Abstract:Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) are an important family of catalytic enzymes that generate reactive oxygen species (ROS), which mediate the regulation of diverse cellular functions. Although phagocyte Nox2/gp91phox is closely associated with the activation of host innate immune responses, the roles of Nox family protein during Toxoplasma gondii (T. gondii) infection have not been fully investigated. Here, we found that T. gondii-mediated ROS production was required for the up… Show more
“… Figure 5 Latently infected cells exhibit increased p38 and JNK stress kinase signaling in response to anisomycin. ( a , b ) Western blots for p-p38 (top) and p-JNK (bottom) expression 46 with and without anisomycin treatment (30 minutes) in uninfected (left) and infected (right) primary T CM cells ( a ), and Jurkat (JK, left) /J-DHIV cells (right) ( b ). Mean intensities were normalized to the alpha-Tubulin loading control 47 and fold increase in mean intensity was quantified (right plot).…”
Viral latency remains the most significant obstacle to HIV eradication. Clinical strategies aim to purge the latent CD4+ T cell reservoir by activating viral expression to induce death, but are undercut by the inability to target latently infected cells. Here we explored the acute signaling response of latent HIV-infected CD4+ T cells to identify dynamic phosphorylation signatures that could be targeted for therapy. Stimulation with CD3/CD28, PMA/ionomycin, or latency reversing agents prostratin and SAHA, yielded increased phosphorylation of IκBα, ERK, p38, and JNK in HIV-infected cells across two in vitro latency models. Both latent infection and viral protein expression contributed to changes in perturbation-induced signaling. Data-driven statistical models calculated from the phosphorylation signatures successfully classified infected and uninfected cells and further identified signals that were functionally important for regulating cell death. Specifically, the stress kinase pathways p38 and JNK were modified in latently infected cells, and activation of p38 and JNK signaling by anisomycin resulted in increased cell death independent of HIV reactivation. Our findings suggest that altered phosphorylation signatures in infected T cells provide a novel strategy to more selectively target the latent reservoir to enhance eradication efforts.
“… Figure 5 Latently infected cells exhibit increased p38 and JNK stress kinase signaling in response to anisomycin. ( a , b ) Western blots for p-p38 (top) and p-JNK (bottom) expression 46 with and without anisomycin treatment (30 minutes) in uninfected (left) and infected (right) primary T CM cells ( a ), and Jurkat (JK, left) /J-DHIV cells (right) ( b ). Mean intensities were normalized to the alpha-Tubulin loading control 47 and fold increase in mean intensity was quantified (right plot).…”
Viral latency remains the most significant obstacle to HIV eradication. Clinical strategies aim to purge the latent CD4+ T cell reservoir by activating viral expression to induce death, but are undercut by the inability to target latently infected cells. Here we explored the acute signaling response of latent HIV-infected CD4+ T cells to identify dynamic phosphorylation signatures that could be targeted for therapy. Stimulation with CD3/CD28, PMA/ionomycin, or latency reversing agents prostratin and SAHA, yielded increased phosphorylation of IκBα, ERK, p38, and JNK in HIV-infected cells across two in vitro latency models. Both latent infection and viral protein expression contributed to changes in perturbation-induced signaling. Data-driven statistical models calculated from the phosphorylation signatures successfully classified infected and uninfected cells and further identified signals that were functionally important for regulating cell death. Specifically, the stress kinase pathways p38 and JNK were modified in latently infected cells, and activation of p38 and JNK signaling by anisomycin resulted in increased cell death independent of HIV reactivation. Our findings suggest that altered phosphorylation signatures in infected T cells provide a novel strategy to more selectively target the latent reservoir to enhance eradication efforts.
“…To prevent oxidative stress, several genes are involved in the maintenance of cellular homeostasis, including NADPH oxidase 4 (NOX4), superoxide dismutase (SOD2), and catalase [13,14]. Primarily expressed in renal and vascular cells, the NOX4 gene is constitutively active and codes for an oxygen-sensing enzyme that can also play a role in antimicrobial defense [15][16][17]. If overexpressed, NOX4 leads to oxidative stress due to its production of superoxide (O 2 − ) radicals and hydrogen peroxide (H 2 O 2 ) molecules [18,19].…”
Thermal stress is a major source of oxidative damage in the broiler chicken (Gallus gallus domesticus) due to the latter’s impaired metabolic function. While heat stress has been extensively studied in broilers, the effects of cold stress on broiler physiologic and oxidative function are still relatively unknown. The present study aimed to understand how thermal manipulation (TM) might affect a broiler’s oxidative response to post-hatch thermal stress in terms of the mRNA expression of the catalase, NADPH oxidase 4 (NOX4), and superoxide dismutase 2 (SOD2) genes. During embryonic days 10 to 18, TM was carried out by raising the temperature to 39 °C at 65% relative humidity for 18 h/day. To induce heat stress, room temperature was raised from 21 to 35 °C during post-hatch days (PD) 28 to 35, while cold stress was induced during PD 32 to 37 by lowering the room temperature from 21 to 16 °C. At the end of the thermal stress periods, a number of chickens were euthanized to extract hepatic and splenic tissue from the heat-stressed group and cardiac, hepatic, muscular, and splenic tissue from the cold-stressed group. Catalase, NOX4, and SOD2 expression in the heart, liver, and spleen were decreased in TM chickens compared to controls after both cold and heat stress. In contrast, the expression levels of these genes in the breast muscles of the TM group were increased or not affected. Moreover, TM chicks possessed an increased body weight (BW) and decreased cloacal temperature (TC) compared to controls on PD 37. In addition, TM led to increased BW and lower TC after both cold and heat stress. Conclusively, our findings suggest that TM has a significant effect on the oxidative function of thermally stressed broilers.
“…Host defense mechanisms against T. gondii infection involve both cellular T-helper 1 (Th-1) and humoral T-helper 2 (Th-2) responses. Specific IgG antibodies can lyse extracellular trophozoites, but activation of T-cells and natural killer cells appear to be more important in preventing disease progression (5).…”
Background: Infection with Toxoplasma gondii (T. gondii) leads to activation of T-helper cells (Th-1 and Th-2) which are involved in the synthesis and release of different cytokines which may lead to endothelial dysfunction. Objectives: To evaluate the endothelial function in patients with acute toxoplasmosis. Methods: This case-control study involved 31 patients with toxoplasmosis aged 19 -47 years matched with 20 healthy subjects. Anti-T. gondii antibody (IgG, IgM, IgA) was determined by direct antigen-antibody reaction. Interleukin-6(IL-6), endothelin-1 (ET-1) and human malondialdehyde (MDA) serum levels were measured. Results: IgM, IgG and IgA levels were high in the infected patients compared with controls (P < 0.01). Furthermore, IL-6 serum level was high in the infected patients compared with controls (P < 0.01). In addition, ET-1 level was high in acute toxoplasmosis (7.29 ± 4.59 pg/mL) compared with controls (3.11 ± 1.69 pg/mL) (P < 0.01). In addition, MDA serum level was high (9.34 ± 4.17 nmol/mL) compared with controls (2.87 ± 1.13 nmol/mL), (P < 0.01). In acute toxoplasmosis IgM serum level was significantly correlated with IgG (r = 0.55, P = 0.001), IgA (r = 0.57, P = 0.0008), IL-6 (r = 0.45, P = 0.01), ET-1 (r = 0.51, P = 0.003) and MDA (r = 0.85, P = 0.0001). Conclusions: Acute toxoplasmosis is associated with significant oxidative stress and pro-inflammatory changes which contribute to development of endothelial dysfunction.
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