The rapid and persistent increase of drug-resistant
(
) infections poses increasing global problems in combatting tuberculosis (TB), prompting for the development of alternative strategies including ...host-directed therapy (HDT). Since
is an intracellular pathogen with a remarkable ability to manipulate host intracellular signaling pathways to escape from host defense, pharmacological reprogramming of the immune system represents a novel, potentially powerful therapeutic strategy that should be effective also against drug-resistant
. Here, we found that host-pathogen interactions in
-infected primary human macrophages affected host epigenetic features by modifying histone deacetylase (HDAC) transcriptomic levels. In addition, broad spectrum inhibition of HDACs enhanced the antimicrobial response of both pro-inflammatory macrophages (Mϕ1) and anti-inflammatory macrophages (Mϕ2), while selective inhibition of class IIa HDACs mainly decreased bacterial outgrowth in Mϕ2. Moreover, chemical inhibition of HDAC activity during differentiation polarized macrophages into a more bactericidal phenotype with a concomitant decrease in the secretion levels of inflammatory cytokines. Importantly,
chemical inhibition of HDAC activity in
-infected zebrafish embryos, a well-characterized animal model for tuberculosis, significantly reduced mycobacterial burden, validating our
findings in primary human macrophages. Collectively, these data identify HDACs as druggable host targets for HDT against intracellular
.
•Patients with active pulmonary tuberculosis − highest proportion of cells T CD4+ TMC IFN-ɣ+ e TNF-α+.•LT CD4+TMC would be an important target of study for the development of more effective ...vaccines.•Patients after treatment of pulmonary TB − highest proportion of cells T CD4+ TMC IL-17+.•Individuals with latent infection by M. tuberculosis and treated for pulmonary tuberculosis − greater response of T lymphocytes CD8+ effector IFN-ɣ+.•Stimulation of 144h with high antigenic load and elimination of the pathogen, more significant generation of T central memory cells.
The cells T CD4+ T and CD8+ can be subdivided into phenotypes naïve, T of central memory, T of effector memory and effector, according to the expression of surface molecules CD45RO and CD27. The T lymphocytes are cells of long life with capacity of rapid expansion and function, after a new antigenic exposure. In tuberculosis, it was found that specific memory T cells are present, however, gaps remain about the role of such cells in the disease immunology. In this study, the phenotypic profile was analyzed and characterized the functionality of CD4+ T lymphocytes and CD8+ T cells of memory and effector, in response to specific stimuli in vitro, in patients with active pulmonary TB, compared to individuals with latent infection with Mycobacterium tuberculosis the ones treated with pulmonary TB. It was observed that the group of patients with active pulmonary tuberculosis was the one which presented the highest proportion of cells T CD4+ of central memory IFN-ɣ+ e TNF-α+, suggesting that in TB, these T of central memory cells would have a profile of protective response, being an important target of study for the development of more effective vaccines; this group also developed lower proportion of CD8+ T effector lymphocytes than the others, a probable cause of specific and less effective response against the bacillus in these individuals; the ones treated for pulmonary tuberculosis were those who developed higher proportion of T CD4+ of memory central IL-17+ cells, indicating that the stimulation of long duration, with high antigenic load, followed by elimination of the pathogen, contribute to more significant generation of such cells; individuals with latent infection by M. tuberculosis and treated for pulmonary tuberculosis, showed greater response of CD8+ T effector lymphocytes IFN-ɣ+ than the controls, suggesting that these cells, as well as CD4+ T lymphocytes, have crucial role of protection against M. tuberculosis. These findings have contributed to a better understanding of the immunologic changes in M. tuberculosis infection and the development of new strategies for diagnosis and prevention of tuberculosis.
Diabetes mellitus is associated with reactive oxygen and nitrogen species accumulation. Behavioral stress increases nitric oxide production, which may trigger a massive impact on vascular cells and ...accelerate cardiovascular complications under oxidative stress conditions such as Diabetes. For this study, type-1 Diabetes mellitus was induced in Wistar rats by intraperitoneal injection of streptozotocin. After 28 days, cumulative concentration-response curves for angiotensin II were obtained in endothelium-intact carotid rings from diabetic rats that underwent to acute restraint stress for 3h. The contractile response evoked by angiotensin II was increased in carotid arteries from diabetic rats. Acute restraint stress did not alter angiotensin II-induced contraction in carotid arteries from normoglycaemic rats. However acute stress combined with Diabetes increased angiotensin II-induced contraction in carotid rings. Western blot experiments and the inhibition of nitric oxide synthases in functional assays showed that neuronal, endothelial and inducible nitric oxide synthase isoforms contribute to the increased formation of peroxynitrite and contractile hyperreactivity to angiotensin II in carotid rings from stressed diabetic rats. In summary, these findings suggest that the increased superoxide anion generation in carotid arteries from diabetic rats associated to the increased local nitric oxide synthases expression and activity induced by acute restrain stress were responsible for exacerbating the local formation of peroxynitrite and the contraction induced by angiotensin II.
Hyperglycemia increases the generation of reactive oxygen species and affects systems that regulate the vascular tone including renin–angiotensin system. Stress could exacerbate intracellular ...oxidative stress during Diabetes upon the activation of angiotensin AT1/NADPH oxidase pathway, which contributes to the development of diabetic cardiovascular complications. For this study, type-I Diabetes was induced in Wistar rats by intraperitoneal injection of streptozotocin. 28 days after streptozotocin injection, the animals underwent to acute restraint stress for 3h. Cumulative concentration–response curves for angiotensin II were obtained in carotid rings pre-treated or not with Nox or cyclooxygenase inhibitors. Nox1 or Nox4 expression and activity were assessed by Western blotting and lucigenin chemiluminescence, respectively. The role of Nox1 and Nox4 on reactive oxygen species generation was evaluated by flow cytometry and Amplex Red assays. Cyclooxygenases expression was assessed by real-time polymerase chain reaction. The contractile response evoked by angiotensin II was increased in diabetic rat carotid. Acute restraint stress increased this response in this vessel by mechanisms mediated by Nox4, whose local expression and activity in generating hydrogen peroxide are increased. The contractile hyperreactivity to angiotensin II in stressed diabetic rat carotid is also mediated by metabolites derived from cyclooxygenase-2, whose local expression is increased. Taken together, our findings suggest that acute restraint stress exacerbates the contractile hyperreactivity to angiotensin II in diabetic rat carotid by enhancing Nox4-driven generation of hydrogen peroxide, which evokes contractile tone by cyclooxygenases-dependent mechanisms. Finally, these findings highlight the harmful role played by acute stress in modulating diabetic vascular complications.
Nox1/NADPH oxidase activity in carotid arteries from diabetic rats is enhanced; angiotensin II increases the generation of superoxide (O2−) and hydrogen peroxide (H2O2), which contribute to angiotensin II-induced contraction by activating the synthesis of contractile metabolites from cyclooxygenases (COX) (A). Acute restraint stress enhances the activity of Nox4/NADPH oxidase during type-1 Diabetes; Nox4 generates high levels of H2O2, which modulates the production of COX metabolites (B). Dashed arrow: activity; continuous arrow: generation; FAD, flavin-adenine dinucleotide; SOD, superoxide dismutase; O2− superoxide anion; H2O2, hydrogen peroxide; VSCM, vascular smooth muscle cell; AngII, angiotensin II; TXA2, thromboxane A2; PGH2, prostaglandin H2.
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The plague, which is an infectious disease caused by Yersinia pestis, still threatens many populations in several countries. The worldwide increase in human plague cases and the potential use of the ...bacteria as a biological weapon reinforce the need to study the immunity that is induced by potential vaccine candidates. To determine the immunogenicity of antigenic preparations based on the F1 protein and the total extract from Y. pestis, we assessed the role of these antigens in inducing an immune response.
The immunogenicity of antigenic preparations based on the Y. pestis (YP) total extract and the Y. pestis fraction 1 capsular antigen protein (F1) was determined in Swiss-Webster mice immunized with 40μg or 20μg for each preparation. Immunophenotyping was performed by flow cytometry.
Animals immunized with the YP total extract did not elicit detectable anti-F1 antibodies (Ab) in the hemaglutination/inhibition (HA/HI) test. Animals immunized with 40μg or 20μg of the F1 protein produced anti-F1 Abs, with titres ranging from 1/16 to 1/8132. The average of CD3+–CD4+ and CD3+–CD8+ T cells did not differ significantly between the groups. Neither YP total extract nor F1 protein induced a significant expression of IFN-γ and IL-10 in CD4+ T lymphocytes. In addition, F1 failed to induce IFN-γ expression in CD8+ T cells, unlike the YP total extract.
The results showed that F1 protein is not an immunogenic T cell antigen, although the YP total extract (40μg dose) favoured CD8+ T cell-mediated cellular immunity.
Temporal consequences of neurocompensation to balloon injury on endothelinergic functionality in rat contralateral carotid were evaluated. Rats underwent balloon injury in left carotid and were ...treated with CP-96345 (NK1 antagonist). Concentration-response curves for endothelin-1 were obtained in contralateral (right) carotid at 2, 8, 16, 30, or 45 days after surgery in the absence or presence of BQ-123 (ETA antagonist), BQ-788 (ETB antagonist), or Tempol (superoxide-dismutase mimic). Endothelin-1-induced calcium mobilization was evaluated in functional assays carried out with BQ-123, BQ-788, or Tempol. Endothelin-1-induced NADPH oxidase-driven superoxide generation was measured by lucigenin chemiluminescence assays performed with BQ-123 or BQ-788. Endothelin-1-induced contraction was increased in contralateral carotid from the sixteenth day after surgery. This response was restored in CP-96345-treated rats. Endothelium removal or BQ-123 did not change endothelin-1-induced contraction in contralateral carotid. This response was restored by BQ-788 or Tempol. Contralateral carotid exhibited an increased endothelin-1-induced calcium mobilization, which was restored by BQ-788 or Tempol. Contralateral carotid exhibited an increased endothelin-1-induced lucigenin chemiluminescence, which was restored by BQ-788. We conclude that the NK1-mediated neurocompensatory response to balloon injury elicits a contractile hyperreactivity to endothelin-1 in rat contralateral carotid by enhancing the muscular ETB-mediated NADPH oxidase-driven generation of superoxide, which activates calcium channels.
Temporal consequences of neurocompensation to balloon injury on endothelinergic functionality in rat contralateral carotid were evaluated. Rats underwent balloon injury in left carotid and were ...treated with CP-96345 (NK
1
antagonist). Concentration-response curves for endothelin-1 were obtained in contralateral (right) carotid at 2, 8, 16, 30, or 45 days after surgery in the absence or presence of BQ-123 (
E
T
A
antagonist), BQ-788 (
E
T
B
antagonist), or Tempol (superoxide-dismutase mimic). Endothelin-1-induced calcium mobilization was evaluated in functional assays carried out with BQ-123, BQ-788, or Tempol. Endothelin-1-induced NADPH oxidase-driven superoxide generation was measured by lucigenin chemiluminescence assays performed with BQ-123 or BQ-788. Endothelin-1-induced contraction was increased in contralateral carotid from the sixteenth day after surgery. This response was restored in CP-96345-treated rats. Endothelium removal or BQ-123 did not change endothelin-1-induced contraction in contralateral carotid. This response was restored by BQ-788 or Tempol. Contralateral carotid exhibited an increased endothelin-1-induced calcium mobilization, which was restored by BQ-788 or Tempol. Contralateral carotid exhibited an increased endothelin-1-induced lucigenin chemiluminescence, which was restored by BQ-788. We conclude that the NK
1
-mediated neurocompensatory response to balloon injury elicits a contractile hyperreactivity to endothelin-1 in rat contralateral carotid by enhancing the muscular
E
T
B
-mediated NADPH oxidase-driven generation of superoxide, which activates calcium channels.
Temporal consequences of neurocompensation to balloon injury on endothelinergic functionality in rat contralateral carotid were evaluated. Rats underwent balloon injury in left carotid and were ...treated with CP-96345 (NK
antagonist). Concentration-response curves for endothelin-1 were obtained in contralateral (right) carotid at 2, 8, 16, 30, or 45 days after surgery in the absence or presence of BQ-123 (ET
antagonist), BQ-788 (ET
antagonist), or Tempol (superoxide-dismutase mimic). Endothelin-1-induced calcium mobilization was evaluated in functional assays carried out with BQ-123, BQ-788, or Tempol. Endothelin-1-induced NADPH oxidase-driven superoxide generation was measured by lucigenin chemiluminescence assays performed with BQ-123 or BQ-788. Endothelin-1-induced contraction was increased in contralateral carotid from the sixteenth day after surgery. This response was restored in CP-96345-treated rats. Endothelium removal or BQ-123 did not change endothelin-1-induced contraction in contralateral carotid. This response was restored by BQ-788 or Tempol. Contralateral carotid exhibited an increased endothelin-1-induced calcium mobilization, which was restored by BQ-788 or Tempol. Contralateral carotid exhibited an increased endothelin-1-induced lucigenin chemiluminescence, which was restored by BQ-788. We conclude that the NK
-mediated neurocompensatory response to balloon injury elicits a contractile hyperreactivity to endothelin-1 in rat contralateral carotid by enhancing the muscular ET
-mediated NADPH oxidase-driven generation of superoxide, which activates calcium channels.
This research studied the thermal requirements of Trichogramma pretiosum and T. acacioi (Hymenoptera: Trichogrammatidae), parasitoids of Nipteria panacea (Lepidoptera: Geometridae), with eggs of the ...alternative hosts Anagasta kuehniella (Lepidoptera: Pyralidae) and Sitotroga cerealella (Lepidoptera: Gelechiidae) aiming to use these natural enemies in biological control programs of this pest in avocado orchards. T. pretiosum needed 151.83 and 160.04 degree-days, above threshold of 10.70 and 10.75°C, while these values were 158.50 and 155.46 degree-days, above threshold of 10.67 and 10.46°C for T. acacioi when exposed to eggs of A. kuehniella and S. cerealella, respectively.
O objetivo desta pesquisa foi estudar as exigências térmicas de Trichogramma pretiosum e T. acacioi (Hymenoptera: Trichogrammatidae), parasitóides de Nipteria panacea (Lepidoptera: Geometridae), em ovos dos hospedeiros alternativos Anagasta kuehniella (Lepidoptera: Pyralidae) e Sitotroga cerealella (Lepidoptera: Gelechiidae) visando utilizar estes inimigos naturais em programas de controle biológico desta praga em pomares de abacate. T. pretiosum apresentou temperaturas base (Tb) de 10.70 e 10.75°C e constantes térmicas (K) de 151.83 e 160.04 graus-dia, sendo estes valores de 10.67 e 10.46°C e 158.50 e 155.46 graus-dia para T. acacioi em ovos de A. kuehniella e S. cerealella, respectivamente.
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