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1.
Molecules ; 26(23)2021 Nov 29.
Article in English | MEDLINE | ID: mdl-34885809

ABSTRACT

Medulloblastoma is a common malignant brain tumor in the pediatric age. The current therapeutics present serious collateral effects. Polyphenols α-mangostin and nordihydroguaiaretic acid (NDGA) exert potent antitumoral activity in different cancer models, although their antitumoral effects have not been described in medulloblastoma cells yet. This study aimed to examine the proapoptotic effects of these polyphenols on human medulloblastoma cells. Medulloblastoma cell line Daoy was incubated with increasing concentrations of α-mangostin or NDGA for 24 h. The cell viability was analyzed using crystal violet and trypan blue dyes. Determination of the glutathione (GSH)/glutathione disulfide (GSSG) ratio and levels of carbonylated proteins was performed to evaluate the oxidative stress. Cell cycle progression and induction of cell death by fluorochrome-couple and TUNEL assays were evaluated using flow cytometry assays. Individual treatments with α-mangostin or NDGA decreased the viability of Daoy cells in a dose-dependent manner, inducing G2/M and S-G2/M cell cycle arrest, respectively. Both polyphenols induced cell death and increased oxidative stress. Very interestingly, α-mangostin showed more potent effects than NDGA. Our results indicate that α-mangostin and NDGA exert important cytostatic and cytotoxic effects in the Daoy cell line. These data highlight the potential usefulness of these compounds as an alternative strategy in medulloblastoma treatment.


Subject(s)
Apoptosis , Cell Cycle Checkpoints , Cerebellar Neoplasms/pathology , Masoprocol/pharmacology , Medulloblastoma/pathology , Oxidative Stress , Polyphenols/pharmacology , Xanthones/pharmacology , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Models, Biological , Oxidative Stress/drug effects
2.
J Alzheimers Dis ; 28(1): 93-107, 2012.
Article in English | MEDLINE | ID: mdl-21955814

ABSTRACT

Air pollution exposures have been linked to neuroinflammation and neuropathology. Autopsy samples of the frontal cortex from control (n = 8) and pollution-exposed (n = 35) children and young adults were analyzed by RT-PCR (n = 43) and microarray analysis (n = 12) for gene expression changes in oxidative stress, DNA damage signaling, NFκB signaling, inflammation, and neurodegeneration pathways. The effect of apolipoprotein E (APOE) genotype on the presence of protein aggregates associated with Alzheimer's disease (AD) pathology was also explored. Exposed urbanites displayed differential (>2-fold) regulation of 134 genes. Forty percent exhibited tau hyperphosphorylation with pre-tangle material and 51% had amyloid-ß (Aß) diffuse plaques compared with 0% in controls. APOE4 carriers had greater hyperphosphorylated tau and diffuse Aß plaques versus E3 carriers (Q = 7.82, p = 0.005). Upregulated gene network clusters included IL1, NFκB, TNF, IFN, and TLRs. A 15-fold frontal down-regulation of the prion-related protein (PrP(C)) was seen in highly exposed subjects. The down-regulation of the PrP(C) is critical given its important roles for neuroprotection, neurodegeneration, and mood disorder states. Elevation of indices of neuroinflammation and oxidative stress, down-regulation of the PrP(C) and AD-associated pathology are present in young megacity residents. The inducible regulation of gene expression suggests they are evolving different mechanisms in an attempt to cope with the constant state of inflammation and oxidative stress related to their environmental exposures. Together, these data support a role for air pollution in CNS damage and its impact upon the developing brain and the potential etiology of AD and mood disorders.


Subject(s)
Air Pollution/adverse effects , Encephalitis/metabolism , Plaque, Amyloid/metabolism , Prions/metabolism , tau Proteins/metabolism , Adolescent , Adult , Age Factors , Child , Child, Preschool , Cohort Studies , Down-Regulation , Encephalitis/pathology , Female , Frontal Lobe/metabolism , Frontal Lobe/pathology , Gene Regulatory Networks , Humans , Infant , Male , Mexico , Phosphorylation , Plaque, Amyloid/pathology , Young Adult
3.
Int J Dev Neurosci ; 29(4): 365-75, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21458557

ABSTRACT

We assessed brainstem inflammation in children exposed to air pollutants by comparing brainstem auditory evoked potentials (BAEPs) and blood inflammatory markers in children age 96.3±8.5 months from highly polluted (n=34) versus a low polluted city (n=17). The brainstems of nine children with accidental deaths were also examined. Children from the highly polluted environment had significant delays in wave III (t(50)=17.038; p<0.0001) and wave V (t(50)=19.730; p<0.0001) but no delay in wave I (p=0.548). They also had significantly longer latencies than controls for interwave intervals I-III, III-V, and I-V (all t(50)>7.501; p<0.0001), consisting with delayed central conduction time of brainstem neural transmission. Highly exposed children showed significant evidence of inflammatory markers and their auditory and vestibular nuclei accumulated α synuclein and/or ß amyloid(1-42). Medial superior olive neurons, critically involved in BAEPs, displayed significant pathology. Children's exposure to urban air pollution increases their risk for auditory and vestibular impairment.


Subject(s)
Air Pollution/adverse effects , Brain Stem/drug effects , Brain Stem/pathology , Evoked Potentials, Auditory, Brain Stem/drug effects , Evoked Potentials, Auditory, Brain Stem/physiology , Adolescent , Biomarkers/blood , Brain Stem/physiology , Child , Female , Humans , Male , Mexico , Prospective Studies , Young Adult
4.
Int J Toxicol ; 29(6): 604-15, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21030725

ABSTRACT

Mexico City (MC) residents exposed to fine particulate matter and endotoxin exhibit inflammation of the olfactory bulb, substantia nigra, and vagus nerve. The goal of this study was to model these endpoints in mice and examine the neuroprotective effects of chocolate. Mice exposed to MC air received no treatment or oral dark chocolate and were compared to clean-air mice either untreated or treated intraperitoneally with endotoxin. Cyclooxygenase-2 (COX-2), interleukin 1 beta (IL-1ß), and CD14 messenger RNA (mRNA) were quantified after 4, 8, and 16 months of exposure in target brain regions. After 16 months of exposure, the dorsal vagal complex (DVC) exhibited significant inflammation in endotoxin-treated and MC mice (COX-2 and IL-1ß P<.001). Mexico City mice had olfactory bulb upregulation of CD14 (P=.002) and significant DVC imbalance in genes for antioxidant defenses, apoptosis, and neurodegeneration. These findings demonstrate sustained DVC inflammation in mice exposed to MC air, which is mitigated by chocolate administration.


Subject(s)
Air Pollution/adverse effects , Brain Stem/drug effects , Cacao , Encephalitis/prevention & control , Neuroprotective Agents/administration & dosage , Urban Health , Vagus Nerve/drug effects , Air Pollution/legislation & jurisprudence , Animals , Brain Stem/immunology , Brain Stem/metabolism , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Encephalitis/chemically induced , Endotoxins/analysis , Endotoxins/toxicity , Female , Gene Expression Regulation/drug effects , Lipopolysaccharide Receptors/genetics , Lipopolysaccharide Receptors/metabolism , Mexico , Mice , Mice, Inbred BALB C , Neuritis/chemically induced , Neuritis/prevention & control , Neurons/drug effects , Neurons/immunology , Neurons/metabolism , Olfactory Bulb/drug effects , Olfactory Bulb/immunology , Olfactory Bulb/metabolism , Organ Specificity , Particulate Matter/chemistry , Particulate Matter/toxicity , RNA, Messenger/metabolism , Vagus Nerve/immunology , Vagus Nerve/metabolism
5.
Acta Biol Hung ; 61(2): 135-44, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20519168

ABSTRACT

Our aim was to evaluate the effects of marijuana (Mar) and diazepam (Dz) on lipid peroxidation (TBARS), Na + , K + ATP ase activity, levels of glutathione (GSH) and 5-hydroxytryptophan (5-HTP). Male Wistar rats were given a single dose per group: extract of Mar (100 microL/kg), Dz (5 mg/kg), Mar plus Dz, and NaCl for control. Sixty mins after treatment, animals were sacrificed, and their brains extracted and homogenised to measure GSH, TBARS and 5-HTP levels. Na + , K + ATP ase and total ATP ase activities. GSH and TBARS did not show differences respect to controls. Na + , K + ATP ase activity was similar as well. However, groups treated with Mar, total ATPase activity decreased significantly (p < 0.05). Levels of 5-HTP decreased significantly (p = 0.0001) in rats treated either with Mar and or Dz. Mar and Dz induced biochemical effects on the serotonergic metabolism, which can alter the development and function in rat brain, because it has also been involved in scavenging free radicals present there.


Subject(s)
5-Hydroxytryptophan/pharmacology , Cannabis/metabolism , Diazepam/pharmacology , Glutathione/metabolism , Lipid Peroxidation/drug effects , Sodium-Potassium-Exchanging ATPase/metabolism , Adenosine Triphosphatases/chemistry , Animals , Anti-Anxiety Agents/pharmacology , Brain/metabolism , Male , Rats , Rats, Wistar , Serotonin/chemistry , Time Factors
6.
Exp Toxicol Pathol ; 62(1): 91-102, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19297138

ABSTRACT

Mexico City (MC) residents are exposed to severe air pollution and exhibit olfactory bulb inflammation. We compared the olfactory function of individuals living under conditions of extreme air pollution to that of controls from a relatively clean environment and explore associations between olfaction scores, apolipoprotein E (APOE) status, and pollution exposure. The olfactory bulbs (OBs) of 35 MC and 9 controls 20.8+/-8.5 years were assessed by light and electron microscopy. The University of Pennsylvania Smell Identification Test (UPSIT) was administered to 62 MC/25 controls 21.2+/-2.7 years. MC subjects had significantly lower UPSIT scores: 34.24+/-0.42 versus controls 35.76+/-0.40, p=0.03. Olfaction deficits were present in 35.5% MC and 12% of controls. MC APOE epsilon 4 carriers failed 2.4+/-0.54 items in the 10-item smell identification scale from the UPSIT related to Alzheimer's disease, while APOE 2/3 and 3/3 subjects failed 1.36+/-0.16 items, p=0.01. MC residents exhibited OB endothelial hyperplasia, neuronal accumulation of particles (2/35), and immunoreactivity to beta amyloid betaA(42) (29/35) and/or alpha-synuclein (4/35) in neurons, glial cells and/or blood vessels. Ultrafine particles were present in OBs endothelial cytoplasm and basement membranes. Control OBs were unremarkable. Air pollution exposure is associated with olfactory dysfunction and OB pathology, APOE 4 may confer greater susceptibility to such abnormalities, and ultrafine particles could play a key role in the OB pathology. This study contributes to our understanding of the influences of air pollution on olfaction and its potential contribution to neurodegeneration.


Subject(s)
Air Pollution/adverse effects , Smell/drug effects , Adolescent , Adult , Apolipoproteins E/blood , Child , Child, Preschool , Cohort Studies , Female , Humans , Male , Mexico , Microscopy, Electron , Olfaction Disorders/chemically induced , Olfactory Bulb/drug effects , Olfactory Bulb/ultrastructure , Urban Population , Young Adult
7.
Toxicol Pathol ; 37(5): 644-60, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19638440

ABSTRACT

Residency in cities with high air pollution is associated with neuroinflammation and neurodegeneration in healthy children, young adults, and dogs. Nonsteroidal anti-inflammatory drugs may offer neuroprotection. The authors measured the plasma concentrations of 3-nitrotyrosine and the cerebro-spinal-fluid concentrations of prostaglandin E2 metabolite and the oligomeric form of amyloid derived diffusible ligand; measured the mRNA expression of cyclooxygenase-2, interleukin 1beta, CD14, and Aquaporin-4 in target brain areas; and evaluated brain MRI, cognition, and neuropathology in 8 dogs treated with a preferential cyclooxygenase-2 inhibitor (Nimesulide) versus 7 untreated litter-matched Mexico City dogs. Nimesulide significantly decreased nitrotyrosine in plasma (p < .0001), frontal gray IL1beta (p = .03), and heart IL1beta (p = .02). No effect was seen in mRNA COX2, amyloid, and PGE2 in CSF or the MRI white matter lesions. All exposed dogs exhibited olfactory bulb and frontal accumulation of Abeta(42) in neurons and blood vessels and frontal vascular subcortical pathology. White matter hyperintense MRI frontal lesions were seen in 4/6 non-treated and 6/8 treated dogs. Nonsteroidal anti-inflammatory drugs may offer limited neuroprotection in the setting of severe air pollution exposures. The search for potentially beneficial drugs useful to ameliorate the brain effects of pollution represents an enormous clinical challenge.


Subject(s)
Air Pollution/adverse effects , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2/metabolism , Dogs/metabolism , Sulfonamides/pharmacology , Amyloid beta-Peptides/metabolism , Animals , Aquaporin 4/metabolism , Brain/anatomy & histology , Brain/pathology , Chi-Square Distribution , Cyclooxygenase 2/genetics , Cyclooxygenase 2 Inhibitors/pharmacokinetics , Frontal Lobe/metabolism , Immunohistochemistry , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Lipopolysaccharide Receptors/metabolism , Magnetic Resonance Imaging , Mexico , Nasal Mucosa/metabolism , Ozone/adverse effects , Pilot Projects , Prostaglandins E/metabolism , Statistics, Nonparametric , Sulfonamides/pharmacokinetics , Tyrosine/metabolism
8.
Toxicol Pathol ; 37(2): 161-9, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19171930

ABSTRACT

Environmental pollutants, chemicals, and drugs have an impact on children's immune system development. Mexico City (MC) children exposed to significant concentrations of air pollutants exhibit chronic respiratory inflammation, systemic inflammation, neuroinflammation, and cognitive deficits. We tested the hypothesis that exposure to severe air pollution plays a role in the immune responses of asymptomatic, apparently healthy children. Blood measurements for markers of immune function, inflammatory mediators, and molecules interacting with the lipopolysaccharide recognition complex were obtained from two cohorts of matched children (aged 9.7 +/- 1.2 years) from southwest Mexico City (SWMC) (n = 66) and from a control city (n = 93) with criteria pollutant levels below current standards. MC children exhibited significant decreases in the numbers of natural killer cells (p = .003) and increased numbers of mCD14+ monocytes (p < .001) and CD8+ cells (p = .02). Lower concentrations of interferon gamma (p = .009) and granulocyte-macrophage colony-stimulating factor (p < .001), an endotoxin tolerance-like state, systemic inflammation, and an anti-inflammatory response were also present in the highly exposed children. C-reactive protein and the prostaglandin E metabolite levels were positively correlated with twenty-four- and forty-eight-hour cumulative concentrations of PM(2.5). Exposure to urban air pollution is associated with immunodysregulation and systemic inflammation in children and is a major health threat.


Subject(s)
Air Pollutants/toxicity , Air Pollution/adverse effects , Environmental Exposure/adverse effects , Inflammation/chemically induced , Inflammation/immunology , Air Pollutants/analysis , Air Pollution/analysis , Case-Control Studies , Child , Cohort Studies , Environmental Exposure/prevention & control , Female , Humans , Inflammation/blood , Inhalation Exposure/adverse effects , Inhalation Exposure/prevention & control , Male , Mexico , Particle Size , Particulate Matter , Retrospective Studies , Urban Health
9.
Toxicol Pathol ; 36(2): 289-310, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18349428

ABSTRACT

Air pollution is a serious environmental problem. We investigated whether residency in cities with high air pollution is associated with neuroinflammation/neurodegeneration in healthy children and young adults who died suddenly. We measured mRNA cyclooxygenase-2, interleukin-1beta, and CD14 in target brain regions from low (n = 12) or highly exposed residents (n = 35) aged 25.1 +/- 1.5 years. Upregulation of cyclooxygenase-2, interleukin-1beta, and CD14 in olfactory bulb, frontal cortex, substantia nigrae and vagus nerves; disruption of the blood-brain barrier; endothelial activation, oxidative stress, and inflammatory cell trafficking were seen in highly exposed subjects. Amyloid beta42 (Abeta42) immunoreactivity was observed in 58.8% of apolipoprotein E (APOE) 3/3 < 25 y, and 100% of the APOE 4 subjects, whereas alpha-synuclein was seen in 23.5% of < 25 y subjects. Particulate material (PM) was seen in olfactory bulb neurons, and PM < 100 nm were observed in intraluminal erythrocytes from lung, frontal, and trigeminal ganglia capillaries. Exposure to air pollution causes neuroinflammation, an altered brain innate immune response, and accumulation of Abeta42 and alpha-synuclein starting in childhood. Exposure to air pollution should be considered a risk factor for Alzheimer's and Parkinson's diseases, and carriers of the APOE 4 allele could have a higher risk of developing Alzheimer's disease if they reside in a polluted environment.


Subject(s)
Air Pollutants/adverse effects , Amyloid beta-Peptides/metabolism , Blood-Brain Barrier/drug effects , Encephalitis/chemically induced , Peptide Fragments/metabolism , Urban Health , alpha-Synuclein/metabolism , Adolescent , Adult , Blood-Brain Barrier/pathology , Brain/drug effects , Brain/metabolism , Child , Child, Preschool , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Encephalitis/metabolism , Encephalitis/pathology , Female , Humans , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Lipopolysaccharide Receptors/genetics , Lipopolysaccharide Receptors/metabolism , Male , Neurons/drug effects , Neurons/metabolism , Olfactory Bulb/drug effects , Olfactory Bulb/metabolism , Olfactory Bulb/pathology , Particulate Matter/adverse effects , RNA, Messenger/metabolism , Up-Regulation/drug effects , Vagus Nerve/drug effects , Vagus Nerve/pathology
10.
Toxicol Pathol ; 30(3): 373-89, 2002.
Article in English | MEDLINE | ID: mdl-12051555

ABSTRACT

Exposure to complex mixtures of air pollutants produces inflammation in the upper and lower respiratory tract. Because the nasal cavity is a common portal of entry, respiratory and olfactory epithelia are vulnerable targets for toxicological damage. This study has evaluated, by light and electron microscopy and immunohistochemical expression of nuclear factor-kappa beta (NF-kappaB) and inducible nitric oxide synthase (iNOS), the olfactory and respiratory nasal mucosae, olfactory bulb, and cortical and subcortical structures from 32 healthy mongrel canine residents in Southwest Metropolitan Mexico City (SWMMC), a highly polluted urban region. Findings were compared to those in 8 dogs from Tlaxcala, a less polluted, control city. In SWMMC dogs, expression of nuclear neuronal NF-kappaB and iNOS in cortical endothelial cells occurred at ages 2 and 4 weeks; subsequent damage included alterations of the blood-brain barrier (BBB), degenerating cortical neurons, apoptotic glial white matter cells, deposition of apolipoprotein E (apoE)-positive lipid droplets in smooth muscle cells and pericytes, nonneuritic plaques, and neurofibrillary tangles. Persistent pulmonary inflammation and deteriorating olfactory and respiratory barriers may play a role in the neuropathology observed in the brains of these highly exposed canines. Neurodegenerative disorders such as Alzheimer's may begin early in life with air pollutants playing a crucial role.


Subject(s)
Air Pollutants/adverse effects , Brain Diseases/etiology , Cerebral Cortex/drug effects , Olfactory Bulb/drug effects , Animals , Apoptosis , Blood-Brain Barrier , Brain Diseases/chemically induced , Cerebral Cortex/blood supply , Cerebral Cortex/ultrastructure , Dogs , Female , Lung/drug effects , Male , Mexico , NF-kappa B/metabolism , Nasal Mucosa/drug effects , Neuroglia/drug effects , Neurons/drug effects , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II , Olfactory Mucosa/drug effects
11.
Rev. invest. clín ; 52(3): 284-95, mayo-jun. 2000. ilus, tab, CD-ROM
Article in Spanish | LILACS | ID: lil-292134

ABSTRACT

Esta revisión describe y discute los factores genéticos que al menos en parte, determinan la resistencia a la infección y que controlan el curso progresivo de la enfermedad en las personas infectadas por el virus de la inmunodeficiencia humana. Los factores genéticos podrían explicar la no progresión o la progresión lenta de la enfermedad, de una proporción de individuos infectados por VIH denominados no progresores a largo plazo. En general, este grupo permanece sin síntomas durante más de 10 años, mantiene estable sus niveles circulantes de cT CD4+ y habitualmente tiene baja carga viral. No obstante que los fenómenos de la no progresión y de la progresión rápida son aún incomprendidos, es probable que ciertos alelos de clase I y clase II del complejo principal de histocompatibilidad se asocien con un riesgo menor o mayor para desarrollar el síndrome de inmunodeficiencia adquirida...


Subject(s)
HIV/pathogenicity , Immunity, Innate/genetics , Acquired Immunodeficiency Syndrome/genetics , Chemokines/pharmacokinetics , Genes, MHC Class I/genetics
13.
Rev. mex. reumatol ; 14(2): 63-6, mar.-abr. 1999. ilus
Article in Spanish | LILACS | ID: lil-266825

ABSTRACT

El factor de necrosis tumoral-alfa (TNF-Ó) es una citocina relevante en los procesos inflamatorios y de inmunoestimulación; la principal fuente de su producción son los macrófagos activados. El gen codifica para el TNF-Ó (TNFA) y se localiza en el brazo corto del cromosoma 6 dentro de la región clase III del complejo principal de histocompatibilidad (CPH). Debido a la actividad del TNF y a la localización cromosómica del gen estructural parece importante en la fisiopatogenia de enfermedades infecciosas y autoinmunes tales como lupus eritematoso generalizado (LEG), artritis reumatoide (AR) y sarcoidosis, entre otras. Recientemente se han descrito variantes polimórficas en el promotor del TNFA que parecen regular la actividad transcripcional de dicho gen; en este sentido la variante TNF1 (la más común) se ha correlacionado con niveles bajos de TNF-Ó mientras que la variante TNF2 es con niveles elevados de la citocina. El LEG se ha asociado con los alelos HLA-B8, HLA-DR3 y HLA-DR2 en diferentes poblaciones. Por otro lado, el gen TNF2 se encuentra en desequilibrio genético con el HLA-DR3 y la elevada frecuencia de la variante TNF2 en pacientes caucásicos con LEG parece ser secundaria a la presencia del HLA-DR3. Sin embargo, el TNF2 también es frecuente en otras enfermedades como AR y sarcoidosis. Para conocer el gen o genes relevantes en la fisiopatogenia de las enfermedades autoinmunes, es deseable el estudio de los polimorfismos de cada uno de ellos en diversas poblaciones preferentemente heterogénas


Subject(s)
Humans , Autoimmune Diseases/genetics , Tumor Necrosis Factor-alpha/genetics , Major Histocompatibility Complex/genetics , Polymorphism, Genetic , Arthritis, Rheumatoid/genetics , Lupus Erythematosus, Systemic/genetics
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