Little is known about the mechanisms as to how nutrients affect plasma corticosteroids in cold-stressed and starved animals. Therefore, cold-stressed rats (maintained at 7 °C) were fasted (control) or fed a balanced diet (casein 20wt%, fat 5 wt%, starch 70 wt% and vitamin-mineral premix 5 wt%) or the following dietary nutrients for 72 h: casein, lard, starch, glycerol, stearic acid, leucine or glutamic acid. The animals were then killed and plasma corticosteroid concentrations (PCC) were determined. PCC were significantly reduced (p < 0.05) in cold-stressed animals fed a balanced diet (16.95 µg/100 ml plasma) compared to the fasted cold-stressed controls (FCSC) (24.16µg/100ml plasma). Additionally, corticosteroid concentrations (µg/100 ml plasma) of animals fed the following specific nutrients were also significantly lower than the FCSC values: starch (15.53), lard (12.01), stearic acid (12.74), glycerol (13.32) and leucine (16.03). Casein and glutamic acid did not significantly alter plasma corticosteroid levels relative to the FCSC concentration. It is concluded that certain specific building blocks of nutrient classes, i.e. stearic acid or glycerol, can alter PCC to the same extent as the parent compound (lard), however the individual components of casein, a complex nutrient, i.e. leucine, a ketogenic amino acid, versus glutamic acid, a glycogenic amino acid, may elicit a different PCC effect.
The Author and a Colleague Reply: We agree with Domagala et al. that future clinical development of PARP inhibitors may rely on a more thorough understanding of the role of PARP expression within tumors. Indeed, von Minckwitz recently reported that cytoplasmic PARP1 correlated with rates of pathological complete response after neoadjuvant chemotherapy treatment of breast cancer. 1 However, it is worth noting that iniparib probably has additional targets that have not yet been identified. An earlier study showed covalent binding of a metabolite of iniparib to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in a RAS-transformed cell line and dose-dependent inhibition of GAPDH by the same metabolite in biochemical assays. 2 The relative importance of this and other potential targets is yet unknown and remains a topic of investigation.Because of the likely existence of additional clinically relevant targets of iniparib, we are taking an approach that is mechanism-independent and based on profiling of messenger RNA expression to identify markers that are predictive of iniparib activity. This approach uses preclinical models and archival human tissues.
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