RESUMEN
This Review emphasizes the impact of APOE4-the most significant genetic risk factor for Alzheimer's disease (AD)-on peripheral and neural effects starting in childhood. We discuss major mechanistic players associated with the APOE alleles' effects in humans to understand their impact from conception through all life stages and the importance of detrimental, synergistic environmental exposures. APOE4 influences AD pathogenesis, and exposure to fine particulate matter (PM2.5), manufactured nanoparticles (NPs), and ultrafine particles (UFPs) associated with combustion and friction processes appear to be major contributors to cerebrovascular dysfunction, neuroinflammation, and oxidative stress. In the context of outdoor and indoor PM pollution burden-as well as Fe, Ti, and Al alloys; Hg, Cu, Ca, Sn, and Si UFPs/NPs-in placenta and fetal brain tissues, urban APOE3 and APOE4 carriers are developing AD biological disease hallmarks (hyperphosphorylated-tau (P-tau) and amyloid beta 42 plaques (Aß42)). Strikingly, for Metropolitan Mexico City (MMC) young residents ≤ 40 y, APOE4 carriers have 4.92 times higher suicide odds and 23.6 times higher odds of reaching Braak NFT V stage versus APOE4 non-carriers. The National Institute on Aging and Alzheimer's Association (NIA-AA) framework could serve to test the hypothesis that UFPs and NPs are key players for oxidative stress, neuroinflammation, protein aggregation and misfolding, faulty complex protein quality control, and early damage to cell membranes and organelles of neural and vascular cells. Noninvasive biomarkers indicative of the P-tau and Aß42 abnormal protein deposits are needed across the disease continuum starting in childhood. Among the 21.8 million MMC residents, we have potentially 4 million APOE4 carriers at accelerated AD progression. These APOE4 individuals are prime candidates for early neuroprotective interventional trials. APOE4 is key in the development of AD evolving from childhood in highly polluted urban centers dominated by anthropogenic and industrial sources of pollution. APOE4 subjects are at higher early risk of AD development, and neuroprotection ought to be implemented. Effective reductions of PM2.5, UFP, and NP emissions from all sources are urgently needed. Alzheimer's Disease prevention ought to be at the core of the public health response and physicians-scientist minority research be supported.
Asunto(s)
Contaminación del Aire , Enfermedad de Alzheimer , Apolipoproteína E4 , Material Particulado , Suicidio , Humanos , Contaminación del Aire/efectos adversos , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides , Apolipoproteína E4/genética , Encéfalo/patología , Ciudades/epidemiología , Interacción Gen-Ambiente , Heterocigoto , México/epidemiología , Enfermedades Neuroinflamatorias/etiología , Enfermedades Neuroinflamatorias/genética , Material Particulado/efectos adversos , Suicidio/estadística & datos numéricosRESUMEN
There is an increasing concern over the harmful effects that metallic nanoparticles (NP) may produce on human health. Due to their redox properties, nickel (Ni) and Ni-containing NP are particularly relevant. Hence, the aim of this study was to establish the toxicological mechanisms in the cardiorespiratory oxidative metabolism initiated by an acute exposure to Ni-doped-NP. Mice were intranasally instilled with silica NP containing Ni (II) (Ni-NP) (1 mg Ni (II)/kg body weight) or empty NP as control, and 1 h after exposure lung, plasma, and heart samples were obtained to assess the redox metabolism. Results showed that, NP were mainly retained in the lungs triggering a significantly increased tissue O2 consumption rate, leading to Ni-NP-increased reactive oxygen species production by NOX activity, and mitochondrial H2O2 production rate. In addition, an oxidant redox status due to an altered antioxidant system showed by lung GSH/GSSG ratio decreased, and SOD activity increased, resulting in an increased phospholipid oxidation. Activation of circulating polymorphonuclear leukocytes, along with GSH/GSSG ratio decreased, and phospholipid oxidation were found in the Ni-NP-group plasma samples. Consequently, in distant organs such as heart, Ni-NP inhalation alters the tissue redox status. Our results showed that the O2 metabolism analysis is a critical area of study following Ni-NP inhalation. Therefore, this work provides novel data linking the redox metabolisms alterations elicited by exposure to Ni (II) adsorbed to NP and cardiorespiratory toxicity.
Asunto(s)
Nanopartículas del Metal/toxicidad , Níquel/química , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/metabolismo , Femenino , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Nanopartículas del Metal/química , Ratones , Mitocondrias/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Dióxido de Silicio/químicaRESUMEN
Glaucoma is a neurodegenerative disease that affects eye structures and brain areas related to the visual system. Oxidative stress plays a key role in the development and progression of the disease. The aims of the present study were to evaluate the mitochondrial function and its participation in the brain redox metabolism in an experimental glaucoma model. 3-month-old female Wistar rats were subjected to cauterization of two episcleral veins of the left eye to elevate the intraocular pressure. Seven days after surgery, animals were sacrificed, the brain was carefully removed and the primary visual cortex was dissected. Mitochondrial bioenergetics and ROS production, and the antioxidant enzyme defenses from both mitochondrial and cytosolic fractions were evaluated. When compared to control, glaucoma decreased mitochondrial ATP production (23%, p < 0.05), with an increase in superoxide and hydrogen peroxide production (30%, p < 0.01 and 28%, p < 0.05, respectively), whereas no changes were observed in membrane potential and oxygen consumption rate. In addition, the glaucoma group displayed a decrease in complex II activity (34%, p < 0.01). Moreover, NOX4 expression was increased in glaucoma compared to the control group (27%, p < 0.05). Regarding the activity of enzymes associated with the regulation of the redox status, glaucoma showed an increase in mitochondrial SOD activity (34%, p < 0.05), mostly due to an increase in Mn-SOD (50%, p < 0.05). A decrease in mitochondrial GST activity was observed (11%, p < 0.05). GR and TrxR activity were decreased in both mitochondrial (16%, p < 0.05 and 20%, p < 0.05 respectively) and cytosolic (21%, p < 0.01 and 50%, p < 0.01 respectively) fractions in the glaucoma group. Additionally, glaucoma showed an increase in cytoplasmatic GPx (50%, p < 0.01). In this scenario, redox imbalance took place resulting in damage to mitochondrial lipids (39%, p < 0.01) and proteins (70%, p < 0.05). These results suggest that glaucoma leads to mitochondrial function impairment in brain visual targets, that is accompanied by an alteration in both mitochondrial and cytoplasmatic enzymatic defenses. As a consequence of redox imbalance, oxidative damage to macromolecules takes place and can further affect vital cellular functions. Understanding the role of the mitochondria in the development and progression of the disease could bring up new neuroprotective therapies.
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Glaucoma/metabolismo , Mitocondrias/metabolismo , Corteza Visual/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Glaucoma/patología , Mitocondrias/patología , Proteínas Mitocondriales/metabolismo , NADPH Oxidasa 4/metabolismo , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismo , Corteza Visual/patologíaRESUMEN
The aim of the study was to evaluate the time course of the effects of urban air pollutants on the ocular surface, focusing on the morphological changes, the redox balance, and the inflammatory response of the cornea. 8-week-old mice were exposed to urban or filtered air (UA-group and FA-group, respectively) in exposure chambers for 1, 2, 4, and 12â¯weeks. After each time, the eyes were enucleated and the corneas were isolated for biochemical analysis. UA-group corneas exhibited a continuous increase in NADPH oxidase-4 levels throughout the exposure time, suggesting an increased production of reactive oxygen species (ROS). After 1â¯week, an early adaptive response to ROS was observed as an increase in antioxidant enzymes. After 4â¯weeks, the enzymatic antioxidants were decreased, meanwhile an increase of the glutathione was shown, as a later compensatory antioxidant response. However, redox imbalance took place, evidenced by the increased oxidized proteins, which persisted up to 12â¯weeks. At this time point, corneal epithelium hyperplasia was also observed. The inflammatory response was modulated by the increase in IL-10 levels after 1â¯week, which early regulates the release of TNF-α and IL-6. These results suggest that air pollution alters the ocular surface, supported by the observed cellular hyperplasia. The redox imbalance and the inflammatory response modulated by IL-10 play a key role in the response triggered by air pollutants on the cornea. Taking into account this time course study, the ocular surface should also be considered as a relevant target of urban air pollutants.
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Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/efectos adversos , Epitelio Corneal/patología , Animales , Brasil , Ciudades , Epitelio Corneal/efectos de los fármacos , Hiperplasia/inducido químicamente , Hiperplasia/patología , Interleucina-10/metabolismo , Masculino , Ratones , NADPH Oxidasa 4/metabolismo , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Factores de Tiempo , Pruebas de Toxicidad Subaguda , Pruebas de Toxicidad SubcrónicaRESUMEN
Safety concerns for fetus development of zidovudine (AZT) administration as prophylaxis of vertical transmission of HIV persist. We evaluated the participation of the ATP-binding cassette efflux transporter ABCG2 in the penetration of AZT into the fetal brain and the relevance for drug safety. Oral daily doses of AZT (60mg/kg body weight) or its vehicle were administered between post gestational days 11 (E11) and 20 (E20) to Sprague-Dawley pregnant rats. At E21, animals received an intravenous bolus of 60mg AZT/kg body weight in the presence or absence of the ABCG2 inhibitor gefitinib (20mg/kg body weight, ip) and AZT in maternal plasma and fetal brain were measured by HPLC-UV. ABCG2 protein expression in placenta and fetal brain, as well as mitochondrial function and ultrastructure in fetal brain were also analyzed. In utero chronic exposure to AZT markedly induced ABCG2 expression in placenta and fetal brain whereas did not significantly alter mitochondrial functionality in the fetal brain. The area-under-the-concentration-time-curve of AZT significantly decreased in fetal brains isolated from AZT-exposed fetuses compared to control group, but this effect was abolished by ABCG2 inhibition. Our results suggest that the absence of mitochondrial toxicity in the fetal brain after chronic in utero administration of AZT could be attributed to its low accumulation in the tissue caused, at least in part, by ABCG2 overexpression. We propose that any interference with ABCG2 activity due to genetic, pathological or iatrogenic factors would increase the amount of AZT reaching the fetal brain, which could increase the risk of toxicity of this drug on the tissue.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/biosíntesis , Fármacos Anti-VIH/farmacocinética , Encéfalo/metabolismo , Inhibidores de la Transcriptasa Inversa/farmacocinética , Zidovudina/farmacocinética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Animales , Fármacos Anti-VIH/farmacología , Disponibilidad Biológica , Encéfalo/efectos de los fármacos , Femenino , Feto/efectos de los fármacos , Feto/metabolismo , Gefitinib , Peroxidación de Lípido/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Embarazo , Quinazolinas/farmacología , Ratas , Ratas Sprague-Dawley , Inhibidores de la Transcriptasa Inversa/farmacología , Zidovudina/farmacologíaRESUMEN
Several epidemiological studies have shown a positive correlation between daily increases in airborne particulate matter (PM) concentration and the occurrence of respiratory and cardiovascular diseases. Transition metals present in air PM were associated with adverse health effects after PM exposure. The aim of this work was to study lung O2 metabolism after an acute exposure to transition metal-coated nanoparticles (NPs). Female Swiss mice (25g) were intranasally instilled with a suspension of silica NP containing Ni (II), Cd (II), Fe (III), or Cr (VI) at 0, 0.01, 0.05, 0.1, and 1.0mg metal/kg body weight. Lung O2 consumption was found to be significantly increased after the exposure to most doses of Ni-NP and Fe-NP, and the 0.05mg metal/kg body weight dose of Cr-NP, while no changes were observed for Cd-NP. Lucigenin chemiluminescence (as an indicator of NADPH oxidase (NOX) activity) was evaluated in lung homogenates. Only Ni-NP and Fe-NP have shown the ability to induce a significant increase in lucigenin chemiluminescence. In order to establish the possible occurrence of pulmonary oxidative stress, TBARS levels and the GSH/GSSG ratio were determined. The higher doses of Ni-NP and Fe-NP were able to induce an oxidative stress condition, as shown by changes in both TBARS levels and the GSH/GSSG ratio. Taken together, the present results show differential effects for all the metals tested. These findings emphasize the importance of transition metals present air PM in PM adverse health effects, and contribute to the understanding of the pathological mechanisms triggered by the exposure to environmental PM.
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Pulmón/efectos de los fármacos , Oxígeno/metabolismo , Material Particulado , Elementos de Transición/toxicidad , Animales , Relación Dosis-Respuesta a Droga , Exposición a Riesgos Ambientales , Femenino , Pulmón/química , Ratones , Modelos Animales , Oxígeno/química , Material Particulado/química , Material Particulado/toxicidad , Elementos de Transición/químicaRESUMEN
PURPOSE: During the postnatal stage, cardiovascular nitric oxide (NO) system and caveolins (cav) may be regulated differentially in response to hypovolemic state induced by water restriction. Our aim was to examine the effects of water restriction on NO synthases (NOS) and cav in the atria, ventricle and aorta of growing rats. METHODS: Male Sprague-Dawley rats aged 25 and 50 days were divided into (n = 15): WR: water restriction 3 days; WAL: water ad libitum 3 days. Systolic blood pressure, NOS activity and NOS/cav protein levels were measured. RESULTS: Dehydration induced a larger increase in SBP in WR25 group. Ventricular NOS activity, endothelial NOS (eNOS) and neuronal isoform (nNOS) of WR25 pups were increased, and both cav were decreased. In the WR50 group, NOS activity remained unchanged. In the atria, NOS activity, eNOS and nNOS decreased in WR25 associated with increased cav-1; in the WR50 group, NOS activity was increased without changes in NOS isoforms. In the aorta of WR25, NOS activity and inducible NOS (iNOS) were decreased; NOS activity was unchanged in WR50, despite the decreased levels of eNOS and increased iNOS, cav-1 and cav-3. CONCLUSIONS: NO system adjustments in cardiovascular system under osmotic stress in vivo depend on postnatal age, being eNOS and nNOS, the isoforms that determine NOS activity in cardiac tissue in 25-day-old pups. Changes in cav abundance during hypovolemic state may contribute to age-related NO production.
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Sistema Cardiovascular/metabolismo , Caveolina 1/metabolismo , Caveolina 3/metabolismo , Deshidratación , Óxido Nítrico Sintasa de Tipo I/metabolismo , Animales , Presión Sanguínea , Caveolina 1/genética , Caveolina 3/genética , Endotelio/metabolismo , Atrios Cardíacos/metabolismo , Ventrículos Cardíacos/metabolismo , Hemodinámica , Hipovolemia/metabolismo , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Presión Osmótica , Ratas , Ratas Sprague-Dawley , Sustancias Reactivas al Ácido TiobarbitúricoRESUMEN
The aim of this work was to study the time course of the oxidative metabolism in mice lung after exposure to ambient particles (ROFA). Swiss mice were intranasally instilled with a ROFA suspension (0.20 mg/kg). Animals were sacrificed 1 or 3 h after the exposure. Eighty percentage of increased oxygen consumption was observed in tissue cubes after 1 h of exposure. This observation was accompanied by an increased NADPH oxidase activity (40%) and mitochondrial oxygen consumption in state 3 (19%). NO production by lung homogenates was found to be increased by 43% after 3 h of exposure. Phospholipid oxidation in lung homogenates showed a 29% increase after 1 h of exposure, while a 30% increase in the carbonyl content was found only after 3 h of exposure. Our data show the relative importance of different sources of reactive oxygen species (NADPH oxidase activity and mitochondrial respiration) to the increased tissue oxygen consumption, oxidative damage and antioxidant status observed in an acute model of ROFA particles exposure.
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Contaminantes Atmosféricos/toxicidad , Exposición a Riesgos Ambientales , Pulmón/efectos de los fármacos , Estrés Oxidativo , Oxígeno/metabolismo , Material Particulado/toxicidad , Animales , Femenino , Pulmón/enzimología , Pulmón/metabolismo , Ratones , NADPH Oxidasas/metabolismoRESUMEN
PURPOSE: To evaluate the relationship between oxidative stress markers and increased intraocular pressure in experimental glaucoma. METHODS: In vivo chemiluminescence (CL), total antioxidant capacity (TRAP), nitrite concentration (NC), and lipid peroxidation markers (TBARS) were evaluated. Wistar rats (n=18 for each time point) underwent operation, and two episcleral veins were cauterized. RESULTS: Decreases of 22%, 35%, and 27% at 7, 15, and 30 days and an increase of 22% at 60 days in CL were observed in glaucomatous eyes. In optic nerve, TBARS values were 6.9+/-0.5 nmol/mg protein (7 days), 9.4+/-0.4 nmol/mg protein (15 days), 18.0+/-1.2 nmol/mg protein (30 days), and 43.1+/-5.3 nmol/mg protein (60 days) (control, 6.2+/-0.4 nmol/mg protein; P<0.001). NC was 37.0+/-1.8 microM (7 days), 31.4+/-1.2 microM (15 days), 39.6+/-1.3 microM (30 days), and 40.0+/-1.3 microM (60 days) (control, 21.1+/-1.7 microM; P<0.001). In glaucomatous vitreous humor, TRAP decreased by 42% at 15 days and 78% at 60 days (control, 414+/-29 microM; P<0.001). In glaucomatous aqueous humor, TRAP values were 75+/-7 microM (7 days), 54+/-4 microM (15 days), 25+/-4 microM (30 days), and 50+/-3 microM (60 days) (control, 90+/-10 microM; P<0.001). CONCLUSIONS: Reactive species were increased in glaucoma, as evidenced by the increases in CL, TBARS, and NC. The decrease in the antioxidant levels may be a consequence of an increase in oxidative processes.
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Biomarcadores/metabolismo , Glaucoma/metabolismo , Presión Intraocular/fisiología , Estrés Oxidativo/fisiología , Animales , Antioxidantes/metabolismo , Humor Acuoso/metabolismo , Modelos Animales de Enfermedad , Femenino , Peroxidación de Lípido/fisiología , Luminiscencia , Nitritos/metabolismo , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Cuerpo Vítreo/metabolismoRESUMEN
Nitric oxide and cytokines constitute the molecular markers and the intracellular messengers of inflammatory conditions which are derived from the activation of the NF-kappaB pathway and the transcription of proinflammatory genes. Sepsis occurs with an exacerbated inflammatory response that damages tissue mitochondria and impairs bioenergetic processes. One of the current hypotheses for the molecular mechanisms underlying the complex condition of sepsis is that enhanced NO production by mtNOS leads to excessive peroxynitrite production and protein nitration in the mitochondrial matrix, causing mitochondrial dysfunction and organ failure. The mechanism of particulate matter-health effects are believed to involve inflammation and oxidative stress. Components in particles that elicit inflammation are poorly investigated, although recent research points out to the contribution of compositional elements and particle size. Nitric oxide and reactive oxygen species appears to be involved in the inflammatory conditions associated to particulate matter inhalation.
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Contaminantes Atmosféricos/toxicidad , Inflamación/metabolismo , Óxido Nítrico/metabolismo , Oxígeno/metabolismo , Material Particulado/toxicidad , Sepsis/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Inflamación/inducido químicamente , Estrés OxidativoRESUMEN
PURPOSE: Oxidative stress and antioxidant status in eye tissues may be associated with glaucomatous damage. The aim of this study was to establish the antioxidant status of aqueous humor of patients with primary open-angle glaucoma. For this purpose the authors measured the total reactive antioxidant potential (TRAP) and the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase. DESIGN: Case control study. METHODS: Aqueous humor was obtained at the time of surgery from 24 patients with glaucoma and 24 cataract patients; TRAP was measured by chemiluminescence. Activities of the antioxidant enzymes were measured spectrophotometrically. Superoxide dismutase activity was determined by inhibition of the rate of adrenochrome formation at 480 nm. Catalase activity was evaluated by decrease of H(2)O(2) absorbance at 240 nm. Glutathione peroxidase (GPx) activity was determined following nicotinamide adenine dinucleotide phosphate oxidation at 340 nm. RESULTS: Total reactive antioxidant potential value of the cataract group was 124 +/- 5 micromol/l Trolox. This value was significantly decreased, by 64%, in glaucoma patients. An increase of 57% in SOD activity was observed in glaucoma patients when compared with cataract patients (41.7 +/- 2.7 U SOD/ml). Glutathione activity was threefold higher in glaucoma patients than in the cataract group (6.1 +/- 0.6 U/ml). No significant changes were found in catalase levels. CONCLUSIONS: Oxidative stress may lead to an induction of antioxidant enzymes and contribute to TRAP decrease. Superoxide dismutase, GPx activities, and TRAP may be useful oxidative stress markers in aqueous humor of glaucoma patients.