OBJECTIVE: The study set out to determine if the HIV protease inhibitor, indinavir, alters responsiveness of alpha7-nicotinic acetylcholine receptors to acetylcholine. DESIGN: Treatment with HAART has dramatically reduced development of HIV-associated dementia and more severe forms of cognitive impairment. However, many individuals continue to experience cognitive decline of uncertain cause. Previous studies have failed to demonstrate significant alterations of functional brain connectivity, structural brain changes, or changes in cerebral blood flow sufficient to explain cognitive decline in virally suppressed individuals. This suggests that the mechanisms underlying development and progression of cognitive problems likely occurs at a micro rather than macro level, such as disruptions in neurotransmitter system signaling. MATERIALS AND METHODS: Indinavir's effects on alpha7-nicotinic acetylcholine receptor activity was tested using a ScreenPatch IonWorks Barracuda-based assay in a mammalian cell model. RESULTS: At low concentrations (0.0003-10 mumol/l) indinavir acts as a positive allosteric modulator (EC50 = 0.021 mumol/l), whereas at concentrations greater than 10 mumol/l (30-100 mumol/l) indinavir acts as an inhibitor of the alpha7-nicotinic acetylcholine receptor. CONCLUSION: At concentrations greater than 10 mumol/l indinavir reduces synaptic transmission in the acetylcholine neurotransmitter system, which could possibly contribute to cognitive dysfunction. These results suggest that further experiments should be considered to assess whether patients might benefit from treatment with cholinesterase inhibitors that counteract the effects of indinavir.
Title: Lancemaside A isolated from Codonopsis lanceolata and its metabolite echinocystic acid ameliorate scopolamine-induced memory and learning deficits in mice Jung IH, Jang SE, Joh EH, Chung J, Han MJ, Kim DH Ref: Phytomedicine, 20:84, 2012 : PubMed
The rhizome of Codonopsis lanceolata (family Campanulaceae), which contains lancemaside A as a main constituent, has been used as herbal medicine to treat inflammation, insomnia, and hypomnesia. Lancemaside A and echinocystic acid, which is its metabolite by intestinal microflora, potently inhibited acetylcholinesterase activity in a dose-dependent manner, with IC(50) value 13.6muM and 12.2muM, respectively. Its inhibitory potency is comparable with that of donepezil (IC(50)=10.9muM). Lancemaside A and echinocystic acid significantly reversed scopolamine-induced memory and learning deficits on passive avoidance task. Lancemaside A orally administered 5h before treatment with scopolamine reversed scopolamine-induced memory and learning deficits more potently than one orally administered 1h before. Echinocystic acid more potently reversed it than lancemaside A. Lancemaside A and echinocystic acid significantly reversed scopolamine-induced memory and learning deficits on the Y-maze and Morris water maze tasks. Lancemaside A and echinocystic acid also increased the expression of brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element binding protein (p-CREB). Based on these findings, orally administered lancemaside A may be metabolized to echinocystic acid, which may be absorbed into the blood and ameliorate memory and learning deficits by inhibiting AChE activity and inducing BDNF and p-CREB expressions.
Title: Effect of Weissella cibaria isolates on the formation of Streptococcus mutans biofilm Kang MS, Chung J, Kim SM, Yang KH, Oh JS Ref: Caries Res, 40:418, 2006 : PubMed
The objective of this study was to isolate and identify lactic acid bacteria able to inhibit the in vitro formation of Streptococcus mutans biofilm as well as the in vivo formation of oral biofilm. Two strains, CMS1 and CMS3, exhibiting profound inhibitory effects on the formation of S. mutans biofilm and the proliferation of S. mutans, were isolated from children's saliva and identified as Weissella cibaria by 16S rDNA sequencing. The water-soluble polymers produced from sucrose by the W. cibaria isolates also inhibited the formation of S. mutans biofilm. According to the results of thin-layer chromatographic analysis, the hydrolysates of water-soluble polymers produced by the isolates were identical to those of dextran, forming mostly alpha-(1-6) glucose linkages. In the clinical study, the subjects mouthrinsed with a solution containing W. cibaria CMS1 evidenced plaque index reduction of approximately 20.7% (p < 0.001). These results indicate that the W. cibaria isolates possess the ability to inhibit biofilm formation, both in vitro and in vivo.
Phthalate is a metabolic intermediate of the pathway of fluorene (FN) degradation via angular dioxygenation. A gene cluster responsible for the conversion of phthalate to protocatechuate was cloned from the dibenzofuran (DF)- and FN-degrading bacterium Terrabacter sp. strain DBF63 and sequenced. The genes encoding seven catabolic enzymes, oxygenase large subunit of phthalate 3,4-dioxygenase (phtA1), oxygenase small subunit of phthalate 3,4-dioxygenase (phtA2), cis-3,4-dihydroxy-3,4-dihydrophthalate dehydrogenase (phtB), [3Fe-4S] or [4Fe-4S] type of ferredoxin (phtA3), ferredoxin reductase (phtA4), 3,4-dihydroxyphthalate decarboxylase (phtC) and putative regulatory protein (phtR), were found in the upstream region of the angular dioxygenase gene (dbfA1A2), encoded in this order. Escherichia coli carrying phtA1A2BA3A4 genes converted phthalate to 3,4-dihydroxyphthalate, and the 3,4-dihydroxyphthalate decarboxylase activity by E. coli cells carrying phtC was finally detected with the introduction of a Shine-Dalgarno sequence in the upstream region of its initiation codon. Homology analysis on the upstream region of the pht gene cluster revealed that there was an insertion sequence (IS) (ISTesp2; ORF14 and its flanking region), part of which was almost 100% identical to the orf1 and its flanking region adjacent to the extradiol dioxygenase gene ( bphC1) involved in the DF degradation of Terrabacter sp. strain DPO360 [Schmid et al. (1997) J Bacteriol 179:53-62]. This suggests that ISTesp2 plays a role in the metabolism of aromatic compounds in Terrabacter sp. strains DBF63 and DPO360.
