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Cardiovascular Disease and Oxidative Stress
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Marco Fernandes, Alisha Patel, Holger Husi
Counter-balance of the deleterious effects of oxidative-stress can also be attainable by promoting activation of up-stream factors responsible for the regulation of cell-mediated response to oxidative stress (Gazaryan and Thomas, 2016). This is in part orchestrated by binding of the nuclear factor erythroid 2-related factor 2 (NFE2L2) to cis-regulatory elements, commonly known as antioxidant response elements (ARE) in the promotor region of target genes (Huang et al., 2000). Without external oxidoreductive stimuli, the Kelch-like ECH-associated protein 1(KEAP) promotes continuous ubiquitination and consequent proteasome degradation of NFE2L2, leading to suppression of its transcriptional activity (Lo et al., 2006). Along this line, a number of drugs are currently being developed to attempt to explore how to disrupt the NFE2L2-KEAP1 interface, like the tecfidera (dimethyl fumarate), bardoxolone, and BTB domain and CNC homolog 1 (Bach1) and consequently activating the NFE2L2/ARE pathway. This would then lead to an increased expression of ROS detoxifying enzymes and/or synthesis of pro-antioxidant molecules (Gazaryan and Thomas, 2016; Gesslbauer and Bochkov, 2017). Another approach encompasses mechanisms to cope with damage induced by oxidative stress without changing either basal activity of detoxifying enzymes or levels of pro-antioxidant molecules (Gesslbauer and Bochkov, 2017), thereby lessen the effect of inflammation and aiming to correct disrupted intracellular events due to ROS-induction damage (Gesslbauer and Bochkov, 2017). Attenuation of inflammation by pharmacological intervention has been addressed by altering or interfering with key players in the inflammatory process, such as acting on secretory mediators like inhibiting IL-18, chemokines, and TNF-alpha, using compounds such as Anakinra (Brown, 1989; Toldo et al., 2012), Etanercept (Gao et al., 2015), Infliximab (Gerlach et al., 2014), and Evasin-3 (Montecucco et al., 2010).
Mucosal immune responses to microbes in genital tract
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Following sexual transmission, HSV-2 infects stratified squamous epithelium of the vagina and ectocervix. Virus infection is detected by the infected epithelial cells and by submucosal dendritic cells in a MyD88-dependent manner. Recognition of infection by both hematopoietic and stromal compartments is required for successful induction of protective TH1 immunity. However, directly infected cells are incapable of priming T cells because HSV-2 blocks MHC I and MHC II presentation and is highly lytic. Uninfected submucosal DCs pick up viral antigens and migrate to the draining lymph nodes, where they present antigenic peptides to cognate CD8+ and CD4+ T cells. Natural immunity that develops following genital HSV infection fails to clear the virus because the virus can invade and establish latent infection in the innervating ganglia prior to the onset of highly effective immunity. Latent virus cannot be cleared by T cells or antibody, although CD8+ T cells provide important immune surveillance of the infected neurons through nonlytic mechanisms. Both CD4+ and CD8+ TRM confer protection against disease following vaginal HSV-2 challenge in the mouse model, suggesting that vaccines that can induce a high frequency of tissue-resident T cells in the female reproductive tract are desirable. Multiple clinical trials of HSV-2 vaccines have failed to confer protection. The failure of vaccines may be due to the fact that conventional vaccines do not elicit TRMs. In addition, antibody responses are rendered ineffective by the fact that the HSV-2 envelope is studded with glycoproteins that evade the effector function of antibodies. The gC binds complement component C3 and inhibits complement-mediated virus neutralization and lysis of infected cells. In addition, the gE/gI complex acts as an FcR decoy on viral envelope. These immuno-evasins collectively render Abs ineffective in control of HSV. Future vaccines against HSV-2 will need to overcome both of these hurdles. The ability of IgG antibodies to be transported into and out of luminal surfaces by FcRn, an IgG-transporting receptor (see Chapter 11) may also be important in protection against and responses to HSV-2.
CXCL2, a new critical factor and therapeutic target for cardiovascular diseases
Published in Clinical and Experimental Hypertension, 2020
Lin-Ya Guo, Fang Yang, Li-Jun Peng, Yan-Bing Li, Ai-Ping Wang
Ischemic stroke (IS) is the leading cause of disability worldwide and one of the leading causes of death (73). Recent studies have revealed that IS was associated with rupture of arterial plaque (74). Therefore, researchers believe that effective stroke treatment could prevent the rupture of arterial plaque. Immediately after the onset of cerebral ischemia, a pathophysiological cascade triggers oxidative microvascular damage, blood–brain barrier (BBB) dysfunction, and postischemic inflammation, mediating cerebral ischemic injury. Many studies have clearly demonstrated that the inflammatory response has been found to play an important role in the pathogenesis of arterial plaque rupture. The inflammatory response involves a series of continuous processes involving increased expression of endothelial cell adhesion molecules and chemokines (75,76). Neutrophil inflammation may have pathophysiological effects on carotid plaque rupture and ischemic stroke injury (77). It has been shown that focal cerebral ischemia results in dynamic and extensive activation of inflammatory cytokines, chemokines and chemokine receptors in the peripheral immune system, and cytokine-induced neutrophil chemoattractant-1 (CINC-1/CXCL1) is a major chemokine involved in the recruitment of neutrophils to the brain and spinal cord; however, cerebral ischemia also increases the expression of neutrophil-related CXCR2 and its ligands CXCL1 and CXCL2 in the brain after cerebral ischemia, and treatment with CXCR2 antagonists can significantly reduce CXCL2 expression and neutrophil infiltration after stroke (78). This suggests that the expression of CXCL2 is significantly increased in the process of driving neutrophil-induced inflammation and causing plaque rupture, and inhibition of the expression of CXCL2 can slow the occurrence of inflammation. Therefore, CXCL2, a postischemic chemokine (79), is a potential factor in the IS pathway. In addition, Jean-Christophe Chopin et al demonstrated that Evasin-3 (which was recently shown to effectively inhibit neutrophil-mediated cardiac injury after acute myocardial infarction) can selectively inhibit the CXCL2 pathway in the early poststroke treatment (40,77). Further experiments showed that treatment with Evasin-3 selectively reduced the neutrophil-mediated inflammation and potentially reduced recruitment to plaques in mice. It is expected that the infiltration of neutrophils into the plaque will be eliminated by inhibition of CXCL2. This treatment may be an effective strategy to prevent ischemic stroke caused by atherosclerosis (77). Therefore, it is believed that the selective inhibition of the CXCL2 pathway may be of particular importance for the prevention of rupture of arterial plaques rather than ischemic brain damage (77).