Protection of Rat Skeletal Muscle Fibers by Either L-Carnitine or Coenzyme Q10 Against Statins Toxicity Mediated by Mitochondrial Reactive Oxygen Generation.

Protection of rat skeletal muscle fibers by either L-carnitine or coenzyme Q10 against statins toxicity mediated by mitochondrial reactive oxygen generation.

Front Physiol. 2013; 4: 103
La Guardia PG, Alberici LC, Ravagnani FG, Catharino RR, Vercesi AE

Mitochondrial redox imbalance has been implicated in mechanisms of aging, various degenerative diseases and drug-induced toxicity. Statins are safe and well-tolerated therapeutic drugs that occasionally induce myotoxicity such as myopathy and rhabdomyolysis. Previous studies indicate that myotoxicity caused by statins may be linked to impairment of mitochondrial functions. Here, we report that 1-h incubation of permeabilized rat soleus muscle fiber biopsies with increasing concentrations of simvastatin (1-40 ?M) slowed the rates of ADP-or FCCP-stimulated respiration supported by glutamate/malate in a dose-dependent manner, but caused no changes in resting respiration rates. Simvastatin (1 ?M) also inhibited the ADP-stimulated mitochondrial respiration supported by succinate by 24% but not by TMPD/ascorbate. Compatible with inhibition of respiration, 1 ?M simvastatin stimulated lactate release from soleus muscle samples by 26%. Co-incubation of muscle samples with 1 mM L-carnitine, 100 ?M mevalonate or 10 ?M coenzyme Q10 (Co-Q10) abolished simvastatin effects on both mitochondrial glutamate/malate-supported respiration and lactate release. Simvastatin (1 ?M) also caused a 2-fold increase in the rate of hydrogen peroxide generation and a decrease in Co-Q10 content by 44%. Mevalonate, Co-Q10 or L-carnitine protected against stimulation of hydrogen peroxide generation but only mevalonate prevented the decrease in Co-Q10 content. Thus, independently of Co-Q10 levels, L-carnitine prevented the toxic effects of simvastatin. This suggests that mitochondrial respiratory dysfunction induced by simvastatin, is associated with increased generation of superoxide, at the levels of complexes-I and II of the respiratory chain. In all cases the damage to these complexes, presumably at the level of 4Fe-4S clusters, is prevented by L-carnitine. HubMed – drug


Semi-Nested Real-Time Reverse Transcription Polymerase Chain Reaction Methods for the Successful Quantitation of Cytokeratin mRNA Expression Levels for the Subtyping of Non-Small-Cell Lung Carcinoma Using Paraffin-Embedded and Microdissected Lung Biopsy Specimens.

Acta Histochem Cytochem. 2013 Apr 30; 46(2): 85-96
Nakanishi Y, Shimizu T, Tsujino I, Obana Y, Seki T, Fuchinoue F, Ohni S, Oinuma T, Kusumi Y, Yamada T, Takahashi N, Hashimoto S, Nemoto N

In patients with inoperable advanced non-small cell lung carcinomas (NSCLCs), histological subtyping using small-mount biopsy specimens was often required to decide the indications for drug treatment. The aim of this study was to assess the utility of highly sensitive mRNA quantitation for the subtyping of advanced NSCLC using small formalin fixing and paraffin embedding (FFPE) biopsy samples. Cytokeratin (CK) 6, CK7, CK14, CK18, and thyroid transcription factor (TTF)-1 mRNA expression levels were measured using semi-nested real-time quantitative (snq) reverse-transcribed polymerase chain reaction (RT-PCR) in microdissected tumor cells collected from 52 lung biopsies. Our results using the present snqRT-PCR method showed an improvement in mRNA quantitation from small FFPE samples, and the mRNA expression level using snqRT-PCR was correlated with the immunohistochemical protein expression level. CK7, CK18, and TTF-1 mRNA were expressed at significantly higher levels (P<0.05) in adenocarcinoma (AD) than in squamous cell carcinoma (SQ), while CK6 and CK14 mRNA expression was significantly higher (P<0.05) in SQ than in AD. Each histology-specific CK, particularly CK18 in AD and CK6 in SQ, were shown to be correlated with a poor prognosis (P=0.02, 0.02, respectively). Our results demonstrated that a quantitative CK subtype mRNA analysis from lung biopsy samples can be useful for predicting the histology subtype and prognosis of advanced NSCLC. HubMed – drug


Genetic and epigenetic variants contributing to clofarabine cytotoxicity.

Hum Mol Genet. 2013 May 29;
Eadon MT, Wheeler HE, Stark AL, Zhang X, Moen EL, Delaney SM, Im HK, Cunningham PN, Zhang W, Dolan ME

Clofarabine, a purine nucleoside analog, is used in the treatment of hematologic malignancies and as induction therapy for stem cell transplantation. The discovery of pharmacogenomic markers associated with chemotherapeutic efficacy and toxicity would greatly benefit the utility of this drug. Our objective was to identify genetic and epigenetic variants associated with clofarabine toxicity using an unbiased, whole genome approach. To this end, we employed International HapMap lymphoblastoid cell lines (190 LCLs) of European (CEU) or African (YRI) ancestry with known genetic information to evaluate cellular sensitivity to clofarabine. We measured modified cytosine levels to ascertain the contribution of genetic and epigenetic factors influencing clofarabine-mediated cytotoxicity. Association studies revealed 182 single nucleotide polymorphisms (SNPs) and 143 modified cytosines associated with cytotoxicity in both populations at the threshold p???0.0001. Correlation between cytotoxicity and baseline gene expression revealed 234 genes at p???3.98×10(-6). Six genes were implicated as: (1) their expression was directly correlated to cytotoxicity, (2) they had a targeting SNP associated with cytotoxicity, and (3) they had local modified cytosines associated with gene expression and cytotoxicity. We identified a set of 3 SNPs and 3 CpG sites targeting these six genes explaining 43.1% of the observed variation in phenotype. siRNA knockdown of the top three genes (SETBP1, BAG3, KLHL6) in LCLs revealed altered susceptibility to clofarabine, confirming relevance. As clofarabine’s toxicity profile includes acute kidney injury, we examined the effect of siRNA knockdown in HEK293 cells. siSETBP1 led to a significant change in HEK293 cell susceptibility to clofarabine. HubMed – drug


Drug-Target interaction prediction through Domain-Tuned Network Based Inference.

Bioinformatics. 2013 May 29;
Alaimo S, Pulvirenti A, Giugno R, Ferro A

MOTIVATION: The identification of Drug-Target Interaction (DTI) represents a costly and time consuming step in the drug discovery and design. Computational methods capable to predict reliable DTI play an important role in the field. Recently recommendation methods relying on Network Based Inference (NBI) have been proposed. However, such approaches implement naive topology based inference and do not take into account important features within the drug-target domain. RESULTS: In this paper we present a new Network Based Inference method, called Domain Tuned-Hybrid (DT-Hybrid), which extends a well establish recommendation technique by domain-based knowledge including drugs and targets similarity. DT-Hybrid has been extensively tested using the last version of experimentally validated drug-target interaction database obtained from DrugBank. Comparison with other recently proposed NBI methods clearly show that DT-Hybrid is capable of predicting more reliable drug-target interactions. AVAILABILITY: DT-Hybrid has been developed in R, and is available, along with all the results on the predictions, through an R package at the following url CONTACT: HubMed – drug



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