Jin Wook Cha

Hyperoside protects primary rat cortical neurons from neurotoxicity induced by amyloid β-protein via the PI3K/Akt/Bad/BclXL-regulated mitochondrial apoptotic pathway

Amyloid β-protein (Aβ), which is deposited in neurons as neurofibrillary tangles, is known to exert cytotoxic effects by inducing mitochondrial dysfunction. Additionally, the PI3K/Akt-mediated interaction between Bad and Bcl(XL) plays an important role in maintaining mitochondrial integrity. However, the application of therapeutic drugs, especially natural products in Alzheimers disease therapy via PI3K/Akt/Bad/Bcl(XL)-regulated mitochondrial apoptotic pathway has not aroused extensive attention. In the present study, we investigated the neuroprotective effects of hyperoside, a bioactive flavonoid compound from Hypericum perforatum, on Aβ(25-35)-induced primary cultured cortical neurons, and also examined the potential cellular signaling mechanism for Aβ detoxication. Our results showed that treatment with hyperoside significantly inhibited Aβ(25-35)-induced cytotoxicity and apoptosis by reversing Aβ-induced mitochondrial dysfunction, including mitochondrial membrane potential decrease, reactive oxygen species production, and mitochondrial release of cytochrome c. Further study indicated that hyperoside can activate the PI3K/Akt signaling pathway, resulting in inhibition of the interaction between Bad and Bcl(XL), without effects on the interaction between Bad and Bcl-2. Furthermore, hyperoside inhibited mitochondria-dependent downstream caspase-mediated apoptotic pathway, such as that involving caspase-9, caspase-3, and poly ADP-ribose polymerase (PARP). These results demonstrate that hyperoside can protect Aβ-induced primary cultured cortical neurons via PI3K/Akt/Bad/Bcl(XL)-regulated mitochondrial apoptotic pathway, and they raise the possibility that hyperoside could be developed into a clinically valuable treatment for Alzheimers disease and other neuronal degenerative diseases associated with mitochondrial dysfunction.

Neuroprotective effect of modified Chungsimyeolda-tang, a traditional Korean herbal formula, via autophagy induction in models of Parkinson's disease.

AIM OF THE STUDY Previous studies in our laboratory revealed the neuroprotective effect of modified Yeoldahanso-tang (MYH) in models of Parkinson׳s disease (PD). In this study, we investigated another traditional Korean herbal formula, modified Chungsimyeolda-tang (termed DG), as a potential treatment for PD. Chungsimyeolda-tang has been used in Korea to treat cerebrovascular diseases, such as stroke. Here, we verify the neuroprotective and autophagy-inducing effects of DG to evaluate any potential anti-parkinsonian properties. MATERIALS AND METHODS 1-Methyl-4-phenylpyridinium (MPP(+)) and rotenone were used to induce cytotoxicity in nerve growth factor (NGF)-differentiated rat pheochromocytoma (PC12) cells. Cell viability was measured using an MTT assay. Induction of autophagy by DG in NGF-differentiated PC12 cells was measured using an immunoblotting assay with an LC3 antibody. The proteasomal inhibitor lactacystin was used to induce ubiquitin-proteasome system (UPS) dysfunction in NGF-differentiated PC12 cells. DG-mediated clearance of aggregated proteins was measured using an immunoblotting assay with a ubiquitin antibody. RESULTS AND CONCLUSIONS Our findings indicate that DG robustly protects NGF-differentiated PC12 cells against the neurotoxic effects of MPP(+) and rotenone in an in vitro model. Furthermore, DG protects NGF-differentiated PC12 cells against lactacystin-induced cell death. This effect is partially mediated by an increased autophagy associated with the enhanced degradation of aggregated proteins. This study suggests that DG is an attractive candidate drug for inducing autophagy and, therefore, may represent a promising strategy to prevent diseases associated with misfolded/aggregated proteins in various neurodegenerative disorders, including Parkinson׳s disease.

Salinazinones A and B: Pyrrolidinyl-Oxazinones from Solar Saltern-Derived Streptomyces sp. KMF-004

Salinazinones A (1) and B (2), two unprecedented pyrrolidinyl-oxazinones, were isolated from the culture broth of Streptomyces sp. KMF-004 from a solar saltern at Aphae Island, Korea. The structures of these salinazinones, which are unusual and consist of 2-methylpropenyl-1,3-oxazin-6-one bearing 1-oxopyrrolidinyl substituents, were assigned by spectral and chemical analyses using Moshers method, circular dichroism (CD), and calculated ECD. Salinazinones are the first examples of a natural alkaloid class composed of an oxazinone-pyrrolidone conjugate.

Pontemazines A and B, phenazine derivatives containing a methylamine linkage from Streptomyces sp. UT1123 and their protective effect to HT-22 neuronal cells.

New phenazine derivatives with a methylamine linker, Pontemazines A (1) and B (2), were isolated from the culture broth of Streptomyces sp. UT1123. The structures of compounds 1 and 2 were determined by NMR spectroscopy and high-resolution mass spectrometry. These compounds consist of a 9-mehoxyphenazine connected to a benzamide functional group by a unique methylamine linker instead of the more common methyl ether. Pontemazines A and B possess a neuronal cell protective effect on glutamate-induced mouse hippocampal HT-22 cell damage.

Effect of Lycoris chejuensis and Its Active Components on Experimental Models of Alzheimer’s Disease

We found that an extract of Lycoris chejuensis and its three isolated active components, narciclasine, 7-deoxynarciclasine, and 7-deoxy-trans-dihydronarciclasine, each significantly reduced the formation of amyloid-β peptides in HeLa cells transfected with an amyloid precursor protein carrying the Swedish mutation up to 45 ± 3.6%. The extract down-regulated amyloid precursor protein, especially the mature form by up to 88%, and reduced the ability of secretases to generate toxic amyloid-β. Double-transgenic mice treated with the extract for 4 months also showed significantly reduced levels of amyloid-β and plaques while exhibiting improved memory functions in the Morris water maze and novel object recognition tests. In conclusion, the extract and isolated active components of L. chejuensis decreased the production of amyloid-β by attenuating amyloid precursor protein levels. Furthermore, the extract improved the disrupted memory functions in animals while inhibiting amyloid plaque formation. Thus, this extract, as well as its active components, could prove beneficial in the treatment of Alzheimers disease.