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      Central administration of tert -butylhydroquinone attenuates hypertension via regulating Nrf2 signaling in the hypothalamic paraventricular nucleus of hypertensive rats

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          Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis.

          Oxidative stress has been implicated in the etiology of neurodegenerative disease, cancer and aging. Indeed, accumulation of reactive oxygen and nitrogen species generated by inflammatory cells that created oxidative stress is thought to be one of the major factor by which chronic inflammation contributes to neoplastic transformation as well as many other diseases. We have recently reported that mice lacking nuclear factor-erythroid 2-related factor 2 (Nrf2) are more susceptible to dextran sulfate sodium (DSS)-induced colitis and colorectal carcinogenesis. Nrf2 is a basic leucine zipper redox-sensitive transcriptional factor that plays a center role in ARE (antioxidant response element)-mediated induction of phase II detoxifying and antioxidant enzymes. We found that increased susceptibility of Nrf2 deficient mice to DSS-induced colitis and colorectal cancer was associated with decreased expression of antioxidant/phase II detoxifying enzymes in parallel with upregulation of pro-inflammatory cytokines/biomarkers. These findings suggest that Nrf2 may play an important role in defense against oxidative stress possibly by activation of cellular antioxidant machinery as well as suppression of pro-inflammatory signaling pathways. In addition, in vivo and in vitro data generated from our laboratory suggest that many dietary compounds can differentially regulate Nrf2-mediated antioxidant/anti-inflammatory signaling pathways as the first line defense or induce apoptosis once the cells have been damaged. In this review, we will summarize our thoughts on the potential cross-talks between Nrf2 and NFkappaB pathways. Although the mechanisms involved in the cross-talk between these signaling pathways are still illusive, targeting Nrf2-antioxidative stress signaling is an ideal strategy to prevent or treat oxidative stress-related diseases.
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            A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo.

            The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates expression of genes required for free radical scavenging, detoxification of xenobiotics, and maintenance of redox potential. Previously, activation of this pleiotropic response was neuroprotective in cell culture models that simulate components of stroke damage. However, the role of Nrf2 in limiting stroke damage in vivo remained unclear. We report that Nrf2 activation protects the brain from cerebral ischemia in vivo. Acute (1-3 d) intracerebroventricular or intraperitoneal pretreatment with tert-butylhydroquinone (tBHQ), an Nrf2 activity inducer, reduced cortical damage and sensorimotor deficit at 24 h and even 1 month after ischemia-reperfusion in rats. Cortical glutathione levels robustly increased with tBHQ administration to rats and Nrf2-expressing mice, but not Nrf2(-/-) mice. Basal and inducible activities of antioxidant/detoxification enzymes in Nrf2(-/-) mice were reduced when compared with Nrf2(+/+) controls. Interestingly, larger infarcts were observed in Nrf2(-/-) mice at 7 d after stroke, but not at 24 h, suggesting that Nrf2 may play a role in shaping the penumbra well after the onset of ischemia. Neuronal death caused by a "penumbral" model of stroke, using intracortical endothelin-1 microinjection, was attenuated by tBHQ administration to Nrf2(+/+), but not to Nrf2(-/-) mice, confirming the Nrf2-specific action of tBHQ in vivo. We conclude that Nrf2 plays a role in modulating ischemic injury in vivo. Accordingly, Nrf2 activation by small molecule inducers may be a practical preventative treatment for stroke-prone patients.
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              Brain nuclear factor-kappa B activation contributes to neurohumoral excitation in angiotensin II-induced hypertension.

              Angiotensin II (ANG II)-induced inflammatory and oxidative stress responses contribute to the pathogenesis of hypertension. In this study, we determined whether nuclear factor-kappa B (NF-kappaB) activation in the hypothalamic paraventricular nucleus (PVN) increases oxidative stress and contributes to the ANG II-induced hypertensive response. Rats were infused intravenously with ANG II (10 ng/kg per min) or saline for 4 weeks. These rats received either vehicle or losartan (LOS, 20 microg/h), an angiotensin II type 1 receptor (AT1-R) antagonist; pyrrolidine dithiocarbamate (PDTC, 5 microg/h), a NF-kappaB inhibitor; tempol (TEMP, 80 microg/h), a superoxide scavenger; LOS (20 microg/h), and PDTC (5 microg/h); or TEMP (80 microg/h) and PDTC (5 microg/h), given intracerebroventricularly (ICV) via osmotic minipump. ANG II infusion resulted in increased mean arterial pressure, renal sympathetic nerve activity, plasma proinflammatory cytokines (PIC), norepinephrine, and aldosterone. These rats also had higher levels of Fra-LI (an indicator of chronic neuronal activation), PIC, phosphorylated IKKbeta, NF-kappaB subunits, AT1-R, superoxide, and gp91phox (a subunit of NADP(H) oxidase) and lower levels of IkappaBalpha in the PVN than control animals. ICV treatment with LOS, PDTC, or TEMP attenuated these changes, and combined treatment with ICV LOS and PDTC, or ICV TEMP and PDTC prevented these ANG II-induced hypertensive responses. These findings suggest that an ANG II-induced increase in the brain renin-angiotensin system activates NF-kappaB in the PVN and contributes to sympathoexcitation in hypertension. The increased superoxide in the PVN contributes to NF-kappaB activation and neurohumoral excitation in hypertension.
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                Author and article information

                Journal
                Toxicology and Applied Pharmacology
                Toxicology and Applied Pharmacology
                Elsevier BV
                0041008X
                October 2017
                October 2017
                : 333
                : 100-109
                Article
                10.1016/j.taap.2017.08.012
                © 2017

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