Sandra B.R. Castro

Intestinal Microbiota as Modulators of the Immune System and Neuroimmune System: Impact on the Host Health and Homeostasis

Many immune-based intestinal disorders, such as ulcerative colitis and Crohns disease, as well as other illnesses, may have the intestines as an initial cause or aggravator in the development of diseases, even apparently not correlating directly to the intestine. Diabetes, obesity, multiple sclerosis, depression, and anxiety are examples of other illnesses discussed in the literature. In parallel, importance of the gut microbiota in intestinal homeostasis and immunologic conflict between tolerance towards commensal microorganisms and combat of pathogens is well known. Recent researches show that the immune system, when altered by the gut microbiota, influences the state in which these diseases are presented in the patient directly and indirectly. At the present moment, a considerable number of investigations about this subject have been performed and published. However, due to difficulties on correlating information, several speculations and hypotheses are generated. Thus, the present review aims at bringing together how these interactions work—gut microbiota, immune system, and their influence in the neuroimmune system.

Antibacterial activity of plant extracts from Brazil against fish pathogenic bacteria

The aim of this work was to evaluate the antibacterial activity of Brazilian plants extracts against fish pathogenic bacteria. Forty six methanolic extracts were screened to identify their antibacterial properties against Streptococcus agalactiae, Flavobacterium columnare and Aeromonas hydrophila. Thirty one extracts showed antibacterial activity.

Immunomodulatory effects and improved prognosis of experimental autoimmune encephalomyelitis after O-tetradecanoyl-genistein treatment

Experimental autoimmune encephalomyelitis (EAE) is a murine autoimmune disease used to study multiple sclerosis (MS), a human inflammatory demyelinating disease of the central nervous system. Genistein, an isoflavonoid phytoestrogenic compound found in soy, is known to reverse clinical signs of EAE. Although genistein has some potential in clinical application, it has some disadvantages related to its chemical structure, such as rapid in vivo metabolism and a fast decline in serum after oral administration. The present work investigates the treatment of EAE by using 7-O-tetradecanoyl-genistein (TDG), a more lipophilic analog of genistein obtained by esterification. The clinical course of EAE was investigated in C57Bl/6 mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG)(35-55) in complete Freunds adjuvant supplemented with Mycobacterium tuberculosis H37RA. After 14 days of MOG immunization, mice were treated with TDG for seven days. Numbers of IL-17-producing cells and Foxp3 by CD4(+) T cells and CTLA-4 expression by CD3(+) T cells from brain were determined by flow cytometry. Levels of IL-6, IFN-γ and IL-10 were evaluated by ELISA. Brain sections were stained by hematoxylin and eosin method. The data obtained indicate that TDG treatment ameliorates the clinical signs of EAE, which correlates with a decrease of IL-17-producing cells and an increase in Foxp3(+)CD4(+) cells in the brain. TDG is also shown to enhance IL-10 production and CTLA-4 expression and to reduce IFN-γ and IL-6. Altogether, these findings suggest an immunomodulatory therapeutic role for TDG in EAE and multiple sclerosis.

Lower production of IL-17A and increased susceptibility to Mycobacterium bovis in mice coinfected with Strongyloides venezuelensis

The presence of intestinal helminths can down-regulate the immune response required to control mycobacterial infection. BALB/c mice infected with Mycobacterium bovis following an infection with the intestinal helminth Strongyloides venezuelensis showed reduced interleukin-17A production by lung cells and increased bacterial burden. Also, small granulomas and a high accumulation of cells expressing the inhibitory molecule CTLA-4 were observed in the lung. These data suggest that intestinal helminth infection could have a detrimental effect on the control of tuberculosis (TB) and render coinfected individuals more susceptible to the development of TB.

Preparation of Amino Alcohols Condensed with Carbohydrates: Evaluation of Cytotoxicity and Inhibitory Effect on NO Production

This work reports the preparation of several amino alcohols condensed with d‐arabinose, d‐glucose, and d‐galactose derivatives. These compounds were evaluated in vitro for their cytotoxicity and ability to decrease nitric oxide production in J774A.1 cells. Arabinofuranoside derivatives 5a, 5b and 5c showed a significant inhibition of nitric oxide production (>80% at 5 μg/mL), while the galactopyranoside derivative 8d showed a notable nitric oxide inhibitory activity (126% at 0.5 μg/mL).

Synthesis of Lipophilic Genistein Derivatives and Their Regulation of IL‐12 and TNF‐α in Activated J774A.1 Cells

Genistein modulates inflammatory responses in part by reducing the production of the pro‐inflammatory cytokines IL‐12, TNF‐α, and nitric oxide, by activated macrophages in response to lipopolysaccharide stimulus. Previous studies have shown that synthetic lipophilic genistein glycosides were significantly more active than hydrophilic glycosides. The aims of this study were to synthesize and to evaluate the effect of novel lipophilic genistein derivatives on IL‐12, TNF‐α, and nitric oxide production by J774A.1 cells. The results show that the modification of genistein enables the generation of non‐cytotoxic compounds with increased IL‐12 inhibition. However, these derivatives failed to inhibit TNF‐α. The nitric oxide production was notably inhibited by the monoester (2, 3) and monoether (6, 7) compounds in a dose‐dependent manner.

Optical neuritis induced by different concentrations of myelin oligodendrocyte glycoprotein presents different profiles of the inflammatory process.

Abstract Optical neuritis (ON) is characterized by inflammation of the optic nerve, and is one of the first clinical signs of multiple sclerosis (MS). Experimental autoimmune encephalomyelitis (EAE) is the animal model used to study MS and ON. The present study evaluated the induction, development and progression of ON using an EAE model induced by 100 μg or 300 μg of MOG35–55. An EAE model was induced in C57BL/6 mice by tail base injection of 100 μg or 300 μg of MOG35–55 in complete Freund’s adjuvant, supplemented with Mycobacterium tuberculosis. On the day of injection and 48 h later, animals received intraperitoneally 300 ng of pertussis toxin. On days 7, 10, 14, 21 and 58 the optic nerve was dissected for histological analysis, production of CCL5 and immunohistochemical detection of CD4 and CD8. The histological changes observed in the optic nerves consisted of inflammatory cell infiltrates showing varying degrees of ON in the two groups. The onset of ON in the 300 μg of MOG35–55 group was coincident with higher production of CCL5, on day 10 after induction. However, the 100 μg MOG35–55 group showed more intense inflammatory infiltrate on day 14 after induction, with higher amounts of CD4 and CD8, reaching an excessive demyelination process on days 21 and 58 after induction. The results suggest that two different concentrations of MOG35–55 lead to different forms of evolution of optic neuritis.

Synthesis of genistein coupled with sugar derivatives and their inhibitory effect on nitric oxide production in macrophages

The isoflavone genistein 1 and some derivatives modulate IL-12, TNF-α and NO production by macrophages and lung cancer cell lines, and improve the clinical signs of experimental autoimmune encephalomyelitis (EAE). Seven genistein derivatives connected at C-6 position of a sugar, such as d-glucose and d-galactose, were synthesized. The ability to modulate macrophage response was evaluated, showing variable inhibition capacity of NO and TNF-α production in J774.A1 and RAW 264.7. Five of the seven compounds were non-cytotoxic; compound 8 was more effective to inhibit NO and TNF-α production, without affecting cell viability.

Different MOG35–55 concentrations induce distinguishable inflammation through early regulatory response by IL-10 and TGF-β in mice CNS despite unchanged clinical course

Multiple sclerosis (MS) shows distinct clinical courses. Experimental autoimmune encephalomyelitis (EAE), a model to study multiple sclerosis, can be induced by different protocols, which show distinct cytokine and antibody production. The factors involved in this heterogeneity remain unclear. The relevance of MOG concentration in triggering a regulatory response in the chronic model of EAE is imprecise. The aim of this study was investigate if 100 or 300 μg of MOG(35-55) could induce different EAE profiles. Modifications in the concentration of MOG were able to change the patterns of chemokines, cytokines, percentage of cells, inflammatory infiltrate and the development of a regulatory response. However, these changes were unable to modify the intensity of response, which explains the chronic progression of the disease in both concentrations. The results presented in this study contribute to understanding the intricate mechanisms that trigger EAE and provide insights into the pathogenesis of various forms of MS.

Early IFN-γ production together with decreased expression of TLR3 and TLR9 characterizes EAE development conditional on the presence of myelin

Abstract Experimental autoimmune encephalomyelitis (EAE) is a model for the study of multiple sclerosis, which is an inflammatory and demyelinating disease of the central nervous system (CNS). Despite increased efforts to elucidate the function of toll-like receptors (TLRs) in autoimmune diseases of the CNS, the relative contribution of other factors, including the immunomodulatory properties of TLR signaling, role of the innate response and the presence or absence of myelin peptides remain unclear. The aim was to evaluate TLR expression in the CNS during EAE development by investigating the expression of TLRs in the initial phase of EAE and establishing correlations with the modulation of inflammatory factors. Mice were subcutaneously immunized at the tail base with 100 μg of myelin oligodendrocyte glycoprotein peptide (MOG35–55), emulsified in complete Freund’s adjuvant (CFA) supplemented with 400 μg of attenuated Mycobacterium tuberculosis H37RA. Pertussis toxin (300 ng per animal) was intraperitoneally injected on the day of immunization and 48 h later. Another group (MOG−) received an equal emulsion of CFA and M. tuberculosis, without MOG35–55, and the same protocol of Pertussis toxin. The immunized mice presented signs of disease with increased IFN-γ production and presence of NK cells on Day 2 postimmunization and reduced the expression of TLR-3 and TLR-9. In the spinal cord, CCL5 and CCL20 were higher in EAE. This study establishes a correlation between TLR-3 and TLR-9 expression with the development of EAE. In addition, evidence of a role for the myelin peptide in targeting the innate inflammatory response to the CNS is presented.