RESUMO
Cadmium (Cd) as a ubiquitous toxic heavy metal is reported to affect the nervous system. Selenium (Se) has been shown to have antagonistic effects against heavy metal toxicity. In addition, it shows potential antioxidant and anti-inflammatory properties. Thus, the purpose of this study was to determine the possible mechanism of brain injury after high Cd exposure and the mitigation of Nano-selenium (Nano-Se) against Cd-induced brain injury. In this study, the Cd-treated group showed a decrease in the number of neurons in brain tissue, swelling of the endoplasmic reticulum and mitochondria, and the formation of autophagosomes. Nano-Se intervention restored Cd-caused alterations in neuronal morphology, endoplasmic reticulum, and mitochondrial structure, thereby reducing neuronal damage. Furthermore, we found that some differentially expressed genes were involved in cell junction and molecular functions. Subsequently, we selected eleven (11) related differentially expressed genes for verification. The qRT-PCR results revealed the same trend of results as determined by RNA-Seq. Our findings also showed that Nano-Se supplementation alleviated Cx43 phosphorylation induced by Cd exposure. Based on immunofluorescence colocalization it was demonstrated that higher expression of GFAP and lower expressions of Cx43 were restored by Nano-Se supplementation. In conclusion, the data presented in this study establish a direct association between the phosphorylation of Cx43 and the occurrence of autophagy and neuroinflammation. However, it is noteworthy that the introduction of Nano-Se supplementation has been observed to mitigate these alterations. These results elucidate the relieving effect of Nano-Se on Cd exposure-induced brain injury.
Assuntos
Lesões Encefálicas , Cérebro , Selênio , Humanos , Selênio/farmacologia , Cádmio/toxicidade , Conexina 43/metabolismo , Conexinas/metabolismo , Fosforilação , Cérebro/metabolismoRESUMO
Wulfenioidones A - K (1-11) were abietane diterpenoids with highly oxidized 6/6/6 aromatic tricyclic skeleton isolated from the whole plant of Orthosiphon wulfenioides, and their planar structures and absolute configurations were elucidated by spectroscopic data interpretation, electronic circular dichroism calculation as well as X-ray crystallography analysis. Bioactivity screening indicated that compounds 1-4, 6 and 8 exhibited lactate dehydrogenase (LDH) inhibition effect with IC50 values ranging from 0.23 to 3.43 µM by preventing the mononuclear macrophage cell pyroptosis induced by double signal stimulation of LPS and nigericin. Western Blot analyses of Caspase-1 and IL-1ß down-regulation exhibited that compound 1 could selectively inhibit NLRP3 inflammasome, and the cell morphological observation further supported that compound 1 prevented macrophage cell pyroptosis.
Assuntos
Inflamassomos , Orthosiphon , Proteína 3 que Contém Domínio de Pirina da Família NLR , Abietanos/farmacologia , Abietanos/química , MacrófagosRESUMO
Twelve new clerodane diterpenoids named callicarpanes A-L (1-12), together with eight known compounds (13-20), were isolated from Callicarpa integerrima. Their structures were determined by comprehensive spectroscopic data. The calculated chemical shifts were used to identify relative configurations using DP4+ analysis. The absolute configurations (AC) were assigned based on quantum chemical calculations and X-ray single-crystal diffraction methods. Compoundsâ 1, 3, 5, 9, 10, 12, 15, 16, and 19 showed significant inhibitory activity for NLRP3 inflammasome activation, with the IC50 against lactate dehydrogenase (LDH) release ranging from 0.08 to 4.78â µM. Further study revealed that compound 10 repressed IL-1ß secretion and caspase-1 maturation in J774A.1 cell as well as blocked macrophage pyroptosis.
Assuntos
Callicarpa , Diterpenos Clerodânicos , Diterpenos Clerodânicos/farmacologia , Diterpenos Clerodânicos/química , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Callicarpa/química , MacrófagosRESUMO
Eight new aspulvinone analogues, aspulvins A-H (1-8) and aspulvinones D, M, O, and R (9-12), were isolated from cultures of the endophytic fungus Cladosporium sp. 7951. Detailed spectroscopic analyses were conducted to determine the structures of the new compounds. All isolates displayed different degrees of inhibitory activity against the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 Mpro) at 10 µM. Notably, compounds 9, 10, and 12 showed potential SARS-CoV-2 Mpro inhibition with IC50 values of 10.3 ± 0.6, 9.4 ± 0.6, and 7.7 ± 0.6 µM, respectively. For all compounds except 3 and 4, the anti-inflammatory activity occurred by inhibiting the release of lactate dehydrogenase (LDH) with IC50 values ranging from 0.7 to 7.4 µM. Compound 10 showed the most potent anti-inflammatory activity by inhibiting Casp-1 cleavage, IL-1ß maturation, NLRP3 inflammasome activation, and pyroptosis. The findings reveal that the aspulvinone analogues 9, 10, and 12 could be promising candidates for coronavirus disease 2019 (COVID-19) treatment as they inhibit SARS-CoV-2 infection and reduce inflammatory reactions caused by SARS-CoV-2.
Assuntos
Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Anti-Inflamatórios/farmacologia , Antivirais/química , Cladosporium , HumanosRESUMO
Myxofibrosarcoma is a common soft-tissue sarcoma in elderly patients, characterized by an infiltrative growth pattern and a high risk for persistent local recurrence. A 35-years-old woman was diagnosed with myxofibrosarcoma on the right upper arm and the tumor is surgically resected. The tumor relapsed 7 months later. Then the patient received five cycles of low power cumulative high-intensity focused ultrasound (HIFU) treatments, which completely ablated the tumor without complications. Now the patient is disease free with a high quality of life more than 30 months. This case indicates HIFU ablation might be a novel, promising therapy for recurrent myxofibrosarcoma.
Assuntos
Fibrossarcoma , Ablação por Ultrassom Focalizado de Alta Intensidade , Neoplasias de Tecidos Moles , Adulto , Idoso , Feminino , Fibrossarcoma/terapia , Ablação por Ultrassom Focalizado de Alta Intensidade/efeitos adversos , Humanos , Recidiva Local de Neoplasia , Qualidade de Vida , Neoplasias de Tecidos Moles/terapiaRESUMO
Contrast-induced acute kidney injury (CI-AKI) is associated with increasing in-hospital and long-term adverse clinical outcomes in high-risk patients undergoing percutaneous coronary intervention (PCI). Contrast media (CM)-induced renal tubular cell apoptosis is reported to participate in this process by activating endoplasmic reticulum (ER) stress. An angiotensin II type 1 receptor (AT1R) antagonist can alleviate ER stress-induced renal apoptosis in streptozotocin (STZ)-induced diabetic mice and can reduce CM-induced renal apoptosis by reducing oxidative stress and reversing the enhancement of bax mRNA and the reduction of bcl-2 mRNA, but the effect of the AT1R blocker on ER stress in the pathogenesis of CI-AKI is still unknown. In this study, we explored the effect of valsartan on meglumine diatrizoate-induced human renal tubular cell apoptosis by measuring changes in ER stress-related biomarkers. The results showed that meglumine diatrizoate caused significant cell apoptosis by up-regulating the expression of ER stress markers, including glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), CCAAT/enhancer-binding protein-homologous protein (CHOP) and caspase 12, in a time- and dose-dependent manner, which could be alleviated by preincubation with valsartan. In conclusion, valsartan had a potential nephroprotective effect on meglumine diatrizoate-induced renal cell apoptosis by inhibiting ER stress.
Assuntos
Apoptose/fisiologia , Meios de Contraste/toxicidade , Estresse do Retículo Endoplasmático/fisiologia , Valsartana/farmacologia , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Túbulos Renais/citologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/fisiologia , Camundongos , Substâncias Protetoras/farmacologiaRESUMO
BACKGROUND: Oral anticoagulation (OAC) following catheter ablation (CA) of nonvalvular atrial fibrillation (NVAF) is essential for the prevention of thrombosis events. Inappropriate application of OACs does not benefit thrombosis prevention but may be associated with a higher risk of bleeding. Therefore, this study aims to develop clinical data-driven machine learning (ML) methods to predict the risk of thrombosis and bleeding to establish more precise anticoagulation strategies for patients with NVAF. METHODS: Patients with NVAF underwent CA therapy were enrolled from Southwest Hospital from 2015 to 2023. This study compared eight ML algorithms to evaluate the predictive power for both thrombosis and bleeding. Model interpretations were recognized by feature importance and SHapley Addictive exPlanations methods. With potential essential risk factors, simplified ML models were proposed to improve the feasibility of the tool. RESULTS: A total of 1055 participants were recruited, including 105 patients with thrombosis and 252 patients with bleeding. The models based on XGBoost achieved the best performance with accuracies of 0.704 and 0.781 for thrombosis and bleeding. Age, BNP and the duration of heparin and are closely related to the high risk of thrombosis, whereas anticoagulation strategy, BNP and lipids play a crucial role in the occurrence of bleeding. The optimized models enrolling crucial risk factors, RF-T for thrombosis and Xw-B for bleeding, achieved the best recalls of 0.774 and 0.780, respectively. CONCLUSIONS: The optimized models will have a great clinical application in predicting thrombosis and bleeding among NVAF patients and will form the basis for future score scales.
RESUMO
Cadmium (Cd) is a transition metal ion that is extremely harmful to human and animal biological systems. Cd is a toxic substance that can accumulate in the food chain and cause various health issues. Sulforaphane (SFN) is a natural bioactive compound with potent antioxidant properties. In our study, 80 1 day-old chicks were fed with Cd (140 mg/kg BW/day) and/or SFN (50 mg/kg BW/day) for 90 days. The blood-thymus barrier (BTB) is a selective barrier separating T-lymphocytes from blood and cortical capillaries in the thymus cortex. Our research revealed that Cd could destroy the BTB by downregulating Wnt/ß-catenin signaling and induce immunodeficiency, leading to irreversible injury to the immune system. The study emphasizes the health benefits of SFN in the thymus. SFN could ameliorate Cd-triggered BTB dysfunction and pyroptosis in the thymus tissues. SFN modulated the PI3K/AKT/FOXO1 axis, improving the level of claudin-5 (CLDN5) in the thymus to alleviate BTB breakdown. Our findings indicated the toxic impact of Cd on thymus, and BTB could be the specific target of Cd toxicity. The finding also provides evidence for the role of SFN in maintaining thymic homeostasis for Cd-related health issues.
Assuntos
Cádmio , Galinhas , Isotiocianatos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Sulfóxidos , Timo , Animais , Isotiocianatos/farmacologia , Cádmio/toxicidade , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Timo/efeitos dos fármacos , Timo/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Transdução de Sinais/efeitos dos fármacos , Humanos , MasculinoRESUMO
Methylmercury (MeHg) production in aquatic ecosystems is a global concern because of its neurotoxic effect. Dissolved organic matter (DOM) plays a crucial role in biogeochemical cycling of Hg. However, owing to its complex composition, the effects of DOM on net MeHg production have not been fully understood. Here, the Hg isotope tracer technique combined with different DOM treatments was employed to explore the influences of DOM with divergent compositions on Hg methylation/demethylation and its microbial mechanisms in eutrophic lake waters. Our results showed that algae-derived DOM treatments enhanced MeHg concentrations by 1.42-1.53 times compared with terrestrial-derived DOM. Algae-derived DOM had largely increased the methylation rate constants by approximately 1-2 orders of magnitude compared to terrestrial-derived DOM, but its effects on demethylation rate constants were less pronounced, resulting in the enhancement of net MeHg formation. The abundance of hgcA and merB genes suggested that Hg-methylating and MeHg-demethylating microbiomes responded differently to DOM treatments. Specific DOM components (e.g., aromatic proteins and soluble microbial byproducts) were positively correlated with both methylation rate constants and the abundance of Hg-methylating microbiomes. Our results highlight that the DOM composition influences the Hg methylation and MeHg demethylation differently and should be incorporated into future Hg risk assessments in aquatic ecosystems.
Assuntos
Mercúrio , Compostos de Metilmercúrio , Poluentes Químicos da Água , Compostos de Metilmercúrio/metabolismo , Matéria Orgânica Dissolvida , Lagos/química , Ecossistema , Mercúrio/análise , Água , Poluentes Químicos da Água/químicaRESUMO
BACKGROUND: Decreased estimated glomerular filtration rate (eGFR) is a strong predictor of both mortality and subsequent cardiac events after percutaneous coronary intervention. The safety and efficacy of drug-eluting (DESs) versus bare-metal stents (BMSs) in this population have not been evaluated adequately. STUDY DESIGN: A systematic review and meta-analysis. SETTING & POPULATION: Studies involving the comparison of clinical outcomes between DESs and BMSs in patients with eGFR <60 mL/min/1.73 m(2). Studies exclusively involving patients with ST-segment elevation myocardial infarction were excluded. SELECTION CRITERIA FOR STUDIES: MEDLINE (on Ovid), EMBASE, and the Cochrane Library databases from 2002-2013 were searched for studies comparing DESs with BMSs in patients with eGFR <60 mL/min/1.73 m(2). INTERVENTION: DES versus BMS implantation. OUTCOMES: Mortality, repeat revascularization, myocardial infarction, and stent thrombosis. RESULTS: Data from 26 comparative studies with 66,840 patients were included. Compared with BMSs, DESs were associated with significant reductions in repeat revascularization (OR, 0.61; 95% CI, 0.50-0.74; P < 0.001) and myocardial infarction (OR, 0.85; 95% CI, 0.79-0.92; P < 0.001), with no detectable difference in stent thrombosis (OR, 0.72; 95% CI, 0.46-1.12; P = 0.1). The superiority of DESs over BMSs in decreasing mortality also was documented (OR, 0.77; 95% CI, 0.65-0.90; P = 0.01). This survival benefit of DESs over BMSs was attenuated in randomized controlled trials or adjusted observational studies versus unadjusted observational studies. LIMITATIONS: Most studies were observational studies. Meta-analysis was not performed on individual patient data. CONCLUSIONS: DES use in patients with eGFR <60 mL/min/1.73 m(2) is associated with a reduced rate of repeat revascularization and myocardial infarction without increased risk of stent thrombosis. The true effect of DESs versus BMSs on mortality needs to be confirmed by randomized controlled trials.
Assuntos
Stents Farmacológicos , Taxa de Filtração Glomerular , Infarto do Miocárdio/epidemiologia , Trombose/epidemiologia , Humanos , Desenho de Prótese , Stents , Resultado do TratamentoRESUMO
OBJECTIVE: To explore the effects of allitridi capsules on endothelial function and clinical prognosis after percutaneous coronary intervention (PCI) in coronary artery disease (CAD) patients with diabetes mellitus (DM). METHODS: A total of 120 CAD patients with DM undergoing PCI were randomly assigned to receive conventional (control, n = 60) and additional allitridi treatment (120 mg/day, n = 60) for 3 months.Serum nitric oxide (NO) and intercellular adhesion molecule 1 (ICAM-1) levels were determined by enzyme-linked immunosorbent assay (ELISA) immediately and at 3 months post-PCI. Endothelial function was assessed by endothelium dependent flow-mediated dilation (FMD). Duration of follow-up was 1 year after PCI. RESULTS: The clinical characteristics, serum NO and ICAM-1 levels and FMD at baseline were not different between two groups. At Month 3 post-PCI, serum NO level was markedly higher ((147 ± 32) vs (112 ± 24) µmol/L, P = 0.009) and serum ICAM-1 level was significantly lower ((182 ± 21) vs (232 ± 29) µmol/L, P = 0.021) in the allitridi group than in the control group.Furthermore, treatment of allitridi resulted in a significant improvement of FMD (8.2% ± 2.4% vs 6.4% ± 2.3%, P = 0.013). At Year 1 post-PCI, the incidence of major adverse cardiovascular event (MACE) was lower in the allitridi group than that in the control group (10.5% vs 17.2%, P = 0.022). CONCLUSIONS: Allitridi capsules significantly improve the clinical prognosis after PCI in CAD patients with DM. Its mechanism may lies in improved endothelial function and vascular inflammatory state.
Assuntos
Compostos Alílicos/uso terapêutico , Doença da Artéria Coronariana/metabolismo , Angiopatias Diabéticas/metabolismo , Sulfetos/uso terapêutico , Idoso , Cápsulas , Doença da Artéria Coronariana/terapia , Angiopatias Diabéticas/terapia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Humanos , Molécula 1 de Adesão Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/sangue , Intervenção Coronária Percutânea , Período Pós-OperatórioRESUMO
Cadmium is highly toxic and present in the environment and can be accumulated among various levels of the food chain. Both humans and animals are at risk from toxicity associated with cadmium. However, the neurological endpoint caused by cadmium has not been revealed. The aim of our research is to explore the potential target of cadmium attack when causing neurotoxicity. 80 male chickens (one day old, weighing 36.49 ± 2.88 g) were randomly divided into four groups and independently treated with 0, 35, 70, or 140 mg/kg CdCl2 in diet for 90 days. The result showed that the striatum was damaged due to a high dose of cadmium in the brain, which was characterized by degeneration of neurons and astrocyte dysfunction. Transcriptome analysis demonstrated that striatal astrocytes were transformed into the A1 state under cadmium exposure. Deeper investigation revealed that the internalization of gap junction protein connexin 43 was responsible for this transformation. Eventually, we can conclude that the internalized gap junction protein connexin 43 of astrocytes is the target of cadmium anchoring, and this process was accompanied by the transformation of astrocytes into the A1 subtype. This study provides a new direction for exploring the effects of cadmium on the nervous system and the treatment of subsequent nervous system diseases.
Assuntos
Conexina 43 , Conexinas , Humanos , Animais , Masculino , Conexinas/metabolismo , Conexinas/farmacologia , Conexina 43/genética , Conexina 43/metabolismo , Cádmio/metabolismo , Astrócitos/metabolismo , Galinhas/metabolismoRESUMO
Di(2-ethylhexyl) phthalate (DEHP) is a highly harmful and persistent environmental pollutant. Due to its unique chemical composition, it frequently dissolves and enters the environment to endanger human and animal health. Lycopene is a natural bioactive component that can potentially reduce the risk of environmental factor-induced chronic diseases. The present study sought to explore the role and underlying mechanism of lycopene (LYC) on DEHP-induced renal inflammatory response and apoptosis. In this study, mice were orally treated with LYC (5 mg/kg BW/day) and/or DEHP (500 or 1000 mg/kg BW/day) for 28 days. Our results indicated that LYC prevented DEHP-induced histopathological alterations and ultrastructural injuries, including decreased mitochondrial membrane potential (ΔΨm), PINK1/Parkin pathway-mediated mitophagy, and mitochondrial energetic deficit. When damaged mitochondria release mitochondrial DNA (mtDNA) into cytosol, LYC can alleviate inflammation and apoptosis caused by DEHP exposure by activating the cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signal pathway. Collectively, our data demonstrate that LYC can reduce mitophagy caused by DEHP exposure by activating the PINK1/Parkin pathway and then reduce renal inflammation and apoptosis through the cGAS-STING pathway.
Assuntos
Dietilexilftalato , Animais , Camundongos , Dietilexilftalato/toxicidade , DNA Mitocondrial/metabolismo , Inflamação/genética , Interferons , Rim/metabolismo , Licopeno , Nucleotidiltransferases/metabolismo , Proteínas Quinases/metabolismo , Transdução de Sinais , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: As a major complication of non-valvular atrial fibrillation (NVAF), left atrial appendage (LAA) thrombosis is associated with cerebral ischemic strokes, as well as high morbidity. Due to insufficient incorporation of risk factors, most current scoring methods are limited to the analysis of relationships between clinical characteristics and LAA thrombosis rather than detecting potential risk. Therefore, this study proposes a clinical data-driven machine learning method to predict LAA thrombosis of NVAF. METHODS: Patients with NVAF from January 2014 to June 2022 were enrolled from Southwest Hospital. We selected 40 variables for analysis, including demographic data, medical history records, laboratory results, and the structure of LAA. Three machine learning algorithms were adopted to construct classifiers for the prediction of LAA thrombosis risk. The most important variables related to LAA thrombosis and their influences were recognized by SHapley Addictive exPlanations method. In addition, we compared our model with CHADS2 and CHADS2-VASc scoring methods. RESULTS: A total of 713 participants were recruited, including 127 patients with LAA thrombosis and 586 patients with no obvious thrombosis. The consensus models based on Random Forest and eXtreme Gradient Boosting LAA thrombosis prediction (RXTP) achieved the best accuracy of 0.865, significantly outperforming CHADS2 score and CHA2DS2-VASc score (0.757 and 0.754, respectively). The SHAP results showed that B-type natriuretic peptide, left atrial appendage width, C-reactive protein, Fibrinogen and estimated glomerular filtration rate are closely related to the risk of LAA thrombosis in nonvalvular atrial fibrillation. CONCLUSIONS: The RXTP-NVAF model is the most effective model with the greatest ROC value and recall rate. The summarized risk factors obtained from SHAP enable the optimization of the treatment strategy, thereby preventing thromboembolism events and the occurrence of cardiogenic ischemic stroke.
Assuntos
Apêndice Atrial , Fibrilação Atrial , Acidente Vascular Cerebral , Tromboembolia , Trombose , Humanos , Fibrilação Atrial/complicações , Trombose/etiologia , Tromboembolia/complicações , Fatores de Risco , Acidente Vascular Cerebral/complicaçõesRESUMO
Cadmium (Cd) is a non-biodegradable widespread environmental pollutant, which can cross the blood-brain barrier (BBB) and cause cerebral toxicity. However, the effect of Cd on the BBB is still unclear. In this study, a total of 80 (1-day-old) Hy-Line white variety chicks (20 chickens/group) were selected and randomly divided into four (4) groups: the control group (Con group) (fed with a basic diet, n = 20), the Cd 35 group (basic diet with 35 mg/kg CdCl2, n = 20), the Cd 70 group (basic diet with 70 mg/kg CdCl2, n = 20) and the Cd 140 group (basic diet with 140 mg/kg CdCl2, n = 20), and fed for 90 days. The pathological changes, factors associated with the BBB, oxidation level and the levels of Wingless-type MMTV integration site family, member 7 A (Wnt7A)/Wnt receptor Frizzled 4 (FZD4)/ß-catenin signaling axis-related proteins in brain tissue were detected. Cd exposure induced capillary damage and neuronal swelling, degeneration and loss of neurons. Gene Set Enrichment Analysis (GSEA) showed the weakened Wnt/ß-catenin signaling axis. The protein expression of the Wnt7A, FZD4, and ß-catenin was decreased by Cd expusure. Inflammation generation and BBB dysfunction were induced by Cd, as manifested by impaired tight junctions (TJs) and adherens junctions (AJs) formation. These findings underscore that Cd induced BBB dysfunction via disturbing Wnt7A/FZD4/ß-catenin signaling axis.
Assuntos
Barreira Hematoencefálica , beta Catenina , Animais , Barreira Hematoencefálica/fisiologia , beta Catenina/metabolismo , Cádmio/toxicidade , Cádmio/metabolismo , Galinhas/metabolismo , Via de Sinalização Wnt/genéticaRESUMO
Cadmium is a global ecological toxic pollutant; in animals, hepatotoxic fibrosis is caused by bioaccumulation of Cd through food chains. We determined the path of nano-Se antagonism in Cd-induced hepatocyte pyroptosis by targeting the APJ-AMPK-PGC1α pathway, using an in vivo model of hepatotoxicity. All 1-day-old chicks were treated with Cd (140 mg/kg BW/day) and/or nano-Se (0.3 or 0.6 mg/kg BW/day) for 90 days. The result showed that Cd (1.55 ± 0.148) activated NLRP3 inflammasome 49.903% as compared to the Con group (1.034 ± 0.008) to release the inflammasome as a result of hepatocyte pyroptosis (2.824 ± 0.057). Compared with the Con group (1.010 ± 0.021), Kupffer cells were 219.109% more to activate astrocytes through the APJ-AMPK-PGC1α pathway, resulting in 185.149% more hepatic fibrosis. However, the fibrosis degree of the H-Se + Cd group (1.252 ± 0.056) was 56.5278% (p < 0.001) lower than that of the Cd group (2.880 ± 0.124). Therefore, this study established that pyroptotic hepatocytes and Kupffer cells could be targeted for nano-Se antagonizing Cd toxicity, which reveals a potential new approach targeting astrocytes for the treatment of liver fibrosis triggered by Cd pollution.
Assuntos
Cádmio , Selênio , Animais , Cádmio/toxicidade , Galinhas , Selênio/farmacologia , Inflamassomos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Proteínas Quinases Ativadas por AMP , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , FígadoRESUMO
BACKGROUND: The benefits of healthy lifestyles are well recognized. However, the extent to which improving unhealthy lifestyles reduces cardiovascular disease (CVD) risk needs to be discussed. We evaluated the impact of lifestyle improvement on CVD incidence using data from the China-PAR project (Prediction for Atherosclerotic Cardiovascular Disease Risk in China). METHODS: A total of 12,588 participants free of CVD were followed up for three visits after the baseline examination. Changes in four lifestyle factors (LFs) (smoking, diet, physical activity, and alcohol consumption) were assessed through questionnaires from the baseline to the first follow-up visit. Cox proportional hazard models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). The risk advancement periods (RAPs: the age difference between exposed and unexposed participants reaching the same incident CVD risk) and population-attributable risk percentage (PAR%) were also calculated. RESULTS: A total of 909 incident CVD cases occurred over a median follow-up of 11.14 years. Compared with maintaining 0-1 healthy LFs, maintaining 3-4 healthy LFs was associated with a 40% risk reduction of incident CVD (HR = 0.60, 95% CI: 0.45-0.79) and delayed CVD risk by 6.31 years (RAP: -6.31 [-9.92, -2.70] years). The PAR% of maintaining 3-4 unhealthy LFs was 22.0% compared to maintaining 0-1 unhealthy LFs. Besides, compared with maintaining two healthy LFs, improving healthy LFs from 2 to 3-4 was associated with a 23% lower risk of CVD (HR = 0.77, 95% CI: 0.60-0.98). CONCLUSIONS: Long-term sustenance of healthy lifestyles or improving unhealthy lifestyles can reduce and delay CVD risk.
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OBJECTIVE AND DESIGN: We investigated a possible imbalance between T helper (Th)17 and CD4+ CD25+ forkhead/winged helix transcription factor (Foxp3) T regulatory (Treg) cells in patients with carotid artery plaques. MATERIAL OR SUBJECTS: From November 2009 to September 2010, we enrolled 126 males and 104 females with mean age 68.24 ± 6.71 years. TREATMENT: Based on carotid artery sonography, the 230 subjects were categorized into three groups: plaque negative; stable plaques; and unstable plaques. METHODS: Th17 and Treg cell frequencies, relevant plasma cytokines (IL-17, IL-6, IL-23, and TNF-α), and RORγt mRNA levels were determined. RESULTS: Compared to plaque negative, Th17 cells, Th17-related cytokines (IL-17, IL-6, IL-23, and TNF-α), and RORγt mRNA levels were higher with stable plaques, and highest with unstable plaques. The opposite trend was found for Treg cells, Treg-related cytokines (IL-10 and TGF-ß1), and Foxp3 mRNA. Th17 cell frequencies were significantly negatively correlated with Treg cell frequencies. CONCLUSIONS: Our investigation demonstrated that there is a Th17/Treg functional imbalance in patients with unstable carotid atherosclerotic plaques. Th17 cells may promote atherogenesis, while Treg cells may have a protective role against atherosclerosis plaques. An imbalance of Th17/Treg cells may offer a new direction for the treatment of atherosclerosis.
Assuntos
Estenose das Carótidas/imunologia , Fatores de Transcrição Forkhead/genética , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Idoso , Idoso de 80 Anos ou mais , Estenose das Carótidas/sangue , Estenose das Carótidas/genética , Células Cultivadas , Quimiocina CCL2/genética , Citocinas/sangue , Feminino , Humanos , Leucócitos Mononucleares/citologia , Masculino , Pessoa de Meia-Idade , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , RNA Mensageiro/metabolismoRESUMO
Di-(2-ethylhexyl) phthalate (DEHP) is widely used as a plasticizer in plastic products, consumer products, and packaging materials. It is of great health concern in both animals and humans as it released into the environment and entered into the body from plastic products over time, thereby resulting in neurotoxicity. As a pivotal regulator of the central nervous system (CNS), astrocytes, are crucial for maintaining brain homeostasis. Nevertheless, the underlying reason for astrocyte neurotoxicity due to DEHP exposure remains incompletely understood. Here, using an in vivo model of neurotoxicity in quail, this study summarizes that Cx43 is internalized by phosphorylation and translocated to the nucleus as a consequence of DEHP exposure in astrocytes. This study further demonstrated that astrocytes transformed to pro-inflammatory status and induced the formation of autophagosomes. Of note, integrated immunofluorescent codetection approaches revealed an overexpression of the glial fibrillary acidic protein (GFAP) and down-expression of Cx43 in astrocytes. Therefore, in terms of neurotoxicity, this experiment in vivo models directly linked Cx43 internalization to autophagy and neuroinflammation and ultimately locked these changes to the astrocytes of the brain. These findings unveil a potential approach targeting Cx43 internalization for the treatment of neurodegeneration caused by DEHP exposure in astrocytes.
Assuntos
Dietilexilftalato , Síndromes Neurotóxicas , Animais , Astrócitos/metabolismo , Conexina 43/genética , Conexina 43/metabolismo , Conexinas/metabolismo , Dietilexilftalato/metabolismo , Dietilexilftalato/toxicidade , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Ácidos Ftálicos , Plásticos/metabolismoRESUMO
BACKGROUND: A higher red blood cell distribution width (RDW) predicts major adverse cardiac events in patients with coronary artery disease (CAD). However, there are only a few studies regarding the relationship between RDW and vulnerable plaques. Thus, the purpose of the present study is to retrospectively explore the predictive value of the association between RDW and plaque vulnerability assessed by optical coherence tomography (OCT) in patients with cardiovascular (CV) diseases. METHODS: This study included 35 patients with stable angina pectoris (SAP) and 70 patients with the acute coronary syndrome (ACS). We documented clinical features as well as peripheral RDW. Plaque vulnerability was determined by OCT. We defined thin-cap fibroatheroma (TCFA) as a lipid-rich plaque (fibrous cap <65 µm thick). RESULTS: Plaque rupture was detected more frequently in patients with ACS compared with patients with SAP (62.9 vs. 2.9%, p<0.001, and the corresponding TCFA were 50.69±15.68 vs. 80.03±21.60 µm, p<0.001, respectively). A higher RDW was found in patients with ACS than in patients with SAP (p<0.001). A cut-off value of RDW >13.85% could detect ruptured plaque with a sensitivity of 72.3% and a specificity of 62%. CONCLUSION: TCFA and plaque rupture were detected more frequently in patients with ACS compared with SAP. Elevated RDW was positively the predictive value of the association between plaque vulnerability.