Spice phenolics inhibit human PMNL 5-lipoxygenase

A wide variety of phenolic compounds and flavonoids present in spices possess potent antioxidant, antimutagenic and anticarcinogenic activities. We examined whether 5-lipoxygenase (5-LO), the key enzyme involved in biosynthesis of leukotrienes is a possible target for the spices. Effect of aqueous extracts of turmeric, cloves, pepper, chili, cinnamon, onion and also their respective active principles viz., curcumin, eugenol, piperine, capsaicin, cinnamaldehyde, quercetin, and allyl sulfide were tested on human PMNL 5-LO activity by spectrophotomeric and HPLC methods. The formation of 5-LO product 5-HETE was significantly inhibited in a concentration-dependent manner with IC(50) values of 0.122-1.44 mg for aqueous extracts of spices and 25-83 microM for active principles, respectively. The order of inhibitory activity was of quercetin>eugenol>curcumin>cinnamaldehyde>piperine>capsaicin>allyl sulfide. Quercetin, eugenol and curcumin with one or more phenolic ring and methoxy groups in their structure showed high inhibitory effect, while the non-phenolic spice principle allyl sulfide showed least inhibitory effect on 5-LO. The inhibitory effect of quercetin, curcumin and eugenol was similar to that of synthetic 5-LO inhibitors-phenidone and NDGA. Moreover, the inhibitory potency of aqueous extracts of spice correlated with the active principles of their respective spices. The synergistic or antagonistic effect of mixtures of spice active principles and spice extracts were investigated and all the combinations of spice active principles/extracts exerted synergistic effect in inhibiting 5-LO activity. These findings clearly suggest that phenolic compounds present in spices might have physiological role in modulating 5-LO pathway.     

Differential modulation of voltage-dependent K+ currents in colonic smooth muscle by oxidants

The effect of oxidants on voltage-dependent K⁺ currents was examined in mouse colonic smooth muscle cells. Exposure to either chloramine-T (Ch-T), an agent known to oxidize both cysteine and methionine residues, or the colon-specific oxidant monochloramine (NH₂Cl) completely suppressed the transient outward K⁺ current (I_to) while simultaneously enhancing the sustained delayed rectifier K⁺ current (I_dr). In contrast, the cysteine-specific oxidants hydrogen peroxide (H₂O₂) and 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) exhibited partial and slow suppression of I_to by inducing a shift in channel availability of -18 mV without affecting I_dr. After enhancement by NH₂Cl or Ch-T, I_dr was sensitive to 10 mM tetraethylammonium but not to other K⁺ channel blockers, suggesting that it represented activation of the resting I_dr and not a separate K⁺ conductance. Extracellular dithiothreitol (DTT) partially reversed the effect of H₂O₂ and DTNB on I_to but not the actions of NH₂Cl and Ch-T on either I_dr or I_to. Dialysis of myocytes with GSH (5 mM) or DTT (5 mM) prevented suppression of I_to by H₂O₂ and DTNB but did not alter the effects of NH₂Cl or Ch-T on either I_dr or I_to. Ch-T and NH₂Cl completely blocked I_to generated by murine K_v4.1, 4.2, and 4.3 in Xenopus oocytes, an effect not reversible by intracellular DTT. In contrast, intracellular DTT reversed the effect of H₂O₂ and DTNB on the cloned channels. These results suggest that I_to is suppressed via modification of both methionine and cysteine residues, whereas enhancement of I_dr likely results from methionine oxidation alone. colon; colitis; redox; ion channel     

Lymphoplasmacytic sclerosing pancreato-cholangitis: a case report and review of the literature

Autoimmune pancreatitis is a rare but important cause of pancreatitis that is becoming increasingly recognized in the West. Lymphoplasmacytic sclerosing pancreatitis (LPSP) is a benign form of chronic pancreatitis characterized clinically by infrequent attacks of abdominal pain, jaundice, and weight loss, and pathologically by focal or diffuse chronic or lymphoplasmacytic inflammatory infiltrates centered around pancreatic ducts and ductules, accompanied by obliterative phlebitis, acinar atrophy, and interstitial fibrosis. It has been described alone or as a part of the spectrum of autoimmune gallbladder and biliary tract disease, with clinical, radiological, and pathological overlap reported with primary sclerosing cholangitis. It has been described as "primary sclerosing pancreatitis," "sclerosing cholangitis," "non-alcoholic duct destructive chronic pancreatitis," and "autoimmune pancreatitis." We report a case of LPSP that mimicked pancreatic adenocarcinoma and was subsequently treated with a pylorus-preserving Whipple procedure. This may point towards a primary biliary autoimmune process involving the pancreatic duct, causing a benign form of chronic pancreatitis that may be difficult to characterize pre-operatively to avoid surgery. This case typifies the growing awareness of this relatively recently characterized clinical entity, its similar presentation to pancreatic carcinoma, and the importance for LPSP to be included in the differential diagnosis of pancreaticobiliary disease. Finally, we review the literature.     

Somatic embryogenesis in Centella asiatica L. an important medicinal and neutraceutical plant of India

Leaf segments excised from Centella asiatica, a medicinal and neutraceutical plant, produced abundant somaticembryoswhen cultured onMS mediumwith 9.29 Mkinetin in combination with 2.26 M2,4-D. Granular, white,shiny clusters of callus developed after 1 week of culture, and then formed heart and cotyledonary stage embryoson the same medium after 4 weeks. Somatic embryos matured and germinated in the presence of MS mediumcontaining 2.32 M kinetin with (2.89M) GA3. Plantlets were successfully transferred to pots containing amixture of soil and vermiculite (1:1).     

AP endonuclease-independent DNA base excision repair in human cells

The paradigm for repair of oxidized base lesions in genomes via the base excision repair (BER) pathway is based on studies in Escherichia coli, in which AP endonuclease (APE) removes all 3' blocking groups (including 3' phosphate) generated by DNA glycosylase/AP lyases after base excision. The recently discovered mammalian DNA glycosylase/AP lyases, NEIL1 and NEIL2, unlike the previously characterized OGG1 and NTH1, generate DNA strand breaks with 3' phosphate termini. Here we show that in mammalian cells, removal of the 3' phosphate is dependent on polynucleotide kinase (PNK), and not APE. NEIL1 stably interacts with other BER proteins, DNA polymerase beta (pol beta) and DNA ligase IIIalpha. The complex of NEIL1, pol beta, and DNA ligase IIIalpha together with PNK suggests coordination of NEIL1-initiated repair. That NEIL1/PNK could also repair the products of other DNA glycosylases suggests a broad role for this APE-independent BER pathway in mammals.     

Effect of formulation variables on preparation and evaluation of gelled self-emulsifying drug delivery system (SEDDS) of ketoprofen

The purpose of this study was to formulate a gelled self-emulsifying drug delivery system (SEDDS) containing ketoprofen as an intermediate in the development of sustained release solid dosage form. Captex 200 (an oil), Tween 80 (a surfactant), and Capmul MCM (a cosurfactant) were used to formulate SEDDS. Silicon dioxide was used as a gelling agent, which may aid in solidification and retardation of drug release. Effect of concentrations of cosurfactant and gelling agent on emulsification process and in vitro drug diffusion was studied using 3² factorial design. Multiple regression analysis data and response surfaces obtained showed that liquid crystal phase viscosity increased significantly with increasing amount of silicon dioxide, which in turn caused an increase in average droplet size of resultant emulsion and slower drug diffusion. Drug release from the formulation increased with increasing amount of cosurfactant.     

Health risks of low dose ionizing radiation in humans: a review

Radiobiologists have been struggling to estimate the health risks from low doses of radiation in humans for decades. Health risks involve not only neoplastic diseases but also somatic mutations that may contribute to other illnesses (including birth defects and ocular maladies) and heritable mutations that may increase the risk of diseases in future generations. Low dose radiation-induced cancer in humans depends on several variables, and most of these variables are not possible to correct for in any epidemiologic study. Some of the confounding factors include (i) interaction of radiation with other physical (UV light), chemical, and biological mutagens and carcinogens in a synergistic manner; (ii) variation in repair mechanisms that depend on dose; (iii) variation in sensitivity of bystander cells to subsequent radiation exposure that depends on whether they have been pre- or postirradiated; and (iv) variation in adaptive response that depends on radiation doses and protective substances (antioxidants). In our opinion, both the linear no-threshold-response and the threshold-response models might not be suitable in predicting cancer risk at low radiation doses in a quantitative sense. Low doses of ionizing radiation should not be considered insignificant for risks of somatic and heritable mutations and neoplastic and nonneoplastic diseases in humans.     

Synthesis and antihyperglycemic activity profiles of novel thiazolidinedione derivatives

A number of thiazolidine-2,4-diones derivatives having carboxylic ester appendage at N-3 were synthesized and their antihyperglycemic activity was evaluated. Many of these derivatives as well as their corresponding carboxylic acid showed significant improvement on post-prandial hyperglycemia in normal rats, in contrast to their poor agonist activity at PPARgamma.     

Overexpression and rapid purification of Escherichia coli formamidopyrimidine-DNA glycosylase

Formamidopyrimidine DNA glycosylase (Fpg) is a DNA glycosylase with an associated AP lyase activity. As a DNA repair enzyme, Fpg excises several modified bases from DNA associated with exposure to oxidizing agents such as free radicals. Experiments in many laboratories have been limited by the availability of the enzyme, and its production required at least a week of work to complete its purification. We have devised a new method that decreases the time and expense of purification of Fpg that should render this protein accessible to any laboratory. Fpg was subcloned into a gamma P(L) promoter-containing vector (pRE) and overproduced in the appropriate Escherichia coli host cells to about 25% of the total cellular protein. Fpg was purified to homogeneity in a simple two-step procedure with a 50% saving in time when compared to the previously known procedure. Comparative studies showed that the excision of 8-hydroxyguanine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, and 4,6-diamino-5-formamidopyrimidine, and to a lesser extent, 8-hydroxyadenine was virtually identical for the Fpg purified using this method and for the Fpg purified by the original method. Therefore, this method should prove useful for a large number of laboratories and further research on oxidative DNA damage.