2.1. Inflammatory Pathway-
It has been established that FOXOs are crucial for hepatic metabolism
(Fig 3). Inhibiting cell growth, oxidative stress, and the development
of apoptogenic signals, which are mediated by the overexpression of
Bcl-2-associated X protein (Bax) and FOXO-1 expression and the
downregulation of B-cell leukemia/lymphoma 2 protein (Bcl-2), are some
of the ways that cyclic isoprenoid (I) inhibits DENA-induced HCC
significantly (Abd-Elbaset et al., 2020). βI also reduced the expression
of the proliferative marker Ki-67 mRNA and prevented
hepatocarcinogenesis. The abnormal pro-inflammatory mediators expressed
involving nitric oxide (NO), Prostaglandin E2 (PGE2), as well as Tumor
necrosis factor alpha (TNF-α), which are generated by microglial cells,
are a hallmark of immunological diseases like AD. Therefore,
downregulating pro-inflammatory mediators is a promising method for
managing brain inflammatory diseases. Recent research has found that βI
has strong anti-proliferative along with anti-cancerous effects. The
study also showed that βI suppresses Akt-dependent NF-kB activity as
well as dephosphorylates Mitogen-activated protein kinase (MAPKs) to
decrease the expressed mediators of pro-inflammation along with their
regulatory genes in BV2 microglia that have been activated by LPS (Chen
et al., 2010). Both studies demonstrate the anticancer as well as
anti-inflammatory characteristics of β-ionone, which further reduce
liver injury and AD respectively. Studies have shown that inflammation
in the liver results in the onset of AD. The mechanism behind this is
not clear and no study has yet implicated the link between them (Kang et
al., 2013). Therefore, future studies can be done to confirm the above.
Inhibiting the FOXO1 improved lipid-persuaded stress of ER as well as
necroptosis, which is one of the protecting Inhibition of FOXO1 in a
mouse model of non-alcoholic fatty liver disease has certain
characteristics. Mice, however, displayed reduced levels of steatosis
when fed a fat-rich diet, and treatment was done with a FOXO1 inhibitor.
Intriguingly, postulate that the FOXO1 inhibitor AS1842856 functions by
hindering the phosphorylation pathway (Wang et al., 2016). It was seen
that AS1842856 specifically inhibits FOXO1 without changing its
phosphorylation. Inhibitors were utilized to reduce FOXO1 function in
this case as opposed to a gene deletion (Nagashima et al., 2010).
Inhibiting FOXO1 prevents the development of ER stress as well as
necrosis and also prevents NAFLD. The cause of NASH, or a deteriorating
condition known as liver fibrosis, is yet unknown (Ding et al., 2020).
ER stress has been found in the postmortem brains of AD-affected people,
animals, and also the vitro models, suggesting that ER disruption has a
significant part in the development of AD. It was established that ER
stress has a significant role in AD etiology. Nearly all of the brain
pathology developments linked with AD, involving presenilin1 gene
mutation, presenilin2 unusually cut mRNA, formation of β-amyloid, tau
phosphorylation, as well as cell death, are allied to ER stress.
Additionally, given their roles in the etiology of AD, ER stress and
unfolded protein response have potential therapeutic roles (Li et al.,
2015). Recent research has revealed that ER stress activates
inflammation reactions via several UPR transducers. The most effective
pathways include “inositol-requiring enzyme1- Tumor necrosis factor
receptor-associated factor-2 (IRE1-TRAF2), Protein kinase RNA- like
endoplasmic reticulum kinase- Eukaryotic Initiation Factor 2α
(PERK-eIF2α), and GSK-3, activating transcription factor 6 -
cAMP-responsive element-binding protein H (ATF6-CREBH)”, also the
pathways induced by inflammation of caspase. Some theories explain the
connection between ER stress in neurons, inflammation, and the
development of pathogenic alterations in AD. From the above-mentioned
studies, it was demonstrated that ER stress provides clues for the
progression of NAFLD and AD. There are no studies that have implicated
the link between ER stress causing NAFLD, which leads to Alzheimer’s and
is attenuated by FOXO inhibition
(Salminen et al., 2009).