Biochimica et biophysica acta
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Biochim. Biophys. Acta · May 2007
Predominant expression of lysosomal N-acylethanolamine-hydrolyzing acid amidase in macrophages revealed by immunochemical studies.
Bioactive N-acylethanolamines, including anandamide (an endocannabinoid), N-palmitoylethanolamine (an anti-inflammatory substance), and N-oleoylethanolamine (an anorexic substance) are enzymatically hydrolyzed to fatty acids and ethanolamine. Fatty acid amide hydrolase plays a major role in this reaction. In addition, we cloned cDNA of an isozyme termed "N-acylethanolamine-hydrolyzing acid amidase (NAAA)" [K. ⋯ Conformably, the mRNA and protein levels and activity of NAAA in alveolar macrophages were much higher than those in the whole lung tissue. In brain, intraventricular macrophages were positively stained with anti-NAAA antibody, while microglia appeared to be negative. These results strongly suggested the importance of macrophages as an expression site of NAAA in rat tissues.
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Biochim. Biophys. Acta · Mar 2007
ReviewClinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes.
For many drugs, pharmacogenetic polymorphisms are known affecting biotransformation and clinical outcome. The clinical importance of these variants depends on allele-frequency and the effect size of the clinical outcome parameters. Further, it depends on the therapeutic range of the drug which is affected, on predictability of drug response as well as on duration until onset of therapeutic efficacy. ⋯ They can be derived from pharmacokinetic data with the aim to obtain equal drug concentrations in each individual. Prospective validation of dose adjustments based on pharmacogenetics should be performed before routine application of such strategies. A controlled prospective clinical trial with one arm receiving genotype-based dose adjustments and the other arm receiving therapy as usual will elucidate the benefit of pharmacogenomics-based individualization of certain drug therapies.
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Biochim. Biophys. Acta · Feb 2007
ReviewMolecular and cellular basis of calpainopathy (limb girdle muscular dystrophy type 2A).
Limb girdle muscular dystrophy type 2A results from mutations in the gene encoding the calpain 3 protease. Mutations in this disease are inherited in an autosomal recessive fashion and result in progressive proximal skeletal muscle wasting but no cardiac abnormalities. Calpain 3 has been shown to proteolytically cleave a wide variety of cytoskeletal and myofibrillar proteins and to act upstream of the ubiquitin-proteasome pathway. In this review, we summarize the known biochemical and physiological features of calpain 3 and hypothesize why mutations result in disease.
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Biochim. Biophys. Acta · Feb 2007
Neuroprotective effect of TNFalpha against the beta-amyloid neurotoxicity mediated by CDK5 kinase.
The tumor necrosis factor alpha (TNFalpha) plays a dual role in producing either neurodegeneration or neuroprotection in the central nervous system. Despite that TNFalpha was initially described as a cell death inductor, neuroprotective effects against cell death induced by several neurotoxic insults have been reported. Tau hyperphosphorylation and neuronal death found in Alzheimer disease is mediated by deregulation of the cdk5/p35 complex induced by Abeta treatments. ⋯ We observed that the pretreatment of neurons with TNFalpha reduces tau hyperphosphorylation. Taken together, these results define a novel neuroprotective effect of TNFalpha in preventing neuronal cell death and cdk5-dependent tau hyperphosphorylation. This phenomenon, taken together with other previous findings, suggests that the inflammatory response due to Abeta peptide plays a key role in the development of Alzheimer etiopathogenesis.
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Biochim. Biophys. Acta · Jan 2007
Comparative StudyExpression and purification of two anti-CD19 single chain Fv fragments for targeting of liposomes to CD19-expressing cells.
Antibody-targeted liposomal anticancer drugs combine the specificity of antibodies with large payloads of entrapped drugs. We previously showed that liposomal doxorubicin (DXR) targeted via anti-CD19 monoclonal antibodies (mAb) or their Fab' fragments against the B-cell antigen CD19 led to improved therapeutic effects in murine B-cell lymphoma models relative to non-targeted liposomal DXR. We now are examining the use of anti-CD19 single chain fragments of the antibody variable region (scFv) as a targeting moiety, to test the hypothesis that scFv have advantages over full-sized mAb or Fab' fragments. ⋯ When coupled to liposomes, the HD37-CCH scFv showed increased binding in vitro to CD19-positive Raji cells, compared to non-targeted liposomes. Cytotoxicity data showed that HD37-CCH scFv-targeted liposomes loaded with DXR were more cytotoxic than non-targeted liposomal DXR. Our results suggest that anti-CD19 scFv constructs should be explored further for their potential in treating B-lymphoid leukemias and lymphomas.