4 1 Background
Considering the evolutionary conservation of NO signaling among organisms,
we assumed that NO may also protect tumor cells from antitumor drugs. Indeed, we
observed that ART exerts its coordinated antitumor activity by covalently conjugating
NOS in the hepatoma cell line HepG 2. We also noticed that the transient heme bio-
synthesis is synchronous to potent NO burst and correlates with a higher survival rate
following incubating HepG 2 with 50 μM ART. In contrast, ART at above 100 μM
leads to the sharp decline of NO levels and remarkable decrease of survival rates of
cultured HepG 2 cells. It can be concluded, therefore, that ART plays a beneficial or
harmful role to tumor cells in a concentration-dependent pattern. A high level of NO
that is induced by 100 μM ART is toxic to tumor cells, whereas a lower level of NO
that is induced by 50 μM ART protects tumor cells (Zeng and Zhang 2011 ).
In 2012, we further discovered that the overload of bacteria, even with nonpath-
ogenic E. coli, in mouse gastrointestinal tracts by live bacterial feeding induces
inflammatory synovial lesions. The daily feeding of E. coli upregulates proinflam-
matory cytokines, elicits NO burst, drives hypoxic responses, and stimulates angi-
ogenesis and hyperplasia, suggesting that a sustained infection might be, in part,
responsible for the onset of synovitis and eventual development to RA (Bao et al.
2012 ). In mice with bacteria-induced synovitis, anti-inflammation by ART and
rapamycin (RAP) can abrogate NO production, mitigate hypoxia induction, and
considerably ameliorate or even completely abort synovitis, hence highlighting
that NO may serve as an initiator of inflammatory arthritis (Bao et al. 2012 ; Wu
et al. 2012 ). In 2013, we further observed that both endogenous and exogenous
NO enable the tumor-like neoplasia in hypodermal and synovial tissues, which can
be blocked by ART and betulilic acid (BLA) (Gao et al. 2015 ).
In the last year, we validated the covalent conjugation of ART to heme and the
synchronous induction of COX in yeast, assuming the inhibition of COX activ-
ity and upregulation of its expression. Interestingly, we found with surprise that
a trace amount of ART can mimic CR to extend yeast lifespan through an inter-
action of ART with COX similar with NOS, which initiates a cascade response
of metabolic conversions from biosynthesis to degradation (Wang et al. 2015a). It
has been documented that COX can be reversibly inhibited by NO via a competi-
tive heme binding, which leads to the so-called metabolic hypoxia, i.e., COX can-
not accept O 2 even there is enough O 2 (Xu et al. 2005 ). An essential consequence
of the metabolic hypoxia is mitochondrial uncoupling without energy production
albeit electron transport maintaining (Cerqueira et al. 2011 ).
We also investigated the effect of ART on telomere lengths and expression pro-
files by CR, NO, and H 2 O 2. Intriguingly, all of those treatments downregulate the
ubiquitylation pathway genes including tumor suppressor genes and other DNA
repair genes, but do not upregulate telomerase reverse transcriptase gene (Tert),
suggesting that an alleviation of chromosomal DNA damage may predispose the
compromise of telomere shortening rather than the elongation of telomeres (Wang
et al. 2015b).
Recently, we found that ART, 2,4-dinitrophenol (DNP), and nitroglycerin
(NG) exert weight-reducing effects in inflammatory obese mice induced by
HFD + LPS. All the examined drug monomers allow a substantial decline of