Manganese Inhalation as a Parkinson Disease Model

The present study examines the effects of divalent and trivalent Manganese (Mn2+/Mn3+) mixture inhalation on mice to obtain a novel animal model of Parkinson disease (PD) inducing bilateral and progressive dopaminergic cell death, correlate those alterations with motor disturbances, and determine whether L-DOPA treatment improves the behavior, to ensure that the alterations are of dopaminergic origin. CD-1 male mice inhaled a mixture of Manganese chloride and Manganese acetate, one hour twice a week for five months. Before Mn exposure, animals were trained to perform motor function tests and were evaluated each week after the exposure. By the end of Mn exposure, 10 mice were orally treated with 7.5 mg/kg L-DOPA. After 5 months of Mn mixture inhalation, striatal dopamine content decreased 71%, the SNc showed important reduction in the number of TH-immunopositive neurons, mice developed akinesia, postural instability, and action tremor; these motor alterations were reverted with L-DOPA treatment. Our data provide evidence that Mn2+/Mn3+ mixture inhalation produces similar morphological, neurochemical, and behavioral alterations to those observed in PD providing a useful experimental model for the study of this neurodegenerative disease

Seroprevalence of Toxoplasma gondii and Toxocara canis in a human rural population of Southern Rio Grande do Sul

Due to the growing population of pets, especially homeless dogs and cats, zoonoses still represent a significant public health problem. Toxoplasma gondii and Toxocara spp. are epidemiologically important zoonotic agents as they are etiological factors of human toxoplasmosis and toxocariasis, respectively. These parasites remain neglected even though they are substantially prevalent in rural areas. The aim of this study was to investigate T. gondii and T. canis seroprevalence and risk factors of seropositivity in a rural population in Pelotas municipality, Brazil. The study participants (n=344) were patients of a Basic Healthcare Unit (BHU) located in Cerrito Alegre. Blood samples were collected and tested for T. gondii antibodies by indirect immunofluorescence and T. canis antibodies by an indirect ELISA that targets an excreted-secreted antigen (TES). T. gondii seropositivity was 53.2%, with higher titers (1:256 - 1:1,024) in individuals who habitually eat pork, beef, or chicken, while T. canis seropositivity was 71.8% and concomitant T. gondii and T. canis seropositivity was 38.3%. Among the seropositivity risk factors assessed, only habitual undercooked meat consumption was significant (p = 0.046; OR = 3.7) for T. gondii and none of them were associated with T. canis seropositivity. Both parasites have a high prevalence in rural areas, which reinforces the need to invest in rural community education and health

Proteome-wide analysis of Trypanosoma cruzi exponential and stationary growth phases reveals a subcellular compartment-specific regulation

Trypanosoma cruzi, the etiologic agent of Chagas disease, cycles through different life stages characterized by defined molecular traits associated with the proliferative or differentiation state. In particular, T. cruzi epimastigotes are the replicative forms that colonize the intestine of the Triatomine insect vector before entering the stationary phase that is crucial for differentiation into metacyclic trypomastigotes, which are the infective forms of mammalian hosts. The transition from proliferative exponential phase to quiescent stationary phase represents an important step that recapitulates the early molecular events of metacyclogenesis, opening new possibilities for understanding this process. In this study, we report a quantitative shotgun proteomic analysis of the T. cruzi epimastigote in the exponential and stationary growth phases. More than 3000 proteins were detected and quantified, highlighting the regulation of proteins involved in different subcellular compartments. Ribosomal proteins were upregulated in the exponential phase, supporting the higher replication rate of this growth phase. Autophagy-related proteins were upregulated in the stationary growth phase, indicating the onset of the metacyclogenesis process. Moreover, this study reports the regulation of N-terminally acetylated proteins during growth phase transitioning, adding a new layer of regulation to this process. Taken together, this study reports a proteome-wide rewiring during T. cruzi transit from the replicative exponential phase to the stationary growth phase, which is the preparatory phase for differentiation

Effect of Chronic L-Dopa or Melatonin Treatments after Dopamine Deafferentation in Rats: Dyskinesia, Motor Performance, and Cytological Analysis

The present study examines the ability of melatonin to protect striatal dopaminergic loss induced by 6-OHDA in a rat model of Parkinson's disease, comparing the results with L-DOPA-treated rats. The drugs were administered orally daily for a month, their therapeutic or dyskinetic effects were assessed by means of abnormal involuntary movements (AIMs) and stepping ability. At the cellular level, the response was evaluated using tyrosine hydroxylase immunoreactivity and striatal ultrastructural changes to compare between L-DOPA-induced AIMs and Melatonin-treated rats. Our findings demonstrated that chronic oral administration of Melatonin improved the alterations caused by the neurotoxin 6-OHDA. Melatonin-treated animals perform better in the motor tasks and had no dyskinetic alterations compared to L-DOPA-treated group. At the cellular level, we found that Melatonin-treated rats showed more TH-positive neurons and their striatal ultrastructure was well preserved. Thus, Melatonin is a useful treatment to delay the cellular and behavioral alterations observed in Parkinson's disease

Manganese Inhalation Induces Dopaminergic Cell Loss: Relevance to Parkinson’s Disease

Parkinson’s disease (PD) experimental models are crucial in the assessment of possible therapies. Nevertheless, even though PD was one of the first neurodegenerative conditions to be modeled, there are limitations such as spontaneous recovery; lack of bilateral damage, which is a PD characteristic; animal intensive care after neurotoxin administration; and ultrastructural and biochemical nonspecific alterations but mostly the neurodegenerative time course observed in humans. In this chapter, we investigated the effects of divalent and trivalent manganese inhalation on rats and mice to obtain a novel PD animal model inducing bilateral and progressive dopaminergic cell death. We found that after 5 or 6 months of inhalation, there was more than 70% decrease in the number of TH-immunopositive neurons, and these alterations are correlated with an evident motor performance deficits manifested as akinesia, postural instability, and action tremor. More interesting is the fact that these alterations were reverted with l-DOPA treatment, implying that the motor alterations are associated with nigrostriatal dopaminergic innervation, postulating new light for the understanding of manganese neurotoxicity as an appropriate PD experimental model. Our results are contributing to the development of a suitable PD animal model, reproducible, sensitive, time-efficient, and readily applicable behavioral tests

Alzheimer-Like Cell Alterations after Vanadium Pentoxide Inhalation

Vanadium (V), a widely distributed transition metal, has been considered toxic, which depends on the valence of the compound. V pentoxide (V2O5) is considered the most harmful. Its long-term exposure produces neurotoxicity. Mice exposed to inhaled V2O5 displayed less tubulin+ in testicular cells and dendritic spines loss, cell death, and CA1 neuropil modifications, considered as the result of V interaction with the cytoskeleton, which made us suppose that V2O5 inhalation could initiate CA1 cell alterations comparable to what happen in the brains of Alzheimer disease (AD) patients. This study intends to demonstrate pyramidal CA1 cytoskeletal changes in rats which inhaled V2O5. Twenty rats were exposed to V2O5 0.02 M one hour, three times a week for several months. Our findings showed that V2O5-exposed rats had cell death that reached 56,57% after six months; we also observed collapsed strong argyrophilic nuclei and characteristic flame-shaped somas in all V2O5-exposed animals hippocampus CA1 compared to controls. We also found somatodendritic deformations. Neurite’s cytoskeleton exhibited visible thickening and nodosities and prominent dendritic spine loss. Our results demonstrate that V2O5 induces AD-like cell death with evident cytoskeletal and synaptic alterations

Behavioral and Cytological Differences between Two Parkinson’s Disease Experimental Models

The knowledge about the biochemical and behavioral changes in humans with PD has allowed proposing animal models for its study; however, the results obtained so far have been heterogeneous. Recently, we established a novel PD model in rodents by manganese chloride (MnCl2) and manganese acetate (Mn (OAc)3) mixture inhalation. After inhaling, the rodents presented bilateral loss of SNc dopaminergic neurons. Later, we conclude that the alterations are of dopamine origin since L-DOPA reverted the alterations. After six months, SNc significantly reduced the number of cells, and striatal dopamine content decreased by 71%. The animals had postural instability, action tremor, and akinesia; these symptoms improved with L-DOPA, providing evidence that Mn mixture inhalation induces comparable alterations that those in PD patients. Thus, this study aimed to compare the alterations in two different PD experimental models: 6-OHDA unilateral lesion and Mn mixture inhalation through open field test, rotarod performance and the number of SNc dopaminergic neurons. The results show that the Mn-exposed animals have motor alterations and bilateral and progressive SNc neurons degeneration; in contrast, in the 6-OHDA model, the neuronal loss is unilateral and acute, demonstrating that the Mn exposure model better recreates the characteristics observed in PD patients

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research