Yukmijihwang-Tang is widely used in traditional Korean medicine to treat age-related disorders. In the present study, we re-prescribed Gami-Yukmijihwang-Tang (YJT), which is slightly modified from Yukmijihwang-Tang by adding more medicinal plants to evaluate its pharmacological effects on underlying mechanisms against repeated lipopolysaccharide (LPS)-injection-induced neuroinflammation in the hippocampus regions. C57BL/6J male mice (16–24 weeks old) were divided into six groups: (1) the control group (DW with 0.9% saline injection), (2) LPS group (DW with LPS injection), YJT groups ((3) 100, (4) 200, or (5) 400 mg/kg of YJT with LPS injection), and (6) glutathione (GSH) group (100 mg/kg of GSH with LPS injection), respectively. Mice were orally administrated with various doses of YJT or glutathione (GSH) for the first five days. Neuroinflammation in the hippocampus region was induced by repeated injection of LPS during the last three days. As predicted, LPS not only increased oxidative stress–related markers including malondialdehyde, 4-hydroxynonenal, nitrotryptophan, and hydrogen peroxide, but also drastically enhanced inflammatory reactions including nitric oxide, inducible nitric oxide synthase, p65, and toll-like receptor 4, respectively. YJT administration, on the other hand, notably decreased the above pathological alterations by enhancement of antioxidant capacities such as superoxide dismutase and catalase activities. To explain the underlying pharmacological actions of YJT, we focused on a representative epigenetic regulator, a nicotinamide adenine dinucleotide + (NAD+)–dependent chromatin enzyme, Sirtuin 6 (Sirt6). Neuroinflammation in hippocampus regions depleted Sirt6 at the protein level and this alteration directly affected the nuclear factor erythroid 2–related factor (Nrf2)/hemeoxygenase (HO)-1 signaling pathway in the LPS group; however, YJT significantly recovered the Sirt6 protein levels, and it could recover the abnormal status of Nrf2/HO-1 signaling pathways in the hippocampus regions. Additionally, Sirt6 led to the up-regulation of GSH sub-enzymes of mRNA expression and protein levels of total GSH content. These findings suggest that YJT can protect against LPS-induced neuroinflammation and oxidative stress by regulating the Sirt6-related pathways and normalizing the GSH redox cycle.

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Familial British dementia (FBD), is an autosomal dominant neurodegenerative disorder,with biochemical and pathological similarities to Alzheimer's disease. One notable similarity is the production of an amyloid peptide (ABri) due to point mutation of a stop codon in the BRI gene. The mutation extends the wild-type protein, and following proteolytic cleavage, results in the 34 residue ABri peptide isolated from plaques in FBD brain sections. Examination of the ABri sequence and the limited literature suggested that a constraining intramolecular disulphide bond might exist in ABri. Therefore we synthesized oxidized (cyclic) and reduced forms (linear) of both the ABri peptide and the analogous wild-type peptide. Fibrils were observed by negative-staining EM of aged solutions of ABri, and Congo Red stained samples of the same solution exhibited birefringence. Furthermore, CD spectra of solutions of the cyclic ABri peptide showed p structure, whereas the reduced form was random coil.Based on literature of amyloid proteins, and knowledge of p-strand register and turn prediction, we propose a model for ABri monomers that is consistent with a two or three stranded p-sheet monomer with a predominantly hydrophobic face for p-sheet aggregation. Further structure/function analysis of ABri peptides will complement the study of causes of dementia in diseases such as Alzheimer's, that are related to changes in protein aggregation and folding.