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.     

Roles of matrix metalloproteinases in development,immunology, and ovulation in fruit Fly (Drosophila)

Matrix metalloproteinase (MMP), a protease enzyme, participates in proteolytic cleavage of extracellular matrix proteins from Drosophila and mammals. But, recent studies have revealed other physiologically important roles of MMP in Drosophila. MMP contributes to cardioblast movement and distribution of collagen proteins during cardiogenesis in developing Drosophila. Tissue remodeling, especially tracheal development is also maintained by MMP. MMP regulates certain immunological functions in Drosophila such as wound repairing, plasmatocyte assemblage at the injured site of the basement membrane and glial response to axon degeneration in Drosophila nervous system. But, the contribution of MMP to tumor formation and metastasis in Drosophila has made it an interesting topic among researchers. Ovulation and egg laying are also found to be affected positively by MMP in Drosophila.     

Structural basis for the functional and inhibitory mechanisms of β-hydroxyacyl-acyl carrier protein dehydratase (FabZ) of Plasmodium falciparum

The β-hydroxyacyl-acyl carrier protein dehydratase of Plasmodium falciparum (PfFabZ) catalyzes the third and important reaction of the fatty acid elongation cycle. The crystal structure of PfFabZ is available in hexameric (active) and dimeric (inactive) forms. However, PfFabZ has not been crystallized with any bound inhibitors until now. We have designed a new condition to crystallize PfFabZ with its inhibitors bound in the active site, and determined the crystal structures of four of these complexes. This is the first report on any FabZ enzyme with active site inhibitors that interact directly with the catalytic residues. Inhibitor binding not only stabilized the substrate binding loop but also revealed that the substrate binding tunnel has an overall shape of “U”. In the crystal structures, residue Phe169 located in the middle of the tunnel was found to be in two different conformations, open and closed. Thus, Phe169, merely by changing its side chain conformation, appears to be controlling the length of the tunnel to make it suitable for accommodating longer substrates. The volume of the substrate binding tunnel is determined by the sequence as well as by the conformation of the substrate binding loop region and varies between organisms for accommodating fatty acids of different chain lengths. This report on the crystal structures of the complexes of PfFabZ provides the structural basis of the inhibitory mechanism of the enzyme that could be used to improve the potency of inhibitors against an important component of fatty acid synthesis common to many infectious organisms.     

Environmental variables responsible for Zebu cattle thermal comfort acquisition

International Journal of Biometeorology - The aim of this study was to estimate, using data mining, which microclimate and behavioral variables affect the behavior of animals to seek shaded or...     

Effect of 30 kDa and above buffalo follicular fluid protein treatment and immunization on ovarian functions in goats (Capra hircus)

Information on the use of buffalo follicular fluid (buFF) in modulation of ovarian functions in farm animals is scanty compared to other species. This is an attempt to investigate the effect of direct administration and active immunization of 30 kDa and above buFF proteins on ovarian functions in goats. Treatment of goats (n = 6) with steroid free 30 kDa and above buFF protein fraction during late-luteal phase for 4 days (days 12 or 13 to days 15 or 16) of the natural cycle, delayed the onset of estrus by 24 h compared to control although the mean duration of estrus was unaffected. A 71% increase (P = 0.06) in mean ovulation number was also observed following treatment. However, the population of large (> or =5 mm diameter) follicle was not affected. The ovarian activity calculated as total of ovulation and large follicles increased (1.6 times) significantly (P = 0.02) in treated animals. Active immunization of goats (n = 5) against these proteins did not affect the onset and duration of estrus. Similarly, the ovulation rate, number of large follicles and the ovarian activity did not differ significantly between immunized and control groups. The study revealed that 30 kDa and above buffalo follicular fluid contains some factor(s) that cause delay in the onset of estrus in goats and increase the ovulation rate. Active immunization against these proteins in goat did not show any effect either on onset, duration of estrus or ovulation rate and large follicle population. Detailed study on these buffalo follicular fluid proteins may help to use them further for modulation of ovarian function in farm animals.     

Effect of glutamine analogue-acivicin on tumor induced angiogenesis in Ehrlich ascites carcinoma

The inhibition of tumor growth and tumor induced angiogenesis by the glutamine antimetabolite acivicin was evaluated in 6-7 weeks old male Swiss albino mice bearing Ehrlich ascites carcinoma (EAC) transplanted by intraperitoneal (ip) injections of EAC cells. Treatment involving ip injections with two different doses of acivicin (0.05 and 0.41microg/g body weight/day) in saline revealed decrease in tumor volumes and reduced number of blood vessels on peritoneal wall after 10 and 15 days of treatment when compared to control (i.e. injected with saline only). Vascular hyperpermeability was found to be lesser in the treated groups of mice than the control as indicated by the FITC- D and colloidal carbon assay. Serum VEGF level was found to decrease in the drug treated groups both after 10 and 15 days of treatment. The results thus suggest that acivicin may suppress tumoral angiogenesis through regulation of VEGF level.     

Curcumin regulates expression and activity of matrix metalloproteinases 9 and 2 during prevention and healing of indomethacin-induced gastric ulcer

Matrix metalloproteinases (MMPs) are suggested to play a critical role in extracellular matrix degradation and remodeling during inflammation and wound healing processes. However, the role of MMPs in indomethacin-induced gastric ulcer and its healing process are not clearly understood. This study is aimed at determining the regulation of MMP-9 and -2 activities in indomethacin-induced acute gastric ulceration and healing. Indomethacin-ulcerated stomach extracts exhibit significant up-regulation of pro-MMP-9 (92 kDa) activity and moderate reduction of MMP-2 activity, which strongly correlate with indomethacin dose and severity of ulcer. The anti-inflammatory and antioxidant properties of curcumin, an active component of turmeric, suggest that curcumin may exert antiulcer activity through scavenging reactive oxygen species, by regulating MMP activity, or both. To test these possibilities, the effect of curcumin in indomethacin-induced gastric ulcer is examined by biochemical and histological methods. The results show that curcumin exhibits potent antiulcer activity in acute ulcer in rat model by preventing glutathione depletion, lipid peroxidation, and protein oxidation. Denudation of epithelial cells during damage of gastric lumen is reversed by curcumin through re-epithelialization. Furthermore, both oral and intraperitoneal administration of curcumin blocks gastric ulceration in a dose-dependent manner. It accelerates the healing process and protects gastric ulcer through attenuation of MMP-9 activity and amelioration of MMP-2 activity. Omeprazole, an established antiulcer drug does not inhibit MMP-9 while protecting indomethacin-induced gastric ulcer. We conclude that antiulcer activity of curcumin is primarily attributed to MMP-9 inhibition, one of the major path-ways of ulcer healing.     

Protein Turnover in Response to Transient Exposure to Exogenous Auxin is Necessary for Restoring Auxin Autotrophy in a Stressed Arachis hypogea Cell Culture

An auxin autotrophic Arachis hypogea cell culture was sensitive to stress treatments leading to water loss whereas the growth of its auxin-supplemented counterpart was unaffected under similar conditions. Here we show that an hour of transient auxin treatment in the post stress period was sufficient for restoring the auxin autotrophic growth potential of the stress driven quiescent Arachis cells. Qualitative proteome analysis revealed protein turnover to have a role in mediating auxin-originated signals in these cells. In consonance, MG132 a cell permeable inhibitor of the ubiquitin mediated protein turnover completely inhibited the auxin dependent growth restoration of the stressed Arachis cells. Thus protein turnover is a necessary downstream event in exogenous auxin mediated stress tolerance in Arachis cells.