Hormesis and the universal cell response

(a) Gurevich, K. G., Agutter, P. S. & Wheatley, D. N. (2003) Stochastic description of the ligand-receptor interaction of biologically active substances at extremely low doses. Cell Signal. 15, 447-453. PMID: 12618219

Abstract: Signalling molecules can be effective at extraordinarily low concentrations (down to attomolar levels). To handle such cases, probabilistic methods have been used to describe the formal kinetics of action of biologically active substances in these low doses, although it has been necessary to review what is meant by such a term.

The mean numbers of transformed/degraded molecules and their dispersions were calculated for the possible range of ligand-receptor binding schemes. We used both analytical equations and numerical simulations to calculate the coefficients of variation (ratio of standard deviation to mean) and demonstrated that the distribution of the coefficient is highly dependent on the reaction scheme.

It may, therefore, be used as an additional factor for discriminating between cooperative and noncooperative models of ligand-receptor interaction over extreme ranges of ligand dilution. The relevance to signalling behaviour is discussed.

(b) Agutter, P. S. (2007) Cell mechanics and stress: from molecular details to the 'universal cell reaction' and hormesis. BioEssays 29, 324-333. PMID: 17373655

Abstract: The 'universal cell reaction' (UCR), a coordinated biphasic response to external (noxious and other) stimuli observed in all living cells, was described by Nasonov and his colleagues in the mid-20th century. This work has received no attention from cell biologists in the West, but the UCR merits serious consideration.

Although it is non-specific, it is likely to be underpinned by precise mechanisms and, if these mechanisms were characterized and their relationship to the UCR elucidated, then our understanding of the integration of cellular function could be improved. As a step towards identifying such mechanisms, I review some recent advances in understanding cell mechanics and the stress response and I suggest potentially testable hypotheses.

There is a particular need for time-course studies of cellular responses to different stimulus doses or intensities. I also suggest a correspondence with hormesis; re-investigation of the UCR using modern biophysical and molecular-biological techniques might throw light on this much-discussed phenomenon.

(c) Agutter, P. S. (2008) Elucidating the mechanism(s) of hormesis at the cellular level: the ‘universal cell response’. Am. J. Pharmacol.3, 97-107.

Abstract: Many environmental stressors elicit biphasic effects from single cells. Such ‘cellular hormesis’ may be interpreted in terms of (a) the superimposition of simple biochemical processes or (b) the non-specific behaviour of the cell. The latter approach is emphasized in this article and identified with the ‘universal cell response’ (UCR); however, the importance of identifying molecular-level concomitants of the UCR is also acknowledged.

One difficulty is that when the dose of ligand is very low, mass-action assumptions become invalid and reliable analysis of receptor-ligand interactions requires knowledge of the binding mechanism; this difficulty is discussed. The UCR (cellular hormesis) and its possible underlying mechanisms are considered in the framework of a general scheme of ‘cell life’, which logically implies cellular homeostasis or homeorhesis. This framework may be particularly helpful for elucidating and perhaps quantifying ‘conditioning hormesis’ (adaptation to stressors).

The findings of studies on the UCR cannot be extrapolated unequivocally to hormesis in whole organisms or populations, and cellular-level hormesis cannot be inferred from whole-organism hormesis. Nevertheless, it has been argued that a better understanding of the underlying cellular mechanisms, i.e. of the UCR, may facilitate the analysis of whole-organism and population data.