Cypc19*17 Polymorphism as a Risk-factor for Nsaids-induced Ulcers

The new risk-factors for peptic ulcers induced by the use of nonsteroidal antiinflammatory drugs, such as polymorphism of different isoenzymes of cytochrome P450 were considered in the article. The aim of the research was to study different genetic polymorphism of several ferments CYP2C9 and CYP2C19 in inclination to NSAIDS-gastropathies by the way of estimation the risk of appearance of Helicobacter pylori (HP)-positive or Hp-negative NSAIDS- induced peptic ulcers, complicated or not with upper gastrointestinal bleeding.124 persons were examined (76 men, 48 women in the age of 56,2+/–9,1 years) with Hp-positive or Hp-negative NSAIDS-induced peptic ulcers, that were performed genotyping of isoferments of cytochrome system (CYP2C9, CYP2C19). Based on investigations of 5 different isoenzymes (CYP 2C9*2, CYP 2C9*3, CYP 2C19*2, CYP 2C19*3 and CYP 2C19*17). It was founded that peptic ulcers are strictly associated only with CYP 2C19*17-genotype, possibly due to its involvement in arachidonic acid metabolism and gastroprotection. Thus, polymorphism CYP 2C19*17 can be considered as one of the risk factors for NSAID-gastropathy though the future researches are needed

The effect of cyclophosphamide on salt taste in mice

Chemotherapy is a common cancer treatment, yet it has many severe side effects including altered taste. Patients report that salt taste is most affected by chemotherapy. The salt taste transduction system has yet to be fully elucidated. Type I taste cells are thought to be responsible in part for salt taste. The goal of this study was to determine how cyclophosphamide (CYP), a common chemotherapeutic agent, affects salt taste in mice. This involved two experiments. The first experiment examined how an induced conditioned taste aversion (CTA) to NaCl (salt) would change following CYP treatment. The second used a brief access test to observe how NaCl preference changed before and after either a single dose or multiple dose CYP treatment. We hypothesized that CYP would affect Type I taste cells leading to changes in salt preference, that CYP would reduce salt aversion, and that multiple doses would affect multiple salt taste cell types leading to more significant changes in salt preference. Our results demonstrated that after treatment, CYP mice had higher NaCl lick rates than control mice. This occurred in two phases, initially around day 8 and again around day 18. CTA mice maintained an aversion to NaCl following treatment, indicating a pathway protected from CYP disturbance. A single CYP injection and multiple CYP injections had the same effects on mice, indicating that this methodology is not useful in disturbing multiple salt taste cell populations. These data support that there are at least two salt taste transduction pathways in mice

50,000 Facebook views from a $30 investment: CYP-Media’s use of open practices to increase access to learning in the children and young people’s sector<i></i>

In 2015 Tony Coughlan was awarded the Open Education Consortium award for Creative Innovation, recognising the impact of his CYP-Media project in using open educational practices (OEP) to increase access to learning in the children and young people’s sector. Core to CYP-Media is a blog (www.cyp-media.org) in which Tony curates and evaluates free e-learning, textbooks and journals for working with children of different ages and needs. The reach of these blog posts is maximised by dissemination through Facebook and Twitter. The CYP-Media.org blog cost only $30 to set up, yet its impact is substantial. The CYP-Media Facebook page has an average reach of 7,244 per item, with a maximum of about 500 shares or 50,000 views of an individual item, and Tony himself has been identified as one of the top 50 most influential social media-using professionals in UK higher education. CYP-Media shows how just one person can make a huge difference to achieving educational and social equity with a tiny financial investment and a commitment to openness. This paper outlines the conceptual background to CYP-Media, with its roots in Perryman and Coughlan’s (2013) ‘public open scholar’ research, Weller’s (2011) concept of the ‘digital scholar’, and the emerging practice and theories of digital curation. The paper details CYP-Media’s multi-platform social media strategy and the challenges encountered since the project’s inception in 2010, in addition to presenting a mixed methods analysis of CYP-Media’s reception within the children and young people’s sector. We conclude that openness does not have to be the province of institutions and organisations, or even smaller projects and that by listening to the needs of your target audience, rather than adopting a top-down approach, real educational transformation through OEP is within the reach of anyone.</i

Cyclophilin-A is bound to through its peptidylprolyl isomerase domain to the cytoplasmic dynein motor protein complex

Although cyclophilin A (CyP-A) is a relatively abundant small immunophilin present in the cytoplasm of all mammalian cells, its general function(s) in the absence of the immunosuppressant drug cyclosporin A is not known. In contrast, the high molecular weight hsp90-binding immunophilins appear to play a role in protein trafficking in that they have been shown to link glucocorticoid receptor-hsp90 and p53.hsp90 complexes to the dynein motor protein for retrograde movement along microtubules. These immunophilins link to cytoplasmic dynein indirectly through the association of the immunophilin peptidylprolyl isomerase (PPIase) domain with dynamitin, a component of the dynein-associated dynactin complex (Galigniana, M. D., Harrell, J. M., O'Hagen, H. M., Ljungman, M., and Pratt, W. B. (2004) J. Biol. Chem. 279, 22483-22489). Here, we show that CyP-A exists in native heterocomplexes containing cytoplasmic dynein that can be formed in cell-free systems. Prolyl isomerase activity is not required for forming the dynein complex, but the PPIase domain fragment of FKBP52 blocks complex formation and CyP-A binds to dynamitin in a PPIase domain-dependent manner. CyP-A heterocomplexes containing tubulin and dynein can be formed in cytosol prepared under microtubule-stabilizing conditions, and CyP-A colocalizes in mouse fibroblasts with microtubules. Colocalization with microtubules is disrupted by overexpression of the PPIase domain fragment. Thus, we conclude that CyP-A associates in vitro and in vivo with the dynein/dynactin motor protein complex and we suggest that CyP-A may perform a general function related to the binding of cargo for retrograde movement along microtubules.Fil: Galigniana, Mario Daniel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Michigan; Estados UnidosFil: Morishima, Yoshihiro. University of Michigan; Estados UnidosFil: Gallay, Philippe A.. The Scripps Research Institute; Estados UnidosFil: Pratt, William B.. University of Michigan; Estados Unido

Mitochondrial targeting of cyclosporin A enables selective inhibition of cyclophilin-D and enhanced cytoprotection after glucose and oxygen deprivation

CsA (cyclosporin A) is a hydrophobic undecapeptide that inhibits CyPs (cyclophilins), a family of PPIases (peptidylprolyl cis–trans isomerases). In some experimental models, CsA offers partial protection against lethal cell injury brought about by transient ischaemia; this is believed to reflect inhibition of CyP-D, a mitochondrial isoform that facilitates formation of the permeability transition pore in the mitochondrial inner membrane. To evaluate this further, we have targeted CsA to mitochondria so that it becomes selective for CyP-D in cells. This was achieved by conjugating the inhibitor to the lipophilic triphenylphosphonium cation, enabling its accumulation in mitochondria due to the inner membrane potential. In a cell-free system and in B50 neuroblastoma cells the novel reagent (but not CsA itself) preferentially inhibited CyP-D over extramitochondrial CyP-A. In hippocampal neurons, mitochondrial targeting markedly enhanced the capacity of CsA to prevent cell necrosis brought about by oxygen and glucose deprivation, but largely abolished its capacity to inhibit glutamate-induced cell death. It is concluded that CyP-D has a major pathogenic role in ‘energy failure’, but not in glutamate excitotoxicity, where cytoprotection primarily reflects CsA interaction with extramitochondrial CyPs and calcineurin. Moreover, the therapeutic potential of CsA against ischaemia/reperfusion injuries not involving glutamate may be improved by mitochondrial targeting

The development and evaluation of the paediatric index of emotional distress (PI-ED)

Purpose: Current measures of anxiety and depression for children and young people (CYP) include somatic symptoms and can be lengthy. They can inflate scores in cases where there is also physical illness, contain potentially distressing symptoms for some settings and be impractical in clinical practice. The present study aimed to develop and evaluate a new questionnaire, the paediatric index of emotional distress (PI-ED), to screen for emotional distress in CYP, modelled on the hospital anxiety and depression scale. Methods: A school-based sample (n = 1026) was employed to examine the PI-ED’s psychometric properties and a clinical sample of CYP (n = 143) was used to establish its sensitivity and specificity. Results: Exploratory and confirmatory factor analyses identified a bi-factor model with a general emotional distress factor (‘cothymia’) and anxiety and depression as co-factors. The PI-ED demonstrated good psychometric properties and clinical utility with a cutoff score of 20. Conclusion: The PI-ED is a brief, valid and reliable clinical screening tool for emotional distress in CYP

Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency

Objective: Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency(ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key role in glucocorticoid and sex steroid synthesis. POR also transfers electrons to all major drugmetabolizing CYP enzymes, including CYP3A4 that inactivates glucocorticoid and oestrogens. However, whether ORD results in impairment of in vivo drug metabolism has never been studied. Design:We studied an adult patient with ORD due to homozygous POR A287P, the most frequent POR mutation in Caucasians, and her clinically unaffected, heterozygous mother. The patient had received standard dose oestrogen replacement from 17 until 37 years of age when it was stopped after she developed breast cancer. Methods: Both subjects underwent in vivo cocktail phenotyping comprising the oral administration of caffeine, tolbutamide, omeprazole, dextromethorphan hydrobromide and midazolam to assess the five major drug-metabolizing CYP enzymes. We also performed genotyping for variant CYP alleles known to affect drug metabolism. Results: Though CYP enzyme genotyping predicted normal or high enzymatic activities in both subjects, in vivo assessment showed subnormal activities of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in the patient and of CYP1A2 and CYP2C9 in her mother. Conclusions: Our results provide in vivo evidence for an important role of POR in regulating drug metabolism and detoxification. In patients with ORD, in vivo assessment of drug-metabolizing activities with subsequent tailoring of drug therapy and steroid replacement should be considered

Metabolism of profenofos to 4-bromo-2-chlorophenol, a specific and sensitive exposure biomarker.

Profenofos is a direct acting phosphorothioate organophosphorus (OP) pesticide capable of inhibiting β-esterases such as acetylcholinesterase, butyrylcholinesterase, and carboxylesterase. Profenofos is known to be detoxified to the biologically inactive metabolite, 4-bromo-2-chlorophenol (BCP); however, limited data are available regarding the use of urinary BCP as an exposure biomarker in humans. A pilot study conducted in Egyptian agriculture workers, demonstrated that urinary BCP levels prior to application (3.3-30.0 μg/g creatinine) were elevated to 34.5-3,566 μg/g creatinine during the time workers were applying profenofos to cotton fields. Subsequently, the in vitro enzymatic formation of BCP was examined using pooled human liver microsomes and recombinant human cytochrome P-450s (CYPs) incubated with profenofos. Of the nine human CYPs studied, only CYPs 3A4, 2B6, and 2C19 were able to metabolize profenofos to BCP. Kinetic studies indicated that CYP 2C19 has the lowest Km, 0.516 μM followed by 2B6 (Km=1.02 μM) and 3A4 (Km=18.9μM). The Vmax for BCP formation was 47.9, 25.1, and 19.2 nmol/min/nmol CYP for CYP2B6, 2C19, and 3A4, respectively. Intrinsic clearance (Vmax/Km) values of 48.8, 46.9, and 1.02 ml/min/nmol CYP 2C19, 2B6, and 3A4, respectively, indicate that CYP2C19 and CYP2B6 are primarily responsible for the detoxification of profenofos. These findings support the use of urinary BCP as a biomarker of exposure to profenofos in humans and suggest polymorphisms in CYP 2C19 and CYP 2B6 as potential biomarkers of susceptibility

Xenobiotic metabolism: the effect of acute kidney injury on non-renal drug clearance and hepatic drug metabolism.

Acute kidney injury (AKI) is a common complication of critical illness, and evidence is emerging that suggests AKI disrupts the function of other organs. It is a recognized phenomenon that patients with chronic kidney disease (CKD) have reduced hepatic metabolism of drugs, via the cytochrome P450 (CYP) enzyme group, and drug dosing guidelines in AKI are often extrapolated from data obtained from patients with CKD. This approach, however, is flawed because several confounding factors exist in AKI. The data from animal studies investigating the effects of AKI on CYP activity are conflicting, although the results of the majority do suggest that AKI impairs hepatic CYP activity. More recently, human study data have also demonstrated decreased CYP activity associated with AKI, in particular the CYP3A subtypes. Furthermore, preliminary data suggest that patients expressing the functional allele variant CYP3A5*1 may be protected from the deleterious effects of AKI when compared with patients homozygous for the variant CYP3A5*3, which codes for a non-functional protein. In conclusion, there is a need to individualize drug prescribing, particularly for the more sick and vulnerable patients, but this needs to be explored in greater depth

Regulation of cytochrome P450 mRNA expression in primary porcine hepatocytes by selected secondary plant metabolites from chicory (Cichorium intybus L.)

Chicory (Cichorium intybus) has been shown to induce enzymes of pharmacokinetic relevance (cytochrome P450; CYP). The aim of this study was to investigate the effects of selected secondary plant metabolites with a global extract of chicory root, on the expression of hepatic CYP mRNA (1A2, 2A19, 2C33, 2D25, 2E1 and 3A29), using primary porcine hepatocytes. Of the tested secondary plant metabolites, artemisinin, scoparone, lactucin and esculetin all induced increased expression of specific CYPs, while esculin showed no effect. In contrast, a global extract of chicory root decreased the expression of CYP1A2, 2C33, 2D25 and 3A29 at high concentrations. The results suggest that purified secondary metabolites from chicory affect CYP expression and thereby might affect detoxification in general, and that global extracts of plants can have effects different from individual components