Neuroinflammatory responses induced by amyloid-beta peptide (A?) are important causes in the pathogenesis of Alzheimer's disease (AD). Blockade of A? has emerged as a possible therapeutic approach to control the onset of AD. This study investigated the neuroprotective effects and molecular mechanisms of p-coumaric acid (p-CA) and ursolic acid (UA) from Corni fructus against A?(25-35)-induced toxicity in PC12 cells. p-CA and UA significantly inhibited the expression of iNOS and COX-2 in A?(25-35)-injured PC12 cells. Blockade of nuclear translocation of the p65 subunit of nuclear factor ?B (NF-?B) and phosphorylation of I?B-? was also observed after p-CA and UA treatment. For the upstream kinases, UA exclusively reduced ERK1/2, p-38, and JNK phosphorylation, but p-CA suppressed ERK1/2 and JNK phosphorylation. Both compounds comprehensively inhibited NF-?B activity, but possibly with different upstream pathways. The results provide new insight into the pharmacological modes of p-CA and UA and their potential therapeutic application to AD.
In our ongoing research to find therapeutic compounds for Alzheimer's disease (AD) from natural resources, the inhibitory activity of the BACE1 enzyme by Tenebrio molitor larvae and its major compounds were evaluated. The T. molitor larvae extract and its fractions exhibited strong BACE1 suppression. The major components of hexane fraction possessing both high yield and strong BACE1 inhibition were determined by thin layer chromatography, gas chromatography, and nuclear magnetic resonance analysis. A remarkable composition of unsaturated long chain fatty acids, including oleic acid and linoleic acid, were identified. Oleic acid, in particular, noncompetitively attenuated BACE1 activity with a half-maximal inhibitory concentration (IC??) value of 61.31 ?M and Ki value of 34.3??M. Furthermore, the fatty acids were stably interacted with BACE1 at different allosteric sites of the enzyme bound with the OH of CYS319 and the NH? of TYR320 for oleic acid and with the C=O group of GLN304 for linoleic acid. Here, we first revealed novel pharmacophore features of oleic acids and linoleic acid to BACE1 by in silico docking studies. The present findings would clearly suggest potential guidelines for designing novel BACE1 selective inhibitors.
Generation of amyloid ? peptide through the proteolytic process of amyloid precursor protein by ?-secretase and ?-secretase is a main casual factor of Alzheimers disease, since amyloid ? peptide is a major and crucial component of senile plaques in Alzheimers disease brains. In the process of searching for ?-secretase inhibitors from natural resources, the EtOAc soluble fraction of Geranium thunbergii exhibited significant ?-secretase inhibitory activity. Two compounds, geraniin and corilagin, isolated from the most active EtOAc fraction of G. thunbergii, exhibited predominant inhibition against ?-secretase with IC?? values of 4.0 × 10?? M and 3.4 × 10?? M, respectively. Dixon plot of geraniin and corilagin demonstrated that the ?-secretase inhibition was noncompetitive with the substrate, thus clearly suggesting that these compounds might bind either to the ?-secretase subsites or to another regulatory domain with Ki values of 2.8 × 10?? M and 7.9 × 10?? M, respectively. Both compounds exhibited no significant inhibition against ?-secretase and other serine proteases including trypsin and chymotrypsin, showing that they were relatively specific and selective inhibitors of ?-secretase. These novel findings suggest that geraniin and corilagin from G. thunbergii may be effective therapeutic agents for further drug development in Alzheimers disease.
Progressive cerebral deposition of A? in the brain is a seminal event in the pathogenesis of Alzheimers disease (AD). A? is generated from the amyloid precursor protein (APP) by proteolytic processing of ?-secretase (BACE1) and ?-secretase. Consequently, BACE1, a key enzyme in the production of A?, is a prime target for therapeutic intervention in AD. In the course of screening for natural BACE1 inhibitors from Corni fructus, the ethyl acetate (EtOAc) fraction showed significant inhibitory activity against BACE1. By activity guided purification, three compounds of BACE1 inhibitors p-coumaric acid, gallic acid and ursolic acid were isolated from Corni fructus EtOAc fraction. All isolated compounds suppressed BACE1 in a dose dependent manner. p-Coumaric acid, in particular, exhibited significant inhibitory activity against BACE1 with 9.0?×?10(-5) ?m and a K(i) value of 1.9?×?10(-6) ?m. Also this compound was non-competitive with a substrate in the Dixon plot, suggesting that it might bind either to the ?-secretase subsite or to another regulatory site. All compounds showed no significant attenuation of TACE (?-secretase) and other serine proteases such as chymotrypsin and trypsin, demonstrating that they were relatively selective and specific inhibitors of BACE1. These novel findings suggest that Corni fructus contains biologically active components that may be used to attenuate the progression and/or prevention of Alzheimers disease.
In the course of searching for anti-dementia agents from natural products, loganin isolated from EtOAc fraction of Corni fructus possessed specific inhibitory activity against ?-secretase (BACE1) with 9.2?×?10?? ?M and K(i) value of 5.5?×?10?? M. Loganin exhibited less inhibitory activity to ?-secretase (TACE) and other serine proteases exhibiting that it was a relatively specific inhibitor of BACE1. These novel findings suggest that loganin may be used to attenuate the progression and/or prevention of Alzheimers disease.
Thirty-two different volatile oils were identified from Allomyrina dichotoma (A. dichotoma) larvae by gas chromatography/mass spectrometry (GC/MS). The major volatile components were 2,2,4-trimethyl-3-carboxyisopropyl pentanoic acid isobutyl ester (5.83%), phenol,2,6-bis(a,a-dimethyl ethyl)-4-(1-methyl-1-phenylethyl) (5.72%), heptacosane (5.49%) and phenol,2,4-bis(1-methyl-1-phenylethyl) (5.47%). The composition of the fatty acids in A. dichotoma larvae was also determined by gas chromatography (GC) and fourteen constituents were identified. Oleic acid (19.13%) was the most abundant fatty acid followed by palmitic acid (12.52%), palmitoleic acid (3.71%) and linoleic acid (2.08%) in 100 g of A. dichotoma larvae on a dry weight basis. The quantity of unsaturated fatty acids (64.00%) were higher than that of saturated ones (36.00%). The predominant fatty acids in A. dichotoma consist of monounsaturated fatty acid (MUFA, 57.70%) such as oleic acid, myristoleic acid and palmitoleic acid, followed by saturated fatty acids (36.00%) and polyunsaturated fatty acids (PUFA, 6.50%). In particular, the presence of essential fatty acids, such as linoleic (5.30%) and linolenic acid (0.40%) give A. dichotoma larvae considerable nutritional and functional value and it may be a useful source for food and/or industrial utilization.
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