RESUMEN
Persistent organic pollutants (POPs) affect human health through the aryl hydrocarbon receptor (AhR) pathway and are implicated in mitochondrial dysfunction. Using data from the PIVUS study, we investigated the associations of serum AhR ligand (POP)-mediated luciferase activity (AhRL), mitochondrial ATP production inhibiting substances (MIS-ATP), and those affecting reactive oxygen species (MIS-ROS) with several metabolic syndrome (MetS) and cardiopulmonary function parameters. These include insulin resistance (HOMA-IR), inflammation, oxidative stress, and cardiopulmonary variables (FVC, FEV1, LV-EF, CCA distensibility). MIS-ATP showed significant correlations with HOMA-IR and pulmonary functions, indicating its direct impact of MIS-ATP on metabolic and pulmonary health. MIS-ROS correlated with oxidative stress markers and CCA distensibility, suggesting a role in systemic inflammatory responses. This study highlights the intricate relationships between environmental pollutant mixture and cardiopulmonary health in MetS as indicated by biomarkers of POP exposure in the elderly population, suggesting POP exposure may influence MetS onset and progression through mitochondrial dysfunction.
RESUMEN
Parkinson's disease (PD) is a complex neurodegenerative disease in which neuroinflammation and oxidative stress interact to contribute to pathogenesis. This study investigates the in vivo neuroprotective effects of a patented yeast extract lysate in a lipopolysaccharide (LPS)-induced neuroinflammation model. The yeast extract lysate, named aldehyde-reducing composition (ARC), exhibited potent antioxidant and anti-aldehyde activities in vitro. Oral administration of ARC at 10 or 20 units/kg/day for 3 days prior to intraperitoneal injection of LPS (10 mg/kg) effectively preserved dopaminergic neurons in the substantia nigra (SN) and striatum by preventing LPS-induced cell death. ARC also normalized the activation of microglia and astrocytes in the SN, providing further evidence for its neuroprotective properties. In the liver, ARC downregulated the LPS-induced increase in inflammatory cytokines and reversed the LPS-induced decrease in antioxidant-related genes. These findings indicate that ARC exerts potent antioxidant, anti-aldehyde, and anti-inflammatory effects in vivo, suggesting its potential as a disease-modifying agent for the prevention and treatment of neuroinflammation-related diseases, including Parkinson's disease.
Asunto(s)
Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/metabolismo , Lipopolisacáridos/farmacología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/metabolismo , Enfermedades Neuroinflamatorias , Antioxidantes/farmacología , Antioxidantes/metabolismo , Enfermedades Neurodegenerativas/metabolismo , MicroglíaRESUMEN
Microplastics (MPs) are recognized as environmental pollutants with potential implications for human health. Considering the rapid increase in obesity rates despite stable caloric intake, there is a growing concern about the link between obesity and exposure to environmental pollutants, including MPs. In this study, we conducted a comprehensive investigation utilizing in silico, in vitro, and in vivo approaches to explore the brain distribution and physiological effects of MPs. Molecular docking simulations were performed to assess the binding affinity of three plastic polymers (ethylene, propylene, and styrene) to immune cells (macrophages, CD4+, and CD8+ lymphocytes). The results revealed that styrene exhibited the highest binding affinity for macrophages. Furthermore, in vitro experiments employing fluorescence-labeled PS-MPs (fPS-MPs) of 1 µm at various concentrations demonstrated a dose-dependent binding of fPS-MPs to BV2 murine microglial cells. Subsequent oral administration of fPS-MPs to high-fat diet-induced obese mice led to the co-existence of fPS-MPs with immune cells in the blood, exacerbating impaired glucose metabolism and insulin resistance and promoting systemic inflammation. Additionally, fPS-MPs were detected throughout the brain, with increased activation of microglia in the hypothalamus. These findings suggest that PS-MPs significantly contribute to the exacerbation of systemic inflammation in high-fat diet-induced obesity by activating peripheral and central inflammatory immune cells.
RESUMEN
Obesity is a chronic peripheral inflammation condition that is strongly correlated with neurodegenerative diseases and associated with exposure to environmental chemicals. The aryl hydrocarbon receptor (AhR) is a ligand-activated nuclear receptor activated by environmental chemical, such as dioxins, and also is a regulator of inflammation through interacting with nuclear factor (NF)-κB. In this study, we evaluated the anti-obesity and anti-inflammatory activity of HBU651, a novel AhR antagonist. In BV2 microglia cells, HBU651 successfully inhibited lipopolysaccharide (LPS)-mediated nuclear localization of NF-κB and production of NF-κB-dependent proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6. It also restored LPS-induced mitochondrial dysfunction. While mice being fed a high-fat diet (HFD) induced peripheral and central inflammation and obesity, HBU651 alleviated HFD-induced obesity, insulin resistance, glucose intolerance, dyslipidemia, and liver enzyme activity, without hepatic and renal damage. HBU651 ameliorated the production of inflammatory cytokines and chemokines, proinflammatory Ly6chigh monocytes, and macrophage infiltration in the blood, liver, and adipose tissue. HBU651 also decreased microglial activation in the arcuate nucleus in the hypothalamus. These findings suggest that HBU651 may be a potential candidate for the treatment of obesity-related metabolic diseases.
Asunto(s)
Dieta Alta en Grasa , Receptores de Hidrocarburo de Aril , Animales , Ratones , Citocinas , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Lipopolisacáridos , Ratones Endogámicos C57BL , Ratones Obesos , FN-kappa B/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/etiología , Obesidad/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Factor de Necrosis Tumoral alfaRESUMEN
Chronic exposure to some environmental polluting chemicals (EPCs) is strongly associated with metabolic syndrome, and insulin resistance is a major biochemical abnormality in the skeletal muscle in patients with metabolic syndrome. However, the causal relationship is inconsistent and little is known about how EPCs affect the insulin signaling cascade in skeletal muscle. Here, we investigated whether exposure to 100 pM of 2,3,7,8-tetrachlorodibenzodioxin (TCDD) as a low dose of dioxin induces insulin resistance in C2C12 myocytes. The treatment with TCDD inhibited the insulin-stimulated glucose uptake and translocation of glucose transporter 4 (GLUT4). The low-dose TCDD reduced the expression of insulin receptor ß (IRß) and insulin receptor substrate (IRS)-1 without affecting the phosphorylation of Akt. The TCDD impaired mitochondrial activities, leading to reactive oxygen species (ROS) production and the blockage of insulin-induced Ca2+ release. All TCDD-mediated effects related to insulin resistance were still observed in aryl hydrocarbon receptor (AhR)-deficient myocytes and prevented by MitoTEMPO, a mitochondria-targeting ROS scavenger. These results suggest that low-dose TCDD stress may induce muscle insulin resistance AhR-independently and that mitochondrial oxidative stress is a novel therapeutic target for dioxin-induced insulin resistance.
RESUMEN
Obesity is closely linked to chronic inflammation in peripheral organs and the hypothalamus. Chronic consumption of a high-fat diet (HFD) induces the differentiation of Ly6chigh monocytes into macrophages in adipose tissue, the liver, and the brain, as well as the secretion of pro-inflammatory cytokines. Although cinnamon improves obesity and related diseases, it is unclear which components of cinnamon can affect macrophages and inflammatory cytokines. We performed in silico analyses using ADME, drug-likeness, and molecular docking simulations to predict the active compounds of cinnamon. Among the 82 active compounds of cinnamon, cinnamic acid (CA) showed the highest score of ADME, blood-brain barrier permeability, drug-likeness, and cytokine binding. We then investigated whether CA modulates obesity-induced metabolic profiles and macrophage-related inflammatory responses in HFD-fed mice. While HFD feeding induced obesity, CA ameliorated obesity and related symptoms, such as epididymal fat gain, insulin resistance, glucose intolerance, and dyslipidemia, without hepatic and renal toxicity. CA also improved HFD-induced tumor necrosis factor-α, fat deposition, and macrophage infiltration in the liver and adipose tissue. CA decreased Ly6chigh monocytes, adipose tissue M1 macrophages, and hypothalamic microglial activation. These results suggest that CA attenuates the peripheral and hypothalamic inflammatory monocytes/macrophage system and treats obesity-related metabolic disorders.
RESUMEN
Loss of dopamine (DA) is one of the primary features of Parkinson's disease (PD); however, imbalances of non-dopaminergic neurotransmitters significantly contribute to the disabilities noted in advanced PD patients. DA-9805 is the ethanolic extraction of the root bark of Paeonia × suffruticosa Andrews (Paeoniaceae), the root of Angelica dahurica (Hoffm.) Benth. and Hook.f. ex Franch. and Sav. (Apiaceae) and the root of Bupleurum falcatum L. (Apiaceae), which have been widely utilized as an enhancer of motor function in East Asia. This study aimed to investigate whether DA-9805 modified motor dysfunctions and imbalances associated with DA and other neurotransmitters in a 6-hydroxydopamine-induced PD mouse. We confirmed the expressions of proteins related with neurotransmissions in the striatum. In addition, we measured the striatal neurotransmitters using HPLC and analyzed their correlation. DA-9805 significantly improved motor impairments and restored the altered levels of neurotransmitters in the striatum. Moreover, DA-9805 improved the altered expressions of tyrosine hydroxylase (TH), DA transporter, and choline acetyltransferase (ChAT) in the ipsilateral part of mouse striatum or SNpc, which implies the neuroprotection. We also found that the level of striatal acetylcholine (Ach) has the moderate negative correlation with motor functions and TH expression in the SNpc. This study indicates that DA-9805 restores motor dysfunctions by normalizing the increased levels of striatal Ach via modulating DA transmission and ChAT expressions as well as its neuroprotective effects.
RESUMEN
The early prediction and identification of risk factors for diabetes may prevent or delay diabetes progression. In this study, we developed an interactive online application that provides the predictive probabilities of prediabetes and diabetes in 4 years based on a Bayesian network (BN) classifier, which is an interpretable machine learning technique. The BN was trained using a dataset from the Ansung cohort of the Korean Genome and Epidemiological Study (KoGES) in 2008, with a follow-up in 2012. The dataset contained not only traditional risk factors (current diabetes status, sex, age, etc.) for future diabetes, but it also contained serum biomarkers, which quantified the individual level of exposure to environment-polluting chemicals (EPC). Based on accuracy and the area under the curve (AUC), a tree-augmented BN with 11 variables derived from feature selection was used as our prediction model. The online application that implemented our BN prediction system provided a tool that performs customized diabetes prediction and allows users to simulate the effects of controlling risk factors for the future development of diabetes. The prediction results of our method demonstrated that the EPC biomarkers had interactive effects on diabetes progression and that the use of the EPC biomarkers contributed to a substantial improvement in prediction performance.
Asunto(s)
Diabetes Mellitus , Aplicaciones Móviles , Teorema de Bayes , Biomarcadores , Diabetes Mellitus/epidemiología , Humanos , Aprendizaje AutomáticoRESUMEN
Parkinson's disease (PD) is a multifactorial neurodegenerative disease with damages to mitochondria and endoplasmic reticulum (ER), followed by neuroinflammation. We previously reported that a triple herbal extract DA-9805 in experimental PD toxin-models had neuroprotective effects by alleviating mitochondrial damage and oxidative stress. In the present study, we investigated whether DA-9805 could suppress ER stress and neuroinflammation in vitro and/or in vivo. Pre-treatment with DA-9805 (1 µg/ml) attenuated upregulation of glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and cleaved caspase-3 in SH-SY5Y neuroblastoma cells treated with thapsigargin (1 µg/ml) or tunicamycin (2 µg/ml). In addition, DA-9805 prevented the production of IL-1ß, IL-6, TNF-α and nitric oxide through inhibition of NF-κB activation in BV2 microglial cells stimulated with lipopolysaccharides (LPS). Intraperitoneal injection of LPS (10 mg/kg) into mice can induce acute neuroinflammation and dopaminergic neuronal cell death. Oral administration of DA-9805 (10 or 30 mg/kg/day for 3 days before LPS injection) prevented loss of dopaminergic neurons and activation of microglia and astrocytes in the substantia nigra in LPS-injected mouse models. Taken together, these results indicate that DA-9805 can effectively prevent ER stress and neuroinflammation, suggesting that DA-9805 is a multitargeting and disease-modifying therapeutic candidate for PD.
Asunto(s)
Antiparkinsonianos , Estrés del Retículo Endoplásmico , Inflamación , Extractos Vegetales , Animales , Humanos , Masculino , Ratones , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Línea Celular Tumoral , Neuronas Dopaminérgicas/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estrés del Retículo Endoplásmico/efectos de los fármacos , Inflamación/tratamiento farmacológico , Lipopolisacáridos , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Neuroblastoma/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Sustancia Negra/efectos de los fármacosRESUMEN
In our previous study, 20 nm-sized amorphous silica nanoparticles (20-SiNPs), but not 50 nm-sized amorphous silica nanoparticles (50-SiNPs), induced pulmonary inflammatory response in rats exposed repeatedly for 14 days (12.5, 25, and 50 µg/time, total six times). In this study, we tried to clarify the causes of different responses induced by both SiNPs using mice (12.5, 25, and 50 µg/lung) and mouse alveolar macrophage cells. When exposed to alveolar macrophage cells for 24 h, both SiNPs decreased cell viability and enhanced ROS generation compared to controls. The 20- and 50-SiNPs also formed giant and autophagosome-like vacuoles in the cytoplasm, respectively. Structural damage of organelles was more pronounced in 20-SiNPs-treated cells than in 50-SiNPs-treated cells, and an increased mitochondrial membrane potential and mitochondrial calcium accumulation were observed only in the 20-SiNPs-treated cells. Additionally, a single intratracheal instillation of both sizes of SiNPs to mice clearly elevated the relative proportion of neutrophils and inhibited differentiation of macrophages and expression of an adhesion molecule. Meanwhile, interestingly, the total number of pulmonary cells and the levels of pro-inflammatory mediators more notably increased in the lungs of mice exposed to 20-SiNPs compared to 50-SiNPs. Given that accumulation of giant vacuoles and dilation of the ER and mitochondria are key indicators of paraptosis, we suggest that 20-SiNPs-induced pulmonary inflammation may be associated with paraptosis of alveolar macrophages.
Asunto(s)
Nanopartículas , Neumonía , Animales , Apoptosis , Macrófagos Alveolares , Ratones , Nanopartículas/toxicidad , Neumonía/inducido químicamente , Dióxido de Silicio/toxicidadRESUMEN
BACKGROUND: High circulating levels of dioxins and dioxin-like chemicals, acting via the aryl hydrocarbon receptor (AhR), have previously been linked to diabetes. We now investigated whether the serum AhR ligands (AhRL) were higher in subjects with metabolic syndrome (MetS) and in subjects who had developed a worsened glucose tolerance over time. METHODS: Serum AhRL at baseline was measured by a cell-based AhRL activity assay in 70-year-old subjects (n=911) in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. The main outcome measures were prevalent MetS and worsening of glucose tolerance over 5 years of follow-up. RESULTS: AhRL was significantly elevated in subjects with prevalent MetS as compared to those without MetS, following adjustment for sex, smoking, exercise habits, alcohol intake and educational level (P=0.009). AhRL at baseline was higher in subjects who developed impaired fasting glucose or diabetes at age 75 years than in those who remained normoglycemic (P=0.0081). The odds ratio (OR) of AhRL for worsening glucose tolerance over 5 years was 1.43 (95% confidence interval [CI], 1.13 to 1.81; P=0.003, continuous variables) and 2.81 (95% CI, 1.31 to 6.02; P=0.008, in the highest quartile) adjusted for sex, life style factors, body mass index, and glucose. CONCLUSION: These findings support a large body of epidemiologic evidence that exposure to AhR transactivating substances, such as dioxins and dioxin-like chemicals, might be involved in the pathogenesis of MetS and diabetes development. Measurement of serum AhRL in humans can be a useful tool in predicting the onset of metabolic disorders.
Asunto(s)
Diabetes Mellitus , Síndrome Metabólico , Anciano , Índice de Masa Corporal , Glucosa , Humanos , Síndrome Metabólico/epidemiología , Estudios ProspectivosRESUMEN
Persistent organic pollutants(POPs) are suggested to be potential risk factors for gestational diabetes mellitus(GDM). We examined the hypothesis that the aryl hydrocarbon receptor trans-activating(AhRT) activity, a potential biomarker for the presence of POPs, could be a GDM risk factor in pregnant women. A total of 390 GDM and 100 normal pregnant(non-GDM) subjects in the Korea National Diabetes Program cohort voluntarily participated. We measured AhRT activity and concentrations of ATP and reactive oxygen in the serum collected at the screening of the participants for GDM using recombinant Hepa1c1c7 cells. Odds ratios(ORs) and 95% confidence intervals(CIs) were estimated using multivariable logistic regression models. The sensitivity and specificity of AhRT activity for GDM diagnostics were measured by receiver operating characteristic(ROC) analysis. Body mass index at pre-pregnancy and delivery and systolic blood pressure were significantly higher in the GDM group. AhRT activity was higher, and ATP concentrations were lower in the GDM group than the non-GDM group(P < 0.0001). AhRT activity was significantly higher in the GDM group(OR 29.3, 95% CI 10.9-79.1) compared with non-GDM(P < 0.0001). Serum glucose concentration at 1 h after a 50 g glucose challenge(glucose-50) was moderately correlated with AhRT activity(r2 = 0.387) and negatively correlated with ATP production(r2 = -0.650). In the ROC curve, AhRT activity had 70.9% sensitivity and 90.0% specificity for glucose-50, a GDM screening method. In conclusion, this study suggests that serum AhRT activity is positively associated with the risk of GDM.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/genética , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Orgánicos Persistentes/efectos adversos , Receptores de Hidrocarburo de Aril/genética , Adenosina Trifosfato/sangre , Adulto , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/sangre , Biomarcadores/sangre , Glucemia/metabolismo , Presión Sanguínea , Índice de Masa Corporal , Estudios de Casos y Controles , Diabetes Gestacional/sangre , Diabetes Gestacional/inducido químicamente , Femenino , Expresión Génica , Hemoglobina Glucada/genética , Hemoglobina Glucada/metabolismo , Humanos , Resistencia a la Insulina , Oportunidad Relativa , Embarazo , Curva ROC , Especies Reactivas de Oxígeno/sangre , Receptores de Hidrocarburo de Aril/sangre , Factores de RiesgoRESUMEN
Hepatic hepcidin is a well-known major iron regulator and has been reported to be closely related to hepatitis C virus (HCV) replication. However, pharmacological targeting of the hepcidin in HCV replication has not been reported. A short-chain fatty acid, 4-Phenyl butyrate (4-PBA), is an acid chemical chaperone that acts as a histone deacetylase inhibitor (HDACi) to promote chromosomal histone acetylation. Here, we investigated the therapeutic effect of 4-PBA on hepcidin expression and HCV replication. We used HCV genotype 1b Huh 7.5-Con1 replicon cells and engraftment of NOD/SCID mice as in vitro and in vivo models to test the effect of 4-PBA. It was found that 4-PBA inhibited HCV replication in Huh7.5-Con1 replicon cells in a concentration- and time-dependent manner through the induction of hepcidin expression by epigenetic modification and subsequent upregulation of interferon-α signaling. HCV formed a membranous web composed of double-membrane vesicles and was utilized for RNA replication. Moreover, 4-PBA also disrupted the integrity of the membranous web and interfered with the molecular interactions critical for the assembly of the HCV replication complex. These findings suggest that 4-PBA is a key epigenetic inducer of anti-HCV hepatic hepcidin and might at least in part play a role in targeting host factors related to HCV infection as an attractive complement to current HCV therapies.
Asunto(s)
Epigénesis Genética/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Hepcidinas/genética , Fenilbutiratos/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Replicación Viral/efectos de los fármacos , Animales , Línea Celular Tumoral , Expresión Génica/efectos de los fármacos , Hepacivirus/genética , Hepacivirus/fisiología , Hepatitis C/prevención & control , Hepatitis C/virología , Hepcidinas/metabolismo , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones Endogámicos NOD , Ratones SCID , Estructura Molecular , Fenilbutiratos/química , Bibliotecas de Moléculas Pequeñas/química , Replicación Viral/genéticaRESUMEN
Parkinson's disease (PD) is a multifactorial neurodegenerative disease manifesting mitochondrial damages and neuroinflammation. Qi is defined as a natural power that can regulate the energy flow in Oriental medicine, whereas mitochondria generate energy power in Western medicine. We investigated whether Qi-enhancing component in Oriental herb medicines could activate mitochondrial activities. Quercetin was found as a major bioactive compound in most Qi-activating Oriental herb medicines through online search for active compounds in several Oriental Medicine databases. We then investigated if quercetin could reverse 1-methyl-4-phenylpyridinium (MPP+)-induced mitochondrial dysfunction and lipopolysaccharide (LPS)-induced neuroinflammation. Mitochondrial activities were monitored based on complex 1 NADH dehydrogenase activities, ATP contents, mitochondrial membrane potential, cellular/mitochondrial reactive oxygen species, and oxygen consumption rate in SH-SY5Y cells. Quercetin at concentration up to 20 µg/ml was not cytotoxic to SH-SY5Y cells. Pre-treatment with quercetin significantly protected mitochondrial damages in 1 mM MPP+- or 100 ng/ml LPS-treated cells. Quercetin increased expression levels of tyrosine hydroxylase and mitochondria controlling proteins. When in vivo effects of quercetin were assessed by immunohistochemical staining of tissue sections from LPS-injected mice brains, quercetin reduced the activation of microglia and astrocytes in the hippocampus and substantia nigra of LPS-injected mice. Our data suggest that Qi-activating quercetin might be therapeutically effective for neuroinflammation-mediated neurodegeneration by alleviating mitochondrial damages.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inflamación/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Qi , Quercetina/farmacología , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Apoptosis/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Técnicas In Vitro , Inflamación/metabolismo , Inyecciones Intraperitoneales , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Enfermedad de Parkinson/metabolismo , Quercetina/administración & dosificación , Relación Estructura-Actividad , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Células Tumorales CultivadasRESUMEN
Exposure to environment-polluting chemicals (EPC) is associated with the development of diabetes. Many EPCs exert toxic effects via aryl hydrocarbon receptor (AhR) and/or mitochondrial inhibition. Here we investigated if the levels of human exposure to a mixture of EPC and/or mitochondrial inhibitors could predict the development of diabetes in a prospective study, the Korean Genome and Epidemiological Study (KoGES). We analysed AhR ligands (AhRL) and mitochondria-inhibiting substances (MIS) in serum samples (n = 1,537), collected during the 2008 Ansung KoGES survey with a 4-year-follow-up. Serum AhRL, determined by the AhR-dependent luciferase reporter assay, represents the contamination level of AhR ligand mixture in serum. Serum levels of MIS, analysed indirectly by MIS-ATP or MIS-ROS, are the serum MIS-induced mitochondria inhibiting effects on ATP content or reactive oxygen species (ROS) production in the cultured cells. Among 919 normal subjects at baseline, 7.1% developed impaired glucose tolerance (IGT) and 1.6% diabetes after 4 years. At the baseline, diabetic and IGT sera displayed higher AhRL and MIS than normal sera, which correlated with indices of insulin resistance. When the subjects were classified according to ROC cut-off values, fully adjusted relative risks of diabetes development within 4 years were 7.60 (95% CI, 4.23-13.64), 4.27 (95% CI, 2.38-7.64), and 21.11 (95% CI, 8.46-52.67) for AhRL ≥ 2.70 pM, MIS-ATP ≤ 88.1%, and both, respectively. Gender analysis revealed that male subjects with AhRL ≥ 2.70 pM or MIS-ATP ≤ 88.1% showed higher risk than female subjects. High serum levels of AhRL and/or MIS strongly predict the future development of diabetes, suggesting that the accumulation of AhR ligands and/or mitochondrial inhibitors in body may play an important role in the pathogenesis of diabetes.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Biomarcadores/sangre , Diabetes Mellitus/sangre , Mitocondrias/efectos de los fármacos , Receptores de Hidrocarburo de Aril/genética , Anciano , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/sangre , Diabetes Mellitus/inducido químicamente , Diabetes Mellitus/patología , Biomarcadores Ambientales/genética , Femenino , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/genética , Prueba de Tolerancia a la Glucosa , Humanos , Resistencia a la Insulina/genética , Ligandos , Masculino , Persona de Mediana Edad , Especies Reactivas de Oxígeno/metabolismo , Receptores de Hidrocarburo de Aril/sangre , República de CoreaRESUMEN
PURPOSE: Elevated aryl hydrocarbon receptor (AhR) transactivating (AHRT) activity and uremia in chronic kidney disease (CKD) may interact with each other, further complicating the disease course. In this study, we prospectively estimated serum AHRT activity using a highly sensitive cell-based AhR-dependent luciferase activity assay in CKD patients and compared differences therein according to treatment modality. MATERIALS AND METHODS: Patients undergoing peritoneal dialysis (PD) (n=22) and hemodialysis (HD) (n=38) and patients with pre-dialysis CKD stage IV or V (n=28) were included. AHRT activity and intracellular adenosine triphosphate (ATP) levels were measured. We performed a correlation analysis for AHRT activity, ATP levels, and various clinical parameters. RESULTS: AHRT activity and intracellular ATP levels were inversely correlated and differed according to treatment modalities. AHRT activity was higher in non-dialysis CKD patients than in patients undergoing dialysis and was higher in patients undergoing HD, compared to PD. AHRT activity decreased after HD treatment in HD patients. ATP levels were higher in healthy controls than in patients with pre-dialysis CKD and PD and were further decreased in patients with HD. We noted significant correlations between multiple clinical parameters associated with cardiovascular risk factors and AHRT activity. CONCLUSION: AHRT activity was elevated in CKD patients, while dialysis treatment reduced AHRT activity. Further studies are warranted to specify AHRT activity and to evaluate the precise roles thereof in patients with CKD.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Diálisis Renal , Insuficiencia Renal Crónica/metabolismo , Activación Transcripcional , Adenosina Trifosfato/metabolismo , Femenino , Humanos , Espacio Intracelular/metabolismo , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/fisiopatologíaRESUMEN
α-Naphthoflavone (αNF) is a prototype flavone, also known as a modulator of aryl hydrocarbon receptor (AhR). In the present study, we investigated the molecular mechanisms of αNF-induced cytotoxic effects in HT22 mouse hippocampal neuronal cells. αNF induced apoptotic cell death via activation of caspase-12 and -3 and increased expression of endoplasmic reticulum (ER) stress-associated proteins, including C/EBP homologous protein (CHOP). Inhibition of ER stress by treatment with the ER stress inhibitor, salubrinal, or by CHOP siRNA transfection reduced αNF-induced cell death. αNF activated mitogen-activated protein kinases (MAPKs), such as p38, JNK, and ERK, and inhibition of MAPKs reduced αNF-induced CHOP expression and cell death. αNF also induced accumulation of reactive oxygen species (ROS) and an antioxidant, N-acetylcysteine, reduced αNF-induced MAPK phosphorylation, CHOP expression, and cell death. Furthermore, αNF activated c-Src kinase, and inhibition of c-Src by a kinase inhibitor, SU6656, or siRNA transfection reduced αNF-induced ROS accumulation, MAPK activation, CHOP expression, and cell death. Inhibition of AhR by an AhR antagonist, CH223191, and siRNA transfection of AhR and AhR nuclear translocator reduced αNF-induced AhR-responsive luciferase activity, CHOP expression, and cell death. Finally, we found that inhibition of c-Src and MAPKs reduced αNF-induced transcriptional activity of AhR. Taken together, these findings suggest that αNF induces apoptosis through ER stress via c-Src-, ROS-, MAPKs-, and AhR-dependent pathways in HT22 cells.
Asunto(s)
Apoptosis , Benzoflavonas/metabolismo , Estrés del Retículo Endoplásmico , Hipocampo/metabolismo , Neuronas/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal , Animales , Línea Celular , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas pp60(c-src)/metabolismo , Especies Reactivas de OxígenoRESUMEN
Moutan cortex, Angelica Dahurica root, and Bupleurum root are traditional herbal medicines used in Asian countries to treat various diseases caused by oxidative stress or inflammation. Parkinson's disease (PD) has been associated with mitochondrial dysfunction, but no effective treatment for mitochondrial dysfunction has yet been identified. In this study we investigated the neuroprotective effects of the triple herbal extract DA-9805 in experimental models of PD. DA-9805 was prepared by extracting three dried plant materials (Moutan cortex, Angelica Dahurica root, and Bupleurum root in a 1:1:1 mixture) with 90% ethanol on a stirring plate for 24 h at room temperature and fingerprinted using high-performance liquid chromatography. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP+), which both exert neurotoxic effects on dopaminergic neurons by inhibiting mitochondrial oxidative phosphorylation (OXPHOS) complex I, were used to make experimental models of PD. In MPP+-treated SH-SY5Y cells, DA-9805 ameliorated the suppression of tyrosine hydroxylase expression and mitochondrial damage on OXPHOS complex 1 activity, mitochondrial membrane potential, reactive oxygen species (ROS) generation, and oxygen consumption rate. In the MPTP-induced subacute PD model mice, oral administration of DA-9805 recovered dopamine content as well as bradykinesia, as determined by the rotarod test. DA-9805 protected against neuronal damage in the substantia nigra pars compacta (SNpc) and striatum. In both in vitro and in vivo models of PD, DA-9805 normalized the phosphorylation of AKT at S473 and T308 on the insulin signaling pathway and the expression of mitochondria-related genes. These results demonstrate that the triple herbal extract DA-9805 showed neuroprotective effects via alleviating mitochondria damage in experimental models of PD. We propose that DA-9805 may be a suitable candidate for disease-modifying therapeutics for PD.
Asunto(s)
Mitocondrias/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Extractos Vegetales/farmacología , Angelica/química , Angelica/metabolismo , Animales , Bupleurum/química , Bupleurum/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/metabolismo , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Paeonia/química , Paeonia/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
An excess of reactive oxygen species (ROS) relative to the antioxidant capacity causes oxidative stress, which plays a role in the development of Parkinson's disease (PD). Because mitochondria are both sites of ROS generation and targets of ROS damage, the delivery of antioxidants to mitochondria might prevent or alleviate PD. To transduce the antioxidant protein human metallothionein 1A (hMT1A) into mitochondria, we computationally designed a cell-penetrating artificial mitochondria-targeting peptide (CAMP). The recombinant CAMP-conjugated hMT1A fusion protein (CAMP-hMT1A) successfully localized to the mitochondria. Treating a cell culture model of PD with CAMP-hMT1A restored tyrosine hydroxylase expression and mitochondrial activity and reduced ROS production. Furthermore, injection of CAMP-hMT1A into the brain of a mouse model of PD rescued movement impairment and dopaminergic neuronal degeneration. CAMP-hMT1A delivery into mitochondria might be therapeutic against PD by alleviating mitochondrial damage, and we predict that CAMP could be used to deliver other cargo proteins to the mitochondria.
Asunto(s)
Péptidos de Penetración Celular/uso terapéutico , Metalotioneína/uso terapéutico , Mitocondrias/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Secuencia de Aminoácidos , Animales , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Péptidos de Penetración Celular/química , Péptidos de Penetración Celular/farmacología , Simulación por Computador , Modelos Animales de Enfermedad , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Metalotioneína/farmacología , Ratones , Mitocondrias/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Enfermedad de Parkinson/patología , Transporte de Proteínas , Proteínas Recombinantes de Fusión/uso terapéutico , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
We regret that there is an error in the labeling of Fig. 4 of the published original article. The concentration of MPP+ should be corrected to 1.0 mM instead of 0.5 mM. The corrected figure should be.