Neuroprotective effect of carnosine in the olfactory bulb after vanadium inhalation in a mouse model.

Carnosine (ß-alanyl-L-histidine) is synthesized in the olfactory system, has antioxidant activity as a scavenger of free radicals and has been reported to have neuroprotective action in diseases which have been attributed to oxidative damage. In neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, impairment of olfactory function has been described. Vanadium derivatives are environmental pollutants, and its toxicity has been associated with oxidative stress. Vanadium toxicity on the olfactory bulb was reported previously. This study investigates the neuroprotective effect of carnosine on the olfactory bulb in a mice model of vanadium inhalation. Male mice were divided into four groups: vanadium pentoxide (V2 O5 ) [0.02 mol/L] inhalation for one hour twice a week; V2 O5 inhalation plus 1 mg/kg of carnosine administered daily; carnosine only, and the control group that inhaled saline. The olfactory function was evaluated using the odorant test. Animals were sacrificed four weeks after exposure. The olfactory bulbs were dissected and processed using the rapid Golgi method; cytological and ultrastructural analysis was performed and malondialdehyde (MDA) concentrations were measured. The results showed evidence of olfactory dysfunction caused by vanadium exposure and also an increase in MDA levels, loss of dendritic spines and necrotic neuronal death in the granule cells. But, in contrast, vanadium-exposed mice treated with carnosine showed an increase in dendritic spines and a decrease in neuronal death and in MDA levels when compared with the group exposed to vanadium without carnosine. These results suggest that dendritic spine loss and ultrastructural alterations in the granule cells induced by vanadium are mediated by oxidative stress and that carnosine may modulate the neurotoxic vanadium action, improving the olfactory function.

Oxidative Stress as a Mechanism Involved in Kidney Damage After Subchronic Exposure to Vanadium Inhalation and Oral Sweetened Beverages in a Mouse Model.

Kidney diseases have notably increased in the last few years. This is partially explained by the increase in metabolic syndrome, diabetes, and systemic blood hypertension. However, there is a segment of the population that has neither of the previous risk factors, yet suffers kidney damage. Exposure to atmospheric pollutants has been suggested as a possible risk factor. Air-suspended particles carry on their surface a variety of fuel combustion-related residues such as metals, and vanadium is one of these. Vanadium might produce oxidative stress resulting in the damage of some organs such as the kidney. Additionally, in countries like Mexico, the ingestion of sweetened beverages is a major issue; whether these beverages alone are responsible for direct kidney damage or whether their ingestion promotes the progression of an existing renal damage generates controversy. In this study, we report the combined effect of vanadium inhalation and sweetened beverages ingestion in a mouse model. Forty CD-1 male mice were distributed in 4 groups: control, vanadium inhalation, 30% sucrose in drinking water, and vanadium inhalation plus sucrose 30% in drinking water. Our results support that vanadium inhalation and the ingestion of 30% sucrose induce functional and histological kidney damage and an increase in oxidative stress biomarkers, which were higher in the combined effect of vanadium plus 30% sucrose. The results also support that the ingestion of 30% sucrose alone without hyperglycemia also produces kidney damage.

In vivo CNS infection model of Acanthamoeba genotype T4: the early stages of infection lack presence of host inflammatory response and are a slow and contact-dependent process.

This study was developed in order to describe the early morphological events observed during the invasion of two pathogenic strains of Acanthamoeba (genotype T4); A. castellanii and A. culbertsoni, at the olfactory meatus and cerebral, pulmonary, renal, hepatic and splenic tissues levels, an in vivo invasion study. Histological and immunohistochemical description of the events at 24, 48, 72, and 96 h postintranasal inoculations of BALB/c mice was performed. A. castellanii showed a higher invasion rate than A. culbertsoni, which was only able to reach lung and brain tissue in the in vivo model. The current study supports previous evidence of lack of inflammatory response during the early stages of infection. Acanthamoeba invasion of the CNS and other organs is a slow and contact-dependent process. The early morphological events during the invasion of amoebae include the penetration of trophozoites into different epithelia: olfactory, respiratory, alveolar space, and renal tubule, which resemble the process of amoebae invasion described in corneal tissue. The data suggest that after reaching the nasal epithelium, trophozoites continued invasion, separating and lifting the most superficial cells, then migrating and penetrating between the cell junctions without causing a cytolytic effect on adjacent cells. These results reaffirm the idea that contact-dependent mechanisms are relevant for amoebae of Acanthamoeba genus regardless of the invasion site.

Activation of Janus kinase/signal transducers and activators of transcription pathway involved in megakaryocyte proliferation induced by vanadium resembles some aspects of essential thrombocythemia.

Vanadium (V) is an air pollutant released into the atmosphere by burning fossil fuels. Also, it has been recently evaluated for their carcinogenic potential to establish permissible limits of exposure at workplaces. We previously reported an increase in the number and size of platelets and their precursor cells and megakaryocytes in bone marrow and spleen. The aim of this study was to identify the involvement of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and thrombopoietin (TPO) receptor, and myeloproliferative leukemia virus oncogene (Mpl), in megakaryocyte proliferation induced by this compound. Mice were exposed twice a week to vanadium pentoxide inhalation (0.02 M) and were killed at 4th, 6th, and 8th week of exposure. Phosphorylated JAK2 (JAK2 ph), STAT3 (STAT3 ph), STAT5, and Mpl were identified in mice spleen megakaryocytes by cytofluorometry and immunohistochemistry. An increase in JAK2 ph and STAT3 ph, but a decrease in Mpl at 8-week exposure was identified in our findings. Taking together, we propose that the morphological findings, JAK/STAT activation, and decreased Mpl receptor induced by V leads to a condition comparable to essential thrombocythemia, so the effect on megakaryocytes caused by different mechanisms is similar. We also suggest that the decrease in Mpl is a negative feedback mechanism after the JAK/STAT activation. Since megakaryocytes are platelet precursors, their alteration affects platelet morphology and function, which might have implications in hemostasis as demonstrated previously, so it is important to continue evaluating the effects of toxics and pollutants on megakaryocytes and platelets.

Functional and morphological olfactory bulb modifications in mice after vanadium inhalation.

Neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, have olfaction impairment. These pathologies have also been linked to environmental pollutants. Vanadium is a pollutant, and its toxic mechanisms are related to the production of oxidative stress. In this study, we evaluated the effects of inhaled vanadium on olfaction, the olfactory bulb antioxidant, through histological and ultrastructural changes in granule cells. Mice in control group were made to inhale saline; the experimental group inhaled 0.02-M vanadium pentoxide (V2O5) for 1 hr twice a week for 4 weeks. Animals were sacrificed at 1, 2, 3, and 4 weeks after inhalation. Olfactory function was evaluated by the odorant test. The activity of glutathione peroxidase (GPx) and glutathione reductase (GR) was assayed in olfactory bulbs and processed for rapid Golgi method and ultrastructural analysis. Results show that olfactory function decreased at 4-week vanadium exposure; granule cells showed a decrease in dendritic spine density and increased lipofuscin, Golgi apparatus vacuolation, apoptosis, and necrosis. The activity of GPx and GR in the olfactory bulb was increased compared to that of the controls. Our results demonstrate that vanadium inhalation disturbs olfaction, histology, and the ultrastructure of the granule cells that might be associated with oxidative stress, a risk factor in neurodegenerative diseases.

Time course changes of the striatum neuropil after unilateral dopamine depletion and the usefulness of the contralateral striatum as a control structure.

INTRODUCTION: After unilateral dopamine depletion, some ipsilateral alterations occur and the contralateral structure has been utilized as control. OBJECTIVE: Our aim is to analyse the evolution of the ultrastructural alterations of the ipsilateral and contralateral striata of the 6-hydroxydopamine lesioned rats to demonstrate that the contralateral striatum should not be used as control structure. METHODS: After the surgery and the rotation behavior evaluation, animals were killed from 3 to 120 days after lesioning, and their striata were compared with those of aged rats. RESULTS: The ultrastructural analysis shows increased diameter of the synaptic ending in ipsilateral (since the third day) and contralateral striata (since day 30) and an increase in perforated synaptic contacts. CONCLUSION: Our data suggest that the contralateral striatum should not be taken as control structure at least after 20-30 days after lesioning, as the alterations found here may result in wrong interpretations when comparing with the ipsilateral-lesioned one.

Ultrastructural findings in murine seminiferous tubules as a consequence of subchronic vanadium pentoxide inhalation.

Vanadium (V) is a transition metal emitted to the atmosphere during the combustion of fossil fuels. Its current status as an atmospheric pollutant increases the need for information about the effects that this element might have on the reproductive health of exposed populations. The present study investigated changes in testicular ultrastructure following inhalation exposure of male mice to V (as vanadium pentoxide). Tissue V level was constant during the 12-week time period. We observed necrosis of spermatogonium, spermatocytes and Sertoli cells, as well as pseudo-nuclear inclusion and disruption of cellular junctions. Our findings stressed the importance of the hemato-testicular barrier in supporting the function of Sertoli cells and suggest as a possible target of V, tight junction proteins. Further analysis is needed in order to identify the role that reactive oxidative species (ROS) might have on these cellular junctions, and if a specific protein is the target of its toxic effects. The relevance of this report concerns the impact that metal air pollution could have on male fertility in dense cities with vehicular traffic problems.

Hippocampal cell alterations induced by the inhalation of vanadium pentoxide (V(2)O(5)) promote memory deterioration.

Spatial memory may be severely impaired as a consequence of ageing and neurodegenerative diseases, conditions that include neuronal damage. Vanadium (V) is a metalloid widely distributed in the environment and exerts severe toxic effects on a wide variety of biological systems. Reports about V inhalation toxicity on the CNS are limited, thus the purpose of this study is to determine the effects of Vanadium pentoxide (V(2)O(5)) inhalation (0.02M) on the memory and its correlation with the cytology of the hippocampus CA1. Forty eight CD-1 male mice were trained in spatial memory tasks and inhaled 1h twice a week; after each inhalation animals were evaluated and sacrificed from 1 to 4 weeks, perfused and processed for Golgi method and for ultrastructure evaluation. The cytological analysis consisted in counting the number of dendritic spines of 20 pyramidal neurons of hippocampus CA1, as well as ultrastructural characteristics. Results show that V inhalation produces a time dependent loss of dendritic spines, necrotic-like cell death, and notorious alterations of the hippocampus CA1 neuropile, which correlate with spatial memory impairment. Our data suggest that V induces important cellular and functional alterations, fact that deserves special attention since the concentration's trend of this element in the atmosphere is increasing.

Pollution by metals: Is there a relationship in glycemic control?

There are evidences of environmental pollution and health effects. Metals are pollutants implicated in systemic toxicity. One of the least studied effects, but which is currently becoming more important, is the effect of metals on glycemic control. Metals have been implicated as causes of chronic inflammation and oxidative stress and are associated to obesity, hyperglycemia and even diabetes. Arsenic, iron, mercury, lead, cadmium and nickel have been studied as a risk factor for hyperglycemia and diabetes. There is another group of metals that causes hypoglycemia such as vanadium, chromium, zinc and magnesium by different mechanisms. Zinc, magnesium and chromium deficiency is associated with increased risk of diabetes. This review summarizes some metals involved in glycemic control and pretends to alert health professionals about considering environmental metals as an important factor that could explain the poor glycemic control in patients. Further studies are needed to understand this poorly assessed problem.

Myocardial connexin-43 and N-Cadherin decrease during vanadium inhalation.

Particulate matter air pollution has considerably increased during the last decades; vanadium is a transition element adhered to this particulate matter, and the combustion of fossil fuels is the main source in the atmosphere. It has been reported that air pollution and specifically vanadium exposure increases the probability of suffering arrhythmias; however the biological mechanism of such a relationship remains unknown. It has been established that a diminished presence of N-Cadherin alters the Connexin-43 arrangement, and the consequent altered presence of these proteins predisposes to ventricular heart rate problems. We analyzed myocardial histology and the expression of N-Cadherin and Connexin-43 by immunohistochemistry in mouse that inhaled vanadium. Our results showed a significant and progressive reduction in both N-Cadherin and Connexin-43, as well as the presence of meganucleus; myofibrils disruption, and clumping in the exposed groups were also observed. Our findings add more information about a possible explanation for the arrythmogenic effect observed in dwellers of cities with high particulate matter atmospheric pollution.

Ependymal epithelium disruption after vanadium pentoxide inhalation. A mice experimental model.

The blood-brain barrier (BBB) protects the CNS against chemical insults. Regulation of blood-brain tissue exchange is accomplished by ependymal cells, which possess intercellular tight junctions. Loss of BBB function is an etiologic component of many neurological disorders. Vanadium (V) is a metalloid widely distributed in the environment and exerts potent toxic effects on a wide variety of biological systems. The current study examines the effects of Vanadium pentoxide (V2O5) inhalation in mice ependymal epithelium, through the analysis of the brain metal concentrations and the morphological modifications in the ependymal cells identified by scanning and transmission electron microscopy after 8 weeks of inhalation, in order to obtain a possible explanation about the mechanisms that V uses to enter and alter the CNS. Our results showed that V2O5 concentrations increase from the first week of study, stabilizing its values during the rest of the experiment. The morphological effects included cilia loss, cell sloughing and ependymal cell layer detachment. This damage can allow toxicants to modify the permeability of the epithelium and promote access of inflammatory mediators to the underlying neuronal tissue causing injury and neuronal death. Thus, understanding the mechanisms of BBB disruption would allow planning strategies to protect the brain from toxicants such as metals, which have increased in the atmosphere during the last decades and constitute an important health problem.

Sex differences in bronchiolar epithelium response after the inhalation of lead acetate (Pb).

In order to identify if there were sex differences in lead (Pb) lung concentrations and in bronchiolar response after its inhalation, a mice inhalation model was conducted. Sixty CD-1 adult mice from each sex inhaled separately, lead acetate 0.1 M for 1 h, thrice weekly during 15 days. Animals were evaluated for Pb-lung concentrations by atomic absorption spectrometry and for morphological evaluation by scanning electron microscopy (SEM). Higher Pb-lung concentrations were determined in females, however, more cell damage was found in males, finding that correlated with an increased loss of the nonciliated bronchiolar cells (NCBC) more sloughing and necrosis. Differences in particle clearance, oxidative stress handling, cytokines pathway activation and cytochrome P450 enzymes activity, all influenced by sex hormones, might be a possible explanation for our findings. The relevance of further studies in this field is stressed, as well as its relation to the different development expected for each sex in disease evolution, possible complications and treatment response.

Inhalation of cadmium, lead or its mixture Effects on the bronchiolar structure and its relation with metal tissue concentrations.

The human population in the industrialized world is constantly exposed to chemical mixtures of pollutants such as metals; information about the consequences of the interactions of these compounds on health is scarce. The current study examines the effects of the inhalation of lead (Pb), cadmium (Cd) and Pb-Cd mixture in mice models analyzing the metal concentrations in lung, and the morphological modifications in the bronchiolar epithelium identified by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) after 4 weeks of inhalation. Our results showed that metal concentrations in lung were higher compared to controls; however, Pb concentrations drastically decrease with the mixture. This reduction was also observed in the inhalation chamber. These data correlate with the morphological alterations observed, which consisted of flattened and decreased number of nonciliated bronchiolar cells (NCBC), bald ciliated cells and bundles of NCBC. These modifications were mainly given by Cd, alone or in combination with Pb. The clusters formed by NCBC cells suggest cell proliferation which probably means that after metal inhalation, the cells enhance their proliferative capacity in order to repopulate the bronchiolar wall.

Identification of genetic variants in the TNF promoter associated with COPD secondary to tobacco smoking and its severity.

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease that arises in response to noxious particles or gases. Associations of genetic polymorphisms in TNF have been reported in Asians and Caucasians, but not in Mestizo populations. A case-control study was conducted in two stages: in the first stage, patients with COPD (COPD group, n=165) and smokers without disease (SNC group, n=165) were included and the TNF promoter sequence was determined using direct sequencing. In the second stage, the identified polymorphisms were validated by real-time polymerase chain reaction (PCR) in COPD (n=260) and SNC (n=506). In the first stage, 11 different sets of "contig" alignments were determined, of which contig 10 was found to be associated with susceptibility (P=5.0E-04, OR [odds ratio] =3.64) and contig 1 with Global Initiative for COPD (GOLD) greater grade (P=1.0E-02, OR =3.82). The single nucleotide polymorphisms found in this region were individually identified; the GA genotypes of rs1800629 (P=0.038, OR =2.07), rs56036015 (P=0.0082, OR =3.18), and rs361525 (P=1.0E-02, OR =4.220) were higher in the COPD group vs the SNC group; after second-stage validation, rs1800629 (P=6.00E-03, OR =2.26) and rs56036015 (P=1.10E-03, OR =2.54) are maintained. There are genetic variants in the TNF promoter associated with increased risk of COPD secondary to smoking and with a higher GOLD grade in the Mexican Mestizo population.

Ependymal damage in a Plasmodium yoelii yoelii lethal murine malaria model.

Malaria continues to be a major global health problem, and over 40% of the world's population is at risk. Severe or complicated malaria is defined by clinical or laboratory evidence of vital organ dysfunction, including dysfunction of the central nervous system (CNS). The pathogenesis of complicated malaria has not been completely elucidated; however, the development of the multiorgan affection seems to play an important role in the disruption of the blood brain barrier (BBB) that protects the CNS against chemical insults. Historically, the BBB has received more attention in the pathogenesis of malaria than have the cerebrospinal fluid-brain barrier (CSFBB) and ependymal cells. This perspective may be misguided because, in the context of disease or toxicity, the CSFBB is more vulnerable to many foreign invaders than are the capillaries. Given the lack on studies of the damage to the CSFBB and ependymal epithelium in experimental murine malaria, the present study evaluated morphological changes in the ependymal cells of CD-1 male mice infected with lethal Plasmodium yoelii yoelii (Pyy) via histopathology and scanning electron microscopy (SEM). Samples were taken two, four and six days post-infection (PI). No lesions were observed upon the initial infection. By the fourth day PI, fourth ventricle ependymal samples exhibited disruptions and roughened epithelia. More severe injuries were observed at six days PI and included thickened cilia and deep separations between the ependymal intercellular spaces. In some of the analyzed areas, the absence of microvilli and cell layer detachment were observed, and some areas exhibited blebbing surfaces. The ependymal cell lesions observed in the CD1 male mice infected with lethal Pyy seemed to facilitate the paracellular permeability of the CSFBB and consequently promote the access of inflammatory mediators and toxic molecules through the barrier, which resulted in damage to the brain tissue. Understanding the mechanism of ependymal disruption during lethal murine malaria could help to elucidate the local and systemic factors that are involved in the pathogenesis of the disease and may provide essential clues for the prevention and treatment of complicated human malaria.

Effect of acute ozone exposure on locomotor behavior and striatal function.

Ozone exposure, depending on the dose, is a noninvasive model of oxidative stress. The purpose of this work was to study striatal damage and cell death induced by oxidative stress. Sixty-three male Wistar rats were divided into two groups--Group 1: animals were exposed to an air stream free of ozone for 4 h; and Group 2: animals were exposed to 1 ppm of ozone for 4 h. Four subgroups in each treatment group were then tested 3 h after control or ozone exposure for: (1) exploratory and freezing behavior; (2) lipid peroxidation levels; (3) in vivo release of amino acid and monoamine transmitters, and metabolites and nitric oxide; and (4) striatal ultrastructural changes. Results showed that the ozone decreased exploratory and increased freezing behaviors. It also increased striatal lipoperoxidation levels and basal dopamine, glutamate, and nitric oxide (arginine, citrulline, and nitrate used as indices) concentrations and decreased those of 5-HT. Concentrations of GABA were initially decreased 3 h after ozone but then were increased 3 and 5 days afterwards. Increased lipofucsine, neuronal cytoplasm and dendrite vacuolation, and dilation of rough endoplasmic reticulum cisterns and dark cells were observed in striatal medium spiny neurons in ozone-exposed rats. These alterations suggest a neurodegenerative process caused by oxidative stress after acute ozone exposure.

Single-cell gel electrophoresis assay of nasal epithelium and leukocytes from asthmatic and nonasthmatic subjects in Mexico City.

The prevalence of asthma--a chronic inflammatory respiratory disease--is increasing worldwide. One hypothesis suggests that this trend is related to enhanced exposure to air pollutants. Chronic inflammation generates oxidative stress, and cells involved in an allergic reaction are capable of producing reactive oxygen species that may predispose asthmatics to increased deoxyribonucleic acid (DNA) damage. The authors estimated DNA strand breaks by use of single-cell gel electrophoresis assay on 2 different cell types (i.e., nasal epithelial cells and leukocytes) sampled from asthmatic and nonasthmatic medical students in Mexico City. The authors found that asthmatic subjects had more DNA breaks in their nasal epithelial cells than did their nonasthmatic counterparts. In contrast, asthmatic subjects had less damage in their leukocytes than did nonasthmatic individuals. These findings suggest that the hyperreactivity of the nasal epithelium prevents systemic effects from air pollutants, as reflected by less DNA injury to leukocytes of the asthmatic group. Asthmatic's nasal epithelial cells were more sensitive to DNA damage than were those of nonasthmatics--perhaps as a consequence of increased fragility induced either by air pollution or by a chronic inflammatory response.

Vanadium in ambient air: concentrations in lung tissue from autopsies of Mexico City residents in the 1960s and 1990s.

Vanadium concentrations in lung tissue were determined by atomic absorption spectrometry from autopsy specimens taken from residents of Mexico City during the 1960s and 1990s (20 males and 19 females, and 30 males and 18 females, respectively). Samples from the 1990s had significantly increased mean vanadium concentrations (mean +/- standard deviation: 1.36 +/- 0.08), compared with those from the 1960s (1.04 +/- 0.05). Concentrations were not correlated with gender, smoking habit, age, cause of death, or occupation. These findings suggest that vanadium in ambient air is increasing and it represents a potential health hazard for Mexico City residents. Air pollution monitoring efforts should include vanadium concentrations in suspended particles to follow-up the findings reported herein. Researchers need to acquire a better knowledge of the levels of airborne vanadium exposure at which risk to human health occurs.

Amyloid beta: multiple mechanisms of toxicity and only some protective effects?

Amyloid beta (Aß) is a peptide of 39-43 amino acids found in large amounts and forming deposits in the brain tissue of patients with Alzheimer's disease (AD). For this reason, it has been implicated in the pathophysiology of damage observed in this type of dementia. However, the role of Aß in the pathophysiology of AD is not yet precisely understood. Aß has been experimentally shown to have a wide range of toxic mechanisms in vivo and in vitro, such as excitotoxicity, mitochondrial alterations, synaptic dysfunction, altered calcium homeostasis, oxidative stress, and so forth. In contrast, Aß has also shown some interesting neuroprotective and physiological properties under certain experimental conditions, suggesting that both physiological and pathological roles of Aß may depend on several factors. In this paper, we reviewed both toxic and protective mechanisms of Aß to further explore what their potential roles could be in the pathophysiology of AD. The complete understanding of such apparently opposed effects will also be an important guide for the therapeutic efforts coming in the future.

Las espinas dendríticas, su función y algunas alteraciones / Dendritic spines, its function and some alterations

Resumen Las espinas dendríticas constituyen modificaciones de la membrana celular de las dendritas, ricas en actina, cuya morfología se modifica y puede sugerir la presencia de alteraciones en la comunicación neuronal. Las espinas dendríticas cuentan con un aparato espinoso que participa en la regulación del calcio (Ca) intracelular. Reportes recientes mencionan la relación entre el número de espinas y las alteraciones del sueño, estado fisiológico en el que ocurre la consolidación de la memoria. Diversos estudios asocian cambios en su forma y densidad con ciertas patologías. En esta revisión se identifican las características morfológicas de estas y su relación con el desarrollo del sistema nervioso, el sueño y algunas patologías.

Abstract The dendritic spines are dendritic membrane modifications rich in actin, whose morphology changes could suggest modifications in neural communication. These dendritic spines have a spiny-apparatus that regulates the intracellular calcium concentration. Recent reports mention the relationship between the number of spines and certain sleep disorders, the physiologic state in which memory consolidation takes place. Changes in their morphology and density are associated with several pathologies. In this revision we describe the morphological modifications of dendritic spines, their relationship with the development of the nervous system, sleep disorders and some other pathologies.