1) Diabetes
A chronic metabolic condition called diabetes mellitus (DM) is defined
by hyperglycemia brought on by inadequate or resistant insulin.
According to recent research, oxidative stress brought on by elevated
ROS levels is a major factor in the emergence of diabetic problems
(Hedrick et al., 2000). Numerous biological processes are carried out by
FOXO proteins (Ho et al., 2008). In oxidative stress, the intricate
interaction among the signal transduction pathways as well as FOXO
proteins can have a major impact on apoptosis and autophagy. FOXO
proteins can promote autophagy under oxidative stress circumstances
while also promoting cell survival (Ponugoti et al., 2012). FOXO1 is
deactivated by insulin signaling, which is carried out through AKT and
insulin receptor substrates 1 and -2. Insulin sensitivity is hugely
affected by the nuclear receptor peroxisome proliferator-activated
receptor (PPAR). PPAR It is the molecular target of thiazolidinedione
(TZD) anti-diabetic drugs that enhance in vivo glucose
tolerance, insulin sensitivity, and lipid homeostasis. TZDs improve
insulin sensitivity by modulating gene expression mediated by PPAR
(Hedrick et al., 2000). PPAR is abundant in adipose tissue, where it
functions as a crucial regulator of adipocyte development and, most
likely, also of the preservation of the mature adipocyte phenotype. In
addition to PPAR, FoxO1 has a role in adipocyte development by
inhibiting adipogenesis during an early phase of the development
process. FoxO1 haploinsufficient mice are somewhat protected from the
insulin resistance and diabetes caused by a high-fat diet. FoxO1 has
also been shown to directly bind to and inhibit the PPARγ-2 promoter in
addition to PPAR function (Fan et al., 2009).
HMOX1-
Elevated glucose production that results in hyperglycemia is a defining
trait of insulin resistance. FOXO1 affects the ability of the liver to
generate glucose by controlling the expression of genes that promote
gluconeogenesis. This means that there is a route by which insulin
resistance causes increased activity of FOXO1, overexpression of genes
that stimulate glucose synthesis, and raised serum glucose levels. The
mitochondria are also impacted by the insulin-Akt-FOXO1 balance
disruption (Kalogerakis et al., 2005). Heme oxygenase-1 (HMOX1), which
cleaves heme and damages the mitochondrial electron transport chain, is
induced by activated FOXO1. Thus, increased heme oxygenase-1 expression
happens when insulin resistance increases FOXO1 activity. Increased heme
oxygenase-1 levels disrupt mitochondria and decrease oxidative
respiration, which has a deleterious impact on the oxidation of fatty
acids and the generation of ATP (Hedrick et al., 2000). Additionally,
increased FOXO1 activation alters the expression of mitochondrial fusion
and fission, which impacts mitochondrial biogenesis. Chronically high
insulin levels, inadequate mitochondria, aberrant mitochondrial
morphology, and insulin resistance are all associated with accelerated
aging-related cognitive loss, leading to AD that can be corrected by
deleting the FOXO1 gene (Cameron et al., 2006). There is mounting
evidence that type II DM’s peripheral hyperinsulinemia and insulin
resistance contribute to the etiology of AD. By reducing insulin in the
peripheral and improving the sensitivity of insulin, thiazolidinediones
like Agonists of the nuclear receptor peroxisome proliferator-activated
receptor gamma (PPAR), rosiglitazone as well as pioglitazone, may offer
some beneficial relief for AD (Mannan et al., 2021). Additionally, PPARγ
agonists have been demonstrated to have neuroprotective benefits by
lowering the beta-amyloid buildup and inflammatory mediators. There
hasn’t been a study looking at the properties of pioglitazone on
cognitive performance in AD patients, but it has recently been shown
that 6 months of treatment with rosiglitazone preserved cognitive
function in patients with AD and amnestic moderate cognitive impairment
(MCI). In individuals with AD and MCI with DM, the pilot trial showed
that pioglitazone improved cognitive as well as metabolic functions
(Landreth et al., 2007). The outcomes indicated that pioglitazone might
provide a unique approach for the treatment of AD as well as MCI with
DM. To support these findings, larger double-blind, randomized,
placebo-controlled investigations are required (Watson et al., 2005).
Another study demonstrated that in mice with STZ injections to the
hippocampi, the impact of Biobran on the expression of FOXO protein was
investigated. STZ injection in the brain is linked with tau protein
aggregation, brain insulin resistance, neuroinflammation, oxidative
damage, and Aβ deposition (Ghoneum et al 2021). The expression of the
FOXO protein was noticeably increased in mice that had received STZ
injections. These expressions were dramatically reduced by biobran in a
dose-dependent manner (Cojocaru et al., 2011). It reveals how Biobran
protects mice given STZ from FOXO-mediated apoptosis. However, it might
be having a protective role in diabetes linked with AD but studies for
the same are not implicated yet (Alam et al., 2016). Retinal
neurodegeneration brought on by diabetes happens before obvious
microvascular problems. The development of diabetic retinopathy was
thought to be influenced by oxidative stress and hyperglycemia-induced
ER stress (Huang et al., 2010).
GLP-1-
A common medication in clinics is liraglutide (LIRA), a glucagon-like
peptide-1 (GLP-1) analog that has been shown to have protective effects
against neurodegenerative disorders (Li et al., 2010). By releasing
insulin, gut cells produce GLP-1 to low blood sugar levels. The
glucagon-like peptide-1 receptor, which is broadly articulated in
various organs, counting the colon, pancreas, lungs, heart, and kidney,
and particularly in specific parts of the brain and peripheral neurons,
interacts with GLP-1 and its agonists (Harder et al., 2004). In clinics
today, type 2 diabetes mellitus (T2DM) is treated with LIRA, a
long-acting GLP-1 analog. Recent research shows that GLP-1 analog
exhibits some neuroprotective effects in AD, Aβ-induced SH-SY5Y cells
which are thrice-subcloned cell line derived from the SK-N-SH
neuroblastoma cell line, PD, and traumatic brain damage through crossing
the blood-brain barrier. Nevertheless, the mechanism related to this was
still not entirely understood (Liu et al., 2020).
1.3. JNK/GSK-3
The FOXO response, which plays a key part in the stimulation of cellular
antioxidative pathways along with apoptosis, is linked to Jun N-terminal
kinase (JNK) and Glycogen synthase kinase 3 (GSK-3) activation. At the
same time, hyperglycemia is brought on by the elevation of FOXO
transcriptional activity, which is another element that might be linked
with the pathophysiology of AD. Future strategies will concentrate on
other transcription factors intricated in the etiology of AD, InsRes,
and its consequences that are activated by oxidative stress (Smith et
al., 2005). For instance, oxidative stress has been related to both
diabetes mellitus and the death of neurons by the transcription factor
NF-kB (Nuclear factor kappa B). FOXO proteins are an excellent target
for therapeutics that focus on treating the cause rather than the
symptoms of both diseases due to the integrative role they are shown to
play in cellular stress resistance. Thiazolidinediones, an agent with
both antidiabetic and antioxidant capabilities, had beneficial effects
on both InsRes and AD neuropathology, which offers promising hopes for
this future perspective (Hanyu et al., 2009).