Medicaments: Gifts from the jungle

AMONG natural animal toxins, snake venom causes many fatal consequences in humans in tropical areas and is one of the most frequent dangerous contacts with these animals. Snake venom reaching the blood circulation could lead to, among other events, decreased pulse frequency, drop of blood pressure, and lethal respiratory and circulatory failure. Among the biological activities of the venom, the cardiovascular system cramping effects were most obviously detected and registered. The Brazilian Butantan Institute in Sao Paulo is world famous for its research struggle in creating life saving medicaments and antidotes. The analysis of venom produced by different snakes revealed many active components showing a broad range of therapeutical relevance. Therefore many medicaments now have snake venom-related agents. Pyroglutamyl proline-rich oligopeptides, present in the venom of the pit viper Bothrops jararaca (Bj-PROs), were the first described naturally occurring inhibitors of the angiotensin I-converting enzyme (ACE), the main target in the anti-hypertensive therapy. Recent results suggest ACE inhibition-independent mechanisms for ACE inhibitors (1,2). Using calcium imaging by confocal microscopy and fluorescence imaging plate, Lameu et al. (in this issue) have characterized Bj-PRO-10c-induced [Ca]i transients in rat brain cells as being independent from bradykinin-mediated effects and ACE inhibition. By these experiments, a yet unknown receptor that induced influx and liberation of calcium from internal stores, as well as reduction of intracellular cAMP levels, was detected. The determination of the presence and number of circulating tumor cells (CTCs) is crucial for cancer therapy and follow-up. One potential assay is their magnetic enrichment and fluorescence in situ hybridization (3). Hu et al. (in this issue) have developed a multichromatic flow cytometry assay to determine the number of CTCs in breast cancer patients. The authors used a combined staining for Epithelial-cell adhesion molecule, Cytokeratin 8, 18, 19, and CD45 (to remove the abundant leukocytes). The presence of CTCs in the peripheral blood was found to be related with the presence of primary tumor or metastases and potential relationship is under analysis with the survival time and relapse of the tumor. This flow cytometry assay was proven to have higher specificity of detection of the CTCs than the RT PCR method and has the potential to be a valuable tool for prognosis assessment among breast cancer patients. Recently, Zhao et al. (4) compared histone H2AX phosphorylation with checkpoint 2 kinase (Chk2) activation in a cell culture model during topoisomerase inhibitor induced apoptosis. While H2AX phosphorylation and Chk2 activation were maximal in S-phase cells, Chk2 activation was also much pronounced in G(2)M cells; the least affected by TPT were G(1) cells. MTX-induced H2AX phosphorylation was maximal in G(1) cells, whereas Chk2 activation was maximal in G(2)M and minimal in G(1) cells. Ozawa (5) in turn reported that phosphorylation of serine on histone H3 occurs during cell cycle at G2/M transition but is also down-regulated by DNA damage. Zhao et al’s recent work focuses on histone phosphorylation for the detection of DNA damage response in G1 and Sphase (in this issue). Phosphorylation of H2AX, P53, and some other proteins were detected with phospho-specific Abs and measured by laser scanning cytometry. In relation to the cell cycle phase, the induced responses were found to be selective for S-phase cells. These data are consistent with the mechanism in which stalling of DNA replication ‘‘forks’’ upon collision with the primary UV-induced DNA lesions and likely formation of double-strand DNA breaks triggers DDR. The prior reports (6) on induction of cH2AX in G1 cells by UV may have erroneously identified cells initiating DNA replication