Oncostatin M: Risks and Benefits of a Novel Therapeutic Target for Atherosclerosis.

BACKGROUND: Cardiovascular disease (CVD) is a leading cause of death worldwide. It is predicted that approximately 23.6 million people will die from CVDs annually by 2030. Therefore, there is a great need for an effective therapeutic approach to combat this disease. The European Cardiovascular Target Discovery (CarTarDis) consortium identified Oncostatin M (OSM) as a potential therapeutic target for atherosclerosis. The benefits of modulating OSM - an interleukin (IL)-6 family cytokine - have since been studied for multiple indications. However, as decades of high attrition rates have stressed, the success of a drug target is determined by the fine balance between benefits and the risk of adverse events. Safety issues should therefore not be overlooked. OBJECTIVE: In this review, a risk/benefit analysis is performed on OSM inhibition in the context of atherosclerosis treatment. First, OSM signaling characteristics and its role in atherosclerosis are described. Next, an overview of in vitro, in vivo, and clinical findings relating to both the benefits and risks of modulating OSM in major organ systems is provided. Based on OSM's biological function and expression profile as well as drug intervention studies, safety concerns of inhibiting this target have been identified, assessed, and ranked for the target population. CONCLUSION: While OSM may be of therapeutic value in atherosclerosis, drug development should also focus on de-risking the herein identified major safety concerns: tissue remodeling, angiogenesis, bleeding, anemia, and NMDA- and glutamate-induced neurotoxicity. Close monitoring and/or exclusion of patients with various comorbidities may be required for optimal therapeutic benefit.

Induction of ethoxy-resorufin-O-deethylase activity by halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons in primary hepatocytes of the green frog (Rana esculenta).

In this study, we measured the ethoxy-resorufin-O-deethylase (EROD) activity in primary hepatocytes of the common green frog Rana esculenta as a biomarker for cytochrome P4501A induction. We exposed hepatocytes derived from male and female frogs to several halogenated aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PCDF), polychlorinated biphenyls (PCB-126, PCB-118), and polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BaP), chrysene, anthracene, and pyrene. Exposure to PCB-118, anthracene, and pyrene, up to 1 microM, did not induce EROD activity, whereas TCDD and PCDF induced EROD activity maximally. In our primary frog hepatocytes, exposure to chrysene and BaP resulted in median effective concentration values (EC50) in the high nM range (82-1035 nM). Exposure to TCDD, PCDF, and PCB-126 resulted in EC50 values of 0.4 to 8, 0.07 to 0.7, and 3 to 133 nM, respectively, which is in the same range as EC50 values found in primary hepatocytes of birds. Compared to our frog hepatocytes, primary rat hepatocytes seem to be more sensitive to TCDD, chrysene, and BaP.

Estrogenic effects in fish in The Netherlands: some preliminary results.

Recently, a large-scale field study in The Netherlands has focused on the effects of estrogenic contaminants on feral fish populations. The freshwater bream (Abramis brama) and the estuarine flounder (Platichthys flesus) were sampled at a large number of locations in the spring and autumn of 1999. Concentrations of the yolk protein vitellogenin (VTG) in blood plasma of male flounders were small at most sites. At two sites, however, moderately elevated concentrations were found in autumn. Both sites were situated in the same industrial harbour zone also receiving effluent from sewage treatment works. At many sites VTG levels in male bream were significantly greater than at the control site. The greatest concentrations were observed in individuals collected from a small stream, close to the discharge of a relatively large municipal waste water treatment plant. This was also the only site where considerable intersex occurred; 37% of male bream exhibited ovotestes. Ovotestis was not observed in any of the male flounder captured. The results from The Netherlands are briefly discussed and compared with the well-known case studies in the UK.