Rehmannia glutinosa ameliorates scopolamine-induced learning and memory impairment in rats

Many studies have shown that the steamed root of Rehmannia glutinosa (SRG), which is widely used in the treatment of various neurodegenerative diseases in the context of Korean traditional medicine, is effective for improving cognitive and memory impairments. The purpose of this study was to examine whether SRG extracts improved memory defects caused by administering scopolamine (SCO) into the brains of rats. The effects of SRG on the acetylcholinergic system and proinflammatory cytokines in the hippocampus were also investigated. Male rats were administered daily doses of SRG (50, 100, and 200 mg/kg, i.p.) for 14 days, 1 h before scopolamine injection (2 mg/kg, i.p.). After inducing cognitive impairment via scopolamine administration, we conducted a passive avoidance test (PAT) and the Morris water maze (MWM) test as behavioral assessments. Changes in cholinergic system reactivity were also examined by measuring the immunoreactive neurons of choline acetyltransferase (ChAT) and the reactivity of acetylcholinesterase (AchE) in the hippocampus. Daily administration of SRG improved memory impairment according to the PAT, and reduced the escape latency for finding the platform in the MWM. The administration of SRG consistently significantly alleviated memory-associated decreases in cholinergic immunoreactivity and decreased interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) mRNA expression in the hippocampus. The results demonstrated that SRG had a significant neuroprotective effect against the neuronal impairment and memory dysfunction caused by scopolamine in rats. These results suggest that SRG may be useful for improving cognitive functioning by stimulating cholinergic enzyme activities and alleviating inflammatory responses.     

The pleiohomeotic functions as a negative regulator of <Emphasis Type="Italic">Drosophila even-skipped</Emphasis> gene during embryogenesis

Polycomb group (PcG) proteins maintain the spatial expression patterns of genes that are involved in cell-fate specification along the anterior-posterior (A/P) axis. This repression requires cis-acting silencers, which are called PcG response elements (PREs). One of the PcG proteins, Pleiohomeotic (Pho), which has a zinc finger DNA binding protein, plays a critical role in recruiting other PcG proteins to bind to PREs. In this study, we characterized the effects of a pho mutation on embryonic segmentation. pho maternal mutant embryos showed various segmental defects including pair-rule gene mutant patterns. Our results indicated that engrailed and even-skipped genes were misexpressed in pho mutant embryos, which caused embryonic segment defects.     

Pharmacophore-based strategy for the development of general and specific scFv biosensors for abused antibiotics

We developed fluorescent biosensor systems that are either general or selective to fluoroquinolone antibiotics by using a single-chain variable-fragment (scFv) as a recognition element. The selectivity of these biosensors to fluoroquinolone antibiotics was rationally tuned through the structural modification on the pharmacophore of fluoroquinolone antibiotics and the subsequent selection of scFv receptor modules against these antibiotics-based antigens using phage display. The resulting A2 and F9 scFv's bound to their representative antigen with a moderate affinity (K(D) in micromolar range as determined by surface plasmon resonance). A2 is a specific binder for enrofloxacin and did not cross-react with other fluoroquinolone antibiotics including structurally similar ciprofloxacin, while F9 is a general fluoroquinolone binder that likely bound to the antigen at the common pyridone-carboxylic acid pharmacophore. These scFv-based receptors were successfully applied to the development of one-step fluorescent biosensor which can detect fluoroquinolone antibiotics at concentrations below the level suggested in animal drug application guidelines. The strategy described in this report can be applied to developing convenient field biosensors that can qualitatively detect overused/misused antibiotics in the livestock drinking water.     

Amphotericin B aggregation inhibition with novel nanoparticles prepared with poly(epsilon-caprolactone)/poly(n,n-dimethylamino-2-ethyl methacrylate) diblock copolymer

Diblock copolymers composed of poly(epsilon-caprolactone) (PCL) and poly(N,N-dimethylamino-2-ethyl methacrylate) (PDMAEMA), or methoxy polyethylene glycol(PEG), were synthesized via a combination of ring-opening polymerization and atom-transfer radical polymerization in order to prepare polymeric nanoparticles as an antifungal drug carrier. Amphotericin B (AmB), a natural antibiotic, was incorporated into the polymeric nanoparticles. The physical properties of AmB-incorporated polymeric nanoparticles with PCL-b-PDMAEMA and PCL-b-PEG were studied in relation to morphology and particle size. In the aggregation state study, AmB-incorporated PCL-b- PDMAEMA nanoparticles exhibited a monomeric state pattern of free AmB, whereas AmB-incorporated PCL-b- PEG nanoparticles displayed an aggregated pattern. In in vitro hemolysis tests with human red blood cells, AmBincorporated PCL-b-PDMAEMA nanoparticles were seen to be 10 times less cytotoxic than free AmB (5 microgram/ml). In addition, an improved antifungal activity of AmBincorporated polymeric nanoparticles was observed through antifungal activity tests using Candida albicans, whereas polymeric nanoparticles themselves were seen not to affect activity. Finally, in vitro AmB release studies were conducted, proving the potential of AmB-incorporated PCL-b-PDMAEMA nanoparticles as a new formulation candidate for AmB.     

Computational ligand-based rational design: Role of conformational sampling and force fields in model development

A significant number of drug discovery efforts are based on natural products or high throughput screens from which compounds showing potential therapeutic effects are identified without knowledge of the target molecule or its 3D structure. In such cases computational ligand-based drug design (LBDD) can accelerate the drug discovery processes. LBDD is a general approach to elucidate the relationship of a compound's structure and physicochemical attributes to its biological activity. The resulting structure-activity relationship (SAR) may then act as the basis for the prediction of compounds with improved biological attributes. LBDD methods range from pharmacophore models identifying essential features of ligands responsible for their activity, quantitative structure-activity relationships (QSAR) yielding quantitative estimates of activities based on physiochemical properties, and to similarity searching, which explores compounds with similar properties as well as various combinations of the above. A number of recent LBDD approaches involve the use of multiple conformations of the ligands being studied. One of the basic components to generate multiple conformations in LBDD is molecular mechanics (MM), which apply an empirical energy function to relate conformation to energies and forces. The collection of conformations for ligands is then combined with functional data using methods ranging from regression analysis to neural networks, from which the SAR is determined. Accordingly, for effective application of LBDD for SAR determinations it is important that the compounds be accurately modelled such that the appropriate range of conformations accessible to the ligands is identified. Such accurate modelling is largely based on use of the appropriate empirical force field for the molecules being investigated and the approaches used to generate the conformations. The present chapter includes a brief overview of currently used SAR methods in LBDD followed by a more detailed presentation of issues and limitations associated with empirical energy functions and conformational sampling methods.     

Crystallization of silver through reduction process using Elaeis guineensis biosolid extract

This study presents a special, economically valuable, unprecedented eco-friendly green process for the synthesis of silver nanoparticles. The silver nanoparticles were obtained from a waste material with oil palm biosolid extract as the reducing agent. The use of the oil palm biosolid extract for the nanoparticle synthesis offers the benefit of amenability for large-scale production. An aqueous solution of silver (Ag(+) ) ions was treated with the oil palm biosolid extract for the formation of Ag nanoparticles. The nanometallic dispersion was characterized by surface plasmon absorbance measuring 428 nm. Transmission electron microscopy showed the formation of silver nanoparticles in the range of 5-50 nm. Scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS) and X-ray diffraction analysis of the freeze-dried powder confirmed the formation of metallic silver nanoparticles. Moreover, Fourier Transform Infrared Spectroscopy provided evidence of phenolics or proteins as the biomolecules that were likely responsible for the reduction and capping agent, which helps to increase the stability of the synthesized silver nanoparticles. In addition, we have optimized the production with various parameters.     

Acupuncture enhances the synaptic dopamine availability to improve motor function in a mouse model of Parkinson's disease

Parkinson's disease (PD) is caused by the selective loss of dopaminergic neurons in the substantia nigra (SN) and the depletion of striatal dopamine (DA). Acupuncture, as an alternative therapy for PD, has beneficial effects in both PD patients and PD animal models, although the underlying mechanisms therein remain uncertain. The present study investigated whether acupuncture treatment affected dopamine neurotransmission in a PD mouse model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found that acupuncture treatment at acupoint GB34 improved motor function with accompanying dopaminergic neuron protection against MPTP but did not restore striatal dopamine depletion. Instead, acupuncture treatment increased dopamine release that in turn, may lead to the enhancement of dopamine availability in the synaptic cleft. Moreover, acupuncture treatment mitigated MPTP-induced abnormal postsynaptic changes, suggesting that acupuncture treatment may increase postsynaptic dopamine neurotransmission and facilitate the normalization of basal ganglia activity. These results suggest that the acupuncture-induced enhancement of synaptic dopamine availability may play a critical role in motor function improvement against MPTP.     

The yeast chromatin remodeler RSC complex facilitates end joining repair of DNA double-strand breaks

Repair of chromosome double-strand breaks (DSBs) is central to cell survival and genome integrity. Nonhomologous end joining (NHEJ) is the major cellular repair pathway that eliminates chromosome DSBs. Here we report our genetic screen that identified Rsc8 and Rsc30, subunits of the Saccharomyces cerevisiae chromatin remodeling complex RSC, as novel NHEJ factors. Deletion of RSC30 gene or the C-terminal truncation of RSC8 impairs NHEJ of a chromosome DSB created by HO endonuclease in vivo. rsc30Delta maintains a robust level of homologous recombination and the damage-induced cell cycle checkpoints. By chromatin immunoprecipitation, we show recruitment of RSC to a chromosome DSB with kinetics congruent with its involvement in NHEJ. Recruitment of RSC to a DSB depends on Mre11, Rsc30, and yKu70 proteins. Rsc1p and Rsc2p, two other RSC subunits, physically interact with yKu80p and Mre11p. The interaction of Rsc1p with Mre11p appears to be vital for survival from genotoxic stress. These results suggest that chromatin remodeling by RSC is important for NHEJ.