Effect of dietary fish oil on platelet aggregability: comparison between two oils with different eicosapentaenoic to arachidonic acid ratio.

Rats, acclimatized on a control diet, were fed for 60 days with diets, supplemented with 10% fat of either marine Hilsa fish (Hilsa ilisa) or fresh-water Chital fish (Notopterus chitala). The percentage of eicosapentaenoic acid in chital oil diet was 0.57 times that of the hilsa oil diet, but the eicosapentaenoic to arachidonic acid ratio in the latter (4.08) was 3.2 times that of the former (1.27). Otherwise these two diets were comparable in respect to total saturated, monounsaturated and n-3 polyunsaturated fatty acid contents. Results showed that of the two only hilsa oil diet could significantly lower platelet aggregability and in vitro thromboxane production, through replacement of arachidonic acid in platelet phospholipid by eicosapentaenoic acid. The antithrombic criteria of the oil seems to be a combination of low arachidonic acid content and high eicosapentaenoic to arachidonic acid ratio.     

Books

Book reviewed in this article:
Modelling Change in Integrated Economic and Environmental Systems, edited by S. Mahendrarajah, A. J. Jakeman, and M. McAleer.     

Antimalarial drugs inhibiting hemozoin (beta-hematin) formation: a mechanistic update

Digestion of hemoglobin in the food vacuole of the malaria parasite produces very high quantities of redox active toxic free heme. Hemozoin (beta-hematin) formation is a unique process adopted by Plasmodium sp. to detoxify free heme. Hemozoin formation is a validated target for most of the well-known existing antimalarial drugs and considered to be a suitable target to develop new antimalarials. Here we discuss the possible mechanisms of free heme detoxification in the malaria parasite and the mechanistic details of compounds, which offer antimalarial activity by inhibiting hemozoin formation. The chemical nature of new antimalarial compounds showing antimalarial activity through the inhibition of hemozoin formation has also been incorporated, which may help to design future antimalarials with therapeutic potential against multi-drug resistant malaria.     

Dual role of SnoN in mammalian tumorigenesis

SnoN is an important negative regulator of transforming growth factor beta signaling through its ability to interact with and repress the activity of Smad proteins. It was originally identified as an oncoprotein based on its ability to induce anchorage-independent growth in chicken embryo fibroblasts. However, the roles of SnoN in mammalian epithelial carcinogenesis have not been well defined. Here we show for the first time that SnoN plays an important but complex role in human cancer. SnoN expression is highly elevated in many human cancer cell lines, and this high level of SnoN promotes mitogenic transformation of breast and lung cancer cell lines in vitro and tumor growth in vivo, consistent with its proposed pro-oncogenic role. However, this high level of SnoN expression also inhibits epithelial-to-mesenchymal transdifferentiation. Breast and lung cancer cells expressing the shRNA for SnoN exhibited an increase in cell motility, actin stress fiber formation, metalloprotease activity, and extracellular matrix production as well as a reduction in adherens junction proteins. Supporting this observation, in an in vivo breast cancer metastasis model, reducing SnoN expression was found to moderately enhance metastasis of human breast cancer cells to bone and lung. Thus, SnoN plays both pro-tumorigenic and antitumorigenic roles at different stages of mammalian malignant progression. The growth-promoting activity of SnoN appears to require its ability to bind to and repress the Smad proteins, while the antitumorigenic activity can be mediated by both Smad-dependent and Smad-independent pathways and requires the activity of small GTPase RhoA. Our study has established the importance of SnoN in mammalian epithelial carcinogenesis and revealed a novel aspect of SnoN function in malignant progression.     

Comparative analysis of differential expression of sialic acids and adhesion molecules on mononuclear cells of bone marrow and peripheral blood in childhood acute lymphoblastic leukaemia at diagnosis and clinical remission

Childhood acute lymphoblastic leukaemia (ALL) is characterized by the neoplasm of immature haematopoietic precursor cells (HPCs). We report significant differences between the expression of sialoglycoproteins and adhesion molecules on mononuclear cells (MNCs) of bone marrow (BM) and peripheral blood (PB) from individual children at diagnosis of the disease. Lymphoblasts in PB predominantly expressed 9-O-acetylated sialoglycoproteins (Neu5,9Ac2-GPs), sialic acid, alpha2-3 linked sialic acid, L- and P-selectins and vascular cell adhesion molecule -1 (VCAM-1) on their surface compared to BM, as determined with selective lectins and monoclonal antibodies (mAbs) by flow cytometric analysis. CD34+CD38+ cells present either in diagnostic PB or BM always showed enhanced expression of both alpha2-3 and alpha2-6 linked sialic acids, Neu5,9Ac2-GPs, L- and P-selectins and VCAM-1, compared to CD34+CD38- population, as confirmed by higher mean fluorescence intensity (MFI). Expression of ICAM-1 was reverse. However, MFI of Neu5,9Ac2-GPs was always higher both in CD34+CD38+ and CD34+CD38- population in PB compared to BM. Diverse trend of these cell surface macromolecules was observed during clinical remission. This is the first comparative study between PB and BM, where significant differential distribution of sialylated macromolecules and adhesion molecules was observed. Hence, supervising these cell surface macromolecules at various stages of treatment might help in minimal residual disease detection, identifying mobilization factor(s) and in isolation of normal HPCs for autologous BM transplantation.     

An energy-based population-balance approach to model granule growth and breakage in high-shear wet granulation processes

A mathematical model of high shear wet granulation is proposed, where granule breakage, and not growth, is the dominant process. The energy required for granule breakage is assumed to be provided by the impact of granules between themselves and the granulator parts, and the extent of granule breakage determined by the balance between the impactenergy and the work of adhesion between the agglomerating particles. A specific volume of dry powder per unit crack surface area was allowed to reattach to the surface of broken granules to account for granule growth. To verify proposed model conditions, lactose monohydrate was granulated with a relatively low amount (6%) of the binder phase, polyvinyl-pyrrolidone and water, and was added to the powder before granulation. The trend in granule size distribution during the experiment closely follwed the predicted model with an initial increase in the weight fraction of the larger granules. This increase was possibly due to extensive breakage of weaker granules and less extensive breakage, as if by attrition, of stronger granules, accompanied by the attachment of dry powder to the cracked surfaces. Eventually, larger granules experience increased impact energy and break. When excess binder is added and, higher volumes of powder reattach to the crack surface, more large granules form leading to granule overgrowth. This model highlights the importance of the probability of impact per unit time interval (ie, the rate of impact), the strength of the granules and the volume of powder that could attach to the cracked surface in high shear granulation processes where significant granule breakage is encountered. Published: August 10, 2007     

Challenges and Opportunities for Customizing Polyhydroxyalkanoates

Polyhydroxyalkanoates (PHAs) as an alternative to synthetic plastics have been gaining increasing attention. Being natural in their origin, PHAs are completely biodegradable and eco-friendly. However, consistent efforts to exploit this biopolymer over the last few decades have not been able to pull PHAs out of their nascent stage, inspite of being the favorite of the commercial world. The major limitations are: (1) the high production cost, which is due to the high cost of the feed and (2) poor thermal and mechanical properties of polyhydroxybutyrate (PHB), the most commonly produced PHAs. PHAs have the physicochemical properties which are quite comparable to petroleum based plastics, but PHB being homopolymers are quite brittle, less elastic and have thermal properties which are not suitable for processing them into sturdy products. These properties, including melting point (T_m), glass transition temperature (T_g), elastic modulus, tensile strength, elongation etc. can be improved by varying the monomeric composition and molecular weight. These enhanced characteristics can be achieved by modifications in the types of substrates, feeding strategies, culture conditions and/or genetic manipulations.     

BRCA1 Is Required for Maintenance of Phospho-Chk1 and G2/M Arrest during DNA Cross-Link Repair in DT40 Cells

The Fanconi anemia DNA repair pathway is pivotal for the efficient repair of DNA interstrand cross-links. Here, we show that FA-defective (Fancc⁻) DT40 cells arrest in G₂ phase following cross-link damage and trigger apoptosis. Strikingly, cell death was reduced in Fancc⁻ cells by additional deletion of the BRCA1 tumor suppressor, resulting in elevated clonogenic survival. Increased resistance to cross-link damage was not due to loss of toxic BRCA1-mediated homologous recombination but rather through the loss of a G₂ checkpoint. This proapoptotic role also required the BRCA1-A complex member ABRAXAS (FAM175A). Finally, we show that BRCA1 promotes G₂ arrest and cell death by prolonging phosphorylation of Chk1 on serine 345 after DNA damage to sustain arrest. Our data imply that DNA-induced cross-link death in cells defective in the FA pathway is dependent on the ability of BRCA1 to prolong cell cycle arrest in G₂ phase.