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1.
J Med Virol ; 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32542750

RESUMO

A pandemic of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection broke out all over the world; however, epidemiological data and viral shedding in pediatric patients are limited. We conducted a retrospective, multicenter study, and followed-up with all children from the families with SARS-CoV-2 infected members in Zhejiang Province, China. All infections were confirmed by testing the SARS-CoV-2 RNA with real-time reverse transcription PCR method, and epidemiological data between children and adults in the same families were compared. Effect of antiviral therapy was evaluated observationally and fecal-viral excretion times among groups with different antiviral regiments were compared with Kaplan-Meier plot. By 29 February 2020, 1298 cases from 883 families were confirmed with SARS-CoV-2 infection and 314 of which were families with children. Incidence of infection in child close contacts was significantly lower than that in adult contacts (13.2% vs 21.2%). The mean age of 43 pediatric cases was 8.2 years and mean incubation period was 9.1 days. Forty (93.0%) were family clustering. Thirty-three children had coronavirus disease 2019 (20 pneumonia) with mild symptoms and 10 were asymptomatic. Fecal SARS-CoV-2 RNA detection was positive in 91.4% (32/35) cases and some children had viral excretion time over 70 days. Viral clearance time was not different among the groups treated with different antiviral regiments. No subsequent infection was observed in family contacts of fecal-viral-excreting children. Children have lower susceptibility of SARS-CoV-2 infection, longer incubation, and fecal-viral excretion time. Positive results of fecal SARS-CoV-2 RNA detection were not used as indication for hospitalization or quarantine.

3.
JAMA Netw Open ; 3(6): e2011122, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32525548

RESUMO

Importance: Severe acute respiratory syndrome coronavirus 2 has caused a global outbreak of coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 binds angiotensin-converting enzyme 2 of the rennin-angiotensin system, resulting in hypokalemia. Objective: To investigate the prevalence, causes, and clinical implications of hypokalemia, including its possible association with treatment outcomes, among patients with COVID-19. Design, Setting, and Participants: This cohort study was conducted at Wenzhou Central Hospital and Sixth People's Hospital of Wenzhou, Wenzhou, China, from January 11, 2020, to February 15, 2020. Participants included patients who received a diagnosis of COVID-19 according to the criteria issued by the Chinese Health Bureau and were admitted to the hospital. The patients were classified as having severe hypokalemia (plasma potassium <3 mmol/L), hypokalemia (plasma potassium 3-3.5 mmol/L), and normokalemia (plasma potassium >3.5 mmol/L). The clinical features, therapy, and outcomes were compared between the 3 groups. Data analysis was conducted in March 2020. Interventions: The patients were given general support and antiviral therapy. Their epidemiological and clinical features were collected. Main Outcomes and Measures: The prevalence of hypokalemia and response to treatment with potassium supplements were measured by analyzing plasma and urine potassium levels. Results: One hundred seventy-five patients (87 female patients [50%]; mean [SD] age, 45 [14] years) were classified as having severe hypokalemia (31 patients [18%]), hypokalemia (64 patients [37%]), and normokalemia (80 patients [46%]). Patients with severe hypokalemia had statistically significantly higher body temperature (mean [SD], 37.6 °C [0.9 °C]) than the patients with hypokalemia (mean [SD], 37.2 °C [0.7 °C]; difference, 0.4 °C; 95% CI, 0.2-0.6 °C; P = .02) and the patients with normokalemia (mean [SD], 37.1 °C [0.8 °C]; difference, 0.5 °C; 95% CI, 0.3-0.7 °C; P = .005). Patients with higher levels of hypokalemia also had higher creatine kinase levels (severe hypokalemia, mean [SD], 200 [257] U/L [median, 113 U/L; interquartile range {IQR}, 61-242 U/L]; hypokalemia, mean [SD], 97 [85] U/L; and normokalemia, mean [SD], 82 [57] U/L), higher creatine kinase-MB fraction (severe hypokalemia, mean [SD], 32 [39] U/L [median, 14 U/L; IQR, 11-36 U/L]; hypokalemia, mean [SD], 18 [15] U/L; and normokalemia, mean [SD], 15 [8] U/L), higher lactate dehydrogenase levels (mean [SD], severe hypokalemia, 256 [88] U/L; hypokalemia, 212 [59] U/L; and normokalemia, 199 [61] U/L), and higher C-reactive protein levels (severe hypokalemia, mean [SD], 29 [23] mg/L; hypokalemia, mean [SD], 18 [20] mg/L [median, 12, mg/L; IQR, 4-25 mg/L]; and normokalemia, mean [SD], 15 [18] mg/L [median, 6 U/L; IQR, 3-17 U/L]). Of 40 severely and critically ill patients, 34 (85%) had hypokalemia. Patients with severe hypokalemia were given potassium at a dose of 40 mEq per day, for a total mean (SD) of 453 (53) mEq potassium chloride, during the hospital stay. The patients responded well to potassium supplements as they recovered. Conclusions and Relevance: The correction of hypokalemia is challenging because of continuous renal potassium loss resulting from the degradation of angiotensin-converting enzyme 2. The high prevalence of hypokalemia among patients with COVID-19 suggests the presence of disordered rennin-angiotensin system activity, which increases as a result of reduced counteractivity of angiotensin-converting enzyme 2, which is bound by severe acute respiratory syndrome coronavirus 2.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Hipopotassemia/sangue , Hipopotassemia/virologia , Pneumonia Viral/complicações , Adulto , China/epidemiologia , Estudos de Coortes , Infecções por Coronavirus/sangue , Infecções por Coronavirus/virologia , Feminino , Humanos , Hipopotassemia/epidemiologia , Masculino , Pessoa de Meia-Idade , Pandemias , Peptidil Dipeptidase A/sangue , Pneumonia Viral/sangue , Pneumonia Viral/virologia , Potássio/sangue , Prevalência
4.
Artigo em Inglês | MEDLINE | ID: mdl-32539429

RESUMO

The role of HIV infection in precipitating different clinical features in cryptococcal meningitis (CM) patients remains controversial. One hundred twelve CM patients living with HIV/AIDS (CM+HIV+ patients) and 112 CM patients living without HIV/AIDS (CM+HIV- patients) were enrolled after propensity score matching. Demographic characteristics, symptoms, routine blood tests, and biochemical and cerebrospinal fluid (CSF) profiles were compared between the two groups. Kaplan-Meier analysis and Cox proportional hazards model was used to assess 10-week mortality. CM+HIV+ patients frequently occurred in young (mean age 40.3 ± 10.5) and male (89.3%) populations who also experienced leukopenia, neutropenia, lymphocytopenia, thrombocytopenia, and hypoalbuminemia, less headaches (66.9%), and higher cryptococcemia (23.2%) (all p < .050); they also had higher glucose (2.6 ± 1.1 mmol/L), increased smear positivity (78.8%), and decreased white blood cells [8.0 (2.0-28.0) × 106/L] in initial CSF assay (all p < .050). The 10-week cumulative survival rate was 84.6% for CM+HIV+ patients and 88.5% for CM+HIV- patients (p = .345). Age <35.0 years (hazard ratio (HR) 3.0 (1.0-8.9), p = .046), intracranial pressure (ICP) >250.0 mmH2O (HR: 4.8 (1.1-21.6), p = .041), and treatment lacking amphotericin B [HR: 6.5 (1.9-21.4), p = .003] were independent risk factors for 10-week mortality in CM+HIV+ patients. There are significant clinical differences in CM patients living with or without HIV/AIDS. However, the 10-week survival rate was similar between the two groups. Younger population, high ICP, and treatment lacking amphotericin B were independent risk factors for 10-week mortality of Chinese CM+HIV+ patients.

5.
Molecules ; 25(2)2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31968628

RESUMO

Thrombin, a key enzyme of the serine protease superfamily, plays an integral role in the blood coagulation cascade and thrombotic diseases. In view of this, it is worthwhile to establish a method to screen thrombin inhibitors (such as natural flavonoid-type inhibitors) as well as investigate their structure activity relationships. Virtual screening using molecular docking technique was used to screen 103 flavonoids. Out of this number, 42 target compounds were selected, and their inhibitory effects on thrombin assayed by chromogenic substrate method. The results indicated that the carbon-carbon double bond group at the C2, C3 sites and the carbonyl group at the C4 sites of flavones were essential for thrombin inhibition, whereas the methoxy and O-glycosyl groups reduced thrombin inhibition. Noteworthy, introduction of OH groups at different positions on flavonoids either decreased or increased anti-thrombin potential. Myricetin exhibited the highest inhibitory potential against thrombin with an IC50 value of 56 µM. Purposively, the established molecular docking virtual screening method is not limited to exploring flavonoid structure activity relationships to anti-thrombin activity but also usefully discovering other natural active constituents.

6.
Inorg Chem ; 58(8): 4979-4988, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30933488

RESUMO

Tunable luminescence (quenching or blue shift) of HNA/OS-LRH composites (HNA is 3-hydroxy-2-naphthoic acid; OS is the anionic surfactant of 1-octanesulfonic acid sodium; LRHs are layered rare-earth hydroxides, R = Tb3+, Y3+) in the solid state and delaminated state is reported, which is utilized as an effective fluorescent probe for detecting metal ions. HNA/OS species are intercalated into LRH layers to generate composites of HNA xOS1- x-LTbH ( x = 0.10, 0.15, 0.20 , 0.25) and HNA yOS1- y-LYH ( y = 0.05, 0.10, 0.15, 0.20, 0.25, 0.30). In the solid state, LYH composites exhibit green emissions (from 493 to 504 nm) with a large blue shift in comparison to the 542 nm emission of free HNA- anions, while in the delaminated state in formamide (FM), the composites display blue emission (480 nm) relative to the green emission (512 nm) of an HNA soltuion in FM. However, LTbH composites display coquenched luminescence in both the solid state and delaminated state. Also, HNA0.25OS0.75-1:1-LYH, HNA0.25OS0.75-1:2-LYH, and HNA0.05OS0.95-1:1-LYH (1:1 and 1:2 are HNA:NaOH molar ratios) show significantly elongated fluorescence lifetimes of 15.35, 14.37, and 12.72 ns, respectively, in comparison with free HNA-Na (6.44 ns), and their quantum yields of 23.40%, 21.97%, and 22.31%, respectively, are much larger than that of free HNA-Na (4.86%). The LTbH composite (HNA0.25OS0.75-1:1-LTbH) has also a relatively higher quantum yield of 12.46%. The HNA0.25OS0.75-1:1-LYH colloid exhibits excellent recognition selectivity for Al3+ over other metal ions (Mg2+, Co2+, Ni2+, Cu2+, Zn2+, Pb2+, Cd2+, and Hg2+) with distinct fluorescence sensitization. It shows an intense change in its fluorescence emission when it is bound to Al3+ ions, giving a lower detection limit of 6.32 × 10-6 M. This is novel research on the fluorescence chemosensing of LRH composites.

7.
Int J Med Sci ; 15(13): 1508-1516, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30443172

RESUMO

Cardiac hypertrophy is an independent predictor of cardiovascular morbidity and mortality. To identify the mechanisms by which simvastatin inhibits cardiac hypertrophy induced by pressure overload, we determined effects of simvastatin on 14-3-3 protein expression and autophagic activity. Simvastatin was administered intragastrically to Sprague-Dawley (SD) rats before abdominal aortic banding (AAB). Neonatal rat cardiomyocytes (NRCs) were treated with simvastatin before angiotensin II (AngII) stimulation. 14-3-3, LC3, and p62 protein levels were determined by western blot. Autophagy was also measured by the double-labeled red fluorescent protein-green fluorescent protein autophagy reporter system. Simvastatin alleviated excessive autophagy, characterized by a high LC3II/LC3I ratio and low level of p62, and blunted cardiac hypertrophy while increasing 14-3-3 protein expression in rats that had undergone AAB. In addition, it increased 14-3-3 expression and inhibited excessive autophagy in NRCs exposed to AngII. Our study demonstrated that simvastatin may inhibit excessive autophagy, increase 14-3-3 expression, and finally exert beneficial effects on cardioprotection against pressure overload.


Assuntos
Proteínas 14-3-3/metabolismo , Autofagia/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Sinvastatina/farmacologia , Animais , Western Blotting , Células Cultivadas , Hipertrofia/metabolismo , Masculino , Microscopia Confocal , Ratos , Ratos Sprague-Dawley
8.
Cell Physiol Biochem ; 51(1): 46-62, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30439713

RESUMO

BACKGROUND/AIMS: This study was developed to investigate a potential therapeutic method for myocardial ischemia/reperfusion injury involving the promotion of miR-24-3p expression. METHODS: Microarray analysis was used to screen differentially expressed genes in a myocardial ischemia/reperfusion (I/R) injury mouse model. Gene set enrichment analysis was utilized to determine vital signaling pathways. Targeting verification was conducted with a luciferase reporter assay. Myocardial I/R injury was developed in mice, and the expression levels of RIPK1 and miR-24-3p were investigated by qRT-PCR and Western blot. Hemodynamic parameters and the activity of serum myocardial enzymes were measured to evaluate cardiac function. Infarct area was observed through HE and TTC staining. Myocardial cell apoptosis was examined by TUNEL staining and caspase-3 activity analysis. RESULTS: RIPK1 was an upregulated mRNA found by microarray analysis and a verified target of the downregulated miRNA miR-24-3p. The upregulation of RIPK1 (1.8-fold) and the downregulation of miR-24-3p (0.3-fold) were confirmed in I/R mice. RIPK1 led to impaired cardiac function indexes, increased infarct area and cell apoptosis, while miR-24-3p could reverse the injury by regulating RIPK1. The TNF signaling pathway was proven to be involved in myocardial I/R injury through the detection of the dysregulation of related proteins. CONCLUSION: In conclusion, RIPK1 was upregulated and miR-24-3p was downregulated in a myocardial I/R injury mouse model. RIPK1 could aggravate myocardial I/R injury via the TNF signaling pathway, while miR-24-3p could suppress RIPK1 and therefore exert cardioprotective effects in myocardial I/R injury.


Assuntos
MicroRNAs/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Análise por Conglomerados , Creatina Quinase Forma MB/sangue , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Proteína Serina-Treonina Quinases de Interação com Receptores/química , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais , Fatores de Necrose Tumoral/metabolismo , Função Ventricular Esquerda/fisiologia
9.
Exp Ther Med ; 16(2): 1505-1512, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30112071

RESUMO

Distal myopathy with rimmed vacuoles (DMRV) is a rare, autosomal, recessive inherited disease caused by mutations in the GNE gene. DMRV is an adult-onset disorder characterized by progressive muscle atrophy and weakness, which initially involves the distal muscles with quadriceps sparing. To date, >150 GNE mutations have been reported in different populations from around the world. The present study investigated the clinical, pathological and genetic characteristics of seven unrelated DMRV patients from China. Genetic analysis in these patients revealed three novel mutations (c.455_456insC, p.P421L, and p.A287T) and five previously reported mutations (p.D207V, p.C44S, p.G576R, p.A669P, and p.D218G). In addition, the literature on DMRV was reviewed to provide an overview of the disease and broaden the mutational spectrum of the GNE gene in China.

10.
BMC Neurol ; 18(1): 79, 2018 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-29866061

RESUMO

BACKGROUND: Filamin C-related myofibrillar myopathies (MFM) are progressive skeletal myopathies with an autosomal dominant inheritance pattern. The conditions are caused by mutations of the filamin C gene (FLNC) located in the chromosome 7q32-q35 region. Genetic variations in the FLNC gene result in various clinical phenotypes. CASE PRESENTATION: We describe a 43-year-old woman who suffered filamin C-related MFM, with symptoms first presenting in the proximal muscles of the lower limbs and eventually spreading to the upper limbs and distal muscles. The patient's serum level of creatine kinase was mildly increased. Mildy myopathic changes in the electromyographic exam and moderate lipomatous alterations in lower limb MRI were found. Histopathological examination revealed increased muscle fiber size variability, disturbances in oxidative enzyme activity, and the presence of abnormal protein aggregates and vacuoles in some muscle fibers. Ultrastructural analysis showed inclusions composed of thin filaments and interspersed granular densities. DNA sequencing analysis detected a novel 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the FLNC gene. The patient's father, sister, brother, three paternal aunts, one paternal uncle, and the uncle's son also had slowly progressive muscle weakness, and thus, we detected an autosomal dominant inheritance pattern of the disorder. CONCLUSIONS: A novel heterogeneous 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the Ig-like domain 7 of the FLNC gene was found to cause filamin C-related MFM. This deletion in the FLNC gene causes protein aggregation, abnormalities in muscle structure, and impairment in muscle fiber function, which leads to muscle weakness.


Assuntos
Filaminas/genética , Miopatias Congênitas Estruturais/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Éxons/genética , Feminino , Heterozigoto , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Deleção de Sequência/genética
11.
Front Microbiol ; 9: 444, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29593688

RESUMO

Introduction: The Xpert MTB/RIF is recommended by the World Health Organization as a first line rapid test for the diagnosis of pulmonary tuberculosis (TB); however, China does not routinely use this test, partially due to the lack of a sufficient number of systematic evaluations of this assay in local patients. The aims of this study were to comprehensively assess the diagnostic performance of Xpert MTB/RIF, either alone or in combination with conventional assays for the diagnosis of pulmonary TB in adult Chinese patients. Methods: Xpert MTB/RIF tests were performed in 190 adult patients with suspected pulmonary TB, using bronchoalveolar lavage fluid (BALF) as test specimens. In parallel, conventional tests were carried out using the same BALF samples. Using two different reference standards, the performance of Xpert MTB/RIF, conventional assays and their combinations were evaluated. Results: Using mycobacterial culture as the reference comparator, Xpert MTB/RIF was found to be superior to smear-microscopy in detecting Mycobacterium tuberculosis. When final diagnosis, based on clinical criteria, was employed as the reference standard, Xpert MTB/RIF showed an even higher accuracy of 72.1%, supported by a sensitivity of 61.1% and specificity of 96.6%. Xpert MTB/RIF also demonstrated a powerful capability to identify pulmonary TB cases undetected by culture or smear-microscopy. Combining smear-microscopy and Xpert MTB/RIF was found to be the most accurate early predictor for pulmonary TB. Rifampicin resistance reported by Xpert MTB/RIF slightly deviated from that by phenotypic antibiotic susceptibility testing and requires further study with a larger sample size. Conclusion: This two-center prospective study highlights the value of Xpert MTB/RIF with BALF in diagnosing pulmonary TB in adult Chinese patients. These findings might contribute to the optimization of current diagnostic algorithms for pulmonary TB in China.

12.
Dalton Trans ; 47(15): 5380-5389, 2018 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-29589632

RESUMO

We demonstrate a novel example of tunable luminescence and the application of the delaminated FLN/OS-LRH composites (LRHs are layered rare-earth hydroxides, R = Tb, Y; FLN is the fluorescein named 2-(6-hydroxy-3-oxo-(3H)-xanthen-9-yl)benzoic acid; OS is the anionic surfactant 1-octane sulfonic acid sodium) in detecting Fe(iii) ions. The FLNxOS1-x species (x = 0.02, 0.05, 0.10, and 0.20) are intercalated into the LTbyY1-yH layers (y = 1, 0.9, 0.7, 0.5, 0.3, 0.1 and 0) by ion exchange reactions to yield the composites FLNxOS1-x-LTbyY1-yH. In the solid state, the LYH composites display green emission (564 nm) arising from the organic FLN, while in LTbH composites, the luminescence of the Tb3+ in the layers (545 nm) and the FLN in the interlayers is co-quenched. In the delaminated state in formamide (FM), FLNxOS1-x-LTbH composites display green to yellowish-green luminescence (540-574 nm) following the increasing FLN/OS ratio; while the FLN0.02OS0.98-LTbyY1-yH composites show green emission at ∼540 nm. The fluorescence lifetimes of the composites (4.22-4.63 ns) are comparable to the free FLN-Na, and the quantum yields (31.62-78.70%) of the composites especially that (78.70%) of the FLN0.02OS0.98-LYH are much higher than that (28.40%) of free FLN-Na. The recognition ability of the FLN0.02OS0.98-LYH composite for metal cations is researched. The delaminated FLN0.02OS0.98-LYH colloidal suspension exhibits high selectivity for Fe3+ over other ions (Mg2+, Al3+, Ni2+, Co2+, Cu2+, Zn2+, Mn2+, Pb2+, and Cd2+) with fluorescence quenching, which can work as a kind of turn-off fluorescence sensor for the detection of Fe3+. The detection limit of Fe3+ is determined to be 2.58 × 10-8 M and the quenching constant (Ksv) is 1.70 × 103 M-1. This is the first work on LRH materials working as a chemosensor for recognising metal cations. It provides a new approach for the design of LRH materials to be applied in fluorescence chemosensing.

13.
Dalton Trans ; 46(37): 12724-12731, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-28914950

RESUMO

The organic compound of coumarin-3-carboxylic acid (CCA), deprotonated beforehand by NaOH, and the 1-octane sulfonic acid anion (OS) were co-intercalated into the gallery of the layered europium hydroxide (LEuH) via an ion exchange method. Different molar ratios of CCA/OS and NaOH/CCA gave rise to the composites of CCA1-xOSx-LEuH (x = 0.8-1.0) showing different emission intensities. In formamide (FM), all composites were delaminated and the formed colloidal suspensions exhibited enhanced red luminescence of Eu3+ in comparison with the OS-LEuH without CCA. Also, the red emissions of the composites were different from the violet emission (421 nm) of free CCA- and blue emission (471 nm) of CCA2- anions in different deprotonation states. The energy levels of CCA and Eu3+ were analyzed to explain the sensitization effect for Eu3+ luminescence. The fluorescence lifetimes of CCA0.2OS0.8-LEuH-1 : 1, CCA0.02OS0.98-LEuH-1 : 1, CCA0.2OS0.8-LEuH-1 : 2, and CCA0.02OS0.98-LEuH-1 : 2 were determined to be 0.705, 0.704, 0.699 and 0.638 ms, respectively, indicating significantly longer lifetimes. The PL quantum yields of ∼10% demonstrate the excellent luminescence properties of the as-prepared CCA1-xOSx-LEuH composites. This is the first report on the sensitized luminescence properties of layer Eu3+ ions in LRH composites in the delaminated state. The intriguing red luminescence of delaminated LEuH composites offers a promising approach to achieve efficient luminescent film materials.

14.
Cell Physiol Biochem ; 43(1): 293-307, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28854420

RESUMO

AIMS: Obesity is a major risk for hypertension. Endothelial dysfunction contributes to increased peripheral vascular resistance and subsequent hypertension. Autophagy regulates endothelial function, however, whether autophagy is related to hypertension in obesity remains largely unclear. We wished to ascertain: (i) the role of autophagy in obesity-induced hypertension and the underlying mechanisms; (ii) if tetrahydroxystilbene glycoside (TSG) influences endothelial dysfunction and obesity-associated hypertension. METHODS: (TSG-treated) male Zucker diabetic fatty (ZDF) rats and cultured human umbilical vein endothelial cells (HUVECs) were used. Blood pressure was measured non-invasively with a tail-cuff system. Westernblotting was performed to determine the expression of autophagy-associated proteins. Autophagy flux was assessed by transfection HUVECs with the Ad-mGFP-RFP-LC3. RESULTS: Compared with their lean counterparts, obese ZDF rats exhibited hypertension and endothelial dysfunction, along with impaired Akt/mTOR signaling and upregulated expression of autophagy-associated proteins beclin1, microtubule-associated protein 1 light chain 3 II/I, autophagy protein (ATG)5 and ATG7. Two-week TSG administration restored blood pressure and endothelial function, reactivated Akt/mTOR pathway and decreased endothelial autophagy in ZDF rats. Rapamycin pretreatment blocked the hypotensive effect of TSG in ZDF rats. Suppression of Akt/mTOR expression with siRNA significantly blunted the anti-autophagic effect of TSG in HUVECs as evidenced by abnormal autophagic flux and increased expression of autophagy-associated proteins. CONCLUSION: Endothelial dysfunction in ZDF rats is partially attributable to excessive autophagy. TSG improves endothelial function and exerts hypotensive effects via regulation of endothelial autophagy.


Assuntos
Autofagia/efeitos dos fármacos , Glicosídeos/farmacologia , Hipertensão/patologia , Obesidade/patologia , Estilbenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Glicosídeos/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipertensão/etiologia , Masculino , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Obesidade/complicações , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Ratos , Ratos Zucker , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Estilbenos/química , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
15.
J Colloid Interface Sci ; 496: 353-363, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28237753

RESUMO

This work demonstrates tunable and purified luminescence via one-step delamination of HPTS/OS-LRH composites (HPTS is trisodium 8-hydroxy-pyrene-1,3,6-trisulphonate, OS is sodium salt of 1-octane sulfonic acid, LRH is layered rare-earth hydroxide, R=Tb, Y) along with energy transfer. The HPTSxOS1-x-LTbyY1-yH composites presented varied luminescence behavior depending on their physical state. In solid state, dual-color luminescence was observed: blue-dominant emissions (437nm) for HPTSxOS1-x-LTbH, and blue- (437nm) to green-dominant (516nm) luminescence for HPTS0.02OS0.98-LTbyY1-yH. In delaminated state in famamide, purified luminescence was present: pure blue emission (440nm) for HPTSxOS1-x-LTbH and HPTS0.02OS0.98-LTbyY1-yH (y≥0.5), while pure bluish-green emission (498nm) for HPTS0.02OS0.98-LTbyY1-yH (y≤0.3). Both the delamination of the composites and energy transfer from layer Tb3+ to HPTS contributed to the blue luminescence. The intriguing energy transfer process between photoactive inorganic hosts and organic guests can be utilized to fabricate hybrid materials with superior luminescence property.

16.
JCI Insight ; 1(19): e90931, 2016 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-27882354

RESUMO

Bcl-2-associated athanogene 3 (BAG3) is an evolutionarily conserved protein expressed at high levels in the heart and the vasculature and in many cancers. While altered BAG3 expression has been associated with cardiac dysfunction, its role in ischemia/reperfusion (I/R) is unknown. To test the hypothesis that BAG3 protects the heart from reperfusion injury, in vivo cardiac function was measured in hearts infected with either recombinant adeno-associated virus serotype 9-expressing (rAAV9-expressing) BAG3 or GFP and subjected to I/R. To elucidate molecular mechanisms by which BAG3 protects against I/R injury, neonatal mouse ventricular cardiomyocytes (NMVCs) in which BAG3 levels were modified by adenovirus expressing (Ad-expressing) BAG3 or siBAG3 were exposed to hypoxia/reoxygenation (H/R). H/R significantly reduced NMVC BAG3 levels, which were associated with enhanced expression of apoptosis markers, decreased expression of autophagy markers, and reduced autophagy flux. The deleterious effects of H/R on apoptosis and autophagy were recapitulated by knockdown of BAG3 with Ad-siBAG3 and were rescued by Ad-BAG3. In vivo, treatment of mice with rAAV9-BAG3 prior to I/R significantly decreased infarct size and improved left ventricular function when compared with mice receiving rAAV9-GFP and improved markers of autophagy and apoptosis. These findings suggest that BAG3 may provide a therapeutic target in patients undergoing reperfusion after myocardial infarction.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Miócitos Cardíacos/patologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose , Autofagia , Hipóxia Celular , Células Cultivadas , Feminino , Masculino , Camundongos , Traumatismo por Reperfusão/terapia , Transfecção
17.
Mol Med Rep ; 13(3): 2597-605, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26862035

RESUMO

Patients with essential hypertension undergo endothelial dysfunction, particularly in the conduit arteries. Cilostazol, a type III phosphodiesterase inhibitor, serves a role in the inhibition of platelet aggregation and it is widely used in the treatment of peripheral vascular diseases. Previous studies have suggested that cilostazol suppresses endothelial dysfunction; however, it remains unknown whether cilostazol protects the endothelial function in essential hypertension. The aim of the present study was to investigate whether, and how, cilostazol suppresses angiotensin II (angII)­induced endothelial dysfunction. Human umbilical vein endothelial cells (HUVECs) and Sprague Dawley rats were exposed to angII and treated with cilostazol. Endothelial cell apoptosis and function, nitric oxide and superoxide production, phosphorylation (p) of Akt, and caspase­3 protein expression levels were investigated. AngII exposure resulted in the apoptosis of endothelial cells in vitro and in vivo. In vitro, cilostazol significantly suppressed the angII­induced apoptosis of HUVECs; however, this effect was reduced in the presence of LY294002, a phosphoinositide 3 kinase (PI3K) inhibitor. Furthermore, cilostazol suppressed the angII­induced p­Akt downregulation and cleaved caspase­3 upregulation. These effects were also alleviated by LY294002. In vivo, cilostazol suppressed the angII­induced endothelial cell apoptosis and dysfunction. Cilostazol was also demonstrated to partially reduced the angII­induced increase in superoxide production. The results of the present study suggested that cilostazol suppresses endothelial apoptosis and dysfunction by modulating the PI3K/Akt pathway.


Assuntos
Angiotensina II , Apoptose/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Inibidores da Fosfodiesterase 3/farmacologia , Tetrazóis/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Cilostazol , Células Endoteliais da Veia Umbilical Humana/patologia , Masculino , Óxido Nitroso/metabolismo , Ratos , Superóxidos/metabolismo
18.
J Mol Cell Cardiol ; 92: 10-20, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26796036

RESUMO

Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid anti-apoptotic protein that is constitutively expressed in the heart. BAG3 mutations, including mutations leading to loss of protein, are associated with familial cardiomyopathy. Furthermore, BAG3 levels have been found to be reduced in end-stage non-familial failing myocardium. In contrast to neonatal myocytes in which BAG3 is found in the cytoplasm and involved in protein quality control and apoptosis, in adult mouse left ventricular (LV) myocytes BAG3 co-localized with Na(+)-K(+)-ATPase and L-type Ca(2+) channels in the sarcolemma and t-tubules. BAG3 co-immunoprecipitated with ß1-adrenergic receptor, L-type Ca(2+) channels and phospholemman. To simulate decreased BAG3 protein levels observed in human heart failure, we targeted BAG3 by shRNA (shBAG3) in adult LV myocytes. Reducing BAG3 by 55% resulted in reduced contraction and [Ca(2+)]i transient amplitudes in LV myocytes stimulated with isoproterenol. L-type Ca(2+) current (ICa) and sarcoplasmic reticulum (SR) Ca(2+) content but not Na(+)/Ca(2+) exchange current (INaCa) or SR Ca(2+) uptake were reduced in isoproterenol-treated shBAG3 myocytes. Forskolin or dibutyryl cAMP restored ICa amplitude in shBAG3 myocytes to that observed in WT myocytes, consistent with BAG3 having effects upstream and at the level of the receptor. Resting membrane potential and action potential amplitude were unaffected but APD50 and APD90 were prolonged in shBAG3 myocytes. Protein levels of Ca(2+) entry molecules and other important excitation-contraction proteins were unchanged in myocytes with lower BAG3. Our findings that BAG3 is localized at the sarcolemma and t-tubules while modulating myocyte contraction and action potential duration through specific interaction with the ß1-adrenergic receptor and L-type Ca(2+) channel provide novel insight into the role of BAG3 in cardiomyopathies and increased arrhythmia risks in heart failure.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Canais de Cálcio Tipo L/metabolismo , Cardiomiopatia Dilatada/metabolismo , Insuficiência Cardíaca/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Potenciais de Ação/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Animais , Proteínas Reguladoras de Apoptose/biossíntese , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patologia , Cálcio/metabolismo , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/patologia , Acoplamento Excitação-Contração , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Homeostase , Humanos , Isoproterenol/administração & dosagem , Proteínas de Membrana/metabolismo , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosfoproteínas/metabolismo , RNA Interferente Pequeno/genética , Sarcolema/metabolismo
19.
JACC Basic Transl Sci ; 1(7): 647-656, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28164169

RESUMO

OBJECTIVES: The present study was undertaken to test the hypothesis that gene delivery of BCL2-Associated Athanogene 3 (BAG3) to the heart of mice with left ventricular dysfunction secondary to a myocardial infarction could enhance cardiac performance. BACKGROUND: BAG3 is a 575 amino acid protein that has pleotropic functions in the cell including pro-autophagy and anti-apoptosis. Mutations in BAG3 have been associated with both skeletal muscle dysfunction and familial dilated cardiomyopathy and BAG3 levels are diminished in non-familial heart failure. METHODS: Eight-week-old C57/BL6 mice underwent ligation of the left coronary artery (MI) or sham surgery (Sham). Eight weeks later, mice in both groups were randomly assigned to receive either a retro-orbital injection of rAAV9-BAG3 (MI-BAG3 or Sham-BAG3) or rAAV9-GFP (MI-GFP or Sham GFP). Mice were sacrificed at 3 weeks post-injection and myocytes were isolated from the left ventricle. RESULTS: MI-BAG3 mice demonstrated a significantly (p < 0.0001) higher left ventricular ejection fraction (LVEF) 9 days after rAAV9-BAG3 injection with further improvement in LVEF, fractional shortening and stroke volume at 3 weeks post-injection without changes in LV mass or LV volume. Injection of rAAV9-BAG3 had no effect on LVEF in Sham mice. The salutary benefits of rAAV9-BAG3 were also observed in myocytes isolated from MI hearts including improved cell shortening (p<0.05), increased systolic [Ca2+]i, increased [Ca2+]i transient amplitudes and increased maximal ICa amplitude. IMPLICATIONS: The results suggest that BAG3 gene therapy may provide a novel therapeutic option for the treatment of heart failure.

20.
Sci Rep ; 5: 18578, 2015 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-26687035

RESUMO

Biofilm formation is a major pathogenicity strategy of Staphylococcus epidermidis causing various medical-device infections. Persister cells have been implicated in treatment failure of such infections. We sought to profile bacterial subpopulations residing in S. epidermidis biofilms, and to establish persister-targeting treatment strategies to eradicate biofilms. Population analysis was performed by challenging single biofilm cells with antibiotics at increasing concentrations ranging from planktonic minimum bactericidal concentrations (MBCs) to biofilm MBCs (MBCbiofilm). Two populations of "persister cells" were observed: bacteria that survived antibiotics at MBCbiofilm for 24/48 hours were referred to as dormant cells; those selected with antibiotics at 8 X MICs for 3 hours (excluding dormant cells) were defined as tolerant-but-killable (TBK) cells. Antibiotic regimens targeting dormant cells were tested in vitro for their efficacies in eradicating persister cells and intact biofilms. This study confirmed that there are at least three subpopulations within a S. epidermidis biofilm: normal cells, dormant cells, and TBK cells. Biofilms comprise more TBK cells and dormant cells than their log-planktonic counterparts. Using antibiotic regimens targeting dormant cells, i.e. effective antibiotics at MBCbiofilm for an extended period, might eradicate S. epidermidis biofilms. Potential uses for this strategy are in antibiotic lock techniques and inhaled aerosolized antibiotics.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Infecções Relacionadas a Cateter/tratamento farmacológico , Staphylococcus epidermidis/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Infecções Relacionadas a Cateter/genética , Infecções Relacionadas a Cateter/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Staphylococcus epidermidis/crescimento & desenvolvimento , Staphylococcus epidermidis/patogenicidade
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