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1.
Breast Cancer Res ; 23(1): 89, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488828

RESUMO

BACKGROUND: Telomere maintenance is crucial for the unlimited proliferation of cancer cells and essential for the "stemness" of multiple cancer cells. TAZ is more extensively expressed in triple negative breast cancers (TNBC) than in other types of breast cancers, and promotes proliferation, transformation and EMT of cancer cells. It was reported that TAZ renders breast cancer cells with cancer stem cell features. However, whether TAZ regulates telomeres is still unclear. In this study, we explored the roles of TAZ in the regulation of telomere maintenance in TNBC cells. METHODS: siRNA and shRNA was used to generate TAZ-depleted TNBC cell lines. qPCR and Southern analysis of terminal restriction fragments techniques were used to test telomere length. Co-immunoprecipitation, Western blotting, immunofluorescence, Luciferase reporter assay and Chromatin-IP were conducted to investigate the underlying mechanism. RESULTS: By knocking down the expression of TAZ in TNBC cells, we found, for the first time, that TAZ is essential for the maintenance of telomeres in TNBC cells. Moreover, loss of TAZ causes senescence phenotype of TNBC cells. The observed extremely shortened telomeres in late passages of TAZ knocked down cells correlate with an elevated hTERT expression, reductions of shelterin proteins, and an activated DNA damage response pathway. Our data also showed that depletion of TAZ results in overexpression of TERRAs, which are a group of telomeric repeat-containing RNAs and regulate telomere length and integrity. Furthermore, we discovered that TAZ maintains telomere length of TNBC cells likely by facilitating the expression of Rad51C, a crucial element of homologous recombination pathway that promotes telomere replication. CONCLUSIONS: This study supports the notion that TAZ is an oncogenic factor in TNBC, and further reveals a novel telomere-related pathway that is employed by TAZ to regulate TNBC.

2.
BMC Cancer ; 21(1): 760, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193109

RESUMO

BACKGROUND: Breast cancer is the leading cause of cancer-related deaths in females worldwide. Formin-like protein 2 (FMNL2) is a member of formin family that governs cytokinesis, cell polarity, morphogenesis and cell division. To our knowledge, the function of FMNL2 in breast cancer proliferation still remains uncovered. METHODS: Tumor immune estimation resource (TIMER) analysis was used to detect the correlation between FMNL2 and Ki67 in breast cancer tissues. Quantitative real-time transcription polymerase chain reaction (qRT-PCR) and western blotting were performed to analyze the expression in human breast cancer cells. Moreover, RNA interference (RNAi) and plasmids were performed to silence and overexpress FMNL2 and p27. The CCK8, MTT, cell counting, colony formation, and 5-ethynyl-2-deoxyuridine (EdU) incorporation assays were used to detect cell proliferation, respectively. Flow cytometry analysis was used to detect cell cycle distribution. Further, the distribution of p27 was examined using immunofluorescence. RESULTS: We found that FMNL2 expression was positively associated with Ki67 among collected breast cancer tissues and in TCGA database. Compared to lower proliferative cells MCF7 and T47D, FMNL2 was overexpressed in highly proliferative breast cancer cells MDA-MB-231, BT549 and SUM159, accompanied by reduced levels of p27 and p21, and elevated CyclinD1 and Ki67 expression. FMNL2 silencing significantly inhibited the cell proliferation of MDA-MB-231 and BT549 cells. Meanwhile, FMNL2 overexpression distinctly promoted the cell proliferation of MCF7 cells. Furthermore, FMNL2 suppressed the nuclear levels of p27 and promoted p27 proteasomal degradation in human breast cancer cells. The ubiquitination of p27 was inhibited by FMNL2 silencing in BT549 cells. Besides, p27 silencing markedly elevated Ki67 expression and cell viability, which could be blocked by additionally FMNL2 silencing in MDA-MB-231 and BT549 cells. Furthermore, overexpression of p27WT significantly reversed the increased levels of FMNL2 and Ki67, cell viability and cell cycle progression induced by FMNL2 overexpression in MCF7 cells. More importantly, compared to p27WT group, those effects could be significantly reversed by p27△NLS overexpression. CONCLUSIONS: These results demonstrated that FMNL2 promoted cell proliferation partially by reducing p27 nuclear localization and p27 protein stability in human breast cancer cells, suggesting the pivotal role of FMNL2 in breast cancer progression.

3.
Clin Exp Pharmacol Physiol ; 48(2): 279-287, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33030246

RESUMO

Nucleotide metabolism is the driving force of cell proliferation, and thymidylate synthase (TYMS) catalyzes a rate-limiting step in the initial synthesis of nucleotides. Previous studies reported that TYMS activity significantly affected the proliferation of tumour cells. However, the diagnostic and prognostic significance of TYMS expression in breast cancer remains unclear. Here, we used the Breast Cancer Integrative Platform (BCIP) to investigate the relationship between progression and prognosis of breast cancer with TYMS expression, and then verified the database analysis using immunohistochemical staining. Our results indicated TYMS expression was greater in breast cancer than adjacent normal tissues and greater in triple-negative breast cancer (TNBC) than non-TNBC tissues. TYMS expression also had significant positive correlations with histological grade, tumour size, and ER negativity, and PR negativity. The increased copy number of the TYMS gene appears to be the reason for its upregulation in breast cancer. Breast cancer patients with higher TYMS expression had poorer prognosis. Our data suggest that TYMS has potential use as a diagnostic and prognostic marker for breast cancer patients.

4.
J Diabetes Investig ; 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33244871

RESUMO

AIMS/INTRODUCTION: To explore relationships between polyunsaturated fatty acids (PUFA) and non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes, and whether insulin action has an interactive effect with PUFA on NAFLD progression. MATERIALS AND METHODS: We extracted clinical and omics data of 482 type 2 diabetes patients from a tertiary hospital consecutively from April 2018 to April 2019. NAFLD was estimated by ultrasound at admission. Plasma fasting n3 and n6 fatty acids were quantified by liquid chromatography-tandem mass spectrometry analysis. Restricted cubic spline nested in binary logistic regression was used to select the cut-off point, and estimate odds ratios and 95% confidence intervals. Additive interactions of the n6 : n3 ratio with insulin action for NAFLD were estimated using relative excess risk due to interaction, attributable proportion due to interaction and synergy index. Relative excess risk due to interaction >0, attributable proportion due to interaction >0 or synergy index >1 indicates biological interaction. Spearman correlation analysis was used to obtain partial correlation coefficients between PUFA and hallmarks of NAFLD. RESULTS: Of 482 patients, 313 were with and 169 were without NAFLD. N3 ≥800 and n6 PUFA ≥8,100 µmol/L were independently associated with increased NAFLD risk; n6 : n3 ratio ≤10 was associated with NAFLD (odds ratio 1.80, 95% confidence interval 1.20-2.71), and the effect size was amplified by high C-peptide (odds ratio 8.89, 95% confidence interval 4.48-17.7) with significant interaction. The additive interaction of the n6 : n3 ratio and fasting insulin was not significant. CONCLUSION: Decreased n6 : n3 ratio was associated with increased NAFLD risk in type 2 diabetes patients, and the effect was only significant and amplified when there was the co-presence of high C-peptide.

5.
Food Funct ; 11(5): 4446-4455, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32374314

RESUMO

The objective of the present study was to evaluate the effects of dietary starch structure (amylose/amylopectin ratio, AR) on intestinal health of weaned pigs by determining the intestinal morphology, barrier functions, epithelium apoptosis and digestive enzymes. A total of one hundred and eight pigs (initial body weight 7.51 ± 0.05 kg) were randomly allotted on the basis of their body weight (BW) and litters to one of the six experimental diet treatments with six replicates per treatment and three pigs per replicate. The six diets included a control (corn-soybean meal basal diet, CON) diet and five experimental diets with AR being 2.90, 1.46, 0.68, 0.31 and 0.14, respectively. The diets and water were provided ad libitum for 21 d. Results showed that pigs fed CON and AR 2.90 diets had higher (P < 0.05) villus height and ratio of villus height : crypt depth in the jejunum and ileum compared with the other four starch groups. Pigs of CON and AR 0.14 groups had greater (P < 0.05) activities of sucrase (SA) and maltase (MA) than the pigs of other groups. Additionally, compared with the high amylopectin (AR 0.31 and 0.14) groups, the total apoptotic percentage was significantly decreased in (P < 0.01) CON and high amylose (AR 2.90) groups. Ingestion of CON and high amylose diets upregulated (P < 0.05) the levels of B-cell lymphoma-2 (Bcl-2) and occludin (OCLN) gene expression in duodenum and jejunum. However, no significant differences in the level of zonula occludens 1 (ZO-1) gene expression were observed in pigs fed with different AR diets. Interestingly, CON and high amylose groups enhanced the localization of ZO-1 protein in apical intercellular region of jejunal epithelium. Together, these results suggest that diets with high amylose can influence the intestinal health of young pigs by improving their intestinal barrier functions and reducing the epithelial cell apoptosis.


Assuntos
Ração Animal , Epitélio/fisiologia , Jejuno/fisiologia , Amido , Fenômenos Fisiológicos da Nutrição Animal , Animais , Distribuição Aleatória , Suínos
6.
Animals (Basel) ; 10(3)2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32213990

RESUMO

To investigate the effects of dietary starch structure (amylose/amylopectin ratio, AR) on serum glucose absorption metabolism and intestinal health, a total of ninety weaned piglets (Duroc × (Yorkshire × Landrace)) were randomly assigned to 5 dietary treatments and fed with a diet containing different AR (2.90, 1.46, 0.68, 0.31, and 0.14). The trial lasted for 21 d. In this study, the growth performance was not affected by the dietary starch structure (p > 0.05). Diets with higher amylose ratios (i.e., AR 2.90 and 1.46) led to a significant reduction of the serum glucose concentration at 3 h post-prandium (p < 0.01), while high amylopectin diets (AR 0.31 and 0.14) significantly elevated The expression of gene s at this time point (p < 0.01). High amylopectin diets also increased the apparent digestibility of crude protein (CP), ether extract (EE), dry matter (DM), gross energy (GE), and crude ash (p < 0.001). Interestingly, diet rich in amylose (AR 2.90) significantly elevated the butyric acid content (p < 0.05) and decreased the pH value (p < 0.05) in the cecal digesta. In contrast, diet rich in amylopectin (i.e., AR 0.14) significantly elevated the total bacteria populations in the cecal digesta (p < 0.001). Moreover, a high amylopectin diet (AR 0.14) tended to elevate the mRNA level of fatty acid synthase (FAS, p = 0.083), but significantly decreased the mRNA level of sodium-dependent glucose transporter 1 (SGLT1, p < 0.05) in the duodenal and jejunal mucosa, respectively. These results suggested that blood glucose and insulin concentrations were improved in high AR diets, and the diet also helped to maintain the intestinal health.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32211384

RESUMO

Aging was a biological process under regulations from both inherited genetic factors and various molecular modifications within cells during the lifespan. Multiple studies demonstrated that the chronological age may be accurately predicted using the methylomic data. This study proposed a three-step feature selection algorithm AgeGuess for the age regression problem. AgeGuess selected 107 methylomic features as the gender-independent age biomarkers and the Support Vector Regressor (SVR) model using these biomarkers achieved 2.0267 in the mean absolute deviation (MAD) compared with the real chronological ages. Another regression algorithm Ridge achieved a slightly better MAD 1.9859 using the same biomarkers. The gender-independent age prediction models may be further improved by establishing two gender-specific models. And it's interesting to observe that there were only two methylation biomarkers shared by the two gender-specific biomarker sets and these two biomarkers were within the two known age-associated biomarker genes CALB1 and KLF14.

8.
Front Endocrinol (Lausanne) ; 11: 619422, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33633688

RESUMO

Objective: This study aimed to evaluate how leucine are associated with diabetic nephropathy (DN) in type 2 diabetes (T2D) patients and the gender difference of this association. Methods: We retrieved 1,031 consecutive patients with T2D who meet the inclusion and exclusion criteria from the same tertiary care center and extracted clinical information from electronic medical record. Plasma leucine was measured by liquid chromatography-mass spectrometer. Restricted cubic spline (RCS) was conducted to examine potential non-linear relationship between leucine and the risk of DN. Logistic regression was used to obtain odds ratio (OR) and confidence interval (CI). Additive interaction was used to estimate the interaction effect between leucine and gender for DN. Results: We found there was a negative correlation between leucine and the risk of DN. After stratifying all patients by gender, this relationship only remained significant in women (OR:0.57, CI:0.41-0.79). Conclusions: In conclusion, T2D patients with high levels of leucine have a lower risk of developing DN in female.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/epidemiologia , Leucina/sangue , Caracteres Sexuais , Adulto , Idoso , Biomarcadores/sangue , China/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatias Diabéticas/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
9.
Oncol Lett ; 18(6): 5917-5922, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31788065

RESUMO

Clinical value of ultrasonic imaging in diagnosis of hypopharyngeal cancer with cervical lymph node metastasis was investigated. Eighty-nine patients who were diagnosed with hypopharyngeal cancer in Qilu Hospital of Shandong University (Qingdao) from January 2014 to June 2016 were retrospectively analyzed. Sixty-eight patients were diagnosed with hypopharyngeal cancer with cervical lymph node metastasis by pathological sections. Twenty-one patients did not have cervical lymph node metastasis. All the patients were diagnosed by palpation and ultrasound. The lymph node ultrasound images were quantified by computer, and the long/short diameter ratio, the maximum systolic velocity, blood flow resistance of the metastatic and non-metastatic patients were compared. The diagnostic efficacy of palpation and ultrasound was analyzed in the diagnosis of hypopharyngeal cancer with cervical lymph node metastasis. A correlation analysis was carried out between the image features of ultrasound and lymph node metastasis. The long/short diameter ratio, maximum systolic velocity and resistance index of patients with lymph node metastasis were significantly higher than those without lymph node metastasis, with a significant difference (P<0.05). Forty-one patients were diagnosed with lymph node metastasis by palpation, fifty-nine patients were diagnosed with lymph node metastasis by ultrasound. The sensitivity and diagnostic coincidence rate of ultrasound in diagnosis of hypopharyngeal cancer with cervical lymph node metastasis were significantly higher than those of palpation (P<0.05). Statistically significant differences were observed in lymph node internal echo types, medullary echo characteristics, envelope definition, and blood flow distribution characteristics between the metastasis group and the non-metastasis group (P<0.05). Lymph node internal echo was heterogeneous. There was no medulla, and the disordered blood flow in the lymph node predicted lymph node metastasis. Preoperative ultrasound has a high diagnostic value in diagnosis of hypopharyngeal cancer with cervical lymph node metastasis. The diagnostic results of preoperative ultrasound can be used as a reference for the diagnosis and treatment of hypopharyngeal cancer with cervical lymph node metastasis.

10.
Interdiscip Sci ; 11(2): 237-246, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30993567

RESUMO

Autism was a spectrum of multiple complex diseases that required an interdisciplinary group of experts to make a diagnostic decision. Both genetic and environmental factors play essential roles in causing the onset of Autism. Therefore, this study hypothesized that methylomic biomarkers may facilitate the accurate Autism detection. A comprehensive series of biomarker detection algorithms were utilized to find the best methylomic biomarkers for the Autism detection using the methylomic data of the peripheral blood samples. The best model achieved 99.70% in accuracy with 678 methylomic biomarkers and a tenfold cross validation strategy. Some of the methylomic biomarkers were experimentally confirmed to be associated with the onset or development of Autism.


Assuntos
Transtorno Autístico/sangue , Transtorno Autístico/genética , Biomarcadores/sangue , Metilação de DNA/genética , Leucócitos/metabolismo , Algoritmos , Criança , Humanos
11.
Asian Pac J Trop Med ; 9(5): 503-7, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27261863

RESUMO

OBJECTIVE: To detect the expression of Toll-like receptor 4 (TLR-4) and NF-κB and to discuss the mechanism of TLR-4/NF-κB pathway in the myocardial ischemia reperfusion injury of mouse. METHODS: TLR-4 mutant mice and wild homozygous mice were divided into the model group and sham group. Mice in the model group were given the ligation of left anterior descending coronary artery for the modeling, while mice in the sham group were not given the ligation after threading. The cardiac muscle tissues were collected for the morphological observation. The immunohistochemistry was employed to detect the expression of NF-κB, Western blot was used to detect the expression of TLR-4 and ELISA to detect the expression of serum inflammatory factors. RESULTS: The expression of NF-κB in TLR-4 null mice after the myocardial ischemia reperfusion was significantly lower than that in wild homozygous mice. For the model group and sham group, the expression of TLR-4 in wild homozygous mice was all significantly higher than that in TLR-4 null mice, while the expression of TLR-4 in TLR-4 null mice in the model group was significantly higher than that in sham group, with the statistical difference (P < 0.05). The expression of inflammatory factors in TLR-4 null mice and wild homozygous mice in the model group was significantly higher than that in sham group. The expression of all factors in group A with TLR-4 null was significantly lower than that in group B with wild homozygous type, with the statistical difference (P < 0.05). CONCLUSIONS: TLR-4/NF-κB pathway is closely related to the myocardial ischemia reperfusion injury, which plays its role through the release of inflammatory cytokines.

12.
Environ Health Perspect ; 123(6): 571-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25723814

RESUMO

BACKGROUND: Bisphenol S (BPS) has increasingly been used as a substitute for bisphenol A (BPA) in some "BPA-free" consumer goods and in thermal papers. Wide human exposure to BPS has been reported; however, the biological and potential toxic effects of BPS are poorly understood. OBJECTIVE: In this study, we sought to elucidate the sex-specific rapid effect of BPS in rat hearts and its underlying mechanism. METHODS: We examined the rapid effects of BPS in rat hearts using electrophysiology, confocal and conventional fluorescence imaging, and immunoblotting. Treatment was administered via acute perfusion of excised hearts or isolated cardiac myocytes. RESULTS: In female rat hearts acutely exposed to 10-9 M BPS, the heart rate was increased; in the presence of catecholamine-induced stress, the frequency of ventricular arrhythmia events was markedly increased. BPS-exposed hearts showed increased incidence of arrhythmogenic-triggered activities in female ventricular myocytes and altered myocyte Ca2+ handling, particularly spontaneous Ca2+ release from the sarcoplasmic reticulum. The dose responses of BPS actions were inverted U-shaped. The impact of BPS on myocyte Ca2+ handling was mediated by estrogen receptor ß signaling and by rapid increases in the phosphorylation of key Ca2+ handling proteins, including ryanodine receptor and phospholamban. The proarrhythmic effects of BPS were female specific; male rat hearts were not affected by BPS at the organ, myocyte, or protein levels. CONCLUSION: Rapid exposure to low-dose BPS showed proarrhythmic impact on female rat hearts; these effects at the organ, cellular, and molecular levels are remarkably similar to those reported for BPA. Evaluation of the bioactivity and safety of BPS and other BPA analogs is necessary before they are used as BPA alternatives in consumer products.


Assuntos
Arritmias Cardíacas/fisiopatologia , Cardiotoxinas/toxicidade , Poluentes Ambientais/toxicidade , Coração/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fenóis/toxicidade , Sulfonas/toxicidade , Animais , Arritmias Cardíacas/induzido quimicamente , Relação Dose-Resposta a Droga , Feminino , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fatores Sexuais
13.
Int J Environ Res Public Health ; 11(8): 8399-413, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25153468

RESUMO

Bisphenol A (BPA) is a ubiquitous plasticizing agent used in the manufacturing of polycarbonate plastics and epoxy resins. There is well-documented and broad human exposure to BPA. The potential risk that BPA poses to the human health has attracted much attention from regulatory agencies and the general public, and has been extensively studied. An emerging and rapidly growing area in the study of BPA's toxicity is its impact on the cardiovascular (CV) system. Recent epidemiological studies have shown that higher urinary BPA concentration in humans is associated with various types of CV diseases, including angina, hypertension, heart attack and coronary and peripheral arterial disease. Experimental studies have demonstrated that acute BPA exposure promotes the development of arrhythmias in female rodent hearts. Chronic exposure to BPA has been shown to result in cardiac remodeling, atherosclerosis, and altered blood pressure in rodents. The underlying mechanisms may involve alteration of cardiac Ca2+ handling, ion channel inhibition/activation, oxidative stress, and genome/transcriptome modifications. In this review, we discuss these recent findings that point to the potential CV toxicity of BPA, and highlight the knowledge gaps in this growing research area.


Assuntos
Compostos Benzidrílicos/toxicidade , Doenças Cardiovasculares/epidemiologia , Sistema Cardiovascular/efeitos dos fármacos , Exposição Ambiental , Poluentes Ambientais/toxicidade , Fenóis/toxicidade , Animais , Doenças Cardiovasculares/induzido quimicamente , Humanos , Camundongos , Ratos
14.
Environ Health Perspect ; 122(6): 601-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24569941

RESUMO

BACKGROUND: The need for mechanistic understanding of nonmonotonic dose responses has been identified as one of the major data gaps in the study of bisphenol A (BPA). Previously we reported that acute exposure to BPA promotes arrhythmogenesis in female hearts through alteration of myocyte Ca(2+) handling, and that the dose response of BPA was inverted U-shaped. OBJECTIVE: We sought to define the cellular mechanism underlying the nonmonotonic dose response of BPA in the heart. METHODS: We examined rapid effects of BPA in female rat ventricular myocytes using video-edge detection, confocal and conventional fluorescence imaging, and patch clamp. RESULTS: The rapid effects of BPA in cardiac myocytes, as measured by multiple end points, including development of arrhythmic activities, myocyte mechanics, and Ca(2+) transient, were characterized by nonmonotonic dose responses. Interestingly, the effects of BPA on individual processes of myocyte Ca(2+) handling were monotonic. Over the concentration range of 10(-12) to 10(-6) M, BPA progressively increased sarcoplasmic reticulum (SR) Ca(2+) release and Ca(2+) reuptake and inhibited the L-type Ca(2+) current (I(CaL)). These effects on myocyte Ca(2+) handling were mediated by estrogen receptor (ER) ß signaling. The nonmonotonic dose responses of BPA can be accounted for by the combined effects of progressively increased SR Ca(2+) reuptake/release and decreased Ca(2+) influx through I(CaL). CONCLUSION: The rapid effects of BPA on female rat cardiac myocytes are characterized by nonmonotonic dose responses as measured by multiple end points. The nonmonotonic dose response was produced by ERß-mediated monotonic effects on multiple cellular Ca(2+) handling processes. This represents a distinct mechanism underlying the nonmonotonicity of BPA's actions.


Assuntos
Arritmias Cardíacas/induzido quimicamente , Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Fenóis/toxicidade , Animais , Arritmias Cardíacas/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Relação Dose-Resposta a Droga , Receptor beta de Estrogênio/metabolismo , Feminino , Ratos , Retículo Sarcoplasmático/metabolismo
15.
Endocrinology ; 154(12): 4607-17, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24140712

RESUMO

Previously we showed that bisphenol A (BPA), an environmental estrogenic endocrine disruptor, rapidly altered Ca(2+) handling and promoted arrhythmias in female rat hearts. The underlying molecular mechanism was not known. Here we examined the cardiac-specific signaling mechanism mediating the rapid impact of low-dose BPA in female rat ventricular myocytes. We showed that protein kinase A (PKA) and Ca(2+)/CaM-dependent protein kinase II (CAMKII) signaling pathways are the two major pathways activated by BPA. Exposure to 1 nM BPA rapidly increased production of cAMP and rapidly but transiently increased the phosphorylation of the ryanodine receptors by PKA but not by CAMKII. BPA also rapidly increased the phosphorylation of phospholamban (PLN), a key regulator protein of sarcoplasmic reticulum Ca(2+) reuptake, by CAMKII but not PKA. The increase in CAMKII phosphorylation of PLN was mediated by phospholipase C and inositol trisphosphate receptor-mediated Ca(2+) release, likely from the endoplasmic reticulum Ca(2+) storage. These two pathways are likely localized, impacting only their respective target proteins. The rapid impacts of BPA on ryanodine receptors and PLN phosphorylation were mediated by estrogen receptor-ß but not estrogen receptor-α. BPA's rapid signaling in cardiac myocytes did not involve activation of ERK1/2. Functional analysis showed that PKA but not CAMKII activation contributed to BPA-induced sarcoplasmic reticulum Ca(2+) leak, and both PKA and CAMKII were necessary contributors to the stimulatory effect of BPA on arrhythmogenesis. These results provide mechanistic insight into BPA's rapid proarrhythmic actions in female cardiac myocytes and contribute to the assessment of the consequence and potential cardiac toxicity of BPA exposure.


Assuntos
Arritmias Cardíacas/induzido quimicamente , Compostos Benzidrílicos/toxicidade , Fenóis/toxicidade , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , AMP Cíclico/genética , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Retículo Endoplasmático , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Retículo Sarcoplasmático/genética , Retículo Sarcoplasmático/metabolismo , Transdução de Sinais
16.
J Am Heart Assoc ; 2(5): e000460, 2013 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-24125847

RESUMO

BACKGROUND: A human genetic variant (Ser96Ala) in the sarcoplasmic reticulum (SR) histidine-rich Ca(2+)-binding (HRC) protein has been linked to ventricular arrhythmia and sudden death in dilated cardiomyopathy. However, the precise mechanisms affecting SR function and leading to arrhythmias remain elusive. METHODS AND RESULTS: We generated transgenic mice with cardiac-specific expression of human Ala96 HRC or Ser96 HRC in the null background to assess function in absence of endogenous protein. Ala96 HRC decreased (25% to 30%) cardiomyocyte contractility and Ca2+ kinetics compared with Ser96 HRC in the absence of any structural or histological abnormalities. Furthermore, the frequency of Ca2+ waves was significantly higher (10-fold), although SR Ca2+ load was reduced (by 27%) in Ala96 HRC cells. The underlying mechanisms involved diminished interaction of Ala96 HRC with triadin, affecting ryanodine receptor (RyR) stability. Indeed, the open probability of RyR, assessed by use of ryanodine binding, was significantly increased. Accordingly, stress conditions (5 Hz plus isoproterenol) induced aftercontractions (65% in Ala96 versus 12% in Ser96) and delayed afterdepolarizations (70% in Ala96 versus 20% in Ser96). The increased SR Ca2+ leak was accompanied by hyperphosphorylation (1.6-fold) of RyR at Ser2814 by calmodulin-dependent protein kinase II. Accordingly, inclusion of the calmodulin-dependent protein kinase II inhibitor KN93 prevented Ser2814 phosphorylation and partially reversed the increases in Ca2+ spark frequency and wave production. Parallel in vivo studies revealed ventricular ectopy on short-term isoproterenol challenge and increased (4-fold) propensity to arrhythmias, including nonsustained ventricular tachycardia, after myocardial infarction in Ala96 HRC mice. CONCLUSIONS: These findings suggest that aberrant SR Ca2+ release and increased susceptibility to delayed afterdepolarizations underlie triggered arrhythmic activity in human Ala96 HRC carriers.


Assuntos
Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Proteínas de Ligação ao Cálcio/fisiologia , Cálcio/metabolismo , Animais , Arritmias Cardíacas/genética , Proteínas de Ligação ao Cálcio/genética , Humanos , Camundongos , Camundongos Transgênicos
17.
Artigo em Chinês | MEDLINE | ID: mdl-24044210

RESUMO

OBJECTIVE: To investigate the prevalence of viral pathogen in children with severe pneumonia in Hunan. METHOD: Bronchoalveolar lavage fluid [BALF] were collected from 122 hospitalized children with severe pneumonia in People's Hospital of Hunan province from January 2011 to December 2011. Nested- or reverse transcription Polymerase chain reaction (PCR or RT-PCR) was used to screen Adenovirus (ADV), Human Bocavirus (HBoV), Parainfluenzaviruses1-4 (PIV1-4), Human Respiratory Syneytial virus (RSV), Influenza virus A (IFVA), Influenza virus B (IFVB), Human Rhinovirus(HRV), Human Metapneumovirus (HMPV), human coronaviruses NL63 and HKU1 (HCoV-NL63, HCoV- HKU1). RESULTS: Among the 122 bronchoalveolar lavage fluid, viral agents were detected in 60 samples(49.1%), among which ADV (40.98%) was the most common virus, followed by RSV (7.37%) and HBoV (7.37%). Two viruses were detected in 21 individual (35%) samples, of which 20 were dual positive for ADV (40%). CONCLUSION: ADV is the most frequently detected viral etiology of severe pneumonia in children in Hunan during this year. And its Coinfection with other respiratory viruses was common.


Assuntos
Líquido da Lavagem Broncoalveolar/virologia , Pneumonia/virologia , Vírus/isolamento & purificação , Adenovírus Humanos/isolamento & purificação , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estações do Ano
18.
Am J Physiol Heart Circ Physiol ; 304(10): H1382-96, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23479264

RESUMO

Among its many biological roles, fibroblast growth factor-2 (FGF2) acutely protects the heart from dysfunction associated with ischemia/reperfusion (I/R) injury. Our laboratory has demonstrated that this is due to the activity of the low molecular weight (LMW) isoform of FGF2 and that FGF2-mediated cardioprotection relies on the activity of protein kinase C (PKC); however, which PKC isoforms are responsible for LMW FGF2-mediated cardioprotection, and their downstream targets, remain to be elucidated. To identify the PKC pathway(s) that contributes to postischemic cardiac recovery by LMW FGF2, mouse hearts expressing only LMW FGF2 (HMWKO) were bred to mouse hearts not expressing PKCα (PKCαKO) or subjected to a selective PKCε inhibitor (εV(1-2)) before and during I/R. Hearts only expressing LMW FGF2 showed significantly improved postischemic recovery of cardiac function following I/R (P < 0.05), which was significantly abrogated in the absence of PKCα (P < 0.05) or presence of PKCε inhibition (P < 0.05). Hearts only expressing LMW FGF2 demonstrated differences in actomyosin ATPase activity as well as increases in the phosphorylation of troponin I and T during I/R compared with wild-type hearts; several of these effects were dependent on PKCα activity. This evidence indicates that both PKCα and PKCε play a role in LMW FGF2-mediated protection from cardiac dysfunction and that PKCα signaling to the contractile apparatus is a key step in the mechanism of LMW FGF2-mediated protection against myocardial dysfunction.


Assuntos
Fator 2 de Crescimento de Fibroblastos/fisiologia , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/fisiopatologia , Miofibrilas/metabolismo , Proteína Quinase C/fisiologia , Actomiosina/metabolismo , Animais , Western Blotting , ATPase de Ca(2+) e Mg(2+)/metabolismo , Feminino , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , L-Lactato Desidrogenase/metabolismo , Masculino , Camundongos , Camundongos Knockout , Peso Molecular , Contração Miocárdica/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Fosforilação/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Troponina I/metabolismo , Troponina T/metabolismo
19.
Bing Du Xue Bao ; 28(5): 531-5, 2012 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-23233929

RESUMO

UNLABELLED: To investigate the epidemiological features and types of human adenoviruses (ADV) in children with acute respiratory tract infection in Nanjing area, China. Nasopharyngeal aspirates and nasopharyngeal swabs were collected from 644 outpatients or hospitalized pediatric patients with ARTI at the Children Hospital of Nanjing, Jiangsu Province, China, between August 2010 and July 2011. Adenoviruses were identified and typed from the collected clinical specimens by nested-PCR based on the partial region of the hexon gene. Other 12 respiratory viruses including human bocavirus (HBoV), respiratory syncytial virus (RSV), human rhinovirus (HRV), parainfluenza viruses 1-4 (PIV1-4), influenza virus A/B (IFVA/B), human metapneumovirus (HMPV), human coronavirus NL63 and HKU1 (HCoV-HKU1 and HCoV-NL63) were also identified by PCR method. All PCR positive products were sequenced and phylogenetic analysis was conducted. It was showed that adenoviruses were detected in 171 patients out of 644 (26. 55%) children, 120 (70.18%, 120/171) for ADV3, 16 (9.36%,16/171) for ADV7, 12 (7.02%, 12/171) for ADV1, 10 (5.85%, 10/171) for ADV2, 6 (3.51%, 6/171) for ADV5, 3 (1.75%, 3/171) for ADV6, 3 (1.75%, 3/171) for ADV57, and 1 (0.58%,1/171) for ADV41. ADV infection could occur in any season. There was a higher possibility of ADV infection from April to July in 2011. Most cases (96.49%) were younger than 7 years old. A total of 99 of the 171 ADV-positive children (57.89%) were co-infected with other respiratory viruses. Respiratory syncytial virus (RSV) and human rhinovirus (HRV) were the most common additional respiratory viruses, Lower respiratory tract infections were the most frequent diagnoses made in the hospital, in which there were 52 pneumonia (30.4%) cases. CONCLUSION: ADV is one of the most important pathogens of acute respiratory tract infection in children in Nanjing area, and adenovirus type 3 was the most prevalent serotype. It is important to develop long-term surveillance.


Assuntos
Infecções por Adenoviridae/epidemiologia , Adenoviridae/isolamento & purificação , Infecções Respiratórias/epidemiologia , Adenoviridae/classificação , Adenoviridae/genética , Infecções por Adenoviridae/virologia , Criança , Pré-Escolar , China/epidemiologia , Feminino , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Filogenia , Infecções Respiratórias/virologia
20.
Artigo em Chinês | MEDLINE | ID: mdl-22919743

RESUMO

OBJECTIVE: To study the infected information, clinical symptom and molecular epidemiological characteristics of HuCV infection among children under 5 years old in Nanjing. METHODS: In Nanjing Children's Hospital of Nanjing Medical University from July 2010 to June 2011, we collected 428 stool specimens from children with diarrhea and 428 asymptomatic controls. Human Calicivirus were tested by using RT-PCR. Then we sequenced the nucleic acid of PCR amplifications and identified the genotype and gene group of prevalent strains. RESULTS: 63 (14.72%) out of 428 stool samples were detected as HuCV. 58 were norovirus and 5 were sapovirus, while GII-4 2006b was the predominant strain of NoV. In the 428 control samples, 19 samples were positive for calicivirus, there were 8 NoV and 13 SaV (Including 3 co-infection cases). CONCLUSION: Human caliciviruses with different genotypes circulated among children in Nanjing,and GII. 2006b is the dominant genotype.


Assuntos
Infecções por Caliciviridae/epidemiologia , Caliciviridae/genética , Diarreia/epidemiologia , Caliciviridae/classificação , Caliciviridae/isolamento & purificação , Infecções por Caliciviridae/virologia , Pré-Escolar , China/epidemiologia , Diarreia/virologia , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Epidemiologia Molecular , Filogenia , Estações do Ano
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