Role of Bioactive Compounds in the Regulation of Mitochondrial Dysfunctions in Brain and Age-Related Neurodegenerative Diseases

Mitochondria are multifunctional organelles that participate in a wide range of metabolic processes, including energy production and biomolecule synthesis. The morphology and distribution of intracellular mitochondria change dynamically, reflecting a cell’s metabolic activity. Oxidative stress is defined as a mismatch between the body’s ability to neutralise and eliminate reactive oxygen and nitrogen species (ROS and RNS). A determination of mitochondria failure in increasing oxidative stress, as well as its implications in neurodegenerative illnesses and apoptosis, is a significant developmental process of focus in this review. The neuroprotective effects of bioactive compounds linked to neuronal regulation, as well as related neuronal development abnormalities, will be investigated. In conclusion, the study of secondary components and the use of mitochondrial features in the analysis of various neurodevelopmental diseases has enabled the development of a new class of mitochondrial-targeted pharmaceuticals capable of alleviating neurodegenerative disease states and enabling longevity and healthy ageing for the vast majority of people.

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Pharmacotherapeutic Potential of Garlic in Age-Related Neurological Disorders

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527320666210927101257 ◽

2021 ◽

Vol 20 ◽

Author(s):

Ramin Ahangar-Sirous ◽

Mohadeseh Poudineh ◽

Arina Ansari ◽

Ali Nili ◽

Seyyed Mohammad Matin Alavi Dana ◽

...

Keyword(s):

Public Health ◽

Oxidative Stress ◽

Neurological Disorders ◽

Allium Sativum ◽

Aged Garlic Extract ◽

Neuroprotective Effects ◽

Age Related ◽

Pathologic Features ◽

The Common ◽

Aged Garlic

: Age-related neurological disorders [ANDs] involve neurodegenerative diseases [NDDs] such as Alzheimer's disease [AD], the most frequent kind of dementia in elderly people, and Parkinson's disease [PD], and also other disorders like epilepsy and migraine. Although ANDs are multifactorial, Aging is a principal risk factor for them. The common and most main pathologic features among ANDs are inflammation, oxidative stress, and misfolded proteins accumulation. Since failing brains caused by ANDs impose a notable burden on public health and their incidence is increasing, a lot of works has been done to overcome them. Garlic, Allium sativum, has been used for different medical purposes globally and more than thousands of publications have reported its health benefits. Garlic and aged garlic extract are considered potent anti-inflammatory and antioxidants agents and can have remarkable neuroprotective effects. This review is aimed to summarize knowledge on the pharmacotherapeutic potential of garlic and its components in ANDs.

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PHYSICAL ACTIVITY AS HEALTHY INTERVENTION AGAINST SEVERE OXIDATIVE STRESS IN ELDERLY POPULATION

Journal of Frailty & Aging ◽

10.14283/jfa.2013.20 ◽

2013 ◽

pp. 1-9

Author(s):

C. TOMAS-ZAPICO ◽

E. IGLESIAS-GUTIERREZ ◽

B. FERNANDEZ-GARCIA ◽

D. DE GONZALO-CALVO

Keyword(s):

Oxidative Stress ◽

Physical Activity ◽

Elderly Population ◽

Physiological Basis ◽

Related Disease ◽

Age Related ◽

Wide Range ◽

Health Related ◽

Relevant Risk Factor

Severe oxidative stress is a relevant risk factor for major deleterious health-related events in olderpeople and is thought to be an important contributor to age-related disease. Literature has suggested oxidativestress as a therapeutic target for mitigating the biological decline and attenuating the occurrence of adverseclinical events in aged individuals. However, definitive treatments are not known. Regular and moderate physicalactivity has been proposed as possible intervention for slowing age-related decline. This healthy strategy presentsa wide range of beneficial aspects for elderly, from the reduction of morbidity, disability, frailty and mortalityrates to treatment of many age-related disorders. Importantly, the global benefits on health are not shared by anyother strategies. Nevertheless, the physiological basis by which exercise produces its benefits to the organism isnot fully understood. This review summarizes the evidence for the role of physical activity as potential healthyintervention for mitigating the negative aspects of aging through the modulation of the oxidative mechanisms.

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Neuroinflammation in Primary Open-Angle Glaucoma

Journal of Clinical Medicine ◽

10.3390/jcm9103172 ◽

2020 ◽

Vol 9 (10) ◽

pp. 3172 ◽

Cited By ~ 1

Author(s):

Stefania Vernazza ◽

Sara Tirendi ◽

Anna Maria Bassi ◽

Carlo Enrico Traverso ◽

Sergio Claudio Saccà

Keyword(s):

Oxidative Stress ◽

Immune Response ◽

Trabecular Meshwork ◽

Primary Open Angle Glaucoma ◽

Open Angle Glaucoma ◽

Glaucoma Surgery ◽

Open Angle ◽

Antioxidant Defences ◽

Age Related ◽

Wide Range

Primary open-angle glaucoma (POAG) is the second leading cause of irreversible blindness worldwide. Increasing evidence suggests oxidative damage and immune response defects are key factors contributing to glaucoma onset. Indeed, both the failure of the trabecular meshwork tissue in the conventional outflow pathway and the neuroinflammation process, which drives the neurodegeneration, seem to be linked to the age-related over-production of free radicals (i.e., mitochondrial dysfunction) and to oxidative stress-linked immunostimulatory signaling. Several previous studies have described a wide range of oxidative stress-related makers which are found in glaucomatous patients, including low levels of antioxidant defences, dysfunction/activation of glial cells, the activation of the NF-κB pathway and the up-regulation of pro-inflammatory cytokines, and so on. However, the intraocular pressure is still currently the only risk factor modifiable by medication or glaucoma surgery. This present review aims to summarize the multiple cellular processes, which promote different risk factors in glaucoma including aging, oxidative stress, trabecular meshwork defects, glial activation response, neurodegenerative insults, and the altered regulation of immune response.

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Autophagy Upregulation by the TFEB Inducer Trehalose Protects against Oxidative Damage and Cell Death Associated with NRF2 Inhibition in Human RPE Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/5296341 ◽

2020 ◽

Vol 2020 ◽

pp. 1-18

Author(s):

Samuel Abokyi ◽

Sze wan Shan ◽

Chi-ho To ◽

Henry Ho-lung Chan ◽

Dennis Yan-yin Tse

Keyword(s):

Oxidative Stress ◽

Oxidative Damage ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Mrna Levels ◽

Neuroprotective Effects ◽

Rpe Cells ◽

Age Related ◽

Protein Expressions

Trehalose is a natural dietary molecule that has shown antiaging and neuroprotective effects in several animal models of neurodegenerative diseases. The role of trehalose in the management of age-related macular degeneration (AMD) is yet to be investigated and whether trehalose could be a remedy for the treatment of diseases linked to oxidative stress and NRF2 dysregulation. Here, we showed that incubation of human retinal pigment epithelial (RPE) cells with trehalose enhanced the mRNA and protein expressions of TFEB, autophagy genes ATG5 and ATG7, as well as protein expressions of macroautophagy markers, LC3B and p62/SQTM1, and the chaperone-mediated autophagy (CMA) receptor LAMP2. Cathepsin D, a hydrolytic lysosomal enzyme, was also increased by trehalose, indicating higher proteolytic activity. Moreover, trehalose upregulated autophagy flux evident by an increase in the endogenous LC3B level, and accumulation of GFP-LC3B puncta and free GFP fragments in GFP-LC3 ̶ expressing cells in the presence of chloroquine. In addition, the mRNA levels of key molecular targets implicated in RPE damage and AMD, such as vascular endothelial growth factor- (VEGF-) A and heat shock protein 27 (HSP27), were downregulated, whereas NRF2 was upregulated by trehalose. Subsequently, we mimicked in vitro AMD conditions using hydroquinone (HQ) as the oxidative insult on RPE cells and evaluated the cytoprotective effect of trehalose compared to vehicle treatment. HQ depleted NRF2, increased oxidative stress, and reduced the viability of cells, while trehalose pretreatment protected against HQ-induced toxicity. The cytoprotection by trehalose was dependent on autophagy but not NRF2 activation, since autophagy inhibition by shRNA knockdown of ATG5 led to a loss of the protective effect. The results support the transcriptional upregulation of TFEB and autophagy by trehalose and its protection against HQ-induced oxidative damage in RPE cells. Further investigation is, therefore, warranted into the therapeutic value of trehalose in alleviating AMD and retinal diseases associated with impaired NRF2 antioxidant defense.

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Flavonoid-Rich Ethanol Extract from the Leaves of Diospyros kaki Attenuates D-Galactose-Induced Oxidative Stress and Neuroinflammation-Mediated Brain Aging in Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/8938207 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 13

Author(s):

Yingjuan Ma ◽

Bin Ma ◽

Yuying Shang ◽

Qingqing Yin ◽

Dejie Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Neurodegenerative Diseases ◽

Nuclear Translocation ◽

Brain Aging ◽

Ethanol Extract ◽

Neurological Impairment ◽

Diospyros Kaki ◽

Neuroprotective Effects ◽

Age Related ◽

Y Maze

Aging is a major factor that contributes to neurological impairment and neuropathological changes, such as inflammation, oxidative stress, neuronal apoptosis, and synaptic dysfunction. Flavonoids act as protective antioxidant and anti-inflammatory agents against various age-related neurodegenerative diseases. Here, we investigated the protective effect and mechanisms of the flavonoid-rich ethanol extract from the leaves of Diospyros kaki (FELDK) in the cortex and hippocampus of D-galactose- (gal-) aged mice. Our results showed that FELDK treatment restored memory impairment in mice as determined by the Y-maze and Morris water maze tests. FELDK decreased oxidative stress levels via inhibiting reactive oxygen species (ROS) and malondialdehyde (MDA) production and elevating antioxidative enzymes. FELDK also alleviated D-gal-induced neuroinflammation via suppressing the expression of advanced glycation end products (AGEs) and receptor for AGEs (RAGE) and activating microgliosis and astrocytosis, nuclear factor kappa B (NF-κB) nuclear translocation, and downstream inflammatory mediators. Moreover, FELDK inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt and C-jun N-terminal kinase (JNK) apoptotic signaling pathways and ameliorated the impairment of synapse-related proteins. Hence, these results indicate that FELDK exerts neuroprotective effects on D-gal-induced brain aging. Thus, FELDK may be a potential therapeutic strategy for preventing and treating age-related neurodegenerative diseases such as Alzheimer’s disease.

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Neuroprotective Effects of Cornus officinalis on Stress-Induced Hippocampal Deficits in Rats and H2O2-Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells

Antioxidants ◽

10.3390/antiox9010027 ◽

2019 ◽

Vol 9 (1) ◽

pp. 27 ◽

Cited By ~ 3

Author(s):

Weishun Tian ◽

Jing Zhao ◽

Jeong-Ho Lee ◽

Md Rashedunnabi Akanda ◽

Jeong-Hwi Cho ◽

...

Keyword(s):

Oxidative Stress ◽

Forced Swim Test ◽

Neuroblastoma Cells ◽

Mitogen Activated Protein Kinase ◽

Ros Generation ◽

Neuroprotective Effects ◽

Neuronal Markers ◽

Cornus Officinalis ◽

Immobility Time ◽

Wide Range

Oxidative stress plays a vital role in neurodegenerative diseases. Cornus officinalis (CC) has a wide range of pharmacological activities (e.g., antioxidant, neuroprotective, and anti-inflammatory). The present study was undertaken to elucidate the neuroprotective mechanism of CC and fermented CC (FCC) on stress and H2O2-induced oxidative stress damage in rats and SH-SY5Y cells. A dose of 100 mg/kg CC or FCC was orally administered to rats 1 h prior to immobilization 2 h per day for 14 days. CC, especially FCC administration decreased immobility time in forced swim test (FST), effectively alleviated the oxidative stress, and remarkably decreased corticosterone, β-endorphin and increased serotonin levels, respectively. In cells, CC and FCC significantly inhibited reactive oxygen species (ROS) generation, lactate dehydrogenase (LDH) release and significantly increased the genes expression of antioxidant and neuronal markers, such as superoxide dismutase (SOD), catalase (CAT), and brain-derived neurotrophic factor (BDNF). Moreover, the pro-apoptotic factor Bax and anti-apoptotic factor Bcl-2 (Bax/Bcl-2) ratio was regulated by CC and FCC pretreatment. Both in rats and cells, CC and FCC downregulated mitogen-activated protein kinase (MAPK) phosphorylation. Taken together, these results demonstrated that CC and particularly FCC ameliorated oxidative stress and may be used on the neuroprotection.

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4-PHENYLBUTYRATE: MOLECULAR MECHANISMS AND AGING INTERVENTION POTENTIAL

Innovation in Aging ◽

10.1093/geroni/igz038.379 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S101-S101

Author(s):

Michael R Bene ◽

Kevin Thyne ◽

Jonathan Dorigatti ◽

Adam B Salmon

Keyword(s):

Oxidative Stress ◽

Stress Response ◽

Molecular Mechanisms ◽

Oxidative Stress Response ◽

Chemical Chaperone ◽

Mouse Muscle ◽

Age Related ◽

Primary Mouse ◽

Wide Range

Abstract 4-Phenylbutyrate (PBA) is a FDA approved drug for treating patients with urea cycle disorders. Additionally, PBA acts upon several pathways thought of as important modifiers of aging including: histone deacetylation, proteostasis as a chemical chaperone, and stress resistance by regulating expression of oxidative stress response proteins. PBA has also been shown to extend lifespan and improve markers of age-related health in Drosophila. Due to its wide range of effects PBA has been investigated for use in numerous age-related disorders including neurodegenerative and cardiovascular diseases. To better understand the effects of PBA on the molecular level, we used both in cellulo and in vivo studies. Treatment of primary mouse fibroblasts, C2C12 mouse muscle cells, and NCTC 1469 mouse liver cells with PBA demonstrated differential responses among cell lines to upregulation of oxidative stress response and histone acetylation. Specifically, upregulation of the oxidative stress response protein DJ-1 by PBA was found to have a corresponding dose response curve to histone H3 acetylation in primary fibroblasts. To study effects of PBA in vivo, four cohorts of HET3 mice were treated with PBA at different doses in drinking water for 4 weeks. PBA was well tolerated and led to different effects on body composition dependent on the sex of mice. We are currently investigating the molecular effects of PBA treatment in multiple tissues samples from these mice. The potential of PBA to alter many fundamental pathways, and specifically those related to stress responses, make it an attractive prospect for treatment of many age-related disorders.

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Tissue-Specific Profiling of Oxidative Stress-Associated Transcriptome in a Healthy Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms19103174 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3174 ◽

Cited By ~ 8

Author(s):

Jung Kim ◽

Hyeong Kim ◽

Chang Son

Keyword(s):

Oxidative Stress ◽

Quantitative Polymerase Chain Reaction ◽

Specific Gene ◽

Tissue Specific ◽

Age Related ◽

Wide Range ◽

Liver And Kidney ◽

Specific Variation ◽

Polymerase Chain ◽

Lung And Kidney

Oxidative stress is a common phenomenon and is linked to a wide range of diseases and pathological processes including aging. Tissue-specific variation in redox signaling and cellular responses to oxidative stress may be associated with vulnerability especially to age-related and chronic diseases. In order to provide a basis for tissue-specific difference, we examined the tissue-specific transcriptional features of 101 oxidative stress-associated genes in 10 different tissues and organs of healthy mice under physiological conditions. Microarray analysis results, which were consistent with quantitative polymerase chain reaction (qPCR) results, showed that catalase, Gpx3, and Gpx4 were most highly regulated in the liver, kidney, and testes. We also found the tissue-specific gene expression of SOD1 (liver and kidney), SOD2 (heart and muscle), and SOD3 (lung and kidney). The current results will serve as a reference for animal models and help advance our understanding of tissue-specific variability in oxidative stress-associated pathogenesis.

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Plant-Based Foods and Their Bioactive Compounds on Fatty Liver Disease: Effects, Mechanisms, and Clinical Application

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6621644 ◽

2021 ◽

Vol 2021 ◽

pp. 1-23

Author(s):

Hang-Yu Li ◽

Ren-You Gan ◽

Ao Shang ◽

Qian-Qian Mao ◽

Quan-Cai Sun ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Fatty Liver ◽

Clinical Application ◽

Bioactive Compounds ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Experimental Studies ◽

Alcoholic Fatty Liver ◽

Wide Range

Fatty liver disease (FLD), including nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD), is a serious chronic metabolic disease that affects a wide range of people. Lipid accumulation accompanied by oxidative stress and inflammation in the liver is the most important pathogenesis of FLD. The plant-based, high-fiber, and low-fat diet has been recommended to manage FLD for a long time. This review discusses the current state of the art into the effects, mechanisms, and clinical application of plant-based foods in NAFLD and AFLD, with highlighting related molecular mechanisms. Epidemiological evidence revealed that the consumption of several plant-based foods was beneficial to alleviating FLD. Further experimental studies found out that fruits, spices, teas, coffee, and other plants, as well as their bioactive compounds, such as resveratrol, anthocyanin, curcumin, and tea polyphenols, could alleviate FLD by ameliorating hepatic steatosis, oxidative stress, inflammation, gut dysbiosis, and apoptosis, as well as regulating autophagy and ethanol metabolism. More importantly, clinical trials confirmed the beneficial effects of plant-based foods on patients with fatty liver. However, several issues need to be further studied especially the safety and effective doses of plant-based foods and their bioactive compounds. Overall, certain plant-based foods are promising natural sources of bioactive compounds to prevent and alleviate fatty liver disease.

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Neuroprotective Effects of Glochidion zeylanicum Leaf Extract against H2O2/Glutamate-Induced Toxicity in Cultured Neuronal Cells and Aβ-Induced Toxicity in Caenorhabditis elegans

Biology ◽

10.3390/biology10080800 ◽

2021 ◽

Vol 10 (8) ◽

pp. 800

Author(s):

Chatrawee Duangjan ◽

Panthakarn Rangsinth ◽

Shaoxiong Zhang ◽

Xiaojie Gu ◽

Michael Wink ◽

...

Keyword(s):

Oxidative Stress ◽

Caenorhabditis Elegans ◽

Leaf Extract ◽

Neuronal Cells ◽

Antioxidant Properties ◽

Ros Generation ◽

Protective Effects ◽

Neuroprotective Effects ◽

Antioxidant Genes ◽

Age Related

Oxidative stress plays a crucial role in the development of age-related neurodegenerative diseases. Previously, Glochidion zeylanicum methanol (GZM) extract has been reported to have antioxidant and anti-aging properties. However, the effect of GZM on neuroprotection has not been reported yet; furthermore, the mechanism involved in its antioxidant properties remains unresolved. The study is aimed to demonstrate the neuroprotective properties of GZM extract and their underlying mechanisms in cultured neuronal (HT-22 and Neuro-2a) cells and Caenorhabditis elegans models. GZM extract exhibited protective effects against glutamate/H2O2-induced toxicity in cultured neuronal cells by suppressing the intracellular reactive oxygen species (ROS) generation and enhancing the expression of endogenous antioxidant enzymes (SODs, GPx, and GSTs). GZM extract also triggered the expression of SIRT1/Nrf2 proteins and mRNA transcription of antioxidant genes (NQO1, GCLM, and EAAT3) which are the master regulators of cellular defense against oxidative stress. Additionally, GZM extract exhibited protective effects to counteract β-amyloid (Aβ)-induced toxicity in C. elegans and promoted neuritogenesis properties in Neuro-2a cells. Our observations suggest that GZM leaf extract has interesting neuritogenesis and neuroprotective potential and can possibly act as potential contender for the treatment of oxidative stress-induced Alzheimer’s disease (AD) and related neurodegenerative conditions; however, this needs to be studied further in other in vivo systems.

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