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    • Morin is a flavonoid that

    2021-12-30

    Morin is a flavonoid that has shown to have effective anti-inflammatory and anti-tumor function [118]. Morin was able to block the activation of NF-κB pathway by ROS and inflammatory cytokines, preventing a signaling cascade resulting in cell death [121]. Morin exerted its control over the signaling pathway by inhibiting TNF induced NF-κB activation by inhibiting degradation of IκBα, and morin was also able to inhibit TNF mediated p65 nuclear translocation [120], [125]. Morin inhibited phosphorylation of Akt in a breast cancer cell line, preventing metastases and tumor proliferation [116]. Morin was shown to decrease survival of cancer cells, while increasing viability of normal endothelial TUG-770 [116]. These compounds are involved in the pAkt - NF-κB signaling pathways in neuronal cells to enhance the glyoxalase expression [4]. Flavonoids have shown effectiveness in modulation of glyoxalase pathway and MG detoxification. Our previous research has shown treatment with catechin, morin, and quercetin was able to attenuate the effects of MG toxicity while retaining cellular function. The flavonoids increased glo 1 activity and GSH concentration, while reducing the concentration of MG [4], [126] While a lack of flavonoids does not cause any disease, Exogenous antioxidants can influence cellular health and offer protection against inflammatory and degenerative diseases. A correlation exists between flavonoid consumption and low levels of dementia and neural pathology [127]. Intake of flavonoids can have a protective effect on neural cells in many diseased states [127], [128]. Silymarin and naringin are flavonoids that have shown efficacy in protection against excitotoxicity in dopaminergic neurons. Silymarin protected mice against 1-methyl-4-phenylpyridinium (MPP+) induced toxicity by attenuating production of inflammatory cytokines, and prevented mitochondrial dysfunction [127]. Naringin protected neural cells from toxicity mediated by 6-Hydroxydopamine (6-OHDA), mediated by an increase in Nrf2 activation [127]. Morin has also shown to mitigate the damage caused by ischemia and stroke by downregulating expression and release of proinflammatory cytokines [118]. A grape powder extract was shown to reduce anxiety-like behavior, depression, and memory impairments caused by elevated OS [129].
    Mechanistic interference When under states of stress and cytotoxicity, cells initiate antioxidant defense mechanisms. Nuclear factor erythroid 2-related factor 2 (Nrf2) activation leads to the transcription of proteins involved in counteracting oxidative damage [56]. The Nrf2 pathway is activated during elevated OS. Unstimulated Nrf2 is bound to Keap1 in the cytoplasm, and subsequently ubiquitinated and degraded [130]. Under states of OS, ROS disrupt the association between Keap1 and Nrf2. Nrf2 is released from the complex, and translocates to the nucleus to bind the antioxidant response element (ARE), leading to the production of antioxidant molecules [55]. (Fig. 4) Gene products function in an antioxidant, anti-inflammatory, and neuroprotective fashion [119]. Among the products are glo 1, heme oxygenase-1 (HO-1), gamma-glutamyl-cysteine synthetase (GCS), and glutathione-S-transferase. Keap 1 is a negative regulator of Nrf2. Keap 1 and Cullin-3 contain Nrf2 in the cytoplasm of cells. Cullin-3 ubiquitinates Nrf2 and it is transported to proteasome for degradation. High levels of OS and free radicals phosphorylate targets on Keap 1 and Cullin-3 and disrupt the Keap1-Cullin-3 degradation system. Nrf2 is not degraded, and builds up in the cytoplasm until it is translocated to the nucleus and binds to ARE [131]. Nrf2 is critical for mediating expression of protective genes in response to MG induced OS and toxicity, and Nrf2 expression has been showed to suppress accumulation of AGEs [56]. Neurons treated with a Nrf2 activator were protected from MG mediated damage [132]. The Nrf2 signaling pathway increased intracellular GSH levels, and increased the glyoxalase pathway's detoxification of MG protecting cells from OS mediated damage [133]. Neuron cells treated with N-acetyl serotonin showed enhanced nuclear translocation of Nrf2 from the cytoplasm [134]. Nrf2 activators have shown benefits in PD animal models, Nrf2 expression prevented 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP) induced toxicity in cells [135]. Flavonoids are able to indirectly induce Nrf2 expression by activation of kinase pathways resulting in phosphorylation of Nrf2 and induction of dependent genes [56], [136] Nrf2 also provided a stress-responsive defense against AGEs and lead to transcriptional control of glyoxalase [56] and a temporal dynamic reciprocal regulation of Nrf2 and glo 1 was observed during disease development [137]. Mangiferrin also upregulated glo 1 through activating Nrf2/ARE signaling pathway [138].