Catalytic activity of OGG1 is impaired by Zinc deficiency.

Oxidative stress-induced DNA base modifications, if unrepaired, can increase mutagenesis and genomic instability, ultimately leading to cell death. Cells predominantly use the base excision repair (BER) pathway to repair oxidatively-induced non-helix distorting lesions. BER is initiated by DNA glycosylases, such as 8-oxoguanine DNA glycosylase (OGG1), which repairs oxidatively modified guanine bases, including 7,8-dihydro-8-oxoguanine (8-oxoG) and ring-opened formamidopyrimidine lesions, 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG). The OGG1 protein contains a C2H2 zinc (Zn) finger DNA binding domain. However, the impact of dietary Zn deficiency on OGG1 catalytic activity has not been extensively studied. Zn is a common nutrient of concern with increasing age, and the prevalence of oxidative DNA damage is also concurrently increased during aging. Thus, understanding the potential regulation of OGG1 activity by Zn is clinically relevant. The present study investigates the impact of a range of Zn statuses, varying from severe Zn deficiency to exogenous Zn-supplementation, in the context of young and aged animals to determine the impact of dietary Zn-status on OGG1 activity and oxidative DNA damage in mice. Our findings suggest that nutritional Zn deficiency impairs OGG1 activity and function, without altering gene expression, and that aging further exacerbates these effects. These results have important implications for nutritional management of Zn during aging to mitigate age-associated DNA damage.

Centella asiatica Attenuates Amyloid-ß-Induced Oxidative Stress and Mitochondrial Dysfunction.

BACKGROUND: We previously showed that a water extract of the medicinal plant Centella asiatica (CAW) attenuates amyloid-ß (Aß)-induced cognitive deficits in vivo, and prevents Aß-induced cytotoxicity in vitro. Yet the neuroprotective mechanism of CAW is unknown. OBJECTIVE: The goal of this study was to identify biochemical pathways altered by CAW using in vitro models of Aß toxicity. METHODS: The effects of CAW on aberrations in antioxidant response, calcium homeostasis, and mitochondrial function induced by Aß were evaluated in MC65 and SH-SY5Y neuroblastoma cells. RESULTS: CAW decreased intracellular reactive oxygen species and calcium levels elevated in response to Aß, and induced the expression of antioxidant response genes in both cell lines. In SH-SY5Y cells, CAW increased basal and maximal oxygen consumption without altering spare capacity, and attenuated Aß-induced decreases in mitochondrial respiration. CAW also prevented Aß-induced decreases in ATP and induced the expression of mitochondrial genes and proteins in both cell types. Caffeoylquinic acids from CAW were shown to have a similar effect on antioxidant and mitochondrial gene expression in neuroblastoma cells. Primary rat hippocampal neurons treated with CAW also showed an increase in mitochondrial and antioxidant gene expression. CONCLUSIONS: These data suggest an effect of CAW on mitochondrial biogenesis, which in conjunction with activation of antioxidant response genes and normalizing calcium homeostasis, likely contributes to its neuroprotective action against Aß toxicity.