Design,synthesis, biological evaluation,and molecular modeling studies of chalcone-rivastigmine hybrids as cholinesterase inhibitors

A series of novel chalcone-rivastigmine hybrids were designed, synthesized, and tested in vitro for their ability to inhibit human acetylcholinesterase and butyrylcholinesterase. Most of the target compounds showed hBChE selective activity in the micro- and submicromolar ranges. The most potent compound 3 exhibited comparable IC₅₀ to the commercially available drug (rivastigmine). To better understand their structure activity relationships (SAR) and mechanisms of enzyme-inhibitor interactions, kinetic and molecular modeling studies including molecular docking and molecular dynamics (MD) simulations were carried out. Furthermore, compound 3 blocks the formation of reactive oxygen species (ROS) in SH-SY5Y cells and shows the required druggability and low cytotoxicity, suggesting this hybrid is a promising multifunctional drug candidate for Alzheimer’s disease (AD) treatment.     

DNA microsatellite analysis of naturally occurring colour intermediates between Bactrocera tryoni (Froggatt) and Bactrocera neohumeralis (Hardy) (Diptera: Tephritidae)

Abstract  The sympatric tephritid fruit flies Bactrocera tryoni (Froggatt) (Queensland fruit fly) and B. neohumeralis (Hardy) differ in time of mating and for the colour of the humeral callus ('shoulder pad'), which is typically entirely yellow in B. tryoni and typically entirely brown in B. neohumeralis . Field collections in sympatric regions usually include at least 1% of individuals whose humeral calli show mixed patches of yellow and brown ('intermediates'). Over 40 years, a number of studies have debated the possibility that these intermediates are interspecific hybrids. In the present study, we have used microsatellites to show that few if any of these intermediates are hybrids. Instead, most variation humeral callus appears to be confined to one species, B. tryoni . We discuss these results in the context of geneflow between the two species and suggest directions for future research.     

General Information

A novel cDNA clone encoding a COR413-like gene was isolated by suppression subtraction hybridization and cDNA library screening from sea-island cotton (Gossypium barbadense). This gene (designated as GbCOR413, Accession number: AY761065) has a total length of 893 bp with an open reading frame of 600 bp, encoding a predicated polypeptide of 200 amino acids with a molecular weight of 22.74 kDa and a predicated pI of 9.2. Bioinformatics analyses revealed that this gene belonged to a novel stress-regulated multi-spanning transmembrane protein family without signal peptide. By means of semi-quantities RT-PCR analysis, the expression of GbCOR413 under short-term cold treatment at 4°C, water submergence and abscic acid treatment was investigated. Our studies suggested that the cloned gene was a new member of COR gene family which was slowly responsive to cold stress in cotton. Jin Wang and Kai-Jing Zuo are co-first authors of this paper.     

Separation and enrichment of neural stem cells using segregation in an expanded bed

An expanded bed system has been developed for a novel application in which the separation and enrichment of neural stem cells from a sample containing a mixture of stem and progenitor cells is achieved based on the difference in the sizes of the aggregates of these types of cells. Inert Sephadex beads and flocculated yeast cells were used as experimental controls and references. The characteristics of the separation of neural stem cell aggregates based on size are similar to those achieved with flocculated yeast where cell-to-cell aggregation controls the pattern of size separation different from those of inert Sephadex beads.     

Two new scorpionates vanadium haloperoxidases model complexes: synthesis and structure of VO(O2)(pzH)(HB(pz)3) and VO(O2)(pzH)(B(pz)4) (pzH = pyrazole(C3H4N2))

Using vanadate, poly(1H-pyrazol-1-yl)borate and pyrazole as starting materials, two new neutral peroxovanadium(V) complexes with poly(1H-pyrazol-1-yl)borate, VO(O(2))(pzH)(HB(pz)(3))(1) and VO(O(2))(pzH)(B(pz)(4))(2), were synthesized successfully. Both complexes were characterized by elemental analysis, IR, UV-vis and NMR spectra. And the structure of complex 1 was determined by X-ray diffraction, which is somewhat relevant for haloperoxidase enzymes. Cytotoxic effects also are discussed on 3T3 cell proliferation. In the concentration range (0.1-100mumol), both complexes have an inhibiting cellular proliferation effect. When the cells cultivated with the complexes at high dose, the toxicity effect of both complexes is more and more predominant.     

Effects of fluoride on the intracellular free Ca<Superscript>2+</Superscript> and Ca<Superscript>2+</Superscript>-ATPase of kidney

In the present study, the effect of fluoride on intracellular free calcium ([Ca2+]i) and Ca2+-ATPase of renal cells were examined. Some paradoxical experimental results about the mechanism of fluoride toxicity were observed. In vivo, 48 Wistar rats were divided into 4 groups, and half of rats were treated with sodium fluoride (NaF) by drinking water (per liter of tap water containing 100 mg F-). Compared with the respective control, the level of [Ca2+]i of the kidney in two fluoride-treated rats obviously increased (p < 0.05); and the activity of Ca2+-ATPase in 100 mg F-/L groups with a standard diet did not significantly increase, and the enzyme activity in 100-mg F-/L group with a low-calcium diet decreased significantly compared to the 100 mg F-/L group with a standard diet (p < 0.05). In vitro, renal tubular cells were cultured and respectively exposed to 1.0, 5.0, 7.5, and 12.5 mg/L fluoride in the culture medium. Results showed the significantly elevated activity of Ca2+-ATPase in the cells exposed to 1.0 and 5.0 mg/L fluoride (p < 0.05), and this enzyme activity indicated inhibitory trend in cells of the 7.5- and 12.5-mg/L fluoride-treated group. To sum up, the effect of fluoride on Ca2+-ATPase is a similar to a dose-effect relationship phenomenon characterized by low-dose stimulation and high-dose inhibition, and the increase of [Ca2+]i probably plays a key role on the mechanism of renal injury in fluorosis.     

Fine mapping of S32(t), a new gene causing hybrid embryo sac sterility in a Chinese landrace rice (Oryza sativa L.)

Ketan Nangka, the donor of wide compatibility genes, showed sterility when crossed to Tuanguzao, a landrace rice from Yunnan province, China. Genetic and cytological analyses revealed that the semi-sterility was primarily caused by partial abortion of the embryo sac. Genome-wide analysis of the linkage map constructed from the backcross population of Tuanguzao/Ketan Nangka//Ketan Nangka identified two independent loci responsible for the hybrid sterility located on chromosomes 2 and 5, which explained 18.6 and 20.1% of phenotypic variance, respectively. The gene on chromosome 5 mapped to the previously reported sterility gene S31(t), while the gene on chromosome 2, a new hybrid sterility gene, was tentatively designated as S32(t). The BC₁F₂ was developed for further confirmation and fine mapping of S32(t). The gene S32(t) was precisely mapped to the same region as that detected in the BC₁F₁ but its position was narrowed down to an interval of about 1.9 cM between markers RM236 and RM12475. By assaying the recombinant events in the BC₁F₂, S32(t) was further narrowed down to a 64 kb region on the same PAC clone. Sequence analysis of this fragment revealed seven predicted open reading frames, four of which encoded known proteins and three encoded putative proteins. Further analyses showed that wide-compatibility variety Dular had neutral alleles at loci S31(t) and S32(t) that can overcome the sterilities caused by these two genes. These results are useful for map-based cloning of S32(t) and for marker-assisted transferring of the neutral allele in hybrid rice breeding.     

Cell-specific effects of insulin receptor substrate-1 deficiency on normal and IGF-I-mediated colon growth

Insulin-like growth factor I (IGF-I) potently stimulates intestinal growth. Insulin receptor substrate-1 (IRS-1) mediates proliferative and antiapoptotic actions of IGF-I in cell lines, but its in vivo relevance in intestine is not defined. This study tested the hypothesis that there is cell type-specific dependence on IRS-1 as a mediator of IGF-I action. Length, mass, crypt cell proliferation, and apoptosis were measured in small intestine and colon of IRS-1-null mice and wild-type (WT) littermates and in colon of IRS-1-null or WT mice expressing IGF-I transgenes. Expression of IGF-I receptor and signaling intermediates was examined in intestine of WT and IRS-1-null mice, cultured intestinal epithelial cells, and myofibroblasts. Absolute IRS-1 deficiency reduced mucosal mass in jejunum and colon, but effects were more pronounced in colon. Muscularis mass was decreased in both segments. In IGF-I transgenics, IRS-1 deficiency significantly attenuated IGF-I-stimulated growth of colonic mucosa and abolished antiapoptotic but not mitogenic effects of IGF-I transgene on crypt cells. IGF-I-induced muscularis growth was unaffected by IRS-1 deficiency. In intestinal epithelial cells, IRS-1 was expressed at higher levels than IRS-2 and was preferentially activated by IGF-I. In contrast, IGF-I activated both IRS-1 and IRS-2 in intestinal myofibroblasts and IRS-2 activation was upregulated in IRS-1-null myofibroblasts. We conclude that the intestinal epithelium but not the muscularis requires IRS-1 for normal trophic actions of IGF-I and that IRS-1 is required for antiapoptotic but not mitogenic effects of IGF-I in the intestinal crypts in vivo.