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The methylation and demethylation of CpG dinucleotides that are embedded in promoters play an important role in controlling gene transcription. In the mammalian brain, CpG promoter methylation is a postreplicative process mediated by a group of DNA methyltransferases (DNMT), such as DNMT1 and DNMT3a, DNMT3b. Several studies demonstrate that in addition to DNMTs, promoter methylation in the brain can be regulated by a putative DNA demethylation process that specifically removes the methyl group from the carbon-5 of cytosines. To test the existence of a possible active DNA demethylation activity in postmitotic neuronal or glial cells, we incubated an SssI methylated mouse reelin (Reln) promoter fragment (-720 to +140) with nuclear extracts from the mouse frontal cortex (FC). We observed the presence of DNA demethylation activity, which was increased in FC nuclear extracts from mice treated with valproate (VPA, 2.2 mmol/kg, twice a day for 3 days). VPA not only reduces anxiety, and cognitive deficits, and other symptoms in bipolar disorder (BP) disorder and schizophrenia (SZ) patients but also upregulates Reln and glutamic acid decarboxylase 67 (Gad67) mRNA/protein expression by reducing the methylation of their promoters. We believe that the identification of an enzyme in brain that facilitates DNA-demethylation and an understanding of how drugs induce DNA demethylation are crucial to progress in a new line of pharmacological interventions to treat neurodevelopment, neuropsychiatric, and neurodegenerative diseases.

The effects of tea (Camellia sinensis L.) of three types on excessive free radicals were examined utilizing spin trapping, 1,1-diphenyl-2-picrylhydrazyl radical, lipid peroxidation, and lactate dehydrogenase leakage from cultured cells. Green tea extract presented significant antiradical effects in these four assay systems, whereas oolong tea and black tea extracts showed a rather weak protective effect against free radicals. A more potent scavenger effect using cultured cells was found with a green tea tannin mixture. Similarly to the effects of the green tea tannin mixture, (-)epigallocatechin 3-O-gallate, its main ingredient, had an inhibitory effect on oxidative stress-induced apoptosis. The activities of the antioxidation enzymes in rats after subtotal nephrectomy were increased, suggesting a protective action against oxidative stress. The increased levels of uremic toxins in the blood were also reduced in rats given (-)-epigallocatechin 3-O-gallate. These findings indicate that (-)-epigallocatechin 3-O-gallate helps to inhibit the progression of renal failure by scavenging radicals.

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The effect of ginsenoside-Rd in ischemic-reperfused rats was examined. In control rats, blood and renal parameters and the activities of antioxidative enzymes in renal tissue deviated from the normal range, indicating dysfunction of the kidneys. In contrast, when ginsenoside-Rd was given orally for 30 consecutive days prior to ischemia and reperfusion, the activities of the antioxidation enzymes superoxide dismutase, catalase and glutathione peroxidase were higher, while malondialdehyde levels in serum and renal tissue were lower in the treated rats than in the controls. Decreased levels of urea nitrogen and creatinine in serum demonstrated a protective action against the renal dysfunction caused by ischemia and recirculation. On the other hand, it was demonstrated that ginsenoside-Rd affected cultured proximal tubule cells subjected to hypoxia-reoxygenation, probably by preventing oxygen free radicals from attacking the cell membranes.

Subtotally nephrectomized rats were found to have decreased activities of superoxide dismutase (SOD) and catalase, and spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) showed that the amount of hydroxyl radical in the residual kidney tissue was greater than that in normal rat kidney. This indicated both direct and indirect involvement of free radicals in renal failure. In contrast, rats given magnesium lithospermate B (10 mg/kg body weight) orally for 30 days after subtotal nephrectomy showed restoration of SOD and catalase activities to almost normal levels. Hydroxyl radical, which is highly reactive and for which there is no scavenger system in the body, was decreased markedly in kidney homogenates obtained from rats given magnesium lithospermate B and in an experimental system for hydroxyl radical production to which magnesium lithospermate B was directly added. The increased levels of uremic toxins in the blood were also low in rats given magnesium lithospermate B. This indicates that magnesium lithospermate B helps to inhibit the progression of renal failure by scavenging radicals.

DNA of LLC-PK₁ cells cultured with cisplatin was fragmented to produce low-molecular-weight structures. Agarose gel electrophoresis of the DNA revealed a ladder pattern characteristic of apoptosis, indicating the induction of apoptosis by cisplatin. However, the degree of apoptosis was lower in cells cultured with cisplatin in the presence of ginsenoside-Rd, and this was accompanied by suppressed leakage of lactic dehydrogenase into the culture medium. The ladder pattern was detected on electrophoresis of DNA in renal tissue samples obtained from rats given an intravenous injection of cisplatin. Such DNA fragmentation was less conspicuous in rats given ginsenoside-Rd orally for 30 days prior to cisplatin administration. Significant suppression of the DNA fragmentation was also demonstrated by densitometry, and measurement of urea nitrogen and creatinine in blood also showed a marked decrease in their respective levels in rats administered ginsenoside-Rd. The present findings suggest that ginsenoside-Rd ameliorates cisplatin-induced renal injury, a process in which apoptosis plays a central role, and thereby causes restoration of the renal function.

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