Fig. 1.1
The multifaceted beneficial effects exerted by ART through specifically targeting a variety of hemoproteins. ART artemisinin; bNOS bacterial nitric oxide synthase; COX cytochrome c oxidase; CR calorie restriction; NO nitric oxide; NOS nitric oxide synthase
Practically, if you always keep a steady-state NO level derived from eNOS/nNOS by CR or via supplementation with edible NO, you should have a lower chance to have inflammatory diseases. Similarly, if you use ART to inhibit bNOS or iNOS, you should live healthier because of enabling antitumor, anti-infection, and anti-inflammation. Of course, ART is unable to distinguish eNOS/nNOS from iNOS, so the best way to amplify the beneficial role of ART is to inhibit inflammation at first, and then use trace-amount ART.
1.2 A Uniform NO Threshold Theory in Disease and Health
Aging and longevity are constantly the interesting topics in exploring life secrets since ancient civilization. Even through extensive investigations, it remains mysterious how aging is switched and whether longevity can come true. Nevertheless, it is widely accepted that lifespan is determined by an individual genetic background and multiple environmental factors. Regardless of genetic determinations, it is believed that the natural aging process may be modulated to some extent through artificial interventions such as CR.
For an environmental impact on lifespan, Harman first proposed a free radical theory of aging early in the past century (Harman 1956), and later it was extended to be implicated in the structural and functional adaptation of mitochondria to nutritional stress stimuli (Harman 1972). According to Harman’s aging theory, free radicals are supposed to be responsible for biomolecule damage, which results in cellular changes and thus organismal aging. One of the main criticisms to his aging theory is that it only considers the harmful effects of free radicals, but ignores their beneficial roles (Afanas’ev 2010). Nowadays, it is known that ROS in a sublethal concentration have potentials to induce the antioxidative response and provide protection from further oxidative stress. This phenomenon has been called as “hormesis”‚ through which an intrinsic protective potential can be excited by a traceamount of toxic substance (Kaser 2003).
It has been gradually accepted that ROS are “double-edged swords” for living cells. Whether ROS are harmful or beneficial depends on their relative concentrations. In an extremely high concentration, ROS directly cause cell death, whereas in a relatively low concentration, they allow cell survival. So there must have a concentration threshold for ROS exerting a “good” or “bad” effect. Such a concentration-dependent ROS threshold is apparently governed by the homeostasis of cellular oxidation and antioxidation. When the attacking power from oxidants overwhelms the combating capacity by antioxidants, damage to cells and macromolecules must be ensued (Thannickal et al. 2000).
Except for ROS, free radicals also include reactive nitrogen species (RNS), mainly NO, ONOO−, nitric dioxide (NO2), and trinitric dioxide (N2O3). In general, a lower level of NO promotes cell survival and proliferation, while a higher level of NO favors cell cycle arrest, apoptosis, and senescence (Thomas et al. 2004). Because NO can react with O2 − to produce ONOO−, it means that more ROS predispose more RNS in the case of enhanced NO production. As an essential result, ONOO− must pose oxidative stress-like nitrosative stress to multiple systems and exert pathogenic effects on subjected organs (Patcher et al. 2007). NO has been shown to increase the mitochondrial levels of O2 − and H2O2 (Poderoso et al. 1996). We also found that NO and H2O2 can induce superoxide dismutase (SOD) and catalase (CAT) in yeast (Wang et al. 2015a) as well as in mouse skeletal muscle cells (Wang et al. 2015b).
Mitochondria are major subcellular compartments that generate ROS, which are originated from NO binding to COX. As previously noted, ROS within cells can be modulated by NO-mediated mitochondrial biogenesis (Nisoli and Carruba 2006). NO can thus affect the fate of living cells in either a ROS-independent or dependent manner. Although an extremely high level of NO plays a pathogenic or even lethal role, an appropriate level of NO exerts a beneficial and healthy effect. Such a consideration inspired us suggesting a threshold theory of NO-mediated disease and health effects.
This theory defines why NO has dual impacts on cells and organisms. An optimal 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 O2 supply, low-level NO loses a vasodilating function in blood vessels. NO can also react with O2 − 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 threshold 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 concentration 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 polymerase (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 functions physiologically, high-level NO (>400 nM) from iNOS behaves pathologically (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 insufficient 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 oxidative burst and eliciting antioxidative responses. The competitive binding of NO to COX precludes O2 binding, thereby leading to mitochondrial dysfunction and respiratory uncoupling (Boveris et al. 2010). Due to the mitochondrial NO-COX interaction, respiratory electron transport is forced to deliver electrons to O2. Consequently, O2 − is generated, which activates SOD to produce H2O2. Subsequently, H2O2 can further induce H2O2-degrading enzymes, such as CAT and POX. An appropriate level of NO, therefore, allows the induction of antioxidant enzymes for ROS scavenging, which enables the mitigation of chromosomal DNA damage and compromise of telomere shortening. It is well known that the length of telomeres is correlated with the lifespan of organisms from yeast to mammals (Vera et al. 2013). Therefore, longer telomeres underlies extended lifespan.
High-level NO behaves as an etiological initiator of tumor-like pathogenesis. The inhibitory effect of high-level NO on O2 binding to hemoglobin within red blood cells interprets a preanoxic state occurring due to restricted O2 supply to blood vessel-dispersed tissues. In the case of low O2 and long distance from the capillary, the inhibition of mitochondrial and cellular O2 uptake allows O2 to further diffuse away in the tissue (Poderoso et al. 1996). NO decreases the steepness of the O2 gradient in the preanoxic border, in which O2 becomes a rate-limiting factor for O2 uptake by a low O2/NO ratio, gradually decreases O2 uptake, and leaves O2 to reach cells that would be anoxic (Poderoso et al. 1996). The computational model established by Thomas et al. (2001) has shown that a reversible inhibition of cellular O2 uptake by NO substantially extends the zone of adequate tissue oxygenation away from the blood vessel. However, when NO is overproduced due to pathogenic infection and immune activation, a tumor-like angiogenesis and hyperplasia may take place in the synovial tissues of joints. The thickened pannus with massive vasculatures and infiltrated lymphocytes was observed microscopically upon the histochemical staining of synovial tissues (Bao et al. 2012; Wu et al. 2012).
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