Synthesis and structure-activity relationship on anticonvulsant aryl semicarbazones

Seven series of various substituted aryl semicarbazones were synthesized and evaluated for anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure threshold tests. A comprehensive structure-activity relationship was derived comparing the substituents on the aryl ring and in the carbimino terminal. Generally the order of activity was 4-F > 2-Br = 3-Br = 4-Cl > 4-CH(3) > 4-Br > 3-Cl > 3-CH(3) with respect to the primary aryl group. Most of the compounds exhibited activity both in the MES and scPTZ screens. The 4-fluorophenyl substituted semicarbazones (5a-5y) emerged as the most potent compounds exhibiting anticonvulsant activity in mouse intraperitoneal (i.p.) and rat per oral (p.o.) MES, scPTZ and psychomotor seizure (6 Hz) screens.     

Similarities between heterophilic and homophilic cadherin adhesion

The mechanism that drives the segregation of cells into tissue-specific subpopulations during development is largely attributed to differences in intercellular adhesion. This process requires the cadherin family of calcium-dependent glycoproteins. A widely held view is that protein-level discrimination between different cadherins on cell surfaces drives this sorting process. Despite this postulated molecular selectivity, adhesion selectivity has not been quantitatively verified at the protein level. In this work, molecular force measurements and bead aggregation assays tested whether differences in cadherin bond strengths could account for cell sorting in vivo and in vitro. Studies were conducted with chicken N-cadherin, canine E-cadherin, and Xenopus C-cadherin. Both qualitative bead aggregation and quantitative force measurements show that the cadherins cross-react. Furthermore, heterophilic adhesion is not substantially weaker than homophilic adhesion, and the measured differences in adhesion do not correlate with cell sorting behavior. These results suggest that the basis for cell segregation during morphogenesis does not map exclusively to protein-level differences in cadherin adhesion.     

Influence of Casearia esculenta root extract on protein metabolism and marker enzymes in streptozotocin-induced diabetic rats

The present study investigated the possible protective effects of Casearia esculenta root extract on certain biochemical markers in streptozotocin (STZ)-induced diabetes in rats. STZ treatment (50 mg/kg, ip) caused a hyperglycemic state, that led to various physiological and biochemical alterations. Blood levels of glucose, urea, uric acid and creatinine, plasma levels of albumin and albumin/globulin ratio and the activities of diagnostic marker enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and gamma-glutamyltranspeptidase (gamma-GT) in plasma, liver and kidney were markedly altered in STZ diabetic rats. Oral administration of C. esculenta (200 and 300 mg/kg) for 45 days restored all these biochemical parameters to near normal levels. Thus, the present results have shown that C. esculenta root extract has the antihyperglycemic effect and consequently may alleviate liver and renal damage associated with STZ-induced diabetes in rats.     

Influence of Piper betle on hepatic marker enzymes and tissue antioxidant status in ethanol-treated Wistar rats

Piper betle L. is a commonly used masticatory in Asia. This study was carried out to investigate the hepatoprotective and antioxidant properties of P. betle, using ethanol intoxication as a model of hepatotoxic and oxidative damage. Ethanol-treated rats exhibited elevation of hepatic marker enzymes and disturbances in antioxidant defense when compared with normal rats. Oral administration of P. betle extract (100, 200, or 300 mg/kg body weight) for 30 days significantly (P <.05) decreased aspartate aminotransferase (AST), alanine aminotransferase (ALT), thiobarbituric acid reactive substances (TBARS), and lipid hydroperoxides in ethanol treated rats. The extract also improved the tissue antioxidant status by increasing the levels of nonenzymatic antioxidants (reduced glutathione, vitamin C, and vitamin E) and the activities of free radical-detoxifying enzymes such as superoxide dismutase, catalase, and glutathione peroxidase in liver and kidney of ethanol-treated rats. The highest dose of P. betle extract (300 mg/kg body weight) was most effective. The results were comparable with the known hepatoprotective drug, silymarin. These results indicate that P. betle could afford a significant hepatoprotective and antioxidant effect.     

Effect of Casearia esculenta root extract on blood glucose and plasma antioxidant status in streptozotocin diabetic rats

Our preliminary study shows that an oral administration of an aqueous extract of Casearia esculenta, an indigenous antidiabetic plant popularly used in South India for diabetes mellitus, lowers blood glucose level under normal and glucose load conditions, and in streptozotocin (STZ)-induced diabetes in rats. The study was further undertaken to evaluate the antioxidant potential of C. esculenta in STZ diabetic rats. Oral administration of C. esculenta root extract at doses of 200 and 300 mg/kg for 45 days resulted in significant reduction in plasma thiobarbituric acid reactive substances (TBARS), hydroperoxide and ceruloplasmin and a significant elevation in plasma reduced glutathione (GSH), ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E). The study indicates that C. esculenta root extract at doses of 200 and 300 mg/kg restored all the antioxidant parameters to near normal value.     

Two simultaneous cases of Cyclospora cayatensis enteritis returning from the Dominican Republic

According to the "International Passenger Survey," published in 1996 by the Office of Trading Standards, 534,000 British people traveled to the Caribbean area (personal communication, ABTA, 1998). The Dominican Republic, the eastern end of a large Caribbean island, has become in recent years one of the most popular destinations for UK holidaymakers as well as for travelers from many other countries. Cyclospora cayatensis has been firmly identified as a cause of gastroenteritis among international travelers,1 including human immunodeficiency virus (HIV)-positive individuals,2 but it has not been previously reported in the literature in British individuals returning from this increasingly popular vacation destination.     

Platelet senescence and phosphatidylserine exposure

BACKGROUND: The exposure of phosphatidylserine occurs during platelet (PLT) activation and during in vitro storage. Phosphatidylserine exposure also occurs during apoptosis after the release of mitochondrial cytochrome c. We have examined the role of cytochrome c release, mitochondrial membrane potential (ΔΨm), and cyclophilin D (CypD) in phosphatidylserine exposure due to activation and storage. STUDY DESIGN AND METHODS: The exposure of phosphatidylserine and the loss of ΔΨm were determined in a flow cytometer using fluorescein isothiocyanate–lactadherin and JC‐1, a lipophilic cationic reporter dye. The role of CypD was determined with cyclosporin A and CypD‐deficient murine PLTs. Cytochrome c‐induced caspase‐3 and Rho‐associated kinase I (ROCK1) activation were determined by immunoblotting and using their inhibitors. RESULTS: Collagen‐ and thrombin‐induced exposure of phosphatidylserine was accompanied by a decrease in ΔΨm. Cyclosporin A inhibited the phosphatidylserine exposure and the loss of ΔΨm. CypD^?/? mice had decreased loss of ΔΨm and impaired phosphatidylserine exposure. Collagen and thrombin did not induce the release of cytochrome c nor the activation of caspase‐3 and ROCK1. In contrast, in PLTs stored for more than 5 days, the phosphatidylserine exposure was associated with cytochrome c–induced caspase‐3 and ROCK1 activation. ABT737, a BH3 mimetic that induces mitochondrial pathway of apoptosis, induced cytochrome c release and activation of caspase‐3 and ROCK1 and phosphatidylserine exposure independent of CypD. CONCLUSION: These results show that in stored PLTs cytochrome c release and the subsequent activation of caspase‐3 and ROCK1 mediate phosphatidylserine exposure and it is distinct from activation‐induced phosphatidylserine exposure.     

Hydrothermal Synthesis of Nanocrystalline ZrO2-8Y2O3-xLn2O3 Powders (Ln = La,Gd, Nd,Sm): Crystalline Structure,Thermal and Dielectric Properties

Zirconium dioxide (ZrO₂) is one of the ceramic materials with high potential in many areas of modern technologies. ZrO₂ doped with 8 wt.% (~4.5 mol%) Y₂O₃ is a commercial powder used for obtaining stabilized zirconia materials (8 wt.% YSZ) with high temperature resistance and good ionic conductivity. During recent years it was reported the co-doping with multiple rare earth elements has a significant influence on the thermal, mechanical and ionic conductivity of zirconia, due complex grain size segregation and enhanced oxygen vacancies mobility. Different methods have been proposed to synthesize these materials. Here, we present the hydrothermal synthesis of 8 wt.% (~4.5 mol%) YSZ co-doped with 4, 6 and 8 wt.% La₂O₃, Nd₂O₃, Sm₂O₃ and Gd₂O₃ respectively. The crystalline phases formed during their thermal treatment in a large temperature range were analyzed by X-ray diffraction. The evolution of phase composition vs. thermal treatment temperatures shows as a major trend the formation at temperatures >1000 °C of a cubic solid solutions enriched in the rare earth oxide used for co-doping as major phase. The first results on the thermal conductivities and impedance measurements on sintered pellets obtained from powders co-doped with 8 wt.% Y and 6% Ln (Ln = La, Nd, Sm and Gd) and the corresponding activation energies are presented and discussed. The lowest thermal conductivity was obtained for La co-doped 8 wt.% YSZ while the lowest activation energy for ionic conduction for Gd co-doped 8 wt.% YSZ materials.     

Antimycobacterial activity of novel 1-(5-cyclobutyl-1,3-oxazol-2-yl)-3-(sub)phenyl/pyridylthiourea compounds endowed with high activity toward multidrug-resistant Mycobacterium tuberculosis

OBJECTIVES: The objective of this work was to synthesize 15 new 1-(5-cyclobutyl-1,3-oxazol-2-yl)-3-(sub)phenyl/pyridylthiourea compounds and evaluate their in vitro and in vivo antimycobacterial activities. METHODS: 5-Cyclobutyloxazol-2-amine was reacted with 1,1'-thiocarbonyldiimidazole, followed by various substituted anilines and 2-amino pyridines to yield the 15 compounds, which were subjected to in vitro and in vivo evaluation against Mycobacterium tuberculosis H37Rv (MTB) and a clinical isolate of multidrug-resistant M. tuberculosis (MDR-TB). RESULTS: Among the 15 compounds screened, 7 compounds inhibited both MTB and MDR-TB in vitro with MICs of < 1 microM. In the in vivo screening, compound 1-(5-cyclobutyl-1,3-oxazol-2-yl)-3-(2'-trifluoromethyl)phenylthiourea (compound 8) was equally active as isoniazid at the same dose level. CONCLUSIONS: Compound 8 was found to be the most active, with an in vitro MIC of 0.14 microM and was 2.5 and 80 times more active than isoniazid against MTB and MDR-TB, respectively. Compound 8 was non-toxic to Vero cells up to 183 microM, with a selectivity index of > 1307. In the in vivo animal model, compound 8 decreased the mycobacterium load in lung and spleen tissues with 2.8 and 3.94 log(10) reductions, respectively.     

Acceleration of cutaneous wound healing by brassinosteroids

Brassinosteroids are plant growth hormones involved in cell growth, division, and differentiation. Their effects in animals are largely unknown, although recent studies showed that the anabolic properties of brassinosteroids are possibly mediated through the phosphoinositide 3‐kinase/protein kinase B signaling pathway. Here, we examined biological activity of homobrassinolide (HB) and its synthetic analogues in in vitro proliferation and migration assays in murine fibroblast and primary keratinocyte cell culture. HB stimulated fibroblast proliferation and migration and weakly induced keratinocyte proliferation in vitro. The effects of topical HB administration on progression of wound closure were further tested in the mouse model of cutaneous wound healing. C57BL/6J mice were given a full‐thickness dermal wound, and the rate of wound closure was assessed daily for 10 days, with adenosine receptor agonist CGS‐21680 as a positive control. Topical application of brassinosteroid significantly reduced wound size and accelerated wound healing in treated animals. mRNA levels of transforming growth factor beta and intercellular adhesion molecule 1 were significantly lower, while tumor necrosis factor alpha was nearly suppressed in the wounds from treated mice. Our data suggest that topical application of brassinosteroids accelerates wound healing by positively modulating inflammatory and reepithelialization phases of the wound repair process, in part by enhancing Akt signaling in the skin at the edges of the wound and enhancing migration of fibroblasts in the wounded area. Targeting this signaling pathway with brassinosteroids may represent a promising approach to the therapy of delayed wound healing.