RESUMO
The composition, quantity, and function of peripheral blood mononuclear cells (PBMCs) are closely correlated with tumorigenesis. However, the mechanisms of PBMCs in lung cancer are not clear. Mitochondria are energy factories of cells, and almost all cellular functions rely on their energy metabolism level. The present study aimed to test whether the mitochondrial function of PBMCs directly determines their tumor immune monitoring function. We recruited 211 subjects, including 105 healthy controls and 106 patients with recently diagnosed with lung cancer. The model of lung carcinogenesis induced by BaP was used in animal experiment, and the Bap carcinogenic metabolite, Benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide (BPDE), was used in cell experiment. We found that mitochondrial function of PBMCs decreased significantly in patients with new lung cancer, regardless of age. In vivo, BaP caused PBMC mitochondrial dysfunction in mice before the appearance of visible malignant tissue. Moreover, mitochondrial function decreased significantly in mice with lung cancers induced by BaP compared to those without lung cancer after BaP intervention. In vitro, BPDE also induced mitochondrial dysfunction and reduced the aggressiveness of PBMCs toward cancer cells. Furthermore, the changes in mitochondrial energy metabolism gene expression caused by BPDE are involved in this process. Thus, the mitochondrial function of PBMCs is a potential prognostic biomarker or therapeutic target to improve clinical outcomes in patients with lung cancer.
Assuntos
Leucócitos Mononucleares , Neoplasias Pulmonares , Mitocôndrias , Humanos , Neoplasias Pulmonares/patologia , Leucócitos Mononucleares/metabolismo , Animais , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Masculino , Feminino , Camundongos , Pessoa de Meia-Idade , Carcinogênese , Benzo(a)pireno/toxicidade , Metabolismo Energético , Idoso , Camundongos Endogâmicos C57BLRESUMO
Previous studies have demonstrated that the underlying mechanisms of myocardial ischemia/reperfusion injury (MIRI) are complex and involve multiple types of regulatory cell death, including ferroptosis, apoptosis, and autophagy. Thus, we aimed to identify the mechanisms underlying MIRI and validate the protective role of epigallocatechin-3-gallate (EGCG) and its related mechanisms in MIRI. An in vivo and in vitro models of MIRI were constructed. The results showed that pretreatment with EGCG could attenuate MIRI, as indicated by increased cell viability, reduced lactate dehydrogenase (LDH) activity and apoptosis, inhibited iron overload, abnormal lipid metabolism, preserved mitochondrial function, decreased infarct size, maintained cardiac function, decreased reactive oxygen species (ROS) level, and reduced TUNEL-positive cells. Additionally, EGCG pretreatment could attenuate ferroptosis, apoptosis, and autophagy induced by MIRI via upregulating 14-3-3η protein levels. Furthermore, the protective effects of EGCG could be abolished with pAd/14-3-3η-shRNA or Compound C11 (a 14-3-3η inhibitor) but not pAd/NC-shRNA. In conclusion, EGCG pretreatment attenuated ferroptosis, apoptosis, and autophagy by mediating 14-3-3η and protected cardiomyocytes against MIRI.
Assuntos
Proteínas 14-3-3 , Apoptose , Autofagia , Catequina , Catequina/análogos & derivados , Ferroptose , Traumatismo por Reperfusão Miocárdica , Catequina/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Autofagia/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Proteínas 14-3-3/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Cardiotônicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
Several studies have shown that berberine (BBR) is effective in protecting against myocardial ischemiareperfusion injury (MI/RI). However, the precise molecular mechanism remains elusive. The present study observed the mechanism and the safeguarding effect of BBR against hypoxia/reoxygenation (H/R) myocardial injury in H9c2 cells. BBR pretreatment significantly improved the decrease of cell viability, P62 protein, Rho Family GTPase 3 (RhoE) protein, ubiquinone subunit B8 protein, ubiquinolcytochrome c reductase core protein U, the Bcl2associated X protein/Bcell lymphoma 2 ratio, glutathione (GSH) and the GSH/glutathione disulphide (GSSG) ratio induced by H/R, while reducing the increase in lactate dehydrogenase, microtubuleassociated protein 1 light 3 protein, caspase3 activity, reactive oxygen species, GSSG and malonaldehyde caused by H/R. Transmission electron microscopy and LysoTracker Red DND99 staining results showed that BBR pretreatment inhibited H/Rinduced excessive autophagy by mediating RhoE. BBR also inhibited mitochondrial permeability transition, maintained the stability of the mitochondrial membrane potential, reduced the apoptotic rate, and increased the level of caspase3. However, the protective effects of BBR were attenuated by pAD/RhoEsmall hairpin RNA, rapamycin (an autophagy activator) and compound C (an AMPactivated protein kinase inhibitor). These new findings suggested that BBR protects the myocardium from MI/RI by inhibiting excessive autophagy, maintaining mitochondrial function, improving the energy supply and redox homeostasis, and attenuating apoptosis through the RhoE/AMPactivated protein kinase pathway.
Assuntos
Proteínas Quinases Ativadas por AMP , Autofagia , Berberina , Traumatismo por Reperfusão Miocárdica , Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose , Berberina/farmacologia , Caspase 3/metabolismo , Dissulfeto de Glutationa/metabolismo , Isquemia/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/etiologia , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Animais , RatosRESUMO
Tanshinone IIA (TSN) extracted from danshen (Salvia miltiorrhiza) could protect cardiomyocytes against myocardial ischemia/reperfusion injury (IRI), however the underlying molecular mechanisms of action remain unclear. The aim of the present study was to identify the protective effects of TSN and its mechanisms of action through in vitro studies. An anoxia/reoxygenation (A/R) injury model was established using H9c2 cells to simulate myocardial IRI in vitro. Before A/R, H9c2 cardiomyoblasts were pretreated with 8 µM TSN or 10 µM ferrostatin1 (Fer1) or erastin. The cell counting kit 8 (CCK8) and lactate dehydrogenase (LDH) assay kit were used to detect the cell viability and cytotoxicity. The levels of total iron, glutathione (GSH), glutathione disulfide (GSSG), malondialdehyde (MDA), ferrous iron, caspase3 activity, and reactive oxygen species (ROS) were assessed using commercial kit. The levels of mitochondrial membrane potential (MMP), lipid ROS, cell apoptosis, and mitochondrial permeability transition pore (mPTP) opening were detected by flow cytometry. Transmission electron microscopy (TEM) was used to observed the mitochondrial damage. Protein levels were detected by western blot analysis. The interaction between TSN and voltagedependent anion channel 1 (VDAC1) was evaluated by molecular docking simulation. The results showed that pretreatment with TSN and Fer1 significantly decreased cell viability, glutathione peroxidase 4 (GPX4) protein and GSH expression and GSH/GSSG ratio and inhibited upregulation of LDH activity, prostaglandin endoperoxide synthase 2 and VDAC1 protein expression, ROS levels, mitochondrial injury and GSSG induced by A/R. TSN also effectively inhibited the damaging effects of erastin treatment. Additionally, TSN increased MMP and Bcl2/Bax ratio, while decreasing levels of apoptotic cells, activating Caspase3 and closing the mPTP. These effects were blocked by VDAC1 overexpression and the results of molecular docking simulation studies revealed a direct interaction between TSN and VDAC1. In conclusion, TSN pretreatment effectively attenuated H9c2 cardiomyocyte damage in an A/R injury model and VDAC1mediated ferroptosis and apoptosis served a vital role in the protective effects of TSN.
Assuntos
Ferroptose , Traumatismo por Reperfusão Miocárdica , Humanos , Canal de Ânion 1 Dependente de Voltagem/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Caspase 3/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Dissulfeto de Glutationa/metabolismo , Simulação de Acoplamento Molecular , Miócitos Cardíacos/metabolismo , Apoptose , Ferro/metabolismoRESUMO
Beauvericin is a world-spread mycotoxin isolated from the traditional Chinese medicine, Bombyx batryticatus (BB), which has been widely used to treat various neoplastic diseases. This study investigated the anti-hepatocellular carcinoma (HCC) activity of beauvericin and its potential mechanism. In this study, H22-bearing mice were intraperitoneally injected with 3, 5, 7 mg/kg of beauvericin once per-week over a three-week period. TUNEL staining determined the extent of tumor apoptosis induced by beauvericin. ELISA kits detected the level of IL-2, Perforin, and TNF-α, IFN-γ level in the serum. H22 hepatoma cells were exposed to beauvericin (5, 10, and 20 µmol/L) to investigate the underlying pathway. CCK-8 assay was used to observe the influence of beauvericin on the growth of H22 cells. Flow cytometry was used to detect the cell apoptosis and ROS level. Western blotting was performed to detect apoptotic and PI3K/AKT pathway protein production. The results showed that beauvericin could remarkably inhibit the growth of HCC in mice, combined with elevated TNF-α and IL-2. In vitro, beauvericin significantly promoted the generation of ROS, up-regulated Bax/Bcl-2 ratio and cleaved caspase-9, cleaved caspase-3 levels, down-regulated p-PI3K/PI3K ratio, p-AKT/AKT ratio, promoted the apoptosis of H22 cells, and inhibited the growth of H22 cells. Remarkably, treatment with PI3K/AKT activator (740Y-P and SC79) could prevent beauvericin-induced H22 cell apoptosis. These findings collectively indicate that beauvericin inhibits HCC growth by inducing apoptosis via the PI3K/AKT pathway.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Interleucina-2 , Espécies Reativas de Oxigênio , Fator de Necrose Tumoral alfa , Neoplasias Hepáticas/tratamento farmacológico , ApoptoseRESUMO
Benzene is a toxic environmental pollutant that disrupts the immune system in humans. Benzene exposure reduces the abundance of immune cells in multiple immune organs; however, the biological mechanisms underlying benzene-induced immunotoxicity has not been elucidated. In this study, benzene was used to develop mouse model for immune dysfunction. A significant decrease in IgG, IL-2 and IL-6 levels, an increase in oxidative stress and spleen injury were observed after benzene exposure in a dose-dependent manner. Quantitative proteomics revealed that benzene-induced immune dysfunction was associated with deregulation of the B cell receptor (BCR) signaling pathway. Benzene exposure suppressed the expression of CD22, BCL10 and NF-κb p65. Also, a significant decrease in proliferation and an increase in apoptosis of splenic lymphocytes were found after benzene exposure. Moreover, we found that benzene exposure increased mitochondrial reactive oxygen species (mito-ROS) and decreased adenosine triphosphate (ATP). Overall, we revealed the damaging effects of benzene on spleen-related immune function and the underlying biological mechanism, involving the disruption of BCR signaling pathway, NF-κB deactivation, and mitochondrial dysfunction.
Assuntos
Benzeno , NF-kappa B , Humanos , Camundongos , Animais , NF-kappa B/metabolismo , Benzeno/toxicidade , Baço , Transdução de Sinais , Espécies Reativas de Oxigênio/metabolismo , Apoptose , Receptores de Antígenos de Linfócitos BRESUMO
Benzene can impair peripheral immunity and immune organs; however, the recovery of benzene impairment has rarely been reported. In this study, we developed an immune dysfunction mouse model using a benzene gavage (500 mg/kg). Female Balb/c mice were treated with Bombyx batryticatus (BB, 5 g/kg), raw pinellia (RP, 5 g/kg), or a combination of Valproic acid and Coenzyme Q10 (CM, 150 mg/kg VPA & 100 mg/kg CoQ10) medication for four weeks. The immune function of the peripheral blood mononuclear cells (PBMCs), spleen, and thymus was determined to evaluate whether the observed impairment could be altered by medications in the mouse model. Results showed that medications could alleviate benzene-induced structural and functional damage of spleen and thymus. Benzene exposure decreased the ATP level of PBMC, which can be improved by BB, RP or CM. Importantly, BB, RP or CM could relieve benzene induced-oxidative stress by increasing the activities of glutathione peroxidase (GSH) and superoxide dismutase (SOD) and decreasing the contents of malondialdehyde (MDA). In conclusion, BB, RP, and CM were able to alleviate the benzene-induced immune dysfunction and redox imbalance. Improvement of the oxidative and antioxidant imbalance may represent a mechanism by which medicine prevents benzene-induced immune dysfunction.
Assuntos
Benzeno/toxicidade , Imunidade/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Baço/efeitos dos fármacos , Timo/efeitos dos fármacos , Trifosfato de Adenosina/sangue , Animais , Bombyx/química , Feminino , Glutationa Peroxidase/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pinellia/química , Extratos Vegetais/farmacologia , Organismos Livres de Patógenos Específicos , Superóxido Dismutase/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Ubiquinona/farmacologia , Ácido Valproico/farmacologiaRESUMO
Objective: To study the effects of Cistanche deserticola and its active components Cistanche deserticola polysaccharide and Echinacoside on intestinal flora of antibiotic-associated diarrhea (AAD) mice. Methods: Forty-eight Balb/c mice were randomly divided into control (Con) group, AAD Group, inulin (Inu) group, Cistanche deserticola (RCR) group, Cistanche deserticola polysaccharide (RCRDT) group and Echinacoside (Ech) group with 8 mice in each group. The diarrhea model of mice was induced by intragastric administration of lincomycin hydrochloride(3 g/kg) for 7 days, and then treated by intragastric administration of INU(5 g/kg), RCR(5 g/kg), RCRDT(200 mg/kg) and ECH (60 mg/kg),0.2 ml once a day for 7 days, Con group and AAD group were given the same volume of normal saline. By observing general signs of mice, colon HE staining, 16S rDNA high-throughput sequencing analysis, the effects of Cistanche deserticola, Cistanche deserticola polysaccharide and Echinacea glycoside on the imbalance of intestinal flora induced by antibiotics in mice were evaluated. Results: Compared with Con group, AAD group mice lost weight, presented obvious diarrhea symptoms, inflammatory changes in colon tissue and decreased intestinal flora diversity (Pï¼0.05) indicating the success of the model. Compared with AAD group, the weight and diarrhea of INU, RCR, RCRDT and ECH groups were significantly improved, and the colon pathology of ECH group was restored to normal level. Compared with AAD group, RCR group, RCRDT group and ECH group had significantly decreased intestinal Firmicutes, increased Blautia and Lachnoclostridium, and decreased Clostridium_sensu_stricto_1 (Pï¼0.05) . In ECH group, the abundance and diversity of intestinal microflora were returned to normal level, and the structure of intestinal microflora was well adjusted, the contents of Bacteroides, Flavonifractor, Agathobacter, Lachnoclostridium and Prevotella-9 were increased (Pï¼0.01). Conclusion: Both Cistanche deserticola and its active components cistanche deserticola polysaccharide and echinacoside can regulate the intestinal flora imbalance caused by antibiotics and improve the symptoms of AAD, especially echinacoside.
Assuntos
Antibacterianos , Cistanche , Animais , Camundongos , Disbiose , Diarreia , ColoRESUMO
BACKGROUND: A growing number of people suffered from depression. This study examined the depression prevalence in workers across 10 European countries plus Israel and the reciprocal associations between job strain and depression. METHODS: The study population consisted of 7,879 workers aged 50-63 years at baseline (2004) from the Survey of Health, Ageing, and Retirement in Europe (SHARE). Job demands (physical or psychosocial) and job control variables were derived from the Job Content Questionnaire (JCQ). Two 4-category job strains (physical and psychosocial) were obtained based on the cross-tabulation of these dichotomized demands and control variables. There were 4,284 depression-free, 3,259 high physical strain-free and 3,195 high psychosocial strain-free participants at baseline who were followed up for 2 years to detect incident depression, high physical job strain, or high psychosocial strain, respectively. The reciprocal associations between job strain and depression were analyzed by multivariate logistic regression and multivariate multilevel logistic regression adjusting for potential confounders. RESULTS: The prevalence of depression varied from the lowest 12.5% in Germany to the highest 27.2% in France. Compared to individuals with low strain, a significantly higher risk of depression were found in individuals with high physical strain (OR = 1.39) and high psychosocial strain (OR = 1.55), after adjusting for potential confounders. Depression at baseline was not significantly associated with subsequent high job strain. Similar results were observed from multilevel models that took into consideration of the potential country-level influences. CONCLUSIONS: The prevalence of depression varies across countries in Europe. Avoiding high job strain may be an effective preventive strategy to prevent depression epidemic.
Assuntos
Envelhecimento/psicologia , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/psicologia , Inquéritos Epidemiológicos/estatística & dados numéricos , Estresse Ocupacional/epidemiologia , Estresse Ocupacional/psicologia , Aposentadoria/psicologia , Comorbidade , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prevalência , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: To investigate the reciprocal relationship between psychosocial work stress and quality of life (QoL) and to examine whether the relationship can be moderated by gender or education. DESIGN: Longitudinal, population-based study. SETTING: The Survey of Health, Ageing and Retirement in Europe (SHARE). PARTICIPANTS: The study population was derived from the SHARE, and there were 2006 participants with good QoL at baseline, 1109 with high job control and 1072 with high job reward, respectively, who were followed up for 2 years to detect incidence of poor QoL, low job control and low job reward. MAIN OUTCOME MEASURES: Logistic regression models were employed to explore the reciprocal relationship between psychological work stress and QoL. Stratification analyses by gender and education were performed. RESULTS: Participants with low reward (OR=1.53, 95% CI 1.26 to 1.88) and low control (OR=1.40, 95% CI 1.14 to 1.71) at baseline were at higher risk of poor QoL over the 2-year follow-up. The combination of low reward and low control further increased the risk (OR=1.90, 95% CI 1.46 to 2.48). Stratified analyses revealed that these associations were more pronounced among those who had high levels of education. Further, individuals with poor QoL were at significantly higher risk of having low reward (OR=2.14, 95% CI 1.55 to 2.96) but not low control (OR=1.33, 95% CI0.98 to 1.79) at the 2-year follow-up, especially among those who had medium levels of education. No gender differences were found. CONCLUSIONS: There is a reciprocal relationship between psychological work stress and poor QoL. Education may play an important role in the relationship.
Assuntos
Escolaridade , Estresse Ocupacional/epidemiologia , Qualidade de Vida/psicologia , Fatores Sexuais , Europa (Continente)/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estresse Ocupacional/psicologia , Estudos Prospectivos , Recompensa , Inquéritos e QuestionáriosRESUMO
It has been previously shown that inhaled zinc oxide nanoparticles (ZnO-NPs) can modulate inflammation. MicroRNAs (miRNAs) enclosed in exosomes have been identified as an important signature for inflammatory responses. However, the role of exosomal miRNAs during pathogenic inflammation has not been investigated. Healthy rats were exposed to ZnO-NPs (41.7 nm; 2, 4, and 8 mg/kg) or saline (control) via oropharyngeal aspiration. ZnO-NPs induced significant increases in the serum levels of interleukin 8 (IL-8), interleukin-1 beta (IL-1ß), and tumor necrosis factor α (TNF-α), and elevated the number of cells and the percentage of neutrophils in the blood. Moreover, exposure to ZnO-NPs increased the levels of lactate dehydrogenase (LDH) activity and total protein in bronchoalveolar lavage fluid (BALF). Differential profiling of miRNAs in isolated serum exosomes revealed that 16 miRNAs were up-regulated and 7 down-regulated in ZnO-NP-treated rats compared with the controls. Functional and pathway analysis indicated that miRNAs may participate in inflammation directly and indirectly through protein and vesicle-mediated transport or regulation of IL-1, oxidative stress, apoptosis, and autophagy. These results suggest that miRNAs in serum exosomes are involved in pulmonary neutrophilic inflammation induced by ZnO-NPs.