7This theory defines why NO has dual impacts on cells and organisms. An opti-
mal level of NO that triggers tolerable doses of ROS can induce antioxidative
responses, provide cellular protection, and exert healthy effects. In contrast, when
endogenous NO levels are too high (after infection) or too low (due to aging), an
abnormal or even pathogenic status may occur and maintain. While high-level NO
causes an insufficiency of O 2 supply, low-level NO loses a vasodilating function in
blood vessels. NO can also react with O 2 − to generate ONOO−, which would lead
to a harmful role to cells through nitrosylating/nitrating the target proteins.
The major annotations on our suggested “a threshold theory of NO-mediated
disease and health effects” are summarized as follows:
• A physiological NO level is distinguished from a pathological NO level.
While NO is beneficial to cells at a low level, or at a physiological level, it is
harmful to cells at a high level, or at a pathological level. What is the thresh-
old of NO distinguishing a physiological level from a pathological level?
According to previous analytic data provided by other authors, a sustained NO
concentration of 10–30 nM allows the phosphorylation of extracellular signal-
regulated kinases mediated by cyclic guanosine monophosphate (cGMP), while
30–60 nM NO leads to the phosphorylation of protein kinase B (Thomas et al.
2004 ). A higher NO concentration reaching 100 nM results in the stabilization
of hypoxia inducible factor 1 alpha (HIF-1α) (Thomas et al. 2004 ). At the con-
centration of 400 nM, NO enables the phosphorylation and acetylation of the
tumor suppressor p53 (Ridnour et al. 2004 ). Higher levels of NO from 800 nM
to 1 μM can cause the nitration of polyadenosine diphosphate-ribose polymer-
ase (PARP), which confers the inhibition of mitochondrial respiration (Borutaite
and Brown 2006 ).
• NO levels are determined by distinct NOS isoforms and dependent on
external stimuli. While low-level NO (<200 nM) from eNOS or nNOS func-
tions physiologically, high-level NO (>400 nM) from iNOS behaves pathologi-
cally (Thomas et al. 2010 ). Because proinflammatory cytokines are activated by
pathogenic infection and immunization, it is implied that a physiological NO
level appears under a normal condition, while a pathological NO level occurs in
an aberrant state. In theory, NO-mediated pathogenesis can be avoided via anti-
infection and/or anti-inflammation. Aging organisms may be subjected to insuf-
ficient NO supply due to decreased NO production, especially in the exceptional
mitochondrial dysfunction. It was found that NOS activity within mitochondria
decreases to as low as 45–75 % in aged mouse brain and hippocampus (Navarro
et al. 2008 ).
• Low-level NO exerts longevity-promoting effects through triggering oxi-
dative burst and eliciting antioxidative responses. The competitive binding
of NO to COX precludes O 2 binding, thereby leading to mitochondrial dysfunc-
tion and respiratory uncoupling (Boveris et al. 2010 ). Due to the mitochondrial
NO-COX interaction, respiratory electron transport is forced to deliver electrons
to O 2. Consequently, O 2 − is generated, which activates SOD to produce H 2 O 2.
Subsequently, H 2 O 2 can further induce H 2 O 2 -degrading enzymes, such as CAT and
1.2 A Uniform NO Threshold Theory in Disease and Health