👤 Leroy Hood

We discuss here a new approach to detecting hepatotoxicity by employing concentration changes of liver-specific blood proteins during disease progression. These proteins are capable of assessing the behaviors of their cognate liver biological networks for toxicity or disease perturbations. Blood biomarkers are highly desirable diagnostics as blood is easily accessible and baths virtually all organs. Fifteen liver-specific blood proteins were identified as markers of acetaminophen (APAP)-induced hepatotoxicity using three proteomic technologies: label-free antibody microarrays, quantitative immunoblotting, and targeted iTRAQ mass spectrometry. Liver-specific blood proteins produced a toxicity signature of eleven elevated and four attenuated blood protein levels. These blood protein perturbations begin to provide a systems view of key mechanistic features of APAP-induced liver injury relating to glutathione and S-adenosyl-L-methionine (SAMe) depletion, mitochondrial dysfunction, and liver responses to the stress. Two markers, elevated membrane-bound catechol-O-methyltransferase (MB-COMT) and attenuated retinol binding protein 4 (RBP4), report hepatic injury significantly earlier than the current gold standard liver biomarker, alanine transaminase (ALT). These biomarkers were perturbed prior to onset of irreversible liver injury. Ideal markers should be applicable for both rodent model studies and human clinical trials. Five of these mouse liver-specific blood markers had human orthologs that were also found to be responsive to human hepatotoxicity. This panel of liver-specific proteins has the potential to effectively identify the early toxicity onset, the nature and extent of liver injury and report on some of the APAP-perturbed liver networks. Show less

The neurexins are neuronal proteins that function as cell adhesion molecules during synaptogenesis and in intercellular signaling. Although mammalian genomes contain only three neurexin genes, thousands of neurexin isoforms may be expressed through the use of two alternative promoters and alternative splicing at up to five different positions in the pre-mRNA. To begin understanding how the expression of the neurexin genes is regulated, we have determined the complete nucleotide sequence of all three human neurexin genes: NRXN1, NRXN2, and NRXN3. Unexpectedly, two of these, NRXN1 ( approximately 1.1 Mb) and NRXN3 ( approximately 1.7 Mb), are among the largest known human genes. In addition, we have identified several conserved intronic sequence elements that may participate in the regulation of alternative splicing. The sequences of these genes provide insight into the mechanisms used to generate the diversity of neurexin protein isoforms and raise several interesting questions regarding the expression mechanism of large genes. Show less