A microarray study of MPP(+)-treated PC12 Cells: Mechanisms of toxicity (MOT) analysis using bioinformatics tools

BACKGROUND: This paper describes a microarray study including data quality control, data analysis and the analysis of the mechanism of toxicity (MOT) induced by 1-methyl-4-phenylpyridinium (MPP(+)) in a rat adrenal pheochromocytoma cell line (PC12 cells) using bioinformatics tools. MPP(+ )depletes dopamine content and elicits cell death in PC12 cells. However, the mechanism of MPP(+)-induced neurotoxicity is still unclear. RESULTS: In this study, Agilent rat oligo 22K microarrays were used to examine alterations in gene expression of PC12 cells after 500 μM MPP(+ )treatment. Relative gene expression of control and treated cells represented by spot intensities on the array chips was analyzed using bioinformatics tools. Raw data from each array were input into the NCTR ArrayTrack database, and normalized using a Lowess normalization method. Data quality was monitored in ArrayTrack. The means of the averaged log ratio of the paired samples were used to identify the fold changes of gene expression in PC12 cells after MPP(+ )treatment. Our data showed that 106 genes and ESTs (Expressed Sequence Tags) were changed 2-fold and above with MPP(+ )treatment; among these, 75 genes had gene symbols and 59 genes had known functions according to the Agilent gene Refguide and ArrayTrack-linked gene library. The mechanism of MPP(+)-induced toxicity in PC12 cells was analyzed based on their genes functions, biological process, pathways and previous published literatures. CONCLUSION: Multiple pathways were suggested to be involved in the mechanism of MPP(+)-induced toxicity, including oxidative stress, DNA and protein damage, cell cycling arrest, and apoptosis

Genetic polymorphisms of the RAS-cytokine pathway and chronic kidney disease

Chronic kidney disease (CKD) in children is irreversible. It is associated with renal failure progression and atherosclerotic cardiovascular (CV) abnormalities. Nearly 60% of children with CKD are affected since birth with congenital or inherited kidney disorders. Preliminary evidence primarily from adult CKD studies indicates common genetic risk factors for CKD and atherosclerotic CV disease. Although multiple physiologic pathways share common genes for CKD and CV disease, substantial evidence supports our attention to the renin angiotensin system (RAS) and the interlinked inflammatory cascade because they modulate the progressions of renal and CV disease. Gene polymorphisms in the RAS-cytokine pathway, through altered gene expression of inflammatory cytokines, are potential factors that modulate the rate of CKD progression and CV abnormalities in patients with CKD. For studying such hypotheses, the cooperative efforts among scientific groups and the availability of robust and affordable technologies to genotype thousands of single nucleotide polymorphisms (SNPs) across the genome make genome-wide association studies an attractive paradigm for studying polygenic diseases such as CKD. Although attractive, such studies should be interpreted carefully, with a fundamental understanding of their potential weaknesses. Nevertheless, whole-genome association studies for diabetic nephropathy and future studies pertaining to other types of CKD will offer further insight for the development of targeted interventions to treat CKD and associated atherosclerotic CV abnormalities in the pediatric CKD population

Long-term results after a triple arthrodesis of the hindfoot: function and satisfaction in 36 patients

The long-term functional results of a triple arthrodesis of the hindfoot are not well known. In this retrospective cohort study we therefore investigated pain, function and aligment of the tibiotalar joint, patient satisfaction with the procedure and the prevalence of osteoarthritis (OA) of the tibiotalar joint after a median follow-up of six years. We also aimed to investigate whether there are patient and surgical characteristics associated with the outcome. Patients who underwent a triple arthrodesis for OA between January 1992 and July 2002 were invited to participate. A clinical examination was performed, the Ankle-Hindfoot Scale was completed, and radiographs were taken. Patient characteristics (e.g., age, gender and the indication for operation) and surgical characteristics (e.g., fixation material and use of bone graft) were collected. Sixty-one percent (22 patients) of the patients had a good total score on the Ankle-Hindfoot Scale. Nineteen patients (53%) were satisfied with the result of the operation and 47% of the patients had radiographic OA of the tibiotalar joint. In a univariate regression analysis, male gender and the score on the Ankle-Hindfoot Scale were significantly associated with radiographic OA. Patient satisfaction was significantly associated with a higher score on the Ankle-Hindfoot Scale and better dorsi–flexion of the ankle. Our study shows that 61% of the procedures in 36 patients with a triple arthrodesis for OA had a good score on the Ankle-Hindfoot Scale. Radiographic OA of the ankle was present in 47% of the cases and was not related to patient satisfaction. No patient characteristics or surgical characteristics were associated with the score on the Ankle-Hindfoot Scale

Stepwise oscillatory circuits of a DNA molecule

A DNA molecule is characterized by a stepwise oscillatory circuit where every base pair is a capacitor, every phosphate bridge is an inductance, and every deoxyribose is a charge router. The circuitry accounts for DNA conductivity through both short and long distances in good agreement with experimental evidence that has led to the identification of the so-called super-exchange and multiple-step hopping mechanisms. However, in contrast to the haphazard hopping and super-exchanging events, the circuitry is a well-defined charge transport mechanism reflecting the great reliability of the genetic substance in delivering electrons. Stepwise oscillatory charge transport through a nucleotide sequence that directly modulates the oscillation frequency may have significant biological implications

Merging ExpoCast™ with ToxCast™: Incorporating High-Throughput Exposure Predictions with Dosimetry-Adjusted In Vitro Bioactivity to Inform Toxicity Testing Strategies

Presented at the Annual Society for Toxicology meetin