Stress In Alzheimer's Disease Research Articles

The Role of Endoplasmic Reticulum Stress in Alzheimer's Disease: Molecular Mechanisms and Viral Hypotheses

The Role of Endoplasmic Reticulum Stress in Alzheimer's Disease: Molecular Mechanisms and Viral Hypotheses

Examining the role of antioxidant supplementation in mitigating oxidative stress markers in Alzheimer's disease: a comprehensive review.

Alzheimer's disease is a devastating neurodegenerative disorder that affects millions of people worldwide. One of the key pathological features of Alzheimer's disease is oxidative stress, which is characterized by an imbalance between the production of reactive oxygen species and the body's ability to neutralize them with antioxidants. In recent years, there has been growing interest in the potential role of antioxidant supplementation in mitigating oxidative stress markers in Alzheimer's disease. This review paper aims to provide a comprehensive overview of the current research on antioxidant supplementation in Alzheimer's disease and its effects on oxidative stress markers. The paper will examine the underlying mechanisms of oxidative stress in Alzheimer's disease, the potential benefits of antioxidant supplementation, and the challenges and limitations of using antioxidants as a therapeutic strategy.

Dyadic Comparison of Pain and Stress in Alzheimer's Disease and Caregivers

BackgroundMillions of people live with dementia worldwide, relying heavily on family caregivers. Pain is common in both people living with Alzheimer's disease (PLWAD) and their caregivers, contributing to stress and burden. To our knowledge, this is the first study to examine the relationship between pain, stress, hair cortisol, and mental health in PLWAD and their caregivers, and how these factors are linked to caregiver burden. MethodsThis exploratory pilot study included five PLWAD-caregiver dyads. Participants completed questionnaires on pain, mental health, and demographics. Hair samples were collected for cortisol analysis. Pearson correlation coefficients (r) were used to assess relationships between various factors of the PLWAD and their caregiver. ResultsContrary to expectations, PLWAD's pain and mental health measures displayed a trend of negative correlation with their hair cortisol levels (HCC). Conversely, caregiver pain and mental health measures had a trend of positive correlation with their HCC. There was also a trend that higher pain in PLWAD was associated with higher caregiver burden. ConclusionThis exploratory pilot study found associational trends suggesting a complex relationship between pain, mental health, and stress in PLWAD-caregiver dyads. This preliminary work will inform future studies which can help advance targeted, tailored interventions.

The associations between sleep disturbances and allostatic load, and the role of sex, beta amyloid, and burnout history in a memory clinic sample: the Co‐STAR study

AbstractBackgroundSeveral studies have investigated the link between sleep disturbances and allostatic load (AL), but the results are varied, and less is known about the associations in clinical samples. The goal of this study is to assess the associations between sleep disturbances and AL among memory clinic participants, and to examine differences according to sex, beta‐amyloid status and history of burnout status.MethodThe study was based on 146 memory clinic participants diagnosed with either Mild Cognitive Impairment (MCI) or Subjective Cognitive Impairment (SCI) in the Cortisol and Stress in Alzheimer’s Disease Study (Co‐STAR) (Sweden). Self‐reported sleep was measured using the Karolinska Sleep Questionnaire (KSQ). The AL index is a measure of chronic stress including blood‐based markers reflecting the neuroendocrine, immunological, metabolic, and cardiovascular systems, constructed using 16 biomarkers. Beta‐amyloid was measured from cerebrospinal fluid samples. History of burnout was self‐reported. Linear regressions were conducted to assess the associations between sleep disturbances and allostatic load, while adjusting for age, sex and sleep medications.ResultLower total sleep score (b=‐0.228, p= 0.028) and sleep apnea index (b=‐0.187, p= 0.046) correlated with higher AL index. In stratified analyses, lower total sleep score was associated with higher AL index in women (b=‐0.282, p= 0.049), while higher insomnia levels (b=‐0.295, p= 0.038) were linked to lower AL levels in men. AL was only associated with daytime sleepiness in participants with normal beta‐amyloid levels, where a lower daytime sleepiness score (b=‐0.298, p= 0.038) was linked to higher AL levels. Among those without a history of burnout, higher AL index correlated with lower total sleep score (b=‐0.249, p= 0.045), insomnia score (b=‐0.223, p= 0.045), difficulty waking up score (b=‐0.225, p= 0.038), and non‐restorative sleep index (b=‐0.221, p= 0.043).ConclusionThis study shows varied associations between sleep disturbances and across different subgroups, highlighting the roles of age, sex, beta‐amyloid levels, and history of burnout in the associations. It may be of valuable importance to consider AL when evaluating sleep disturbances and implementing lifestyle interventions for the reduction of chronic stress and sleep disturbances to reduce the risk of cognitive decline.

Molecular Roles of NADPH Oxidase-Mediated Oxidative Stress in Alzheimer's Disease: Isoform-Specific Contributions.

Oxidative stress is linked to the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disorder marked by memory impairment and cognitive decline. AD is characterized by the accumulation of amyloid-beta (Aβ) plaques and the formation of neurofibrillary tangles (NFTs) of hyperphosphorylated tau. AD is associated with an imbalance in redox states and excessive reactive oxygen species (ROS). Recent studies report that NADPH oxidase (NOX) enzymes are significant contributors to ROS generation in neurodegenerative diseases, including AD. NOX-derived ROS aggravates oxidative stress and neuroinflammation during AD. In this review, we provide the potential role of all NOX isoforms in AD pathogenesis and their respective structural involvement in AD progression, highlighting NOX enzymes as a strategic therapeutic target. A comprehensive understanding of NOX isoforms and their inhibitors could provide valuable insights into AD pathology and aid in the development of targeted treatments for AD.

Oxidative Stress in Alzheimer's Disease: The Shortcomings of Antioxidant Therapies.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by gradual and progressive cognitive decline leading to dementia. At its core, the neuropathological features of AD include hallmark accumulations of amyloid-β and hyperphosphorylated tau proteins. Other harmful processes, such as oxidative stress and inflammation, contribute to the disease's neuropathological progression. This review evaluates the role of oxidative stress in AD, placing a spotlight on the disappointing outcomes of various antioxidant clinical trials. Several hypotheses are discussed that might elucidate the failures of these therapies in AD. Specifically: 1) The paradoxical and overlooked harmful implications of prooxidant intermediates, particularly stemming from conventional antioxidants like vitamins E and C; 2) The challenges and failure to appreciate the issue of bioavailability-epitomized by the dictum "no on-site protection, no protection"-and the preeminent, yet often ignored, role played by endogenous antioxidant enzymes in combating oxidative stress; 3) The influence of unrecognized etiologies, such as latent infectious agents and others, as foundational drivers of oxidative stress in AD; 4) The underestimation of the complexity of oxidative mechanisms and the necessity of multi-targeted therapeutic approaches, such as those provided by various diets; and 5) The limitations of clinical trial designs in fully capturing the effects of antioxidants on AD progression. This article also examines the outcomes of select clinical trials while highlighting the challenges and barriers these therapies pose, offering insights into potential mechanisms to overcome their marginal success.

Neuroinflammation, cerebrovascular dysfunction and diurnal cortisol biomarkers in a memory clinic cohort: Findings from the Co-STAR study

Cortisol dysregulation, neuroinflammation, and cerebrovascular dysfunction are biological processes that have been separately shown to be affected in Alzheimer’s disease (AD). Here, we aimed to identify biomarker signatures reflecting these pathways in 108 memory clinic patients with subjective cognitive decline (SCD, N = 40), mild cognitive impairment (MCI, N = 39), and AD (N = 29). Participants were from the well-characterized Cortisol and Stress in Alzheimer’s Disease (Co-STAR) cohort, recruited at Karolinska University Hospital. Salivary diurnal cortisol measures and 41 CSF proteins were analyzed. Principal component analysis was applied to identify combined biosignatures related to AD pathology, synaptic loss, and neuropsychological assessments, in linear regressions adjusted for confounders, such as age, sex, education and diagnosis. We found increased CSF levels of C-reactive protein (CRP), interferon γ-inducible protein (IP-10), thymus and activation-regulated chemokine (TARC), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in MCI patients. Further, markers of cortisol dysregulation (flattened salivary cortisol awakening response and flattened cortisol slope) correlated with increased levels of placental growth factor (PlGF), IP-10, and chitinase 3-like 1 (YKL-40) in the total cohort. A biosignature composed of cortisol awakening response, cortisol slope, and CSF IL-6 was downregulated in AD patients. Moreover, biomarker signatures reflecting overlapping pathophysiological processes of neuroinflammation and vascular injury were associated with AD pathology, synaptic loss, and worsened processing speed. Our findings suggest an early dysregulation of immune and cerebrovascular processes during the MCI stage and provide insights into the interrelationship of chronic stress and neuroinflammation in AD.

The Interplay of Protein Aggregation, Genetics, and Oxidative Stress in Alzheimer's Disease: Role for Natural Antioxidants and Immunotherapeutics.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that comprises amyloid-beta protein (Aβ) as a main component of neuritic plaques. Its deposition is considered a trigger for AD pathogenesis, progression, and the clinical symptoms of cognitive impairment. Some distinct pathological features of AD include phosphorylation of tau protein, oxidative stress, and mitochondrial dysfunction. These pathological consequences tend to produce reactive oxygen species (ROS), resulting in the dysregulation of various signaling pathways of neuroinflammation and neurodegeneration. The relationship between the Aβ cascade and oxidative stress in AD pathogenesis is like a "chicken and egg" story, with the etiology of the disease regarding these two factors remaining a question of "which comes first." However, in this review, we have tried our best to clarify the interconnection between these two mechanisms and to show the precise cause-and-effect relationship. Based on the above hallmarks of AD, several therapeutic strategies using natural antioxidants, monoclonal antibodies, and vaccines are employed as anti-Aβ therapy to decrease ROS, Aβ burden, chronic neuroinflammation, and synaptic failure. These natural antioxidants and immunotherapeutics have demonstrated significant neuroprotective effects and symptomatic relief in various in vitro and in vivo models, as well as in clinical trials for AD. However, none of them have received final approval to enter the drug market for mitigating AD. In this review, we extensively elaborate on the pitfalls, assurances, and important crosstalk between oxidative stress and Aβ concerning current anti-Aβ therapy. Additionally, we discuss future strategies for the development of more Aβ-targeted approaches and the optimization of AD treatment and mitigation.

Exploring Tau Fibril-Disaggregating and Antioxidating Molecules Binding to Membrane-Bound Amyloid Oligomers Using Machine Learning-Enhanced Docking and Molecular Dynamics.

Intracellular tau fibrils are sources of neurotoxicity and oxidative stress in Alzheimer's. Current drug discovery efforts have focused on molecules with tau fibril disaggregation and antioxidation functions. However, recent studies suggest that membrane-bound tau-containing oligomers (mTCOs), smaller and less ordered than tau fibrils, are neurotoxic in the early stage of Alzheimer's. Whether tau fibril-targeting molecules are effective against mTCOs is unknown. The binding of epigallocatechin-3-gallate (EGCG), CNS-11, and BHT-CNS-11 to in silico mTCOs and experimental tau fibrils was investigated using machine learning-enhanced docking and molecular dynamics simulations. EGCG and CNS-11 have tau fibril disaggregation functions, while the proposed BHT-CNS-11 has potential tau fibril disaggregation and antioxidation functions like EGCG. Our results suggest that the three molecules studied may also bind to mTCOs. The predicted binding probability of EGCG to mTCOs increases with the protein aggregate size. In contrast, the predicted probability of CNS-11 and BHT-CNS-11 binding to the dimeric mTCOs is higher than binding to the tetrameric mTCOs for the homo tau but not for the hetero tau-amylin oligomers. Our results also support the idea that anionic lipids may promote the binding of molecules to mTCOs. We conclude that tau fibril-disaggregating and antioxidating molecules may bind to mTCOs, and that mTCOs may also be useful targets for Alzheimer's drug design.

Natural Antioxidants: An Effective Strategy for the Treatment of Alzheimer's Disease at the Early Stage.

The critical role of oxidative stress in Alzheimer's disease (AD) has been recognized by researchers recently, and natural antioxidants have been demonstrated to have anti-AD activity in animal models, such as Ginkgo biloba extract, soy isoflavones, lycopene, and so on. This paper summarized these natural antioxidants and points out that natural antioxidants always have multiple advantages which are help to deal with AD, such as clearing free radicals, regulating signal transduction, protecting mitochondrial function, and synaptic plasticity. Based on the available data, we have created a relatively complete pathway map of reactive oxygen species (ROS) and AD-related targets and concluded that oxidative stress caused by ROS is the core of AD pathogenesis. In the prospect, we introduced the concept of a combined therapeutic strategy, termed "Antioxidant-Promoting Synaptic Remodeling," highlighting the integration of antioxidant interventions with synaptic remodeling approaches as a novel avenue for therapeutic exploration.

Curculigoside, a traditional Chinese medicine monomer, ameliorates oxidative stress in Alzheimer's disease mouse model via suppressing ferroptosis.

Alzheimer's disease (AD) is a neurodegenerative disorder where oxidative stress, induced by ferroptosis, has been linked to neuronal damage and cognitive deficits. The objective of this study is to investigate if the potential therapeutic agent, Curculigoside (CUR), could ameliorate AD by inhibiting ferroptosis. The potential therapeutic targets, such as GPX4 and SLC7A11, were identified using weighted gene co-expression network analysis (WGCNA). Concurrently, CUR was also screened against these potential targets using various analytical methods. For the in vivo studies, intragastric administration of CUR significantly ameliorated cognitive impairment in AD model mice induced by scopolamine and okadaic acid (OA). In vitro, CUR protected neuronal cells by altering the levels of ferroptosis-related specific markers in OA and scopolamine-induced neurotoxicity. The administration of CUR through intragastric route significantly reduced the levels of AD-promoting factors (such as Aβ1-42, p-tau) and ferroptosis-promoting factors in the hippocampus and cortex of AD mice. Furthermore, CUR up-regulated the expression of GPX4 and decreased the expression of SLC7A11 in the ferroptosis signaling pathway, thereby increasing the ratio of glutathione (GSH)/oxidized glutathione (GSSG) in vivo and vitro. In conclusion, the cumulative results suggest that the natural compound CUR may serve as a promising therapeutic agent to ameliorate AD by inhibiting ferroptosis.

NRF2 Deficiency Promotes Ferroptosis of Astrocytes Mediated by Oxidative Stress in Alzheimer's Disease.

Oxidative stress is involved in the pathogenesis of Alzheimer's disease (AD), which is linked to reactive oxygen species (ROS), lipid peroxidation, and neurotoxicity. Emerging evidence suggests a role of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a major source of antioxidant response elements in AD. The molecular mechanism of oxidative stress and ferroptosis in astrocytes in AD is not yet fully understood. Here, we aimed to investigate the mechanism by which Nrf2 regulates the ferroptosis of astrocytes in AD. We found decreased expression of Nrf2 and upregulated expression of the ROS marker NADPH oxidase 4 (NOX4) in the frontal cortex from patients with AD and in the cortex of 3×Tg mice compared to wildtype mice. We demonstrated that Nrf2 deficiency led to ferroptosis-dependent oxidative stress-induced ROS with downregulated heme oxygenase-1 and glutathione peroxidase 4 and upregulated cystine glutamate expression. Moreover, Nrf2 deficiency increased lipid peroxidation, DNA oxidation, and mitochondrial fragmentation in mouse astrocytes (mAS, M1800-57). In conclusion, these results suggest that Nrf2 deficiency promotes ferroptosis of astrocytes involving oxidative stress in AD.

Oxidative stress in Alzheimer's disease: current knowledge of signaling pathways and therapeutics.

Alzheimer's disease's pathophysiology is still a conundrum. Growing number of evidences have elucidated the involvement of oxidative stress in the pathology of AD rendering it a major target for therapeutic development. Reactive oxygen species (ROS) generated by altered mitochondrial function, dysregulated electron transport chain and other sources elevate aggregated Aβ and neurofibrillary tangles which further stimulating the production of ROS. Oxidative stress induced damage to lipids, proteins and DNA result in neuronal death which leads to AD. In addition, oxidative stress induces apoptosis that is triggered by the modulation of ERK1/2 and Nrf2 pathway followed by increased GSK-3β expression and decreased PP2A activity. Oxidative stress exaggerates disease condition by interfering with various signaling pathways like RCAN1, CREB/ERK, Nrf2, PP2A, NFκB and PI3K/Akt. Studies have reported the role of TNF-α in oxidative stress stimulation that has been regulated by drugs like etanercept increasing the level of anti-oxidants. Other drugs like pramipexole, memantine, carvedilol, and melatonin have been reported to activate CREB/RCAN1 and Nrf2 pathways. In line with this, epigallocatechin gallate and genistein also target Nrf2 and CREB pathway leading to activation of downstream pathways like ARE and Keap1 which ameliorate oxidative stress condition. Donepezil and resveratrol reduce oxidative stress and activate AMPK pathway along with PP2A activation thus promoting tau dephosphorylation and neuronal survival. This study describes in detail the role of oxidative stress in AD, major signaling pathways involving oxidative stress induced AD and drugs under development targeting these pathways which may aid in therapeutic advances for AD.

Fangchinoline alleviates cognitive impairments through enhancing autophagy and mitigating oxidative stress in Alzheimer's disease models.

Introduction: Alzheimer's disease (AD) is a debilitating, progressive, neurodegenerative disorder characterized by the deposition of amyloid-β (Aβ) peptides and subsequent oxidative stress, resulting in a cascade of cytotoxic effects. Fangchinoline (Fan), a bisbenzylisoquinoline alkaloid isolated from traditional Chinese herb Stephania tetrandra S. Moorec, has been reported to possess multiple potent biological activities, including anti-inflammatory and antioxidant properties. However, the potential neuroprotective efficacy of Fan against AD remains unknown. Methods: N2AAPP cells, the mouse neuroblastoma N2A cells stably transfected with human Swedish mutant APP695, were served as an in vitro AD model. A mouse model of AD was constructed by microinjection of Aβ1-42 peptides into lateral ventricle of WT mice. The neuroprotective effects of Fan on AD were investigated through a combination of Western blot analysis, immunoprecipitation and behavioral assessments. Results and discussion: It was found that Fan effectively attenuated the amyloidogenic processing of APP by augmenting autophagy and subsequently fostering lysosomal degradation of BACE1 in N2AAPP cells, as reflected by the decrease in P62 levels, concomitant with the increase in Beclin-1 and LC3-II levels. More importantly, Fan significantly ameliorated cognitive impairment in an Aβ1-42-induced mouse model of AD via the induction of autophagy and the inhibition of oxidative stress, as evidenced by an increase in antioxidants including glutathione reductase (GR), total antioxidant capacity (T-AOC), nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and superoxide dismutase-1 (SOD-1) and a decrease in pro-oxidants including hydrogen peroxide (H2O2) and inducible nitric oxide synthase (i-NOS), coupled with a reduction in apoptosis marker, cleaved caspase-3. Taken together, our study demonstrate that Fan ameliorates cognitive dysfunction through promoting autophagy and mitigating oxidative stress, making it a potential therapeutic agent for AD.

Ameliorative effect of β‐pinene targeting mitochondrial dysfunction and oxidative stress in Alzheimer’s disease

AbstractBackgroundSporadic Alzheimer’s disease (sAD) is the most common type of dementia, characterized by the deposition of extracellular senile plaques, neurofibrillary tangles (NFTs), and neurodegeneration, leading to memory impairment and dementia. Intracerebroventricular (ICV) streptozotocin (STZ) mimics sporadic Alzheimer’s disease (sAD) characterized by neurodegeneration arising from oxidative stress, and mitochondrial dysfunction. β‐pinene is a monoterpene having antioxidant properties interlinked with mitochondrial functioning. To study the neuroprotective and cognitive enhancement properties of β‐pinene on mitochondrial dysfunction, oxidative stress, and histological changes in an animal model of Alzheimer’s disease induced by ICV‐STZ.MethodTo establish the sAD model, intracerebroventricular (ICV) streptozotocin (STZ) at a dose of 3 mg/kg was administered bilaterally in rats on a stereotaxic apparatus. Behavioral tests such as Morris water maze (MWM), novel object recognition (NOR) and Actophotometer were performed to evaluate spatial & recognition memory and locomotor functions. Three treatment doses (50mg/kg, 100 mg/kg and 200mg/kg) of Beta pinene (β‐pinene) and Galantamine (2 mg/kg) as a reference drug were given orally to ICV‐STZ induced rats for 21 days. Cortical and hippocampal tissues were dissected. Estimation of oxidative stress, mitochondrial dysfunction as complex I, II, III, IV activity and acetylcholinesterase activity were performed for cholinergic function. Moreover, histopathology was evaluated by hematoxylin and eosin (H&E) staining.Resultβ‐pinene treatment attenuated ICV‐STZ‐induced cognitive impairment in MWM and NOR. There is no significant effect revealed on locomotor activities. Moreover, in the cortex and hippocampal area of the brain, Mitochondrial enzyme complex I, II, III, and IV, and acetylcholinesterase (AchE) activities were normalized. Furthermore, reduced glutathione (GSH), catalase, superoxide dismutase (SOD), and (Lipid peroxidation) LPO were also reversed. β‐pinene prevents neurodegeneration as examined in histopathology.ConclusionIn the ICV‐STZ rat model, β‐pinene was found to be neuroprotective by reducing oxidative stress and mitochondrial dysfunction, consequently enhancing cognitive functions indicated in the behavioral outcomes.

Pengaruh Pemberian Mesenchymal Stem Cells Wharton’s Jelly terhadap Ekspresi Gen PPAR-γ pada Tikus Alzheimer

The increased production of beta-amyloid marks Alzheimer's disease. PPAR-γ shows involvement in Alzheimer's disease. PPAR-γ Gene is suspected to reduce beta-amyloid plaques and reduce inflammation and oxidative stress in Alzheimer's disease. Mesenchymal Stem Cells Wharton's Jelly (MSC-WJ) is expected to increase the PPAR-γ Gene expression. Objective: To observed the PPAR-γ Gene expression in Alzheimer's Mice. Methods: The mice are induced using AlCl3 and were given MSC-WJ. This study was an experimental study with a post-test-only control group design on 18 samples of RNA from Alzheimer's mice that were divided into 3 groups. Negative control group (K-), positive control group (K+), and experimented group (P). The mean of PPAR-γ gene expression was obtained by comparing the PPAR-γ gene with the GAPDH gene. This study used semiquantitative methods using ImageJ. Data analysis was used with the Kruskal-Wallis test. It is significant if the value is <0,05. Results: The mean ratio of PPAR-γ gene expression that was obtained in K-, K+, and P were 0.12, 0.06, and 0.08, respectively. There were significant differences between each group, with a p-value of 0,023 (p<0,05). Conclusion: Giving MSC-WJ could increase the PPAR-γ gene expression. Further study using real-time PCR is highly needed to increase the MSC-WJ treatment in patients with Alzheimer's disease.Keywords: Alzheimer disease, MSC-WJ, PPAR- γ

Evaluation of the relationship among gene expressions and enzyme activities with antioxidant role and presenilin 1 expression in Alzheimer's disease.

It is known that oxidative stress originating from reactive oxygen species plays a role in the pathogenesis of Alzheimer's disease. In this study, the role of antioxidant status associated with oxidative stress in Alzheimer's disease was investigated. Peripheral blood samples were obtained from 28 healthy individuals (as control) and 28 Alzheimer's patients who met the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria. Catalase, glutathione S-transferase and paraoxonase 1 enzyme activities in blood plasma and glutathione S-transferase enzyme activities in erythrocytes were determined by spectrophotometer. Catalase, glutathione S-transferase and presenilin 1 gene expressions in leukocytes were determined using qRT-PCR. Data were analysed with SPSS one-way anova, a LSD post hoc test at p < 0.05. The activity of each enzyme was significantly reduced in Alzheimer's patients compared to control. The catalase gene expression level did not change compared to the control. Glutathione S-transferase and presenilin 1 gene expression levels were increased compared to the control.

An RNAi-Mediated Reduction in Transcription Factor Nrf-2 Blocks the Positive Effects of Dimethyl Fumarate on Metabolic Stress in Alzheimer's Disease.

The prevalence of obesity is rapidly rising around the world, and this will have a significant impact on our society as it is believed to be one of the leading causes of death. One of the main causes of these occurrences is added sugar consumption, which is associated with a higher risk of obesity, heart disease, diabetes, and brain illnesses such as Alzheimer's disease (AD). To this purpose, excess sugar might worsen oxidative damage and brain inflammation: two neuropathological signs of AD. Dimethyl fumarate (DMF) is an orally accessible methyl ester of fumaric acid with putative neuroprotective and immunomodulatory properties. In addition, DMF stimulates the nuclear factor erythroid 2-related factor 2 (Nrf-2), a key regulator of the antioxidant response mechanism in cells. The aim of the current study was to assess the potential therapeutic benefits of DMF in an in vitro model of metabolic stress induced by high and low sugar levels. We discovered that DMF reversed the negative impacts of high and low glucose exposure on the viability and oxidative stress of SH-SY5Y cells. Mechanistically, DMF's actions were mediated by Nrf-2. To this end, we discovered that DMF boosted the expression of the Nrf-2-regulated genes heme-oxygenase-1 (HO1) and manganese superoxide dismutase (MnSOD). More importantly, we found that inhibiting Nrf-2 expression prevented DMF's positive effects. Our combined findings suggest that DMF may be a valuable support for treatments for metabolic diseases.

A Triterpenoid Lupeol as an Antioxidant and Anti-Neuroinflammatory Agent: Impacts on Oxidative Stress in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease illustrated by neuronal dysfunctions, leading to memory weaknesses and personality changes mostly in the aged population worldwide. The exact cause of AD is unclear, but numerous studies have addressed the involvement of oxidative stress (OS), induced by reactive oxygen species (ROS), to be one of the leading causes in developing AD. OS dysregulates the cellular homeostasis, causing abnormal protein and lipid metabolism. Nutrition plays a pivotal role in modulating the antioxidant system and decreases the neuronal ROS level, thus playing an important therapeutic role in neurodegenerative diseases, especially in AD. Hence, medicinal herbs and their extracts have received global attention as a commercial source of antioxidants Lupeol. Lupeol is a pentacyclic triterpenoid and has many biological functions. It is available in fruits, vegetables, and medicinal plants. It has shown effective antioxidant and anti-inflammatory properties, and higher blood–brain barrier permeability. Also, the binding and inhibitory potentials of Lupeol have been investigated and proved to be effective against certain receptor proteins and enzymes in AD studies by computational molecular docking approaches. Therefore, AD-related research has gained interest in investigating the therapeutic effects of Lupeol. However, despite its beneficial effects in AD, there is still a lack of research in Lupeol. Hence, we compiled in this analysis all preclinical research that looked at Lupeol as an antioxidant and anti-inflammatory agent for AD.

Benzenesulfonamide as a novel, pharmaceutical small molecule inhibitor on Aβ gene expression and oxidative stress in Alzheimer's Wistar rats

Alzheimer's disease (AD) is the most prevalent acute neurodegenerative disease described by memory loss and other cognitive functions. Benzenesulfonamide, a novel, potent, and small organic molecule, was synthesized to investigate its effects on the levels of oxidative biomarkers (GPx, ROS, and MDA) and expression of beta-amyloid peptides (Aβ40 and Aβ42) in the pathology of AD. The results were compared with the rivastigmine drug. Applying benzenesulfonamide to Alzheimer's-induced Wistar rats showed a significant increase in the level of oxidative biomarkers (GPx, ROS, and MDA) in both the brain and blood serum as well as amyloid-β40 and 42 gene expressions. Therefore, benzenesulfonamide could be considered a novel therapeutic agent against AD.