Structure of flavonoids influences the degree inhibition of Benzo(a)pyrene – induced DNA damage and micronuclei in HepG2 cells

δ-secretase, also known as asparagine endopeptidase (AEP) or legumain, is a lysosomal cysteine protease that cleaves both amyloid precursor protein (APP) and tau, mediating the amyloid-β and tau pathology in Alzheimer's disease (AD). Here we report the therapeutic effect of an orally bioactive and brain permeable δ-secretase inhibitor in mouse models of AD. We performed a high-throughput screen and identified a non-toxic and selective δ-secretase inhibitor, termed compound 11, that specifically blocks δ-secretase but not other related cysteine proteases. Co-crystal structure analysis revealed a dual active site-directed and allosteric inhibition mode of this compound class. Chronic treatment of tau P301S and 5XFAD transgenic mice with this inhibitor reduces tau and APP cleavage, ameliorates synapse loss and augments long-term potentiation, resulting in protection of memory. Therefore, these findings demonstrate that this δ-secretase inhibitor may be an effective clinical therapeutic agent towards AD.

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“…Nicked DNA was measured as percentage of tail DNA. One hundred comets were scored for each sample39.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease

et al. 2017

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“…Kozics et al [97] performed a useful comparative study of 10 flavonoids, concluding that their effectiveness at protecting against B(a)P-induced SBs and MN depended on their chemical structure. Tested over a relatively low concentration range, fisetin, quercetin, galangin, kaempferol and luteolin (in order of decreasing effectiveness) were more effective than chrysin,7-hydroxyflavone, 7,8-dihydroxyflavone or baicalein, while rutin was without effect.…”

Section: Isolated Phytochemicalsmentioning

confidence: 99%

Polyphenols and DNA Damage: A Mixed Blessing

Azqueta

Collins

2016

Nutrients

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Polyphenols are a very broad group of chemicals, widely distributed in plant foods, and endowed with antioxidant activity by virtue of their numerous phenol groups. They are widely studied as putative cancer-protective agents, potentially contributing to the cancer preventive properties of fruits and vegetables. We review recent publications relating to human trials, animal experiments and cell culture, grouping them according to whether polyphenols are investigated in whole foods and drinks, in plant extracts, or as individual compounds. A variety of assays are in use to study genetic damage endpoints. Human trials, of which there are rather few, tend to show decreases in endogenous DNA damage and protection against DNA damage induced ex vivo in blood cells. Most animal experiments have investigated the effects of polyphenols (often at high doses) in combination with known DNA-damaging agents, and generally they show protection. High concentrations can themselves induce DNA damage, as demonstrated in numerous cell culture experiments; low concentrations, on the other hand, tend to decrease DNA damage.

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“…Recently, 7,8-DHF has been reported to have neurotrophic activities in various neurological diseases, such as stroke and Parkinson's disease (27). Although several studies on the antioxidant effects of 7,8-DHF have been carried out (18,29,30), the molecular mechanisms underlying its anti-inflammatory effects have yet to be reported.…”

Section: 8-dihydroxyflavone Exhibits Anti-inflammatory Propertiesmentioning

confidence: 99%

7,8-Dihydroxyflavone exhibits anti-inflammatory properties by downregulating the NF-κB and MAPK signaling pathways in lipopolysaccharide-treated RAW264.7 cells

et al. 2012

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Abstract. 7,, a member of the flavonoid family, has received considerable attention as a selective tyrosine kinase receptor B agonist. Several studies have indicated that 7,8-DHF has neurotrophic and antioxidant activities. However, little is known about the cellular and molecular mechanisms underlying the anti-inflammatory activity of 7,8-DHF. Therefore, we investigated whether 7,8-DHF affects the expression of inflammatory mediators in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Our results indicated that 7,8-DHF significantly attenuated secretion of LPS-induced inflammatory mediators nitric oxide (NO), prostaglandin E 2 (PGE 2 ) and interleukin-1β (IL-1β) in RAW264.7 cells. Additionally, LPS-induced expression of inducible NO synthase (iNOS), cyclooxygenase (COX)-2 and IL-1β was decreased by pre-treatment with 7,8-DHF. Our results also showed that 7,8-DHF reduces LPS-induced nuclear factor-κB (NF-κB) activity via the suppression of the nuclear translocation of NF-κB p65 and the degradation of inhibitor κB (lκB). In addition, 7,8-DHF inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) such as extracellular-signal-related kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). These results suggest that the anti-inflammatory property of 7,8-DHF is related to the downregulation of iNOS, COX-2 and IL-1β, due to NF-κB inhibition as well as to the negative regulation of MAPK activation in RAW264.7 cells. Thus, 7,8-DHF may be a novel therapeutic agent for the prevention of various inflammatory diseases.

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Structure of flavonoids influences the degree inhibition of Benzo(a)pyrene – induced DNA damage and micronuclei in HepG2 cells

Cited by 26 publications

References 31 publications

Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease

Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease

Polyphenols and DNA Damage: A Mixed Blessing

7,8-Dihydroxyflavone exhibits anti-inflammatory properties by downregulating the NF-κB and MAPK signaling pathways in lipopolysaccharide-treated RAW264.7 cells

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