Effect of Low Doses of Dexamethasone on Experimental Pulmonary Tuberculosis.

Tuberculosis (TB) is the deadliest disease caused by a bacterial agent. Glucocorticoids (GCs) have a typical anti-inflammatory effect, but recently it has been shown that they can present proinflammatory activity, mainly by increasing molecules from innate immunity. In the current study, we evaluated the effect of low doses of dexamethasone on Mycobacterium tuberculosis in vivo and in vitro. We used an established mice model of progressing tuberculosis (TB) in the in vivo studies. Intratracheal or intranasal dexamethasone therapy administered with conventional antibiotics in the late stage of the disease decreased the lung bacilli load and lung pneumonia, and increased the survival of the animals. Finally, the treatment decreased the inflammatory response in the SNC and, therefore, sickness behavior and neurological abnormalities in the infected animals. In the in vitro experiments, we used a cell line of murine alveolar macrophages infected with Mtb. Low-dose dexamethasone treatment increased the clearance capacity of Mtb by MHS macrophages, MIP-1α, and TLR2 expression, decreased proinflammatory and anti-inflammatory cytokines, and induced apoptosis, a molecular process that contributes to the control of the mycobacteria. In conclusion, the administration of low doses of dexamethasone represents a promising adjuvant treatment for pulmonary TB.

Organophosphorus Pesticides as Modulating Substances of Inflammation through the Cholinergic Pathway.

Organophosphorus pesticides (OPs) are widespread insecticides used for pest control in agricultural activities and the control of the vectors of human and animal diseases. However, OPs' neurotoxic mechanism involves cholinergic components, which, beyond being involved in the transmission of neuronal signals, also influence the activity of cytokines and other pro-inflammatory molecules; thus, acute and chronic exposure to OPs may be related to the development of chronic degenerative pathologies and other inflammatory diseases. The present article reviews and discusses the experimental evidence linking inflammatory process with OP-induced cholinergic dysregulation, emphasizing the molecular mechanisms related to the role of cytokines and cellular alterations in humans and other animal models, and possible therapeutic targets to inhibit inflammation.

Sexual Dimorphism of the Neuroimmunoendocrine Response in the Spleen during a Helminth Infection: A New Role for an Old Player?

The interaction of the nervous, immune, and endocrine systems is crucial in maintaining homeostasis in vertebrates, and vital in mammals. The spleen is a key organ that regulates the neuroimmunoendocrine system. The Taenia crassiceps mouse system is an excellent experimental model to study the complex host-parasite relationship, particularly sex-associated susceptibility to infection. The present study aimed to determine the changes in neurotransmitters, cytokines, sex steroids, and sex-steroid receptors in the spleen of cysticercus-infected male and female mice and whole parasite counts. We found that parasite load was higher in females in comparison to male mice. The levels of the neurotransmitter epinephrine were significantly decreased in infected male animals. The expression of IL-2 and IL-4 in the spleen was markedly increased in infected mice; however, the expression of Interleukin (IL)-10 and interferon (IFN)-γ decreased. We also observed sex-associated differences between non-infected and infected mice. Interestingly, the data show that estradiol levels increased in infected males but decreased in females. Our studies provide evidence that infection leads to changes in neuroimmunoendocrine molecules in the spleen, and these changes are dimorphic and impact the establishment, growth, and reproduction of T. crassiceps. Our findings support the critical role of the neuroimmunoendocrine network in determining sex-associated susceptibility to the helminth parasite.

NeuroImmunoEndocrinology: A brief historic narrative.

Although no precise moment or unique event marks its birth, neuroimmunoendocrinology arguably shares a great deal of history with other medical and biologic disciplines. It originated from empirical observations and suppositions that failed to prevail upon the existing axioms. Despite the widespread resistance to embracing novel ideas, the seeming defeats inspired visionary researchers. Those pioneers managed to systematize the emerging knowledge and were able to contribute to science with real foundations. In consequence, new concepts and ideas arose in physiology, anatomy, endocrinology and early immunology. Together, they gave rise to a budding approach on the integration between the nervous, immune and endocrine systems. Then, neuroimmunoendocrinology emerged as a discipline integrating an intricate system with multidirectional functions and interactions that allow for responding to internal and external threats. Such response is mediated by cytokines, hormones and neurotransmitters, involved in different physiologic mechanisms of the organism homeostasis. Neuroimmunoendocrinology is no longer an area of scientific skepticism; on the contrary, it has cemented its position as a biomedical discipline worldwide for the past 70 years. Now, it offers a better understanding of pathologic processes.

Cysticidal effect of a pure naphthoquinone on Taenia crassiceps cysticerci.

Cysticercosis is a disease caused by the metacestode of the parasite Taenia solium (T. solium). In humans, the most severe complication of the disease is neurocysticercosis. The drug of choice to treat this disease is albendazole; however, the bioavailability and efficacy of the drug are variable. Therefore, new molecules with therapeutic effects against this and other parasitic infections caused by helminths must be developed. Naphthoquinones are naphthalene-derived compounds that possess antibacterial, antifungal, antitumoral, and antiparasitic properties. The aim of this work was to evaluate the in vitro anti-helminthic effect of 2-[(3-chlorophenylamino)phenylmethyl]-3-hydroxy-1,4-naphthoquinone, isolated from a natural source and then synthesized (naphthoquinone 4a), using an experimental model of murine cysticercosis caused by Taenia crassiceps (T. crassiceps). This compound causes paralysis in the cysticerci membrane from day 3 of the in vitro treatment. Additionally, it induces changes in the shape, size, and appearance of the cysticerci and a decrease in the reproduction rate. In conclusion, naphthoquinone 4a has in vitro cysticidal activity on T. crassiceps cysticerci depending on the duration of the treatment and the concentration of the compound. Therefore, it is a promising drug candidate to be used in T. crassiceps and possibly T. solium infections.

Matrix metalloproteinases deregulation in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons that results in progressive paralysis and muscular atrophy. There are many molecules and genes involved in neuromuscular degeneration in ALS; among these, matrix metalloproteinases (MMPs). MMPs play an important role in the pathology of ALS, and MMP-1, 2, 3, and 9 might serve as disease progression markers. Tissue inhibitors of metalloproteinases (TIMPS) might also function as progression markers in ALS because they participate in regulating the proteolytic activity of MMPs. Moreover, a diversity of genes also plays a role in the pathogenesis of ALS; most MMPs-coding genes present variants related to the pathological proteolytic activity. This short review, however, will focus on the role of matrix metalloproteinases in ALS.

Serum levels of chemokines in adolescents with major depression treated with fluoxetine.

BACKGROUND: Major depressive disorder (MDD) is a global health issue that affects 350 million people of all ages. Although between 2% and 5.6% of affected individuals are adolescents, research on young patients is limited. The inflammatory response contributes to the onset of depression, and in adult MDD patients, symptom severity has been linked to chemokine levels. AIM: To determine the differences in circulatory levels of chemokines in healthy volunteers (HVs) and adolescents with MDD, and assess the changes induced by fluoxetine consume. METHODS: The 22 adolescents with MDD were monitored during the first 8 wk of clinical follow-up and clinical psychiatric evaluation was done using the Hamilton depresión rating scale (HDRS). The serum levels of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1α, MIP-1ß, interleukin (IL)-8, interferon gamma-induced protein (IP)-10, and eotaxin were measured in patients and HVs. RESULTS: In all cases, significant differences were detected in circulating chemokine levels between patients before treatment and HVs (P < 0.0001). All chemokines decreased at 4 wk, but only MCP-1 and IL-8 significantly differed (P < 0.05) between 0 wk and 4 wk. In the patients, all chemokines rose to their initial concentrations by 8 wk vs 0 wk, but only IP-10 did so significantly (P < 0.05). All patients experienced a significant decrease in HDRS scores at 4 wk (P < 0.0001) and 8 wk (P < 0.0001) compared with 0 wk. CONCLUSION: Despite the consumption of fluoxetine, patients had significantly higher chemokine levels, even after considering the improvement in HDRS score. The high levels of eotaxin, IP-10, and IL-8 partially explain certain aspects that are affected in MDD such as cognition, memory, and learning.

Chronic infection with Mycobacterium lepraemurium induces alterations in the hippocampus associated with memory loss.

Murine leprosy, caused by Mycobacterium lepraemurium (MLM), is a chronic disease that closely resembles human leprosy. Even though this disease does not directly involve the nervous system, we investigated a possible effect on working memory during this chronic infection in Balb/c mice. We evaluated alterations in the dorsal region of the hippocampus and measured peripheral levels of cytokines at 40, 80, and 120 days post-infection. To evaluate working memory, we used the T-maze while a morphometric analysis was conducted in the hippocampus regions CA1, CA2, CA3, and dentate gyrus (DG) to measure morphological changes. In addition, a neurochemical analysis was performed by HPLC. Our results show that, at 40 days post-infection, there was an increase in the bacillary load in the liver and spleen associated to increased levels of IL-4, working memory deterioration, and changes in hippocampal morphology, including degeneration in the four subregions analyzed. Also, we found a decrease in neurotransmitter levels at the same time of infection. Although MLM does not directly infect the nervous system, these findings suggest a possible functional link between the immune system and the central nervous system.

Prolactin as immune cell regulator in Toxocara canis somatic larvae chronic infection.

Toxocariasis is a zoonotic disease produced by ingestion of larval Toxocara spp. eggs. Prolactin (PRL) has been considered to have an important role in Toxocara canis infection. Recent evidence has found that PRL directly can increase parasite growth and differentiation of T. canis The present study, evaluated the effect of high PRL levels on the immune system's response and parasites clearance in chronic infection. Our results showed that hyperprolactinemia did not affect the number of larvae recovered from several tissues in rats. Parasite-specific antibody production, showed no difference between the groups. Lung tissue presented eosinophilic granulomas typical of a chronic infection in all the experimental groups. Flow cytometry analysis was made in order to determine changes in the percentage of innate and adaptive immune cell subpopulations in the spleen, peripheric (PLN) and mesenteric (MLN) lymphatic nodes. The results showed a differential effect of PRL and infection on different immune compartments in the percent of total T cells, T helper cells, T cytotoxic cells, B cells, NK cells, and Tγδ cells. To our knowledge, for the first time it is demonstrated that PRL can have an immunomodulatory role during T. canis chronic infection in the murine host.

Proteomic profile approach of effect of putrescine depletion over Trichomonas vaginalis.

Infection with Trichomonas vaginalis produces a malodorous seropurulent vaginal discharge due to several chemicals, including polyamines. The presence of 1,4-diamino-2-butanone (DAB) reduces the amount of intracellular putrescine by 90%, preventing the cotransport of exogenous spermine. DAB-treated parasites present morphological changes, which are restored by adding exogenous putrescine into the culture medium. However, the effect of polyamines over the trichomonad proteomic profile is unknown. In this study, we used a proteomic approach to analyze the polyamine-depletion and restoration effect by exogenous putrescine on T. vaginalis proteome. In the presence of inhibitor DAB, we obtained 369 spots in polyamine-depleted condition and observed 499 spots in the normal culture media. With DAB treatment, the intensity of 43 spots was increased but was found to be reduced in 39 spots, as compared to normal conditions. Interestingly, in DAB-treated parasites restored with a medium with added exogenous putrescine, 472 spots were found, of which 33 were upregulated and 63 were downregulated in protein intensity. Some of these downregulated proteins in DAB-treated parasites are involved in several cellular pathways such as glycolysis, glycolytic fermentation, arginine dihydrolase pathway, redox homeostasis, host cell binding mediated by carbohydrate, chaperone function, and cytoskeletal remodeling. Interestingly, the intensity of some of the proteins was restored by adding exogenous putrescine. In conclusion, the presence of DAB altered the proteomic profile of T. vaginalis, resulting in a decrease in the intensity of 130 proteins and an increase in the intensity of 43 proteins that was restored by the addition of putrescine.

The 50kDa metalloproteinase TvMP50 is a zinc-mediated Trichomonas vaginalis virulence factor.

Trichomonas vaginalis is a protozoan parasite that can adapt to the trichomonicidal Zn2+ concentrations of the male urogenital tract microenvironment. This adaptation is mediated by molecular mechanisms, including proteinase expression, that are regulated by cations such as Zn2+. Herein, we characterized the previously identified 50kDa metalloproteinase aminopeptidase P (M24 family) member TvMP50 as a new Zn2+-mediated parasite virulence factor. Quantitative RT-PCR and indirect immunofluorescence assays corroborated the positive regulation of both mp50 gene expression and native TvMP50 protein overexpression in the cytoplasm and secretion products of parasites grown in the presence of Zn2+. Furthermore, this active metalloproteinase was characterized as a new virulence factor by assaying cytotoxicity toward prostatic DU145 cell monolayers as well as the inhibition of parasite and secreted soluble protein proteolytic activity in the 50kDa proteolytic region by the specific metalloproteinase inhibitor 1,10-phenanthroline and the chelating agents EDTA and EGTA. Parasite and secreted soluble protein cytotoxicity toward DU145 cells were reduced by treatment with an α-rTvMP50 polyclonal antibody. Our results show that the metalloproteinase TvMP50 is a new virulence factor modulated by Zn2+, which is present during male trichomoniasis, possibly explaining T. vaginalis survival even within the adverse conditions of the male urogenital microenvironment.

Recombinant Trichomonas vaginalis eIF-5A protein expressed from a eukaryotic system binds specifically to mammalian and putative trichomonal eIF-5A response elements (EREs).

Trichomonas vaginalis eIF-5A-like protein (TveIF-5A) belongs to the highly conserved eIF-5A family of proteins that contains a unique polyamine-derived amino acid, hypusine. Recently, we determined that the polyamine putrescine is required for tveif-5a mRNA stability, and it is necessary for stability and maturation of the TveIF-5A protein. Eukaryotic eIF-5A is known to be involved in mRNA turnover and is capable of sequence-specific RNA binding to eIF-5A response elements (EREs). These ERE sequences are present in diverse mammalian mRNAs, including human cyclooxygenase-2 (cox-2). Here, we cloned the complete coding sequence of TveIF-5A and overexpressed it in a eukaryotic system. The recombinant protein (rTveIF-5A) was purified in soluble form using size-exclusion chromatography. Because of the polyamine-dependent regulation of TvCP39 (a protease of T. vaginalis) at the protein and RNA messenger (mRNA) levels, we looked for an ERE-like structure in the 3' region of tvcp39 mRNA. In RNA gel-shift assays, rTveIF-5A bound to transcripts at the EREs of cox-2 or tvcp39 mRNAs. This work shows the eIF-5A/ERE-like interaction in T. vaginalis.

Interleukin-17A Levels Vary in Relapsing-Remitting Multiple Sclerosis Patients in Association with Their Age, Treatment and the Time of Evolution of the Disease.

OBJECTIVE: The present study was specifically designed to discern the possible existence of subgroups of patients with the relapsing-remitting form of multiple sclerosis (RRMS) depending on their gender, age, disease stage (relapsing or remitting), time of disease evolution and response to different treatments. METHODS: We analyzed samples from patients with RRMS (50 females and 32 males) and healthy individuals (25 matched for age and gender) and determined serum concentrations of IFN-γ, IL-10 and IL-17A. We stratified patients by gender, age, treatment and disease evolution time, and subsequently correlated these independent variables with the concentrations of the previously mentioned cytokines. RESULTS: We provided initial evidence that treatment exerted possible differential effects depending on the time of disease duration. Results evidence the existence of different subgroups of patients with MS, who can be classified as follows: (a) male or female under or over 40 years of age; (b) disease duration according to treatment (under or over 8 years of disease); (c) classification according to fluctuating levels of IFN-γ, IL-10 and IL-17A in the following three stages of disease evolution: <5 years, between 5 and 10 years, and >10 years. CONCLUSION: These subgroups must be taken into account for the clinical follow-up of patients with MS in order to provide them with a better and more personalized treatment, and also for a deep and detailed analysis of progressive disease, in an attempt to comprehend fluctuations and clinical variability by means of a better understanding of intrinsically physiological variables of the disease.

Resveratrol in epilepsy: preventive or treatment opportunities?

Resveratrol has been extensively investigated and has been demonstrated to have antioxidant properties, cancer chemopreventive activity, and the capacity to modulate the hepatic synthesis of triglycerides and cholesterol, among others well established actions. A noteworthy feature of resveratrol is its ability to cross the blood-brain barrier and to exhibit neuroprotective actions, mainly by their capacity to regulate redox pathways as well as the Sirtuin (SIRT) system, which in turn modulates gene transcription, controlling inflammation and apoptosis in the brain. Lately, evidence is accumulating with respect to the synergic effect of resveratrol with antiepileptic drugs and also its antiepileptic activity in various models of seizures. We discuss here recent evidence that strongly suggests that resveratrol acts as an anticonvulsant agent and could be a very effective method for reducing damage in neural tissue and even for preventing seizure development in coadjuvant antiepileptic therapy.

Ensheathing cell-conditioned medium directs the differentiation of human umbilical cord blood cells into aldynoglial phenotype cells.

Despite their similarities to bone marrow precursor cells (PC), human umbilical cord blood (HUCB) PCs are more immature and, thus, they exhibit greater plasticity. This plasticity is evident by their ability to proliferate and spontaneously differentiate into almost any cell type, depending on their environment. Moreover, HUCB-PCs yield an accessible cell population that can be grown in culture and differentiated into glial, neuronal and other cell phenotypes. HUCB-PCs offer many potential therapeutic benefits, particularly in the area of neural replacement. We sought to induce the differentiation of HUCB-PCs into glial cells, known as aldynoglia. These cells can promote neuronal regeneration after lesion and they can be transplanted into areas affected by several pathologies, which represents an important therapeutic strategy to treat central nervous system damage. To induce differentiation to the aldynoglia phenotype, HUCB-PCs were exposed to different culture media. Mononuclear cells from HUCB were isolated and purified by identification of CD34 and CD133 antigens, and after 12 days in culture, differentiation of CD34+ HUCB-PCs to an aldynoglia phenotypic, but not that of CD133+ cells, was induced in ensheathing cell (EC)-conditioned medium. Thus, we demonstrate that the differentiation of HUCB-PCs into aldynoglia cells in EC-conditioned medium can provide a new source of aldynoglial cells for use in transplants to treat injuries or neurodegenerative diseases.