Metabolism of carbosulfan II. Human interindividual variability in its in vitro hepatic biotransformation and the identification of the cytochrome P450 isoforms involved

This study aims to characterize interindividual variability and individual CYP enzymes involved in the in vitro metabolism of the carbamate insecticide carbosulfan. Microsomes from ten human livers (HLM) were used to characterize the interindividual variability in carbosulfan activation. Altogether eight phase I metabolites were analyzed by LC–MS. The primary metabolic pathways were detoxification by the initial oxidation of sulfur to carbosulfan sulfinamide (‘sulfur oxidation pathway’) and activation via cleavage of the nitrogen sulfur bond (N–S) to give carbofuran and dibutylamine (‘carbofuran pathway’). Differences between maximum and minimum carbosulfan activation values with HLM indicated nearly 5.9-, 7.0, and 6.6-fold variability in the k_m, V_max and CL_int values, respectively. CYP3A5 and CYP2B6 had the greatest efficiency to form carbosulfan sulfinamide, while CYP3A4 and CYP3A5 were the most efficient in the generation of the carbofuran metabolic pathway. Based on average abundances of CYP enzymes in human liver, CYP3A4 contributed to 98% of carbosulfan activation, while CYP3A4 and CYP2B6 contributed 57 and 37% to detoxification, respectively. Significant correlations between carbosulfan activation and CYP marker activities were seen with CYP3A4 (omeprazole sulfoxidation), CYP2C19 (omeprazole 5-hydroxylation) and CYP3A4 (midazolam 1′-hydroxylation), displaying r² = 0.96, 0.87 and 0.82, respectively. Activation and detoxification pathways were inhibited by ketoconazole, a specific CYP3A4 inhibitor, by 90–97% and 47–94%, respectively. Carbosulfan inhibited relatively potently CYP3A4 and moderately CYP1A1/2 and CYP2C19 in pooled HLM. These results suggest that the carbosulfan activation pathway is more important than the detoxification pathway, and that carbosulfan activation is predominantly catalyzed in humans by CYP3A4.     

Exogenous application of nitric oxide modulates osmolyte metabolism,antioxidants, enzymes of ascorbate-glutathione cycle and promotes growth under cadmium stress in tomato

Experiments were carried out to investigate the role of nitric oxide (NO) in ameliorating the negative effects of cadmium stress in tomato seedlings. Plants treated with cadmium (CdCl₂, 150 μM) showed reduced growth, biomass yield, pigment content, chlorophyll fluorescence, and gas exchange parameters. Exogenous application of NO donor (sodium nitroprusside) with nutrient solution protected chlorophyll pigments, restored chlorophyll fluorescence and gas exchange parameters, and caused significant enhancements in growth and biomass yield. Cadmium triggered the synthesis of proline and glycine betaine; however, application of NO caused further enhancement of their accumulation, reflecting an obvious amelioration of the cadmium-induced decline in relative water content. Activities of the antioxidant enzymes superoxide dismutase, catalase, ascorbate peroxidase, and glutathione reductase, monodehydroascorbate reductase, dehydroascorbate reductase, and other enzymatic activities of ascorbate-glutathione cycle were enhanced following the application of NO, as compared with those in untreated seedlings under control and cadmium stress conditions. NO increased the flavonoid and total phenol content in Cd-stressed tomato plants. Moreover, NO application restricted the uptake of cadmium and enhanced the accumulation of nutrients in different parts of tomato plants. On the basis of the findings of the present study, we propose that NO has a potential role as a growth promoter for tomato under cadmium stress.     

What the snake leaves in its wake: Functional limitations and disabilities among snakebite victims in Ghanaian communities

BackgroundThe estimated five million snakebites per year are an important health problem that mainly affect rural poor populations. The global goal is to halve both mortality and morbidity from this neglected tropical disease by 2030. Data on snakebite morbidity are sparse and mainly obtained from hospital records.MethodsThis community-based study was conducted among 379 rural residents with or without a history of snakebite in the Ashanti and Upper West regions of Ghana. All participants in the snakebite group were bitten at least six months before the day of survey. The World Health Organisation Disability Assessment Schedule 2.0 (WHODAS 2.0) and the Buruli Ulcer Functional Limitation Score were used to obtain patient-reported measure of functioning and disability. Long-term consequences were evaluated based on the severity of the symptoms at the time of the snakebite.FindingsThe median (IQR) time since the snakebite was 8.0 (3.5–16.5) years. The relative risk of disability was 1.54 (95% CI, 1.17–2.03) in the snakebite group compared to the community controls. Among patients with clinical symptoms suggesting envenoming at the time of bite, 35% had mild/moderate disabilities compared to 20% in the control group. The disability domains mainly affected by snakebite envenoming were cognition level, mobility, life activities and participation in society. A combination of the severity of symptoms at the time of the bite, age, gender and region of residence most accurately predicted the odds of having functional limitations and disabilities.ConclusionThe burden of snakebite in the community includes long-term disabilities of mild to moderate severity, which need to be considered when designing appropriate public health interventions. Estimating the total burden of snakebite is complicated by geographic differences in types of snakes and their clinical manifestations.     

Molecular cloning and characterization of an alpha1,3 fucosyltransferase, CEFT-1, from Caenorhabditis elegans

We report on the identification, molecular cloning, and characterization of an alpha1,3 fucosyltransferase (alpha1,3FT) expressed by the nematode, Caenorhabditis elegans . Although C. elegans glycoconjugates do not express the Lewis x antigen Galbeta1-- >4[Fucalpha1-->3]GlcNAcbeta-->R, detergent extracts of adult C.elegans contain an alpha1,3FT that can fucosylate both nonsialylated and sialylated acceptor glycans to generate the Lexand sialyl Lexantigens, as well as the lacdiNAc-containing acceptor GalNAcbeta1-->4GlcNAcbeta1-- >R to generate GalNAcbeta1-->4 [Fucalpha1-->3]GlcNAcbeta1-->R. A search of the C.elegans genome database revealed the existence of a gene with 20-23% overall identity to all five cloned human alpha1,3FTs. The putative cDNA for the C.elegans alpha1,3FT (CEFT-1) was amplified by PCR from a cDNA lambdaZAP library, cloned, and sequenced. COS7 cells transiently transfected with cDNA encoding CEFT-1 express the Lex, but not sLexantigen. The CEFT-1 in the transfected cell extracts can synthesize Lex, but not sialyl Lex, using exogenous acceptors. A second fucosyltransferase activity was detected in extracts of C. elegans that transfers Fuc in alpha1,2 linkage to Gal specifically on type-1 chains. The discovery of alpha-fucosyltransferases in C. elegans opens the possibility of using this well-characterized nematode as a model system for studying the role of fucosylated glycans in the development and survival of C.elegans and possibly other helminths.      

Incidence of sexual dysfunction: a prospective survey in Ghanaian females

Background  

Sexuality is a complex phenomenon that is being influenced by psychological as well as physiological factors. Its dysfunction includes desire, arousal, orgasmic and sex pain disorders. The present study aimed to assess the incidence of sexual dysfunction (SD) and related risk factors in a cohort of Ghanaian women.     

Zinc application mitigates the adverse effects of NaCl stress on mustard [Brassica juncea (L.) Czern & Coss] through modulating compatible organic solutes,antioxidant enzymes,and flavonoid content

This study examined the protective effect of Zn on salt-stressed Brassica juncea plants using some key morphological and biochemical attributes at different developmental stages (30, 60, and 90 days after treatment [DAT]). Salt stress (200?mM) caused suppression in plant height, root length, and dry weight by 58.35%, 41.15%, and 53.33%, respectively, at 90 DAT, but Zn application improved these variables by 15.52%, 16.59%, and 11.45%, respectively. Furthermore, 200?mM NaCl decreased total chlorophyll by 45.32% and relative water content by 27.62% at 90 DAT, whereas Zn application compensated the decrease in the levels of both variables. NaCl (200?mM) increased H₂O₂, malondialdehyde, and electrolyte leakage by 70.48%, 35.25%, and 68.39%, respectively, at 90 DAT, but Zn supplementation appreciably reduced these variables. Except for catalase, enzymatic antioxidant activity increased under NaCl stress. Zn application with salt further increased the activities of superoxide dismutase, catalase, ascorbate peroxidase, glutathione reductase, and glutathione-S-transferase by 33.51%, 9.21%, 10.98%, 17.46%, and 12.87%, respectively, at 90 DAT. At 90 DAT, salt stress increased flavonoids by 24.88%, and Zn supply by a further 7.68%. Overall, Zn mitigated the adverse effects of salt stress through osmotic adjustment, as well as by modulating the oxidative defense system and flavonoid contents.     

Nifedipine loaded chitosan microspheres: characterization of internal structure

In the present investigation, a simple technique was employed to obtain cross-sections of unloaded and nifedipine loaded chitosan microspheres. Microspheres, adhering to a polymerized resin block, were cut with an ultramicrotome and viewed with a scanning electron microscope. Unloaded microspheres exhibited a uniform dense matrix structure while crystals of nifedipine were clearly visible in the drug-loaded microspheres. At 2% drug loading, however, no crystals could be seen in the microspheres indicating that either the drug was molecularly dispersed or dissolved in the matrix at this concentration. This was confirmed by powder X-ray diffractometry studies where no peak due to crystalline nifedipine was observed. At high Span 85 concentration (1.5% w/v), the external surface of the microspheres collapsed, but the internal structure remained dense. When the drug was dispersed in the chitosan solution with stirring during preparation, the entrapment was good and the shape of the crystals was changed. The internal structure of the microspheres following dissolution exhibited the presence of pores.     

Silicon (Si) Supplementation Alleviates NaCl Toxicity in Mung Bean [Vigna radiata (L.) Wilczek] Through the Modifications of Physio-biochemical Attributes and Key Antioxidant Enzymes

Journal of Plant Growth Regulation - Mung bean is an important pulse crop. It is highly nutritive but is vulnerable to salinity stress. Therefore, the present study was aimed to investigate the...