Effects of PM10 Airborne Particles from Different Regions of a Megacity on In Vitro Secretion of Cytokines by a Monocyte Line during Different Seasons.

Several epidemiological studies have demonstrated that particulate matter (PM) in air pollution can be involved in the genesis or aggravation of different cardiovascular, respiratory, perinatal, and cancer diseases. This study assessed the in vitro effects of PM10 on the secretion of cytokines by a human monocytic cell line (THP-1). We compared the chemotactic, pro-inflammatory, and anti-inflammatory cytokines induced by PM10 collected for two years during three different seasons in five different Mexico City locations. MIP-1α, IP-10, MCP-1, TNF-α, and VEGF were the main secretion products after stimulation with 80 µg/mL of PM10 for 24 h. The THP-1 cells showed a differential response to PM10 obtained in the different sites of Mexico City. The PM10 from the north and the central city areas induced a higher pro-inflammatory cytokine response than those from the south. Seasonal pro-inflammatory cytokine secretion always exceeded anti-inflammatory secretion. The rainy-season-derived particles caused the lowest pro-inflammatory effects. We concluded that toxicological assessment of airborne particles provides evidence supporting their potential role in the chronic exacerbation of local or systemic inflammatory responses that may worsen the evolution of some chronic diseases.

Statins as adjuvants in the treatment of ovarian cancer: Controversy and misunderstanding.

Ovarian cancer is frequently detected in advanced stages when the chances of survival are very low. Although chemotherapy is the treatment of choice, it is often rapidly compromised by the development of chemoresistance in patients. There are few pharmacological alternatives for managing chemoresistant ovarian cancer and statins have been suggested as an alternative, but their use is considered controversial. We present an overview of the most relevant epidemiological, in vitro and in vivo studies on the effects of statins in mono- or polytherapy for ovarian cancer. We conclude that the negative or inconclusive results of some epidemiological studies on statin-based cancer treatment are probably due, in large part, to the low doses given to patients, equivalent to those prescribed for hypercholesterolemia. Higher concentrations are well tolerated in animal models and by most patients in clinical trials. Future research is necessary to explore this possibility.

TNFα and IL-6 Responses to Particulate Matter in Vitro: Variation According to PM Size, Season, and Polycyclic Aromatic Hydrocarbon and Soil Content.

BACKGROUND: Observed seasonal differences in particulate matter (PM) associations with human health may be due to their composition and to toxicity-related seasonal interactions. OBJECTIVES: We assessed seasonality in PM composition and in vitro PM pro-inflammatory potential using multiple PM samples. METHODS: We collected 90 weekly PM10 and PM2.5 samples during the rainy-warm and dry-cold seasons in five urban areas with different pollution sources. The elements, polycyclic aromatic hydrocarbons (PAHs), and endotoxins identified in the samples were subjected to principal component analysis (PCA). We tested the potential of the PM to induce tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6) secretion in cultured human monocytes (THP-1), and we modeled pro-inflammatory responses using the component scores. RESULTS: PM composition varied by size and by season. PCA identified two main components that varied by season. Combustion-related constituents (e.g., vanadium, benzo[a]pyrene, benzo[a]anthracene) mainly comprised component 1 (C1). Soil-related constituents (e.g., endotoxins, silicon, aluminum) mainly comprised component 2 (C2). PM from the rainy-warm season was high in C2. PM (particularly PM2.5) from the dry-cold season was rich in C1. Elevated levels of cytokine production were associated with PM10 and C2 (rainy-warm season), whereas reduced levels of cytokine production were associated with PM2.5 and C1 (dry-cold season). TNFα secretion was increased following exposure to PM with high (vs. low) C2 content, but TNFα secretion in response to PM was decreased following exposure to samples containing ≥ 0.1% of C1-related PAHs, regardless of C2 content. The results of the IL-6 assays suggested more complex interactions between PM components and particle size. CONCLUSIONS: Variations in PM soil and PAH content underlie seasonal and PM size-related patterns in TNFα secretion. These results suggest that the mixture of components in PM explains some seasonal differences in associations between health outcomes and PM in epidemiologic studies. CITATION: Manzano-León N, Serrano-Lomelin J, Sánchez BN, Quintana-Belmares R, Vega E, Vázquez-López I, Rojas-Bracho L, López-Villegas MT, Vadillo-Ortega F, De Vizcaya-Ruiz A, Rosas Perez I, O'Neill MS, Osornio-Vargas AR. 2016. TNFα and IL-6 responses to particulate matter in vitro: variation according to PM size, season, and polycyclic aromatic hydrocarbon and soil content. Environ Health Perspect 124:406-412; http://dx.doi.org/10.1289/ehp.1409287.

Induction of c-Jun by air particulate matter (PM10) of Mexico city: Participation of polycyclic aromatic hydrocarbons.

The carcinogenic potential of urban particulate matter (PM) has been partly attributed to polycyclic aromatic hydrocarbons (PAHs) content, which activates the aryl hydrocarbon receptor (AhR). Here we report the effect of PM with an aerodynamic size of 10 µm (PM10) on the induction of AhR pathway in A549 cells, evaluating its downstream targets CYP1B1, IL-6, IL-8 and c-Jun. Significant increases in CYP1B1 protein and enzyme activity; IL-6 and IL-8 secretion and c-Jun protein were found in response to PM10. The formation of PAH-DNA adducts was also detected. The involvement of AhR pathway was confirmed with Resveratrol as AhR antagonist, which reversed CYP1B1 and c-Jun induction. Nevertheless, in IL-6 and IL-8 secretion, the Resveratrol was ineffective, suggesting an effect independent of this pathway. Considering the role of c-Jun in oncogenesis, its induction by PM may be contributing to its carcinogenic potential through induction of AhR pathway by PAHs present in PM10.

Variation in the composition and in vitro proinflammatory effect of urban particulate matter from different sites.

Spatial variation in particulate matter-related health and toxicological outcomes is partly due to its composition. We studied spatial variability in particle composition and induced cellular responses in Mexico City to complement an ongoing epidemiologic study. We measured elements, endotoxins, and polycyclic aromatic hydrocarbons in two particle size fractions collected in five sites. We compared the in vitro proinflammatory response of J774A.1 and THP-1 cells after exposure to particles, measuring subsequent TNFα and IL-6 secretion. Particle composition varied by site and size. Particle constituents were subjected to principal component analysis, identifying three components: C(1) (Si, Sr, Mg, Ca, Al, Fe, Mn, endotoxin), C(2) (polycyclic aromatic hydrocarbons), and C(3) (Zn, S, Sb, Ni, Cu, Pb). Induced TNFα levels were higher and more heterogeneous than IL-6 levels. Cytokines produced by both cell lines only correlated with C(1) , suggesting that constituents associated with soil induced the inflammatory response and explain observed spatial differences.

Estrés oxidativo, péptido beta-amiloide y enfermedad de Alzheimer / Oxidative stress, beta-amyloide peptide and Alzheimer's disease

La enfermedad de Alzheimer es la causa más común de demencia en la población de edad avanzada. Una de las características histopatológicas de esta enfermedad es la formación de placas seniles, cuyo componente proteínico es el péptido β-amiloide (Aβ) en su forma insoluble. Este péptido se produce normalmente en forma monomérica soluble y circula en concentraciones bajas en el líquido cefalorraquídeo y sangre. En concentraciones fisiológicas actúa como factor neurotrófico y neuroprotector, sin embargo con el envejecimiento y sobre todo en la enfermedad de Alzheimer se acumula, forma fibrillas insolubles y causa neurotoxicidad. La toxicidad del Aβ se ha asociado a la generación de radicales libres que causan peroxidación de lípidos y oxidación de proteínas entre otros daños. Se ha planteado que el Aβ pueda reconocer a receptores específicos que median a su vez neurotoxicidad. Entre estos se encuentra el receptor scavenger o pepenador que se expresa en la microglia y es capaz de internalizar agregados de este péptido. Independientemente de la vía de entrada del péptido a la célula, éste genera un estado de estrés oxidativo que eventualmente desencadena la muerte celular. Estudios recientes desarrollados en nuestro laboratorio muestran que el proceso de traducción de proteínas que intervienen en el proceso de endocitosis mediada por un receptor puede ser afectado por una condición de estrés oxidativo. Este es el caso de la β-adaptina, proteína clave en la formación del pozo cubierto.

Alzheimer's disease, the leading cause of dementia in the elderly is characterized by the presence in the brain of senile plaques formed of insoluble fibrillar deposits of beta-amyloid peptide. This peptide is normally produced in a monomeric soluble form and it is present in low concentrations in the blood and spinal fluid. At physiological concentrations, this peptide is a neurotrophic and neuroprotector factor; nevertheless, with aging and particularly in Alzheimer's disease this peptide accumulates, favors the formation of insoluble fibrils and causes neurotoxicity. beta-Amyloid peptide toxicity has been associated with the generation of free radicals that in turn promote lipid peroxidation and protein oxidation. Through the recognition of specific receptors such as the scavenger receptor, the beta-amyloid peptide becomes internalized in the form of aggregates. Independently of the way the peptide enters the cell, it generates oxidative stress that eventually triggers a state of neurotoxicity and cell death. Recent studies in our laboratory have shown the effect caused by an extracellular oxidative stress upon the internalization of the scavenger receptor. We have also demonstrated that the process of protein translation of molecules implicated in the mechanism of endocytosis through the scavenger receptor, such as the case of beta-adaptin, is arrested in microglial cells treated with beta-amyloid.