Dihydroceramides: From Bit Players to Lead Actors

Sphingolipid synthesis involves a highly conserved biosynthetic pathway that produces fundamental precursors of complex sphingolipids. The final reaction involves the insertion of a double bond into dihydroceramides to generate the more abundant ceramides, which are converted to sphingomyelins and glucosylceramides/gangliosides by the addition of polar head groups. Although ceramides have long been known to mediate cellular stress responses, the dihydroceramides that are transiently produced during de novo sphingolipid synthesis were deemed inert. Evidence published in the last few years suggests that these dihydroceramides accumulate to a far greater extent in tissues than previously thought. Moreover, they have biological functions that are distinct and non-overlapping with those of the more prevalent ceramides. Roles are being uncovered in autophagy, hypoxia, and cellular proliferation, and the lipids are now implicated in the etiology, treatment, and/or diagnosis of diabetes, cancer, ischemia/reperfusion injury, and neurodegenerative diseases. This minireview summarizes recent findings on this emerging class of bioactive lipids.     

Difference in the Lubrication Efficiency of Bovine and Vegetable-Derived Magnesium Stearate During Tabletting

The purpose of this work was to evaluate and compare the functionality of bovine fatty acids-derived (MgSt-B) and vegetable fatty acids-derived (MgSt-V) magnesium stearate powders when used for the lubrication of granules prepared by high-shear (HSG) and fluid bed (FBG) wet granulation methods. The work included evaluation of tablet compression and ejection forces during tabletting and dissolution testing of the compressed tablets. Granules prepared by both granulation methods required significantly lower ejection force (p < 0.01) when lubricated with the MgSt-V powder as compared to those lubricated with the MgSt-B powder. Granules prepared by the HSG method and lubricated with the MgSt-V powder also required significantly lower compression force (p < 0.01) to produce tablets of similar weight and hardness as compared to those lubricated with the MgSt-B powder. The dissolution profiles were not affected by these differences and were the same for tablets prepared by same granulation method and lubricated with either magnesium stearate powder. The results indicate significant differences (p < 0.01) between lubrication efficiency of the MgSt-B and the MgSt-V powders and emphasize the importance of functionality testing of the MgSt powders to understand the impact of these differences. The opinions expressed in this work are only of authors, and do not necessarily reflect the policy and statements of the FDA.     

Silencing human NKG2D, DAP10, and DAP12 reduces cytotoxicity of activated CD8+ T cells and NK cells

Human CD8+ T cells activated and expanded by TCR cross-linking and high-dose IL-2 acquire potent cytolytic ability against tumors and are a promising approach for immunotherapy of malignant diseases. We have recently reported that in vitro killing by these activated cells, which share phenotypic and functional characteristics with NK cells, is mediated principally by NKG2D. NKG2D is a surface receptor that is expressed by all NK cells and transmits an activating signal via the DAP10 adaptor molecule. Using stable RNA interference induced by lentiviral transduction, we show that NKG2D is required for cytolysis of tumor cells, including autologous tumor cells from patients with ovarian cancer. We also demonstrated that NKG2D is required for in vivo antitumor activity. Furthermore, both activated and expanded CD8+ T cells and NK cells use DAP10. In addition, direct killing was partially dependent on the DAP12 signaling pathway. This requirement by activated and expanded CD8+ T cells for DAP12, and hence stimulus from a putative DAP12-partnered activating surface receptor, persisted when assayed by anti-NKG2D Ab-mediated redirected cytolysis. These studies demonstrated the importance of NKG2D, DAP10, and DAP12 in human effector cell function.     

Signal Transduction Protocols (R. C. Dickson and M. D. Mendenhall (eds.), in <Emphasis Type="Italic">Methods in Molecular Biology</Emphasis>, Vol. 284, J. M. Walker (Series Editor), Humana Press,Totowa-New Jersey, 2004, 327 p., $ 99.50)

Book Review

Signal Transduction Protocols (R. C. Dickson and M. D. Mendenhall (eds.), in Methods in Molecular Biology, Vol. 284, J. M. Walker (Series Editor), Humana Press, Totowa-New Jersey, 2004, 327 p., $ 99.50)     

Mutations in Cytosine-5 tRNA Methyltransferases Impact Mobile Element Expression and Genome Stability at Specific DNA Repeats

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Photosynthetic activity, pigment composition and antioxidative response of two mustard (Brassica juncea) cultivars differing in photosynthetic capacity subjected to cadmium stress

Photosynthetic performance, contents of chlorophyll and associated pigments, cellular damage and activities of antioxidative enzymes were investigated in two mustard (Brassica juncea L.) cultivars differing in photosynthetic capacity subjected to cadmium (Cd) stress. Exposure to Cd severely restricted the net photosynthetic rate (P(N)) of RH-30 compared to Varuna. This corresponded to the reductions in the activities of carbonic anhydrase (CA) and ribulose-1,5-bisphosphate carboxylase (Rubisco) in both the cultivars. Decline in chlorophyll (Chl) (a+b) and Chl a content was observed but decrease in Chl b was more conspicuous in Varuna under Cd treatments, which was responsible for higher Chl a:b ratio. Additionally, the relative amount of anthocyanin remained higher in Varuna compared to RH-30 even in the presence of high Cd concentration, while percent pheophytin content increased in RH-30 at low Cd concentration. A higher concentration of Cd (100 mg Cd kg(-1) soil) resulted in elevated hydrogen peroxide (H(2)O(2)) content in both the cultivars. However, Varuna exhibited lower content of H(2)O(2) in comparison to RH-30. This was reflected in the increased cellular damage in RH-30, expressed by greater thiobarbituric acid reactive substances (TBARS) content and electrolyte leakage. The enhanced activities of antioxidative enzymes, ascorbate peroxidase (APX), catalase (CAT) and glutathione reductase (GR) and also lower activity of superoxide dismutase (SOD) in Varuna alleviated Cd stress and protected the photosynthetic activity.     

Coenzyme Q10 Alleviated Behavioral Dysfunction and Bioenergetic Function in an Animal Model of Depression

Neurochemical Research - Coenzyme Q10 (CoQ10) is a natural compound, is involved in the mitochondrial electron transfer chain (ETC) and plays an important pattern in adenosine triphosphate (ATP)...     

Comparative Evaluation of Flow for Pharmaceutical Powders and Granules

The objective of the present work was to carry out a systematic evaluation of flow of pharmaceutical powders and granules using compendial and non-compendial methods. Angle of repose, bulk density, tapped density, Carr’s compressibility index, and Hausner ratios were evaluated. Additionally, flow was characterized using a powder rheometer in which a sensitive force transducer monitors the forces generated as a result of the sample displacement. The critical attributes such as cohesivity index, caking strength, and flow stability were determined for samples. The samples consisted of different grades of magnesium stearate powder including bovine, vegetable, and food grade, physical mixture powder blend consisting of a model formulation, granules prepared by various methods including slugging, high shear granulator, and fluid bed dryer. Lubricant efficiency was also determined for granules lubricated with various concentrations of magnesium stearate. It was observed that the compendial methods were often non-discriminating for minor variations in powder flow. The additional characterization such as cohesivity, and caking strength were helpful in understanding the flow characteristics of pharmaceutical systems. The flow stability test determined that the powders were not affected by the test conditions on the rheometer. The non-compendial tests were discriminating to even minor variations in powder flow. The opinions expressed in this work are only of authors, and do not necessarily reflect the policy and statements of the FDA.     

A new approach to 3-substituted tetrahydro-β-carboline derivative via diethyl acetamidomalonate

Strategically a new approach for the synthesis tetrahydro-β-carboline unit with the aid of diethyl acetamidomalonate as a glycine equivalent has been described.     

Kinetic Study on Mutagenic Chemical Degradation through Three Pot Synthesiszed Graphene@ZnO Nanocomposite

The study was taken up with the objective to synthesize graphene-zinc oxide nano particles (NPs) nanocomposite (Gr@ZnO-Nc) via In-situ synthesis method. The structural, optical, thermal, electrical and photocatalytic properties of the synthesized Gr@ZnO-Nc were studied. The characterization data confirmed that the ZnO NPs were successfully incorporated into the graphene sheets. Further, TGA/DTA results exhibited an enhanced thermal stability of the Gr@ZnO-Nc compared with the graphene. The Gr@ZnO-Nc, graphene sheets were uniformly wrapped by ZnO NPs, which can protect graphene and delay their oxidation in air. The synthesized Gr@ZnO-Nc was used for the efficient photodegradation of a carcinogenic methyl orange (MO) dye. The results exhibited promising photodegradation of the MO dye under UV light irradiation through the production of reactive oxygen species (ROS). The promising effect of Gr@ZnO-Nc on the photodegradation properties was conferred by the large surface area which increased adsorption capacity, and the strong electron transfer ability. Thus, it is encouraging to conclude that the synthesized Gr@ZnO-Nc has environmental significance with its utility in remediation in the hazardous MO dye.