , Doença das Coronárias/epidemiologia , Doença das Coronárias/fisiopatologia , Estudos Transversais , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/fisiopatologia , Feminino , Humanos , Hipertensão/sangue , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Trombose Intracraniana/sangue , Trombose Intracraniana/epidemiologia , Trombose Intracraniana/fisiopatologia , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fósforo/sangue
19.
Sci Rep ; 6: 21587, 2016 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-26892229

RESUMO

Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited disease leading to blindness. A mitochondrial DNA point mutation at the 11778 nucleotide site of the NADH dehydrogenase subunit 4 (ND4) gene is the most common cause. The aim of this study was to evaluate the efficacy and safety of a recombinant adeno-associated virus 2 (AAV2) carrying ND4 (rAAV2-ND4) in LHON patients carrying the G11778A mutation. Nine patients were administered rAAV2-ND4 by intravitreal injection to one eye and then followed for 9 months. Ophthalmologic examinations of visual acuity, visual field, and optical coherence tomography were performed. Physical examinations included routine blood and urine. The visual acuity of the injected eyes of six patients improved by at least 0.3 log MAR after 9 months of follow-up. In these six patients, the visual field was enlarged but the retinal nerve fibre layer remained relatively stable. No other outcome measure was significantly changed. None of the nine patients had local or systemic adverse events related to the vector during the 9-month follow-up period. These findings support the feasible use of gene therapy for LHON.


Assuntos
Dependovirus/genética , Terapia Genética/métodos , Mutação , NADH Desidrogenase/genética , Atrofia Óptica Hereditária de Leber/terapia , Administração Oral , Adolescente , Adulto , Criança , Eletrorretinografia , Feminino , Seguimentos , Células HEK293 , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Plasmídeos/genética , Mutação Puntual , Prednisolona/administração & dosagem , Tomografia de Coerência Óptica , Resultado do Tratamento , Adulto Jovem
20.
Ying Yong Sheng Tai Xue Bao ; 27(8): 2629-2635, 2016 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-29733152

RESUMO

A leaf disc bioassay was employed to examine the effects of fenpropathrin and avermectin with a sublethal concentration of LC20 on the development and reproduction of F0, F1 and F2 generations by means of life tables. The results showed that after the treatment of fenpropathrin at the sublethal concentration, the number of eggs laid per female significantly increased in F0 generation, the pre-oviposition duration was significantly shortened and the female ratio of offspring significantly increased both in F1 and F2 generations. The intrinsic rate of increase (rm) and finite rate of increase (λ) values all increased, and the generation time (T) and population doubling time (Dt) were shortened in F1 and F2 generations, with significant difference observed between F2 generations and the control. After exposure to avermectin, the number of eggs laid per female significantly decreased in F0 generation, and progeny (F1 and F2) also produced fewer eggs than the control, while the female ratio of offspring increased both in F1 and F2 generations and the pre-oviposition period was significantly shortened. The rm and λ values all increased, and the T and Dt were shortened in F1 and F2 generations. Such effects were more obvious on the F2 generation than the F1 generation. Generally, the effects of fenpropathrin and avermectin with a sublethal concentration of LC20 were not exactly the same on P. citri. Fenpropathrin could promote the development of the contemporary population, while avermectin had certain inhibition on the contemporary population, but both played a certain role in facilitating the development of future populations, which was of significance in developing integrated pest management strategies.


Assuntos
Inseticidas , Ivermectina/análogos & derivados , Controle de Pragas/métodos , Piretrinas , Tetranychidae/fisiologia , Animais , Feminino , Masculino , Oviposição , Reprodução
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