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BACKGROUND: Researches have found that alteration of intestinal flora may be closely related to the development of autism spectrum disorder (ASD). However, whether probiotics supplementation has a protective effect on ASD remains controversial. This meta-analysis aimed to analyze the outcome of probiotics in the treatment of ASD children. METHODS: The Pubmed, Cochrane Library, Web of Science and Embase were searched until Sep 2022. Randomized controlled trials (RCTs) relevant to the probiotics and placebo treatment on ASD children were screened. Quality assessment of the included RCTs was evaluated by the Cochrane collaboration's tool. The primary outcomes were ASD assessment scales, including ABC (aberrant behavior checklist) and CBCL (child behavior checklist) for evaluating the behavior improvement, SRS (social responsiveness scale) for social assessment, DQ (developmental quotient) for physical and mental development and CGI-I (clinical global impression improvement) for overall improvement. The secondary outcome was total 6-GSI (gastrointestinal severity index). RESULTS: In total, 6 RCTs from 6 studies with 302 children were included in the systemic review. Total 6-GSI (MD=-0.59, 95%CI [-1.02,-0.17], P < 0.05) decreased significantly after oral administration of probiotics. Whereas, there was no statistical difference in ABC, CBCL, SRS, DQ and CGI-I between probiotics and placebo groups in ASD children. CONCLUSION: Probiotics treatment could improve gastrointestinal symptoms, but there was no significant improvement in ASD.
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Transtorno do Espectro Autista , Probióticos , Humanos , Probióticos/uso terapêutico , Transtorno do Espectro Autista/terapia , Criança , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Microbioma GastrointestinalRESUMO
Ginsenoside Rh2 (GRh2) is a monomer isolated from red ginseng that has extensive pharmacological effects. However, whether GRh2 has a protective effect on ischaemia/reperfusion (I/R) in the myocardium has yet to be elucidated. The present study aimed to identify the anti-inflammatory and antioxidant effects of GRh2 on I/R in the myocardium and its underlying mechanism. A rat model of myocardial I/R injury was constructed by ligating the left anterior descending coronary artery, which was subsequently treated with GRh2. A total of 40 male Sprague-Dawley rats were divided into the following four groups: The sham group, the I/R group, the I/R+GRh2 (10 mg/kg) group and the I/R+GRh2 (20 mg/kg) group. Neonatal rat cardiomyocytes were also used to evaluate the protective effect of GRh2 on hypoxia/reoxygenation (H/R)-induced myocardial injury in vitro. The GRh2 pre-treatment reduced the I/R- or H/R-induced release of myocardial enzymes and the production of IL-1ß, IL-18 and TNF-α. GRh2 reduced the area of myocardial infarction and the histological changes in the myocardium and improved cardiac functions. In addition, GRh2 reduced the expression levels of NOD-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein, caspase-1, malondialdehyde and reactive oxygen species and increased the expression levels of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), glutathione peroxidase and superoxide dismutase. In conclusion, the present study confirmed that GRh2 could reduce oxidative stress and inflammation in cardiomyocytes after reperfusion, and its mechanism of action may be related to its regulation of the Nrf2/HO-1/NLRP3 signalling pathway.
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Fluvastatin, a traditional fat-decreasing drug, is widely used for curing cardiovascular disease. Previous reports demonstrated that fluvastatin pretreatment protected against myocardial ischemia/reperfusion (I/R) by inhibiting TLR4 signaling pathway and/or reducing proinflammatory cytokines. However, whether fluvastatin has a cardioprotective effect against apoptosis and autophagy remains unknown. This study aims to evaluate whether the cardioprotective role of fluvastatin in I/R is mediated by high-mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4) pathway via anti-apoptotic and anti-autophagic functions. Sprague-Dawley rats were anesthetized, artificially ventilated and subjected to 30 min of coronary occlusion, followed by 4 h of reperfusion. The animals were randomized into four groups: (i) Sham operation; (ii) I/R; (iii) I/R + low-dosage fluvastatin (10 mg/kg); and (iv) I/R + high-dosage fluvastatin (20 mg/kg). After reperfusion, the hemodynamic parameters, myocardial infarct size, structural alteration of myocardium, apoptosis index, pro-inflammatory cytokine production, Beclin-1, Light chain 3 (LC3), HMGB1, TLR4 and Nuclear factor kappa B (NF-κB) protein levels were measured and recorded. It was found that fluvastatin preconditioning improved left ventricular dysfunction, reduced HMGB1/TLR4/NF-κB expressions, and inhibited cardiomyocyte apoptosis, autophagy, and inflammation reaction. Moreover, treatment with fluvastatin ameliorated myocardial injury by reducing infarct size, causing less damage to cardiac structure, downregulating autophagy-related protein expression and releasing pro-inflammation mediators. Our findings indicate that fluvastatin exerts beneficial effects on cardiac ischemic damage, which may be associated with its anti-autophagic and anti-apoptotic functions via inhibition of HMGB1/TLR4-related pathway during I/R injury.
Assuntos
Apoptose/fisiologia , Autofagia/fisiologia , Fluvastatina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cardiotônicos/metabolismo , Cardiotônicos/farmacologia , China , Fluvastatina/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Masculino , Infarto do Miocárdio/metabolismo , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND AND AIMS: Myocardial ischemia/reperfusion injury (MI/RI) is a result of coronary revascularization, and often increases cell apoptosis and autophagy. Downregulated cellular FADD-like-IL-1ß-converting enzyme-inhibitory protein (cFLIP) was associated with development of several myocardial diseases, whether overexpression of cFLIP can attenuate MI/RI remains unclear. This study aimed to determine the effects of cFLIP on apoptosis and autophagy in MI/RI. METHODS AND RESULTS: Ischemia/reperfusion (I/R) rat model and hypoxia/reoxygenation (H/R) cardiomyocytes model were established. Both I/R injury and H/R injury down-regulated expression of two cFLIP isoforms (cFLIPL and cFLIPS), and instigated apoptosis and autophagy simultaneously. Overexpression of cFLIPL and/or cFLIPS led to a significant increase in cardiomyocytes viability in vitro, and also reduced the myocardial infarct volume in vivo, these changes were associated with suppressed apoptosis and autophagy. Mechanistically, overexpression of cFLIP significantly downregulated pro-apoptotic molecules (Caspase-3, -8, -9), and pro-autophagic molecules (Beclin-1 and LC3-II). Moreover, cFLIP significantly suppressed activity of NF-κB pathway to upregulate the expression of Bcl-2, which is the molecular of interplay of apoptosis and autophagy. CONCLUSION: Overexpression of cFLIP significantly attenuated MI/RI both in vivo and vitro via suppression of apoptosis and lethal autophagy. cFLIP can suppress activity of NF-κB pathway, and further upregulated expression of Bcl-2.
Assuntos
Apoptose , Autofagia , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Células Cultivadas , Modelos Animais de Doenças , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Regulação para CimaRESUMO
miRNA-mediated pyroptosis play crucial effects in the development of myocardial ischaemia/reperfusion (I/R) injury (MIRI). Piperine (PIP) possesses multiple pharmacological effects especially in I/R condition. This study focuses on whether PIP protects MIRI from pyroptosis via miR-383-dependent pathway. Rat MIRI model was established by 30 minutes of LAD ligation and 4 hours of reperfusion. Myocardial enzymes, histomorphology, structure and function were detected to evaluate MIRI. Recombinant adenoviral vectors for miR-383 overexpression or miR-383 silencing or RP105 knockdown were constructed, respectively. Luciferase reporter analysis was used to confirm RP105 as a target of miR-383. Pyroptosis-related markers were measured by Western blotting assay. The results showed that I/R provoked myocardial injury, as shown by the increases of LDH/CK releases, infarcted areas and apoptosis as well as worsened function and structure. Pyroptosis-related mediators including NLRP3, cleaved caspase-1, cleaved IL-1ß and IL-18 were also reinforced after MIRI. However, PIP treatment greatly ameliorated MIRI in parallel with pyroptotic repression. In mechanistic studies, MIRI-caused elevation of miR-383 and decrease of RP105/PI3K/AKT pathway were reverted by PIP treatment. Luciferase reporter assay confirmed RP105 as a miR-383 target. miR-383 knockdown ameliorated but miR-383 overexpression facilitated pyroptosis and MIRI. Moreover, the anti-pyroptotic effect from miR-383 silencing was verified to be relied on the RP105/PI3K/AKT signalling pathway. Additionally, our present study further indicated the miR-383/RP105/AKT-dependent approach resulting from PIP administration against pyroptosis in MIRI. Therefore, PIP treatment attenuates MIRI and pyroptosis by regulating miR-383/RP105/AKT pathway, and it may provide a therapeutic manner for the treatment of MIRI.
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Alcaloides/farmacologia , Antígenos CD/metabolismo , Benzodioxóis/farmacologia , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piroptose , Animais , Cardiotônicos/farmacologia , Masculino , MicroRNAs/genética , Piroptose/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Objective: To compare the efficacy and safety of genotype-guided antiplatelet strategy and standard treatment in patient with coronary artery disease (CAD) after percutaneous coronary intervention (PCI). Methods: Relevant studies published in Medline, Embase, CoChrane Library were searched for randomized controlled trials (RCTs) until August 2020. Studies were screened by selection criteria, quality assessed using the Cochrane Collaboration's tool. Data were extracted from the included studies and statistically analyzed by RevMan 5.3 software. Results: Four RCTs involving 4,604 patients were included in this meta-analysis. Compared with the standard treatment group, the pooled results showed that genotype-guided group associated with lower risk of major adverse cardiovascular events (MACE, OR=0.52, 95%CI:0.35-0.78, P =0.001), any bleeding (OR=0.77, 95%CI: 0.62-0.95, P =0.02) and myocardial infarction (MI, OR=0.48, 95%CI:0.33-0.68, P <0.0001). There was no significant difference in death of any cause (OR=0.53, 95%CI: 0.18-1.54, P =0.25), cardiovascular death (OR=0.74, 95%CI:0.48-1.14, P =0.17), target vessel revascularization (OR=0.66, 95%CI:0.39-1.12, P =0.12) and major bleeding events (OR=0.86, 95%CI: 0.58-1.28, P =0.47). Conclusion: Genotype guided antiplatelet therapy could reduce the risk of MACE, MI and any bleeding events in patients with CAD undergone PCI, compared with standard treatment. Therefore, the findings support that implementation of genotype testing to tailor antiplatelet therapy after PCI.
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Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Genótipo , HumanosRESUMO
BACKGROUND: Cardiac injury is a common condition among hospitalized coronavirus disease 2019 (COVID-19) patients, and is associated with a higher risk of mortality. However, the mechanism of myocardial injury in COVID-19 remains unclear. In this retrospective study, we compared the clinical characteristics of COVID-19 patients with different troponin I (TnI) levels during hospitalization to provide a clinical reference for the identification of those at high-risk. METHODS: In total, 218 patients diagnosed with COVID-19 in Yichang Central People's Hospital and Yichang Third People's Hospital between January 23 and February 19, 2020 were initially included. Of these patients, 89 underwent TnI testing during hospitalization and were finally included in the study. The medical history, clinical signs and symptoms at the time of admission, and laboratory test results were recorded. The patients were assigned to the normal TnI group (TnI <0.01 µg/L; n=67) or the elevated TnI group (TnI >0.01 µg/L; n=22). RESULTS: The incidence of elevated TnI in our patient cohort was 24.7%. There were significant differences between the two groups in the following factors: history of coronary heart disease (CHD), age, lymphocyte count, prothrombin time (PT), activated partial thromboplastin time (APTT), and levels of interleukin (IL)-6, C-reactive protein (CRP), myoglobin (MYO), lactate dehydrogenase (LDH), and albumin (all P<0.05). Binary logistic analysis showed that a history of CHD, age, lymphocyte count, IL-6, APTT, and MYO were influencing factors of elevated serum TnI. CONCLUSIONS: A history of CHD, advanced age, decreased lymphocyte count, increased IL-6, increased MYO, and prolonged APTT were independent influencing factors of elevated TnI in COVID-19 patients. COVID-19 patients with these characteristics are prone to myocardial injury.
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Objective: The optimal duration of dual antiplatelet therapy (DAPT) in patients after PCI with implantation of a drugeluting stent is still controversial. We conducted a meta-analysis to compare the efficacy and safety of short term DAPT (≤ 3 months) followed by P2Y12 inhibitor monotherapy and standard DAPT (12 months) after PCI. Method: Relevant studies published in Medline, Embase, CoChrane Library were searched for randomized controlled trials (RCTs) until November 2019. Studies were screened by selection criteria then quality assessed through the Cochrane Collaboration's tool. Data were extracted from the included studies and statistically analyzed by RevMan 5.3 software. Results: Five RCTs (n=18,357) were included. Compared with standard DAPT, the short term DAPT was associated with a significant decrease in the major bleeding [odds ratio (OR)=0.43, 95% Confidence Interval (CI):0.32-0.58, P <0.00001] and any bleeding [OR=0.56, 95%CI:0.47-0.66, P<0.00001]. There were no significant differences in all-cause death [OR=0.91, 95%CI:0.71-1.16, P =0.45], major adverse cardiac and cerebrovascular event [OR=1.01, 95%CI:0.87-1.17, P =0.91] and stent thrombosis [OR=0.97, 95%CI:0.61-1.54, P =0.91] between with the short term DAPT group and the standard DAPT group. Conclusions: Short term DAPT followed by P2Y12 monotherapy could reduce the risk of bleeding without increasing the incidence of ischemic events after PCI with implantation of second-generation DES compared with standard DAPT. Therefore, short term DAPT may be a promising strategy to balance ischemic events and bleeding complications in patients after PCI.
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Stents Farmacológicos , Intervenção Coronária Percutânea/métodos , Inibidores da Agregação Plaquetária/uso terapêutico , Hemorragia Pós-Operatória/prevenção & controle , Quimioterapia Combinada , Humanos , Isquemia/epidemiologia , Isquemia/prevenção & controle , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Purinérgicos P2Y12/efeitos dos fármacosRESUMO
Apoptosis is the major cause of cardiomyocyte death in myocardial ischemia/reperfusion injury (MI/RI). Increasing evidence suggests that microRNAs (miRNAs) can contribute to the regulation of cardiomyocytes apoptosis by posttranscriptional modulation of gene expression networks. However, the effects of miR-327 in regulating MI/RI-induced cardiomyocytes apoptosis have not been extensively investigated. This study was performed to test whether miR-327 participate in cardiomyocytes apoptosis both in vitro and in vivo, and reveal the potential molecular mechanism of miR-327 regulated MI/RI through targeting apoptosis repressor with caspase recruitment domain (ARC). Sprague-Dawley (SD) rats were subjected to MI/RI by left anterior descending coronary artery occlusion for 30 min and reperfusion for 3 hr. H9c2 cells were exposed to hypoxia for 4 hr and reoxygenation for 12 hr to mimic I/R injury. miRNA-327 recombinant adenovirus vectors were transfected into H9c2 cells for 48 hr and rats for 72 hr before H/R and MI/RI treatment, respectively. The apoptosis rate, downstream molecules of apoptotic pathway, and the target reaction between miRNA-327 and ARC were evaluated. Our results showed that miR-327 was upregulated and ARC was downregulated in the myocardial tissues of MI/RI rats and in H9c2 cells with H/R treatment. Inhibition of miR-327 decreased the expression levels of proapoptotic proteins Fas, FasL, caspase-8, Bax, cleaved caspase-9, cleaved caspase-3, and the release of cytochrome-C, as well as increasing the expression levels of antiapoptotic protein Bcl-2 via negative regulation of ARC both in vivo or vitro. In contrast, overexpression miR-327 showed the reverse effect. Moreover, the results of luciferase reporter assay indicated miR-327 targets ARC directly at the posttranscriptional level. Taken together, inhibition of miR-327 could attenuate cardiomyocyte apoptosis and alleviate I/R-induced myocardial injury via targeting ARC, which offers a new therapeutic strategy for MI/RI.
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Proteínas Reguladoras de Apoptose/genética , MicroRNAs/genética , Proteínas Musculares/genética , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão/genética , Animais , Apoptose/efeitos dos fármacos , Caspase 3/genética , Caspase 9/genética , Modelos Animais de Doenças , Humanos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Uncoupling protein 2 (UCP2), located in the mitochondrial inner membrane, is a predominant isoform of UCP that expressed in the heart and other tissues of human and rodent tissues. Nevertheless, its functional role during myocardial ischemia/reperfusion (I/R) is not entirely understood. Ischemic preconditioning (IPC) remarkably improved postischemic functional recovery followed by reduced lactate dehydrogenase (LDH) release with simultaneous upregulation of UCP2 in perfused myocardium. We then investigated the role of UCP2 in IPC-afforded cardioprotective effects on myocardial I/R injury with adenovirus-mediated in vivo UCP2 overexpression (AdUCP2) and knockdown (AdshUCP2). IPC-induced protective effects were mimicked by UCP2 overexpression, while which were abolished with silencing UCP2. Mechanistically, UCP2 overexpression significantly reinforced I/R-induced mitochondrial autophagy (mitophagy), as measured by biochemical hallmarks of mitochondrial autophagy. Moreover, primary cardiomyocytes infected with AdUCP2 increased simulated ischemia/reperfusion (sI/R)-induced mitophagy and therefore reversed impaired mitochondrial function. Finally, suppression of mitophagy with mdivi-1 in cultured cardiomyocytes abolished UCP2-afforded protective effect on sI/R-induced mitochondrial dysfunction and cell death. Our data identify a critical role for UCP2 against myocardial I/R injury through preventing the mitochondrial dysfunction through reinforcing mitophagy. Our findings reveal novel mechanisms of UCP2 in the cardioprotective effects during myocardial I/R.
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Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/citologia , Proteína Desacopladora 2/genética , Proteína Desacopladora 2/metabolismo , Animais , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , L-Lactato Desidrogenase/metabolismo , Mitofagia , Traumatismo por Reperfusão Miocárdica/genética , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-Dawley , Regulação para CimaRESUMO
Raidoprotective 105 (RP105) was first discovered on the surface of mouse B cells and it has been demonstrated that RP105 can function as an inflammatory regulator in cardiovascular disease (CVD), such as myocardial ischemic reperfusion injury (MI/RI), atherosclerosis and myocardial infarction (MI). As a member of Toll-like receptor (TLR) homolog which is capable of regulating toll-like receptor (TLR4) signaling pathway, RP105 is implicated in various biological processes. Mounting evidence suggests that RP105 regulates the function of TLR4 and phosphoinositide 3-kinase (PI3K) signaling pathways. Here, we review the effect of RP105 on CVD through regulating TLR4/PI3K signaling pathways.
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Antígenos CD/metabolismo , Doenças Cardiovasculares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/metabolismo , Animais , HumanosAssuntos
Coração , Traumatismo por Reperfusão Miocárdica , Humanos , Isquemia Miocárdica , MiocárdioAssuntos
Antígenos CD/genética , Regulação da Expressão Gênica , Terapia Genética/métodos , Traumatismo por Reperfusão Miocárdica/terapia , Miocárdio/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Antígenos CD/biossíntese , Modelos Animais de Doenças , Camundongos , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/patologia , Transdução de SinaisRESUMO
Coronary heart diseases, particularly acute coronary syndrome, have increased in morbidity and mortality in recent decades. Percutaneous coronary intervention, coronary artery bypass grafting and thrombolytic agents are effective strategies to rescue the infarcted myocardium. In addition to acute myocardial infarction, the resulting myocardial ischemiareperfusion injury (MIRI) leads to serious secondary injury of the heart. Studies have demonstrated that activating transcription factor (ATF)/cyclic adenosine monophosphate response element binding family member ATF3 had a negative regulatory role in IRI, particularly in the kidney, cerebrum and liver. The present review expounded the expression characteristics of ATF3 and its protective effects against MIRI, providing a theoretical basis for the overexpression of ATF3 in the myocardium as a promising gene-therapeutic strategy for MIRI.