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1.
Biochem Biophys Res Commun ; 585: 139-145, 2021 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-34801934

RESUMO

The pathogenesis of post-traumatic stress disorder (PTSD) remains largely unclear. A large body of evidence suggests that the abnormal level of serotonin (5-HT) is closely related to the onset of PTSD. Several reports reveal that nitric oxide (NO) affects extracellular 5-HT levels in various brain regions, but no consistent direction of change was found and the underlying mechanisms remain unknown. The most of serotonergic neurons in dorsal raphe nucleus (DRN), a major source of serotonergic input to the forebrain, co-expresses neuronal nitric oxide synthase (nNOS), a synthase derived nitric oxide (NO) in the central nervous system. Here, we found that the excessive expression of nNOS and thereby the high concentration of NO followed by single-prolonged stress (SPS) caused suppression of the activity of DRN 5-HT neurons, inducing PTSD-like phenotype including increased anxiety-like behaviors, enhanced contextual fear memory, and fear generalization. Our study uncovered an important role of DRN nNOS-NO pathway in the pathology of PTSD, which may contribute to new understanding of the molecular mechanism of PTSD.

2.
Lab Invest ; 2021 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-34775493

RESUMO

This study aimed to investigate the effects of renal denervation (RDN) on diabetic cardiomyopathy (DCM) and explore the related mechanisms. Male Sprague-Dawley rats were fed high-fat chow and injected with low-dose streptozotocin to establish a DCM model. Six rats served as controls. The surviving rats were divided into three groups: control group, DCM group and DCM + RDN group. RDN surgery was performed in the fifth week. At the end of the experiment, all rats were subjected to 18F-FDG PET/CT and metabolic cage studies. Cardiac function and structure were evaluated by echocardiography and histology. Myocardial substrate metabolism and mitochondrial function were assessed by multiple methods. In the 13th week, the DCM rats exhibited cardiac hypertrophy and interstitial fibrosis accompanied by diastolic dysfunction. RDN ameliorated DCM-induced cardiac dysfunction (E/A ratio: RDN 1.07 ± 0.18 vs. DCM 0.93 ± 0.12, P < 0.05; E/E' ratio: RDN 10.74 ± 2.48 vs. DCM 13.25 ± 1.99, P < 0.05) and pathological remodeling (collagen volume fraction: RDN 5.05 ± 2.05% vs. DCM 10.62 ± 2.68%, P < 0.05). Abnormal myocardial metabolism in DCM rats was characterized by suppressed glucose metabolism and elevated lipid metabolism. RDN increased myocardial glucose uptake and oxidation while reducing the absorption and utilization of fatty acids. Meanwhile, DCM decreased mitochondrial ATP content, depolarized the membrane potential and inhibited the activity of respiratory chain complexes, but RDN attenuated this mitochondrial damage (ATP: RDN 30.98 ± 7.33 µmol/gprot vs. DCM 22.89 ± 5.90 µmol/gprot, P < 0.05; complexes I, III and IV activity: RDN vs. DCM, P < 0.05). Furthermore, both SGLT2 inhibitor and the combination treatment produced similar effects as RDN alone. Thus, RDN prevented DCM-induced cardiac dysfunction and pathological remodeling, which is related to the improvement of metabolic disorders and mitochondrial dysfunction.

3.
Hum Reprod ; 36(11): 2904-2915, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34545401

RESUMO

STUDY QUESTION: What is the relationship between mitochondria of granulosa cells (GCs) and age and ovarian function in the patients under the POSEIDON classification? SUMMARY ANSWER: Our results revealed obvious abnormal mitochondrial-related changes in low prognosis IVF population, where age and the function of ovarian reserve exerted a divergent effect on mitochondrial content and function. WHAT IS KNOWN ALREADY: Mitochondria have an important role in the cross-talk between GCs and oocytes. However, factors affecting mitochondria of GCs and related mechanisms are still poorly understood. STUDY DESIGN, SIZE, DURATION: GCs samples were obtained from 119 infertile women undergoing IVF from September 2020 to February 2021. Six groups were investigated by the POSEIDON stratification: young with normal prognosis (C1), aging with normal prognosis (C2), young and low prognosis group with normal ovarian reserve (NOR) (G1), aging and low prognosis group with NOR (G2), young and low prognosis group with diminished ovarian reserve (DOR) (G3), and aging and low prognosis group with DOR (G4). PARTICIPANTS/MATERIALS, SETTING, METHODS: The morphology of GC mitochondria was observed by transmission electron microscopy. MtDNA copy number and mitochondrial replication-related genes were detected by real-time quantitative PCR (qPCR). Mitochondrial membrane potential (MMP) and cytosolic reactive oxygen species (ROS) were detected by confocal microscopy. Cellular glycolysis and aerobic respiratory capacity were analyzed by Seahorse XFe96 Analyzer, and related gene expression and protein levels were assessed by qPCR and Western blot. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to the normal prognosis groups, mitochondrial morphology was impaired in the low prognosis groups, where the young groups (G1, G3) with low prognosis showed phenotypes undergoing oxidative stress (round, vacuolated, swollen with decreased matrix density) and the aging groups (G2, G4) revealed typical aging characteristics (an irregular shape with heterogeneous matrix density and cord-like cristae). Additionally, the degree of corresponding change and damage was more obvious in patients with DOR (G3, G4) regardless of age. For mitochondrial content, the mtDNA copy number in GCs was significantly negatively correlated with age in the low prognosis groups (ß = -0.373, P = 0.005). Interestingly, the relationship between mtDNA copy number and anti-Mullerian hormone score differed between the two age groups with low prognosis, with a negative correlation in the young groups (ß = -0.639, P = 0.049) and a positive correlation in the aging groups (ß = 0.505, P = 0.039). In addition, significantly reduced mitochondrial activity (MMP, ROS) and cell metabolism (both glycolysis and OXPHOS) were observed in the low prognosis groups, with the most obvious decrease being observed in the DOR population. However, the metabolism of the GCs in normal prognosis aging women (C2) shifted from OXPHOS to anaerobic glycolysis. LIMITATIONS, REASONS FOR CAUTION: Owing to the difficulties involved in primary GC collection and culture, the sample size was limited. WIDER IMPLICATIONS OF THE FINDINGS: Mitochondrial abnormality is closely linked to the low prognostic outcome in IVF patients. Supplementing the functional mitochondrial content or improving mitochondrial function by autologous mitochondrial transfer or mitochondrial-related regulating drugs may help improve the clinical outcomes in patients with a low prognosis, especially for those with DOR. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (No. 21737001), the Peking University Clinical Medicine + X Youth Project (PKU2020LCXQ011), the Research and Development Program of Peking University People's Hospital (No. RDH2017-03; No. RDX2019-06) and the Application of Clinical Features of Capital Special Subject (Z171100001017130). There were no competing interests. TRIAL REGISTRATION NUMBER: This study was registered with the Chinese Clinical Trial Register (Clinical Trial Number: ChiCTR2100045531).


Assuntos
Infertilidade Feminina , Reserva Ovariana , Feminino , Fertilização In Vitro , Humanos , Infertilidade Feminina/metabolismo , Mitocôndrias , Oócitos/metabolismo , Prognóstico
4.
Front Physiol ; 12: 712338, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421655

RESUMO

Aims: The present study aimed to investigate alterations in neuroinflammation after heart failure (HF) and explore the potential mechanisms. Methods: Male wild-type (WT) and Toll-like receptor 4 (TLR4)-knockout (KO) mice were subjected to sham operation or ligation of the left anterior descending coronary artery to induce HF. 8 weeks later, cardiac functions were analyzed by echocardiography, and intestinal barrier functions were examined by measuring tight junction protein expression, intestinal permeability and plasma metabolite levels. Alterations in neuroinflammation in the brain were examined by measuring microglial activation, inflammatory cytokine levels and the proinflammatory signaling pathway. The intestinal barrier protector intestinal alkaline phosphatase (IAP) and intestinal homeostasis inhibitor L-phenylalanine (L-Phe) were used to examine the relationship between intestinal barrier dysfunction and neuroinflammation in mice with HF. Results: Eight weeks later, WT mice with HF displayed obvious increases in intestinal permeability and plasma lipopolysaccharide (LPS) levels, which were accompanied by elevated expression of TLR4 in the brain and enhanced neuroinflammation. Treatment with the intestinal barrier protector IAP significantly attenuated neuroinflammation after HF while effectively increasing plasma LPS levels. TLR4-KO mice showed significant improvements in HF-induced neuroinflammation, which was not markedly affected by intestinal barrier inhibitors or protectors. Conclusion: HF could induce intestinal barrier dysfunction and increase gut-to-blood translocation of LPS, which could further promote neuroinflammation through the TLR4 pathway.

5.
Cell Death Dis ; 12(7): 701, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262025

RESUMO

The mitochondrial DNA m.3243A > G mutation is well-known to cause a variety of clinical phenotypes, including diabetes, deafness, and osteoporosis. Here, we report isolation and expansion of urine-derived stem cells (USCs) from patients carrying the m.3243A > G mutation, which demonstrate bimodal heteroplasmy. USCs with high levels of m.3243A > G mutation displayed abnormal mitochondrial morphology and function, as well as elevated ATF5-dependent mitochondrial unfolded protein response (UPRmt), together with reduced Wnt/ß-catenin signaling and osteogenic potentials. Knockdown of ATF5 in mutant USCs suppressed UPRmt, improved mitochondrial function, restored expression of GSK3B and WNT7B, and rescued osteogenic potentials. These results suggest that ATF5-dependent UPRmt could be a core disease mechanism underlying mitochondrial dysfunction and osteoporosis related to the m.3243A > G mutation, and therefore could be a novel putative therapeutic target for this genetic disorder.


Assuntos
Fatores Ativadores da Transcrição/genética , DNA Mitocondrial/genética , Mitocôndrias/genética , Doenças Mitocondriais/genética , Mutação , Osteoporose/genética , Células-Tronco/metabolismo , Fatores Ativadores da Transcrição/metabolismo , Adulto , Estudos de Casos e Controles , Separação Celular , Células Cultivadas , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Heteroplasmia , Humanos , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/urina , Osteogênese , Osteoporose/diagnóstico , Osteoporose/urina , Fenótipo , Células-Tronco/ultraestrutura , Resposta a Proteínas não Dobradas , Urina/citologia , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , Adulto Jovem
6.
Invest Ophthalmol Vis Sci ; 62(7): 25, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34160563

RESUMO

Purpose: The ocular surface is considered an important route for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. The expression level of the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is vital for viral infection. However, the regulation of ACE2 expression on the ocular surface is still unknown. We aimed to determine the change in ACE2 expression in inflamed corneal epithelium and explore potential drugs to reduce the expression of ACE2 on the ocular surface. Methods: The expression of the SARS-CoV-2 receptors ACE2 and TMPRSS2 in human corneal epithelial cells (HCECs) was examined by qPCR and Western blotting. The altered expression of ACE2 in inflammatory corneal epithelium was evaluated in TNFα- and IL-1ß-stimulated HCECs and inflamed mouse corneal epithelium, and the effect of resveratrol on ACE2 expression in HCECs was detected by immunofluorescence and Western blot analysis. Results: ACE2 and TMPRSS2 are expressed on the human corneal epithelial cells. ACE2 expression is upregulated in HCECs by stimulation with TNFα and IL-1ß and inflamed mouse corneas, including dry eye and alkali-burned corneas. In addition, resveratrol attenuates the increased expression of ACE2 induced by TNFα in HCECs. Conclusions: This study demonstrates that ACE2 is highly expressed in HCECs and can be upregulated by stimulation with inflammatory cytokines and inflamed mouse corneal epithelium. Resveratrol may be able to reduce the increased expression of ACE2 on the inflammatory ocular surface. Our work suggests that patients with an inflammatory ocular surface may display higher ACE2 expression, which increases the risk of SARS-CoV-2 infection.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , Inibidores Enzimáticos/farmacologia , Epitélio Corneano/enzimologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Ceratite/enzimologia , Resveratrol/farmacologia , SARS-CoV-2/fisiologia , Adulto , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Western Blotting , Células Cultivadas , Epitélio Corneano/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Interleucina-1beta/farmacologia , Ceratite/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Virais/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima
7.
Rev. invest. clín ; 73(3): 164-171, May.-Jun. 2021. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1280453

RESUMO

ABSTRACT Background: Different from the traditional right ventricular pacing, the left bundle branch area pacing (LBBAP) is accomplished with deeper lead implantation and more attempts. However, myocardial damage is unclear in LBBAP. Objective: The objective of the study was to observe the change of troponin T and explore possible factors associated with greater myocardial damage in LBBAP. Methods: Patients with an indication for pacemaker implantation underwent attempts for LBBAP by transventricular septal method. Levels of troponin T were determined before operation, 12 h and 1 week after the operation. Parameters of intraoperation and follow-up were recorded and analyzed. Results: In total, successful LBBAP was achieved in 126 patients. The levels of troponin T increased significantly at 12 h after the operation compared with those before operation (96.45 ± 11.07 [69.06] vs. 16.59 ± 1.84 [11.92] ng/L, p < 0.001), while there were no significant differences between pre- and post-operative levels at 1 week. Correlation and regression analysis showed that only the number of attempts was an independent factor related to the change of troponin T. During 1 year of follow-up, LBBAP was safe and feasible with few complications. Conclusions: Myocardial damage of LBBAP was clinically significant. The number of attempts was an independent factor related to the myocardial damage.

8.
Cont Lens Anterior Eye ; : 101470, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34030907

RESUMO

PURPOSE: To investigate the relationship between axial length (AL) and refractive error (RE). METHODS: Participants comprised Chinese university students. In total, 894 eyes with low hyperopia to emmetropia (-0.50D ≤ spherical equivalent (SE) ≤ +2.00D), and 1007 eyes with moderate to high myopia (-11.00D ≤ SE ≤ -4.00D) were analyzed. Cycloplegic RE and AL were measured with an autorefractor and IOL Master respectively. The association between AL and RE was evaluated by linear regression. Furthermore, differences in the mean AL, as well as the correlation between AL and ocular refraction, were evaluated according to SE, sex, and age. RESULTS: In both the moderate to high myopia and low hyperopia to emmetropia groups, mean AL was significantly longer in men (26.48 mm, confidence interval (CI) 26.41-26.56 mm; 23.82 mm, CI: 23.76-23.88 mm, respectively) than in women (25.78 mm, CI: 25.71-25.86 mm; 23.25 mm, CI: 23.17-23.33 mm, respectively). For both men and women, mean AL significantly differed among four SE groups (+0.50D < SE ≤ +2.00D, -0.50D ≤ SE ≤ +0.50D, -4.00D ≤ SE ≤ -6.00D, SE < -6.00D, P < 0.001). The correlation coefficient between AL and ocular refraction was -0.318 and -0.277 in male and female participants, respectively, with low hyperopia to emmetropia (-0.50D ≤ SE ≤ +2.00D), and -0.545 and -0.437 in male and female participants, respectively, with moderate to high myopia (-11.00D ≤ SE ≤ -4.00D). There were no age-related effects on SE (P = 0.714) or AL (P = 0.952). CONCLUSIONS: Ocular refraction is negatively correlated with AL in Chinese university students. The correlation coefficient is greater in those with moderate to high myopia than in those with low hyperopia to emmetropia. Furthermore, the AL is longer in men than in women.

9.
Front Cardiovasc Med ; 8: 650140, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981735

RESUMO

Aims: The development of neuroinflammation deteriorates the prognosis of myocardial infarction (MI). We aimed to investigate the effect of renal denervation (RDN) on post-MI neuroinflammation in rats and the related mechanisms. Methods and Results: Male adult Sprague-Dawley rats were subjected to sham or ligation of the left anterior descending coronary artery to induce MI. One week later, the MI rats received a sham or RDN procedure. Their cardiac functions were analyzed by echocardiography, and their intestinal structures, permeability, and inflammatory cytokines were tested. The intestinal microbiota were characterized by 16S rDNA sequencing. The degrees of neuroinflammation in the brains of rats were analyzed for microglia activation, inflammatory cytokines, and inflammation-related signal pathways. In comparison with the Control rats, the MI rats exhibited impaired cardiac functions, intestinal injury, increased intestinal barrier permeability, and microbial dysbiosis, accompanied by increased microglia activation and pro-inflammatory cytokine levels in the brain. A RDN procedure dramatically decreased the levels of renal and intestinal sympathetic nerve activity, improved cardiac functions, and mitigated the MI-related intestinal injury and neuroinflammation in the brain of MI rats. Interestingly, the RDN procedure mitigated the MI-increased intestinal barrier permeability and pro-inflammatory cytokines and plasma LPS as well as ameliorated the gut microbial dysbiosis in MI rats. The protective effect of RDN was not significantly affected by treatment with intestinal alkaline phosphatase but significantly reduced by L-phenylalanine treatment in MI rats. Conclusions: RDN attenuated the neuroinflammation in the brain of MI rats, associated with mitigating the MI-related intestinal injury.

10.
Pestic Biochem Physiol ; 173: 104799, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33771268

RESUMO

Metabolic resistance is one of the main causes of acaricide resistance. Many previous studies focused on the function of specific genes in insecticides/acaricides resistance. However, during the development of resistance, the overall dynamic of expression levels of detoxification enzyme genes in mites is still unclear. Tetranychus cinnabarinus, a major agricultural pest, which is notorious for developing resistance to acaricides rapidly. In this study, a field susceptible strain (YS) was continuously selected for 16, 25 and 32 generations, and developed to low resistance (7.83-fold, L), medium resistance (17.23-fold, M) and high resistance (86.05-fold, H), respectively. Transcriptome sequencing was performed in YS, L, M and H strains. Overall, compared with YS strain, the number of differential expression genes increased slightly with the development of cyflumetofen-resistance. As for detoxification genes, the median of fold change of up-regulated P450、CCE and GST genes was higher than those of all up-regulated genes in three resistance level, but only the number and the median of fold change of up-regulated P450 genes was increased slightly with the development of resistance. In addition, synergism experiments also proved that P450 and GST genes were the major contributors to the metabolic resistance of cyflumetofen of T. cinnabarinus. These results showed that the resistance of T. cinnabarinus to cyflumetofen was related to many resistant genes, among which P450 genes could play crucial roles in cyflumefen resistance.


Assuntos
Acaricidas , Tetranychidae , Acaricidas/farmacologia , Animais , Proteínas de Artrópodes/genética , Resistência a Medicamentos/genética , Perfilação da Expressão Gênica , Propionatos , Tetranychidae/genética
11.
Reprod Sci ; 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712995

RESUMO

As the vital organelles for cell energy metabolism, mitochondria are essential for oocyte maturation, fertilization, and embryo development. Abnormalities in quantity, quality, and function of mitochondria are closely related to poor fertility and disorders, such as decreased ovarian reserve (DOR), premature ovarian aging (POA), and ovarian aging, as well as maternal mitochondrial genetic disease caused by mitochondrial DNA (mtDNA) mutations or deletions. Mitochondria have begun to become a therapeutic target for infertility caused by factors such as poor oocyte quality, oocyte aging, and maternal mitochondrial genetic diseases. Mitochondrial replacement therapy (MRT) has attempted to use heterologous or autologous mitochondria to rebuild healthy state of oocyte by increasing the amount of mitochondria (e.g., partial ooplasm transfer, autologous mitochondrial transfer), or to stop the transmission of mtDNA diseases by replacing abnormal maternal mitochondria (e.g., pronuclei transfer, spindle transfer, polar body transfer). Among them, autologous mitochondrial transfer is the most promising therapeutic technology as of today which does not involve using a third party, but its clinical efficacy is controversial due to many factors such as the aging phenomenon of germ line cells, the authenticity of the existence of ovarian stem cells (OSC), and secondary damage caused by invasive surgery to patients with poor ovarian function. Therefore, the research of optimal autologous cell type that can be applied in autologous mitochondrial transfer is an area worthy of further exploration. Besides, the quality of germ cells can also be probably improved by the use of compounds that enhance mitochondrial activity (e.g., coenzyme Q10, resveratrol, melatonin), or by innovative gene editing technologies which have shown capability in reducing the risk of mtDNA diseases (e.g., CRISPR/Cas9, TALENTs). Though the current evidences from animal and clinical trials are not sufficient, and some solutions of technical problems are still needed, we believe this review will guide a new direction in the possible clinical applied mitochondrial-related therapeutic strategies in reproductive medicine.

13.
Nurs Open ; 8(3): 1424-1435, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33528117

RESUMO

AIM: To evaluate whether high-intensity interval training (HIIT) was superior to low-intensity training or usual care among patients after percutaneous coronary intervention. The hypothesis was that HIIT would help patients after percutaneous coronary intervention (PCI) improve cardiopulmonary function, lipid profiles and in-stent restenosis. DESIGN: A systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA)2009 Checklist. METHODS: Randomized controlled trials (RCTs) focusing on HIIT programme in patients after PCI were searched in Cochrane Library, Web of Science Core Collection, EMbase, PubMed, China National Knowledge Infrastructure (CNKI) and SinoMed from the inception to 24 March 2020. Standard Mean difference (SMD) and 95% confidence intervals (CI) were performed to summarize the effect sizes. RESULTS: Six RCTs (247 patients) met the criteria. HIIT programme had a statistically significant effect on raising left ventricular ejection function (LVEF) (SMD = 0.38, 95%CI [0.03, 0.73], I2  = 3%), VO2peak (SMD = 0.94, 95%CI [0.61, 1.28], I2  = 0%), as well as improving the serum level of high-density lipoprotein (SMD = 0.55, 95%CI [0.06, 1.03], I2  = 0%) and late luminal loss (SMD = -0.65, 95%CI [-1.07, -0.23], I2  = 0%). But HIIT had no prominent effect on improving heart rate (SMD = -0.04, 95%CI [-0.29, 0.21], I2  = 0%). Summarily, HIIT programme appears to be favourable for CAD patients after PCI by improving cardiopulmonary function, such as LVEF and VO2peak , as well as reducing late luminal loss in per stented arteries. Nevertheless, HIIT has no advantage for adjusting heart rate. More researches with rigorous methods are warranted to explore the controversy about lipid profiles.


Assuntos
Doença da Artéria Coronariana , Treinamento Intervalado de Alta Intensidade , Intervenção Coronária Percutânea , China , Doença da Artéria Coronariana/cirurgia , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Função Ventricular Esquerda
14.
Kardiol Pol ; 79(3): 294-301, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33463997

RESUMO

BACKGROUND: Left ventricular mechanical dyssynchrony (LVMD) can be induced after stress test. However, no studies have compared the influence of different stress­inducing methods on LVMD parameters. AIMS: The aim of the study was to determine whether there is a difference between exercise and adenosine triphosphate (ATP) stress tests in terms of changes in LVMD parameters assessed using gated single­photon emission computed tomography myocardial perfusion imaging (GSPECT MPI). METHODS: A total of190 patients who underwent 99mTc ­sestamibi GSPECT MPI were consecutively enrolled. Treadmill exercise and ATP stress tests were performed in 95 patients each. Normal myocardial perfusion was defined as the summed stress score (SSS) ≤3 and summed rest score (SRS) ≤3, myocardial ischemia as SSS >3 and SRS ≤3, and myocardial infarction as SSS >3 and SRS >3. Parameters of LVMD, including phase standard deviation (PSD), phase bandwidth (PBW), skewness, and kurtosis were compared. Subtraction was made between values during stress and rest phases to acquire ∆PSD, ∆PBW, ∆skewness, and ∆kurtosis Results: There were no differences in LVMD parameters between the exercise and ATP groups. The same results were obtained in the normal perfusion, ischemia, and infarction subgroups. Furthermore, no differences were observed in ∆PSD (median [interquartile range, IQR], 0.25 [-2.3 to 3.1] vs 0.42 (-1.7 to 3.1]; P = 0.73), ∆PBW (median [IQR], 1 [-7 to 11] vs 1 [-6 to 11]; P = 0.95), ∆skewness (mean [SD], -0.06 [0.63] vs 0 [0.81]; P = 0.53), and ∆kurtosis (median [IQR], -0.47 [-4.2 to 4.3] vs -0.42 [-4.8 to 5.2]; P = 0.73) between the exercise and ATP stress­inducing methods. CONCLUSIONS: There are no differences between the exercise and ATP stress tests in terms of changes in LVMD parameters. Thus, the 2 methods can be used alternatively.


Assuntos
Imagem de Perfusão do Miocárdio , Disfunção Ventricular Esquerda , Trifosfato de Adenosina , Teste de Esforço , Humanos , Tomografia Computadorizada de Emissão de Fóton Único
15.
Sci Rep ; 11(1): 2283, 2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33504817

RESUMO

The anticancer effects of taxanes are attributed to the induction of mitotic arrest through activation of the spindle assembly checkpoint. Cell death following extended mitotic arrest is mediated by the intrinsic apoptosis pathway. Accordingly, factors that influence the robustness of mitotic arrest or disrupt the apoptotic machinery confer drug resistance. Survivin is an inhibitor of apoptosis protein. Its overexpression is associated with chemoresistance, and its targeting leads to drug sensitization. However, Survivin also acts specifically in the spindle assembly checkpoint response to taxanes. Hence, the failure of Survivin-depleted cells to arrest in mitosis may lead to taxane resistance. Here we show that Survivin depletion protects HeLa cells against docetaxel-induced apoptosis by facilitating mitotic slippage. However, Survivin depletion does not promote clonogenic survival of tumor cells but increases the level of cellular senescence induced by docetaxel. Moreover, lentiviral overexpression of Survivin does not provide protection against docetaxel or cisplatin treatment, in contrast to the anti-apoptotic Bcl-xL or Bcl-2. Our findings suggest that targeting Survivin may influence the cell response to docetaxel by driving the cells through aberrant mitotic progression, rather than directly sensitizing cells to apoptosis.


Assuntos
Docetaxel/farmacologia , Mitose/fisiologia , Survivina/metabolismo , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Células HeLa , Humanos , Mitose/genética , Survivina/genética , Proteína X Associada a bcl-2/metabolismo
16.
Nucl Med Commun ; 42(2): 182-189, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33252510

RESUMO

PURPOSES: This study aims to explore the prognostic value of left ventricular mechanical dyssynchrony (LVMD) in hypertrophic cardiomyopathy (HCM) patients with low risk of sudden cardiac death (SCD). METHODS: This retrospective study was performed in 50 patients with HCM who underwent Tc-99m sestamibi GSPECT-MPI. All patients were at low risk of SCD, defined as HCM risk-SCD scores <6%. Phase SD (PSD) and phase histogram bandwidth (PBW) were measured for assessment of LVMD. The primary endpoint was the composite major adverse cardiovascular events (MACE), including all-cause mortality, rehospitalization of heart failure symptoms, new-onset stroke, and new-onset syncope. Variables with significant difference between MACE group and non-MACE group were further assessed by Cox regression analysis. RESULTS: During follow-up, MACE occurred in 20 patients. Systolic-PSD, systolic-PBW, diastolic-PSD, and diastolic-PBW were all significantly greater in the MACE group. Multivariate analysis revealed that history of syncope, history of atrial fibrillation, and all the four LVMD parameters were independent predictors of MACE. All LVMD parameters showed similar accuracy to predict MACE. Sequential models indicated that both systolic and diastolic LVMD parameters added incremental value beyond atrial fibrillation and syncope. CONCLUSION: LVMD parameters are independent predictors of MACE, which add incremental prognostic information in patients with HCM risk-SCD scores <6%.


Assuntos
Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/diagnóstico , Morte Súbita Cardíaca , Disfunção Ventricular Esquerda/complicações , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/fisiopatologia , Diástole , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imagem de Perfusão do Miocárdio , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Sístole
17.
Pediatr Cardiol ; 42(1): 42-46, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33219830

RESUMO

The aim of this study is to evaluate the relationship between maternal single nucleotide polymorphisms (SNPs) of methylenetetrahydrofolate reductase (MTHFR) gene with plasma homocysteine (HCY) level and offspring congenital heart diseases (CHDs). 338 mothers with offspring CHDs as case group and 306 mothers of normal children as control group were recruited. Their pregnant histories were interviewed by questionnaire and the MTHFR rsl801133 and rsl801131 were genotyped. The case-control analysis was used to find out the relationship between maternal SNPs of MTHFR gene and offspring CHDs. And the plasma HCY concentration of the mothers of CHDs children was detected. This case-case study was intended to find out the relevance between maternal HCY level and SNPs of MTHFR gene. There were significant differences in the gender of children, occupation of mothers, family history with CHDs, history of abortion, history of adverse pregnancy, early pregnancy health, fetus during pregnancy, pesticide exposure and drug exposure in CHDs group and control group (P < 0.05). MTHFR rs1801133 was significantly associated with their offspring CHDs in mothers. The polymorphism of maternal MTHFR rs1801133 increased plasma HCY level, especially the homozygous mutation. Besides the environmental factors, our results suggested that the maternal MTHFR rs1801133 polymorphism might be a risk factor of their offspring CHDs, which may be due to the hyperhomocysteinemia by abnormal metabolism of HCY.


Assuntos
Cardiopatias Congênitas/genética , Homocisteína/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Estudos de Casos e Controles , Criança , Feminino , Genótipo , Humanos , Hiper-Homocisteinemia/epidemiologia , Hiper-Homocisteinemia/genética , Masculino , Mães , Mutação , Gravidez , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
18.
Rev Invest Clin ; 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33264800

RESUMO

BACKGROUND: Different from the traditional right ventricular pacing, the left bundle branch area pacing (LBBAP) is accomplished with deeper lead implantation and more attempts. However, myocardial damage is unclear in LBBAP. OBJECTIVE: The objective of the study was to observe the change of troponin T and explore possible factors associated with greater myocardial damage in LBBAP. METHODS: Patients with an indication for pacemaker implantation underwent attempts for LBBAP by transventricular septal method. Levels of troponin T were determined before operation, 12 h and 1 week after the operation. Parameters of intraoperation and follow-up were recorded and analyzed. RESULTS: In total, successful LBBAP was achieved in 126 patients. The levels of troponin T increased significantly at 12 h after the operation compared with those before operation (96.45 ± 11.07 [69.06] vs. 16.59 ± 1.84 [11.92] ng/L, p < 0.001), while there were no significant differences between pre- and post-operative levels at 1 week. Correlation and regression analysis showed that only the number of attempts was an independent factor related to the change of troponin T. During 1 year of follow-up, LBBAP was safe and feasible with few complications. CONCLUSIONS: Myocardial damage of LBBAP was clinically significant. The number of attempts was an independent factor related to the myocardial damage.

19.
JCI Insight ; 5(9)2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32229724

RESUMO

Hydrocephalus is characterized by abnormal accumulation of cerebrospinal fluid (CSF) in the ventricular cavity. The circulation of CSF in brain ventricles is controlled by the coordinated beating of motile cilia at the surface of ependymal cells (ECs). Here, we show that MT1-MMP is highly expressed in olfactory bulb, rostral migratory stream, and the ventricular system. Mice deficient for membrane-type 1-MMP (MT1-MMP) developed typical phenotypes observed in hydrocephalus, such as dome-shaped skulls, dilated ventricles, corpus callosum agenesis, and astrocyte hypertrophy, during the first 2 weeks of postnatal development. MT1-MMP-deficient mice exhibited reduced and disorganized motile cilia with the impaired maturation of ECs, leading to abnormal CSF flow. Consistent with the defects in motile cilia morphogenesis, the expression of promulticiliogenic genes was significantly decreased, with a concomitant hyperactivation of Notch signaling in the walls of lateral ventricles in Mmp14-/- brains. Inhibition of Notch signaling by γ-secretase inhibitor restored ciliogenesis in Mmp14-/- ECs. Taken together, these data suggest that MT1-MMP is required for ciliogenesis and EC maturation through suppression of Notch signaling during early brain development. Our findings indicate that MT1-MMP is critical for early brain development and loss of MT1-MMP activity gives rise to hydrocephalus.


Assuntos
Cílios/patologia , Epêndima , Hidrocefalia , Ventrículos Laterais , Metaloproteinase 14 da Matriz/fisiologia , Animais , Animais Recém-Nascidos , Diferenciação Celular , Células Cultivadas , Epêndima/metabolismo , Epêndima/patologia , Feminino , Hidrocefalia/metabolismo , Hidrocefalia/patologia , Ventrículos Laterais/metabolismo , Ventrículos Laterais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
20.
Elife ; 92020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32208136

RESUMO

At vertebrate neuromuscular junctions (NMJs), the synaptic basal lamina contains different extracellular matrix (ECM) proteins and synaptogenic factors that induce and maintain synaptic specializations. Here, we report that podosome-like structures (PLSs) induced by ubiquitous ECM proteins regulate the formation and remodeling of acetylcholine receptor (AChR) clusters via focal ECM degradation. Mechanistically, ECM degradation is mediated by PLS-directed trafficking and surface insertion of membrane-type 1 matrix metalloproteinase (MT1-MMP) to AChR clusters through microtubule-capturing mechanisms. Upon synaptic induction, MT1-MMP plays a crucial role in the recruitment of aneural AChR clusters for the assembly of postsynaptic specializations. Lastly, the structural defects of NMJs in embryonic MT1-MMP-/- mice further demonstrate the physiological role of MT1-MMP in normal NMJ development. Collectively, this study suggests that postsynaptic MT1-MMP serves as a molecular switch to synaptogenesis by modulating local ECM environment for the deposition of synaptogenic signals that regulate postsynaptic differentiation at developing NMJs.


Assuntos
Metaloproteinase 14 da Matriz/fisiologia , Junção Neuromuscular/embriologia , Junção Neuromuscular/metabolismo , Receptores Colinérgicos/metabolismo , Animais , Células Cultivadas , Matriz Extracelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/fisiologia , Neurogênese , Proteínas Nucleares/fisiologia , Podossomos/fisiologia , Ratos , Receptores Colinérgicos/química , Sinapses/fisiologia , Xenopus laevis
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