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).