Zhu Chen

Atrial fibrillation (AF) is a common cardiac arrhythmia whose molecular etiology is poorly understood. We studied a family with hereditary persistent AF and identified the causative mutation (S140G) in the KCNQ1 (KvLQT1) gene on chromosome 11p15.5. The KCNQ1 gene encodes the pore-forming alpha subunit of the cardiac I(Ks) channel (KCNQ1/KCNE1), the KCNQ1/KCNE2 and the KCNQ1/KCNE3 potassium channels. Functional analysis of the S140G mutant revealed a gain-of-function effect on the KCNQ1/KCNE1 and the KCNQ1/KCNE2 currents, which contrasts with the dominant negative or loss-of-function effects of the KCNQ1 mutations previously identified in patients with long QT syndrome. Thus, the S140G mutation is likely to initiate and maintain AF by reducing action potential duration and effective refractory period in atrial myocytes.

Recent clinical studies in China showed that As2O3 is an effective and relatively safe drug in the treatment of acute promyelocytic leukemia (APL). We found previously that As2O3 can trigger apoptosis of APL cell line NB4 cells, which is associated with downregulation of bcl-2 gene expression and modulation of PML-RAR alpha chimeric protein. To further understand the mechanisms of this alternative therapy for APL, we investigated in this report the effects of a wide range of concentrations of As2O2 on cultured primary APL cells, all-trans retinoic acid (ATRA)-susceptible (NB4 cells) and ATRA-resistant (MR2 subclone) APL cell lines. The results indicated that As2O3 had dose-dependent dual effects on APL cells: inducing preferentially apoptosis at relatively high concentrations (0.5 to 2 micromol/L) and inducing partial differentiation at low concentrations (0.1 to 0.5 micromol/L). The rapid modulation and degradation of PML-RAR alpha proteins, which was induced by As2O3 at 0.1 to 2 micromol/L, could contribute to these two effects. Bone marrow and peripheral blood examination showed that myelocyte-like cells, probably as a result of partial in vivo differentiation, and degenerative cells increased after 2 to 3 weeks of continuous in vivo As2O3 treatment when leukemic promyelocytes decreased. In conclusion, combination of induction of apoptosis and partial differention could be the main cellular mechanisms of As2O3 in the treatment of APL, and PML-RAR alpha could play an important role in determining the specific effects of As2O3 on APL cells.

Phenotypic modification of dorsal root ganglion (DRG) neurons represents an important mechanism underlying neuropathic pain. However, the nerve injury-induced molecular changes are not fully identified. To determine the molecular alterations in a broader way, we have carried out cDNA array on the genes mainly made from the cDNA libraries of lumbar DRGs of normal rats and of rats 14 days after peripheral axotomy. Of the 7,523 examined genes and expressed sequence tags (ESTs), the expression of 122 genes and 51 expressed sequence tags is strongly changed. These genes encompass a large number of members of distinct families, including neuropeptides, receptors, ion channels, signal transduction molecules, synaptic vesicle proteins, and others. Of particular interest is the up-regulation of gamma-aminobutyric acid(A) receptor alpha5 subunit, peripheral benzodiazepine receptor, nicotinic acetylcholine receptor alpha7 subunit, P2Y1 purinoceptor, Na(+) channel beta2 subunit, and L-type Ca(2+) channel alpha2delta-1 subunit. Our findings therefore reveal dynamic and complex changes in molecular diversity among DRG neurons after axotomy. Sequences reported in this paper have been deposited in the GenBank database (accession numbers BG 662484-BG 673712)