Universal Functional Nutrigenomics Code

downregulation of the Nrf2/HO-1 signaling, which reduces anti-oxidant enzyme levels [11], causing neuroinflammation [12], mitochondrial dysfunction [13], immune dysregulation [14], oligodendrocyte loss [15], apoptosis [16], and demyelination [17]. MS is a central nervous system (CNS) demyelinating neurodegenerative disease characterized by the production of focal inflammatory lesions in the brain, optic nerve, and spinal cord [18]. MS predominantly affects young adults [19], with females having a higher prevalence risk than males aged 20–50 years [20]. In MS patients, the thalamus, hippocampus, striatum, brainstem, and cerebellum are mostly affected [21], [22], [23]. Downregulation of the Nrf2/HO-1 transcription factor also triggers many neurophysiological alterations in amyotrophic lateral sclerosis (ALS) [24], Alzheimer's disease (AD) [25], Parkinson's disease (PD) [26], Huntington's disease (HD) [27], cerebral ischemic injury [28], intracerebral haemorrhage [29], and depression [30].  Furthermore, previous research concluded that Nrf2 and HO-1 downregulation exacerbate neuro complications, so we hypothesized that Nrf2/HO-1 might be a major factor in the pathogenesis of MS. On the other hand, Nrf2/HO-1 activators are beneficial in the prevention of various neurological disorders, including MS 

Several studies have indicated that Nrf2 downregulation is vital in the pathogenesis of MS [51]. The absence of Nrf2 has been related to a faster onset and even more severe clinical outcome characterized by increased glial activation, axonal degeneration, spinal cord injury, and an increase in inflammatory cells [8]. Researchers found no mechanistic differences between Nrf2 and HO-1, an antioxidant defense mechanism investigated in the brain and spinal cord. According to the human protein atlas, Nrf2/HO-1 expression is higher in the spinal cord than in the brain; however, some brain areas, such as the midbrain and cerebellum, have more increased Nrf2 and HO-1 expression than the spinal cord [52,53]. Downregulation of Nrf2 and HO-1 causes demyelination of motor neurons in the spinal cord's anterior horn, whereas activation has a protective effect [54]. Spinal cord injury in rats demonstrates the dysfunction of Nrf2/HO-1 leads to oxidative stress, which mediates apoptosis and inflammation in the spinal cord [55]. Aging is associated with Nrf2/HO-1 dysfunction, which leads to white matter degeneration, microgliosis, blood-brain barrier damage, and cognitive impairment. 

Aging is associated with Nrf2/HO-1 dysfunction, which leads to white matter degeneration, microgliosis, blood-brain barrier damage, and cognitive impairment. 

The dysregulation of the Nrf2/HO-1 signaling pathway increases oxidative stress, which leads to the worsening of neurocomplications associated with oxidative stress-mediated ischemia-reperfusion in rats [62]. Nrf2 expression in dopaminergic neurons was reduced in PD patients [36]. Furthermore, loss of Nrf2 worsens MPTP-induced neurotoxicity in a PD mouse model by activating microglia and inducing neuroinflammation . Dopaminergic neuron degeneration and microglial activation were observed in Nrf2 knockout mice . Gpx and SOD1 anti-oxidant enzyme levels were lower in HD patients lacking Nrf2 . Once the Nrf2 signaling pathway is dysregulated, oxidative stress and mitochondrial dysfunction are frequently increased, linked to the progression of motor neuron disorders such as HD [67]. In ALS and dysregulation of the Nrf2/HO-1 signaling mechanism can result in oligodendrocyte destruction and demyelination of motor neurons in the motor cortex and spinal cord [68]. Preclinical studies in stroke conditions indicate that mice lacking Nrf2 have more inflammatory responses, infarcts, and neurological defects than mice expressing Nrf2.

Downregulation of the Nrf2/HO-1 signalling pathway results in a decrease in antioxidative enzymes, which leads to increased oxidative damage [11], neuroinflammation [12], immune dysregulation [14], oligodendrocyte loss [15], demyelination [17], mitochondrial dysfunction [13], apoptosis [16], and neurotransmitter imbalance [70]. All of these pathological markers play a significant role in the progression of 

nvolvement of Nrf2/HO-1 signaling downregulation in the progression of multiple sclerosis

Downregulation of Nrf2 reduced the expression of the HO-1 gene which are involved in the regulation of various anti-oxidant enzyme and promotes the excessive ROS/RNS production that can activate glial cells (astrocytes and microglia) that release proinflammatory cytokines which induce neuroinflammation, neuronal apoptosis which leads to oligodendrocyte destruction, demyelination, and reduced neuronal synaptic plasticity. Downregulation of Nrf2 is also involved in the imbalance of neurotransmitter levels.

Nrf2 is a transcription factor encoded by the NFE2L2 gene in humans. Downregulation of Nrf2/HO-1 negatively regulates its downstream genes, such as GSTP1, GSTM1, and HO-1. All of these are linked to the development of MS-like neurocomplications. In PD, patient NFE2L2 mutations have decreased anti-oxidant enzyme levels. NFE2L2 mutations inhibit ARE-driven gene transcription and reduce the expression of target genes such as GSTP1, GSTM1, NQO1, and HO-1

MS has been associated with mutations in genes encoding anti-oxidant enzymes such as NQO1 and GSTP1 [78]. NQO1 is a Phase II detoxifying enzyme that catalyzes the removal of two electrons from exogenous and endogenous quinones, preventing them from participating in redox cycling and generating hydrogen peroxide (H2O2) [79]. The glutathione S-transferase (GST) supergene family encodes enzymatic activities needed for anti-oxidant protection mechanisms. GSTP1 mutations substantially increase oxidative stress, which is linked to inflammation and demyelination [80]. Baronica's study looks at the impact of the GSTP1 detoxification process on the clinical phenotype of MS patients [81]. Stavropoulou and colleagues successfully investigated the expression of NQO1 genetic variants in 231 MS patients and 380 controls. As a result, NQO1 gene expression decreased in MS patients. The NQO1 gene polymorphism suggests that the NQO1 genetic background may play a role in developing PPMS. These findings provided the first proof that NQO1 mutations contribute to MS prevalence. Downregulation of Nrf2/HO-1 activity causes genetic alterations in the GSTP1 and NQO1 genes, which leads to the development of PPMS