Modulated phases of phospholipid bilayers induced by tocopherols

The influence of α-, γ- and δ-tocopherols on the structure and phase behavior of dipalmitoyl phosphatidylcholine (DPPC) bilayers has been determined from X-ray diffraction studies on oriented multilayers. In all the three cases the main-transition temperature (T(m)) of DPPC was found to decrease with increasing tocopherol concentration up to around 25 mol%. Beyond this the main transition is suppressed in the case of γ-tocopherol, whereas T(m) becomes insensitive to composition in the other two cases. The pre-transition is found to be suppressed over a narrow tocopherol concentration range between 7.5 and 10 mol% in DPPC-γ-tocopherol and DPPC-δ-tocopherol bilayers, and the ripple phase occurs down to the lowest temperature studied. In all the three cases a modulated phase is observed above a tocopherol concentration of about 10 mol%, which is similar to the P(β) phase reported in DPPC-cholesterol bilayers. This phase is found to occur even in excess water conditions at lower tocopherol concentrations, and consists of bilayers with periodic height modulation. These results indicate the ability of tocopherols to induce local curvature in membranes, which could be important for some of their biological functions.     

Synergistic anti-cancer mechanisms of curcumin and paclitaxel for growth inhibition of human brain tumor stem cells and LN18 and U138MG cells

Glioblastoma, the deadliest brain tumor in humans, responds poorly to conventional chemotherapeutic agents because of existence of highly chemoresistant human brain tumor stem cells (HBTSC). An effective therapeutic strategy is urgently needed to target HBTSC as well as other glioblastoma cells. We explored synergistic efficacy of a low dose of curcumin (CCM) and a low dose of paclitaxel (PTX) in HBTSC and human glioblastoma LN18 (p53 mutant and PTEN proficient) and U138MG (p53 mutant and PTEN mutant) cells. The highest expression of the cancer stem cell markers aldehyde dehydrogenase 1 (ALDH1) and CD133 occurred in HBTSC when compared with LN18 and U138MG cells. Combination of 20 μM CCM and 10 nM PTX worked synergistically and more effectively than either drug alone in decreasing viability in all cells. Combination of CCM and PTX was highly effective in inducing both morphological and biochemical features of apoptosis. Apoptosis required activation of caspase-8, cleavage of Bid to tBid, increase in Bax:Bcl-2 ratio, and mitochondrial release of cytochrome c, Smac, and apoptosis-inducing factor (AIF). Phosphorylation of Bcl-2 following combination therapy appeared to promote Bax homodimerization and mitochondrial release of pro-apoptotic factors into the cytosol. Increases in activities of cysteine proteases confirmed the completion of apoptotic process. Combination therapy inhibited invasion of cells, reduced expression of survival and proliferation factors and also angiogenic factors, and prevented HBTSC, LN18, and U138MG cells from promoting network formation. Collectively, the combination of CCM and PTX worked as a promising therapy for controlling the growth of HBTSC and other glioblastoma cells.     

Purification, characterizations of a snake guard seeds lectin with antitumor activity against Ehrlich ascites carcinoma cells in vivo in mice

A lectin was purified (designated as TCSL) from the Snake guard seeds with molecular mass of 56±2 kDa containing two subunits (34±1 and 22±1 kDa.). TCSL exhibited high agglutination activity at the temperature range 30 to 70°C and did not lose its activity between pH 3.0 to 12.0. The lectin was stable in the presence of denaturants and agglutinated mouse, goat, cow, chicken and human erythrocytes. TCSL did not show antifungal activity whereas it agglutinated six pathogenic bacteria and showed less toxicity against brine shrimp nauplii with the LC50 of 261±29 μg/ml. TCSL showed 28% and 72% inhibition against Ehrlich ascites carcinoma (EAC) cells in vivo in mice when administered 1 mg/kg/day and 2 mg/kg/day (i.p.) respectively for five days. TCSL enhanced the number of macrophages remarkably in the normal mice. The lectin reduced the tumor burden to 62% of EAC cells and significantly increased the hemoglobin and RBC. Treating the EAC bearing mice with TCSL at 2 mg/Kg/day for ten days with a monitoring of 20 days decreased the total WBC towards the normal level and it increased the life span by 39%.     

Comparative proteome analysis of high and low cadmium accumulating soybeans under cadmium stress

A comparative proteomic study was performed to unravel the protein networks involved in cadmium stress response in soybean. Ten-day-old seedlings of contrasting cadmium accumulating soybean cultivars—Harosoy (high cadmium accumulator), Fukuyutaka (low cadmium accumulator), and their recombinant inbred line CDH-80 (high cadmium accumulator) were exposed to 100?μM CdCl₂ treatment for 3?days. Root growth was found to be affected under cadmium stress in all. Varietal differences at root protein level were evaluated. NADP-dependent alkenal double bond reductase P1 was found to be more abundant in low cadmium accumulating Fukuyutaka. Leaf proteome analysis revealed that differentially expressed proteins were primarily involved in metabolism and energy production. The results indicate that both high and low cadmium accumulating cultivars and CDH-80 share some common defense strategies to cope with the cadmium stress. High abundance of enzymes involved in glycolysis and TCA cycle might help cadmium challenged cells to produce more energy necessary to meet the high energy demand. Moreover, enhanced expressions of photosynthesis related proteins indicate quick utilization of photoassimilates in energy generation. Increased abundance of glutamine synthetase in all might be involved in phytochelatin mediated detoxification of cadmium ions. In addition, increased abundance of antioxidant enzymes, namely superoxide dismutase, ascorbate peroxidase, catalase, ensures cellular protection from reactive oxygen species mediated damages under cadmium stress. Enhanced expression of molecular chaperones in high cadmium accumulating cultivar might be another additional defense mechanism for refolding of misfolded proteins and to stabilize protein structure and function, thus maintain cellular homeostasis.     

Synthesis, anticancer activity and apoptosis inducing ability of bisindole linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates

A series of bisindole-pyrrolobenzodiazepine conjugates (5a-f) linked through different alkane spacers was prepared and evaluated for their anticancer activity. All compounds exhibited significant anticancer potency and the most potent compounds 5b and 5e were taken up for detailed studies on MCF-7 cell line. Cell cycle effects were examined apart from investigating the inhibition of tubulin polymerization for compounds 2a, 2b, 5b and 5e at 2μM. FACS analysis showed that at higher concentrations (4 and 8μM) there was an increase of sub-G1 phase cells and decrease of G2/M phase cells, thus indicating that compounds 5b and 5e are effective in causing apoptosis in MCF-7 cells. It was also observed that compounds 5b and 5e showed the down regulation of histone deacetylase protein levels such as HDAC1, 2, 3, 8 and increase in the levels of p21, followed by apoptotic cell death. The apoptotic nature of these compounds was further evidenced by increased expression of cleaved-PARP and active caspase-7 in MCF-7 cells.     

Practical access to four stereoisomers of naftidrofuryl and their binding affinity towards 5-hydroxytryptamine 2A receptor

Naftidrofuryl oxalate (Praxilene®, 1) has been used for the treatment of intermittent claudication for more than 30 years. It selectively blocks vascular and platelet 5-hydroxytryptamine 2 (5-HT₂) receptors. This drug is marketed as a mixture of four stereoisomers, and so far there is no individual biological evaluation on the single isomers. The purpose of this study is to provide an improved method for the preparation of all four stereoisomers of naftidrofuryl, and more importantly, to distinguish them in terms of their binding affinity to 5-hydroxytryptamine 2A (5-HT_2A) receptor. The bioassay results revealed that the C-2S configuration of naftidrofuryl was crucial for the binding affinity with 5-HT_2A receptor, and the C-2′ configuration was less important for binding. In conclusion, our study may pave the way to develop single naftidrofuryl isomers with C-2S configuration as inhibitors of 5-HT_2A receptor that have clinical significance as vasodilators and CNS agents.     

Stochastic frontier model approach for measuring stock market efficiency with different distributions

The stock market is considered essential for economic growth and expected to contribute to improved productivity. An efficient pricing mechanism of the stock market can be a driving force for channeling savings into profitable investments and thus facilitating optimal allocation of capital. This study investigated the technical efficiency of selected groups of companies of Bangladesh Stock Market that is the Dhaka Stock Exchange (DSE) market, using the stochastic frontier production function approach. For this, the authors considered the Cobb-Douglas Stochastic frontier in which the technical inefficiency effects are defined by a model with two distributional assumptions. Truncated normal and half-normal distributions were used in the model and both time-variant and time-invariant inefficiency effects were estimated. The results reveal that technical efficiency decreased gradually over the reference period and that truncated normal distribution is preferable to half-normal distribution for technical inefficiency effects. The value of technical efficiency was high for the investment group and low for the bank group, as compared with other groups in the DSE market for both distributions in time-varying environment whereas it was high for the investment group but low for the ceramic group as compared with other groups in the DSE market for both distributions in time-invariant situation.