Human liver steroid sulphotransferase sulphates bile acids.

The sulphation of bile acids is an important pathway for the detoxification and elimination of bile acids during cholestatic liver disease. A dehydroepiandrosterone (DHEA) sulphotransferase has been purified from male and female human liver cytosol using DEAE-Sepharose CL-6B and adenosine 3',5'-diphosphate-agarose affinity chromatography [Falany, Vazquez & Kalb (1989) Biochem. J. 260, 641-646]. Results in the present paper show that the DHEA sulphotransferase, purified to homogeneity, is also reactive towards bile acids, including lithocholic acid and 6-hydroxylated bile acids, as well as 3-hydroxylated short-chain bile acids. The highest activity towards bile acids was observed with lithocholic acid (54.3 +/- 3.6 nmol/min per mg of protein); of the substrates tested, the lowest activity was detected with hyodeoxycholic acid (4.2 +/- 0.01 nmol/min per mg of protein). The apparent Km values for the enzyme are 1.5 +/- 0.31 microM for lithocholic acid and 4.2 +/- 0.73 microM for taurolithocholic acid. Lithocholic acid also competitively inhibits DHEA sulphation by the purified sulphotransferase (Ki 1.4 microM). No evidence was found for the formation of bile acid sulphates by sulphotransferases different from the DHEA sulphotransferase during purification work. The above results suggest that a single steroid sulphotransferase with broad specificity encompassing neutral steroids and bile acids exists in human liver.     

Synthesis and antioxidant properties of novel benzimidazole derivatives

Some novel benzimidazole derivatives carrying thiosemicarbazide and triazole moieties at the N1 position were synthesized and their in vitro effects on rat liver microsomal NADPH-dependent lipid peroxidation (LP) levels determined by measuring the formation of 2-thiobarbituric acid reactive substance. The free radical scavenging properties of the compounds were also examined in vitro by determining the capacity to scavenge superoxide anion formation and the interaction with the stable free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). The compounds showed a significant effect in the above tests except to scavenge superoxide anion formation.     

p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis

Here we show that p38 mitogen-activated protein kinase (p38 MAPK) phosphorylates the spliced form of X-box binding protein 1 (Xbp1s) on its Thr48 and Ser61 residues and greatly enhances its nuclear migration in mice, whereas mutation of either residue to alanine substantially reduces its nuclear translocation and activity. We also show that p38 MAPK activity is markedly reduced in the livers of obese mice compared with lean mice. Further, we show that activation of p38 MAPK by expression of constitutively active MAP kinase kinase 6 (MKK6Glu) greatly enhances nuclear translocation of Xbp1s, reduces endoplasmic reticulum stress and establishes euglycemia in severely obese and diabetic mice. Hence, our results define a crucial role for phosphorylation on Thr48 and Ser61 of Xbp1s in the maintenance of glucose homeostasis in obesity, and they suggest that p38 MAPK activation in the livers of obese mice could lead to a new therapeutic approach to the treatment of type 2 diabetes.     

The effects of isoniazid on hippocampal NMDA receptors: Protective role of Erdosteine

Isoniazid (INH) has neurotoxic effects such as seizure, poor concentration, subtle reduction in memory, anxiety, depression and psychosis. INH-induced toxic effects are thought to be through increased oxidative stress, and these effects have been shown to be prevented by antioxidant therapies in various organs. Increased oxidative stress may be playing a role in these neurotoxic effects. N-methyl D-aspartat receptors (NMDA) are a member of the ionotropic group of glutamate receptors. These receptors are involved in a wide variety of processes in the central nervous system including synaptogenesis, synaptic plasticity, memory and learning. Erdosteine is a potent antioxidant and mucolytic agent. We aimed to investigate adverse effects of INH on rat hippocampal NMDAR receptors, and to elucidate whether erdosteine prevents possible adverse effects of INH. In the present study, compared to control group, NMDAR2A (NR2A) receptors were significantly decreased and malondialdehyde (MDA), end product of lipid peroxidation, production was significantly increased in INH-treated group. On the other hand, administration of erdosteine to INH-treated group significantly increased NR2A receptors and decreased MDA production. In conclusion, decreasing NR2A receptors in hippocampus and increasing lipid peroxidation correlates with the degree of oxidative effects of INH and erdosteine protects above effect of INH on NR2A receptors and membrane damage due to lipid peroxidation by its antioxidant properties.     

Ameliorating role of caffeic acid phenethyl ester (CAPE) against isoniazid-induced oxidative damage in red blood cells

Isoniazid (INH) still remains a first-line drug both for treatment and prophylaxis of tuberculosis, but various organs toxicity frequently develops in patients receiving this drug. We aimed to investigate possible toxic effects of INH on rat red blood cells (RBCs), and to elucidate whether Caffeic acid phenethyl ester (CAPE) prevents a possible toxic effect of INH. Experimental groups were designed as follows: control group, INH group, INH + CAPE group. Compared with the control, the INH caused a significant increase in superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels, and a decrease in glutathione peroxidase (GSH-Px) and catalase (CAT), which are recently used to monitor the development and extent of damage due to oxidative stresses. CAPE administration to INH group ameliorated above changes due to INH.     

May TLR4 Asp299Gly and IL17 His161Arg polymorphism be associated with progression of primary measles infection to subacute sclerosing panencephalitis?

SSPE is a progressive neurological disorder of children. Only some of the children who are infected with measles virus develop SSPE, which supports individual variation. TLR-2 and TLR-4 play an important role in innate immunity by recognizing envelope proteins of MV. Another important cytokine that plays an important role in orchestrating innate immune function is IL-17. The purpose of our study is to elucidate whether the TLR2, TLR4, IL17F and IL17A gene polymorphisms are susceptibility genes for the development of SSPE.     

Immobilization of Candida antarctica lipase B (CALB) on surface-modified rice husk ashes (RHA) via physical adsorption and cross-linking methods

In the present study, the recovery of activity of Candida antarctica lipase B (CALB) immobilized onto surface-modified rice husk ash (RHA) was 90% for both cross-linking and adsorption methods. Both cross-linked and adsorbed immobilized preparations were very stable, retaining more than 48% of their activity over the range of temperatures studied. The optimum temperature and optimum pH values were 37?°C and 7.0, respectively for both immobilized preparations, while the relative activities after storage at 4.0?°C for 60 days were 55% and 65% using cross-linking and adsorption methods, respectively. Also, the activity of the immobilized lipase began to decrease after 10 cycles, more than 58% of the initial activities were still retained after 10 cycles for both immobilization methods. These results indicated that lipase immobilized by cross-linking and adsorption not only effected activity recovery, but also remarkably effected stability, reusability and application adaptability. It can be concluded that, surface-modified RHA can be used as alternative supports for immobilization of CALB for polymerization reactions.     

Benzo[a]pyrene-DNA-adducts and monooxygenase activities in mice treated with benzo[a]pyrene, cigarette smoke or cigarette smoke condensate

Synchronous fluorescence spectrophotometry (SFS), developed to study benzo[a]pyrene-7,8-diol-9,10-epoxide(BPDE)-DNA, was used to measure the in vivo formation of DNA-adducts in genetically responsive C57BL/6 (B6) and non-responsive DBA/2 (D2) mice. Treatment with cigarette smoke by inhalation for 3-16 days, or i.p. injection of cigarette smoke condensate or neutral fraction did not lead to detectable levels of BPDE-DNA-adducts in either lungs or liver, although aryl hydrocarbon hydroxylase (AHH) activity, an indicator of benzo[a]pyrene (BP) metabolism, was clearly induced in lungs of B6 mouse. A dose-dependent amount of BPDE-DNA-adducts in lung and somewhat less in liver was found after i.p. injection with BP (20-80 mg/kg). Mice treated with vehicle or 4 mg/kg of BP were negative for adducts by SFS. In B6 mice AHH was induced both in lungs and livers while there was no AHH induction in D2 mice although the levels of BPDE-DNA-adducts were somewhat higher than in B6 mice. Thus, no clear correlation seems to exist between AHH activity and the formation of BPDE-DNA-adducts. Also, according to our results SFS can be used to quantitate adduct-formation in in vivo animal studies.     

Synthesis, antifungal and antioxidant screening of some novel benzimidazole derivatives

Some novel benzimidazole derivatives were synthesized and their in vitro effects on rat liver microsomal NADPH-dependent lipid peroxidation (LP) level, ethoxyresorufin O-deethylase (EROD) and antifungal activities were determined. A significant decrease in male rat liver microsomal LP level was noted by compounds 4c (52%), 4e (58%) and 4h (43%) at 10(-3) M concentration. Compounds 4c (100.0%), 4h (100.0%), 5c (98.0%) and 5h (100.0%) inhibited the microsomal ethoxyresorufin O-deethylase (EROD) enzyme activity better than that of the specific inhibitor caffeine (85%). Among these compounds, only compounds 4b and 4h exhibited moderate activity against C. albicans whereas the others had weak effects.