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

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 Taraxacum officinale Wigg. Extract on Glutamate-Induced Oxidative Stress in HT22 Cells via HO-1/Nrf2 Pathways

Nutrients ◽

10.3390/nu10070926 ◽

2018 ◽

Vol 10 (7) ◽

pp. 926 ◽

Cited By ~ 6

Author(s):

Shan Huang ◽

Ning Meng ◽

Zhiming Liu ◽

Li Guo ◽

Linsha Dong ◽

...

Keyword(s):

Oxidative Stress ◽

Oxidative Damage ◽

Neurodegenerative Diseases ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Taraxacum Officinale ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Neuroprotective Effects ◽

Ht22 Cells

Oxidative stress-mediated neuron damage is considered an important contributor to the pathogenesis and development of neurodegenerative diseases. Taraxacum officinale has been reported to possess antioxidant activities. However, whether it can protect neurons against oxidative damage and the underlying molecular mechanisms have not been fully determined. In the present study, we examined the neuroprotective effects of ethanol extracts of this plant (ETOW) on glutamate-induced oxidative stress in HT22 cells. Both cell viability and reactive oxygen species (ROS) assays showed that ETOW effectively attenuated glutamate-induced cytotoxicity and ROS generation. Furthermore, our results revealed that ETOW increased the expression of heme oxygenase-1 (HO-1) and promoted the nuclear translocation of nuclear factor erythroid 2-related factor-2 (Nrf2). The inhibitory effects of ETOW on glutamate-stimulated cell toxicity and ROS production were partially reversed by tin protoporphyrin (SnPP), an HO activity inhibitor. Taken together, these results demonstrate that ETOW can protect HT22 cells against glutamate-induced oxidative damage by inducing the Nrf2/HO-1 pathways. Our study supports the idea that Taraxacum officinale Wigg. is a promising agent for preventing neurodegenerative diseases.

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Saponins of Panax japonicus Confer Neuroprotection against Brain Aging through Mitochondrial Related Oxidative Stress and Autophagy in Rats

Current Pharmaceutical Biotechnology ◽

10.2174/1389201021666191216114815 ◽

2020 ◽

Vol 21 (8) ◽

pp. 667-680

Author(s):

Jing-zhi Wan ◽

Rui Wang ◽

Zhi-yong Zhou ◽

Li-li Deng ◽

Chang-cheng Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Superoxide Dismutase ◽

Brain Aging ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

Control Groups ◽

Neuroprotective Effects ◽

Aging Rats ◽

Age Related ◽

Panax Japonicus

Background: Oxidative stress and mitochondrial dysfunction play a vital role in the pathogenesis of brain aging. Saponins from Panax japonicus (SPJ) have attracted much attention for their potential to attenuate age-related oxidative stress as the main ingredient in rhizomes of Panax japonicus. Objective: This study aimed to investigate the neuroprotective effects of SPJ on natural aging rats as well as the underlying mechanisms regarding oxidative stress and mitochondrial pathway. Methods: Sprague-Dawley rats were divided into control groups (3-, 9-, 15- and 24-month old groups) and SPJ-treated groups. For SPJ-treated groups, SPJ were orally administrated to 18-month old rats at doses of 10 mg/kg, 30 mg/kg and 60 mg/kg once daily. Control groups were given the same volume of saline. After the treatment with SPJ or saline for six months, the cortex and hippocampus were rapidly harvested and deposited at -80°C after the rats were decapitated under anesthesia. The neuroprotective effects of SPJ were estimated by histopathological observation, TUNEL detection, biochemical determination and western blotting. Results: SPJ improved pathomorphological changes in neuronal cells and decreased apoptosis in the cortex and hippocampus of aging rats, increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), Na+/K+-ATPase, Ca2+-ATPase and Ca2+/Mg2+-ATPase whereas, decreased malondialdehyde (MDA) contents in the cortex of aging rats. Furthermore, the SPJ increased silent mating type information regulation 2 homolog-1 (SIRT1) protein expression, decreased acetylated level of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in the cortex and hippocampus of aging rats, and reversed the aging-induced decline of Forkhead box O3 (Foxo3a), Superoxide Dismutase 2 (SOD2), microtubule-associated protein light chain 3 (LC3II) and Beclin1 levels in the cortex and hippocampus. Conclusion: Our data showed that SPJ conferred neuroprotection partly through the regulation of oxidative stress and mitochondria-related pathways in aging rats.

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A Flavonoid-Rich Extract of Mandarin Juice Counteracts 6-OHDA-Induced Oxidative Stress in SH-SY5Y Cells and Modulates Parkinson-Related Genes

Antioxidants ◽

10.3390/antiox10040539 ◽

2021 ◽

Vol 10 (4) ◽

pp. 539

Author(s):

Santa Cirmi ◽

Alessandro Maugeri ◽

Giovanni Enrico Lombardo ◽

Caterina Russo ◽

Laura Musumeci ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Neurodegenerative Diseases ◽

Dopaminergic Neurons ◽

Specific Interaction ◽

Food Sources ◽

Human Neuroblastoma Cell ◽

Neuroprotective Effects ◽

Human Neuroblastoma ◽

Mandarin Juice

Parkinson’s disease (PD) is a degenerative disorder of the nervous system due to unceasing impairment of dopaminergic neurons situated in the substantia nigra. At present, anti-PD drugs acting on dopamine receptors are mainly symptomatic and have only very limited neuroprotective effects, whereas drugs slowing down neurodegeneration of dopaminergic neurons and deterioration of clinical symptoms are not yet available. Given that, the development of more valuable pharmacological strategies is highly demanded. Comprehensive research on innovative neuroprotective drugs has proven that anti-inflammatory and antioxidant molecules from food sources may prevent and/or counteract neurodegenerative diseases, such as PD. The present study was aimed at the evaluation the protective effect of mandarin juice extract (MJe) against 6-hydroxydopamine (6-OHDA)-induced SH-SY5Y human neuroblastoma cell death. Treatment of differentiated SH-SY5Y cells with 6-OHDA brought cell death, and specifically, apoptosis, which was significantly inhibited by the preincubation with MJe through caspase 3 blockage and the modulation of p53, Bax, and Bcl-2 genes. In addition, it showed antioxidant properties in abiotic models as well as in vitro, where it reduced both reactive oxygen and nitrogen species induced by 6-OHDA, along with restored mitochondrial membrane potential, and prevented the oxidative DNA damage evoked by 6-OHDA. Furthermore, MJe restored the impaired balance of SNCA, LRRK2, PINK1, parkin, and DJ-1 gene levels, PD-related factors, caused by 6-OHDA oxidative stress. Overall, these results indicate that MJe exerts neuroprotective effects against 6-OHDA-induced cell death in SH-SY5Y cells by mechanisms involving both the specific interaction with intracellular pathways and its antioxidant capability. Our study suggests a novel possible strategy to prevent and/or ameliorate neurodegenerative diseases, such as PD.

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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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Metabolomics of Human Brain Aging and Age-Related Neurodegenerative Diseases

Journal of Neuropathology & Experimental Neurology ◽

10.1097/nen.0000000000000091 ◽

2014 ◽

Vol 73 (7) ◽

pp. 640-657 ◽

Cited By ~ 106

Author(s):

Mariona Jové ◽

Manuel Portero-Otín ◽

Alba Naudí ◽

Isidre Ferrer ◽

Reinald Pamplona

Keyword(s):

Human Brain ◽

Neurodegenerative Diseases ◽

Brain Aging ◽

Age Related

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Memorable Food: Fighting Age-Related Neurodegeneration by Precision Nutrition

Frontiers in Nutrition ◽

10.3389/fnut.2021.688086 ◽

2021 ◽

Vol 8 ◽

Author(s):

Maja Milošević ◽

Aleksandra Arsić ◽

Zorica Cvetković ◽

Vesna Vučić

Keyword(s):

Lipid Metabolism ◽

Neurodegenerative Diseases ◽

Mediterranean Diet ◽

Gut Microbiome ◽

Large Scale ◽

Nitrosative Stress ◽

Low Grade ◽

Neuroprotective Effects ◽

Age Related ◽

The Mediterranean

Healthcare systems worldwide are seriously challenged by a rising prevalence of neurodegenerative diseases (NDDs), which mostly, but not exclusively, affect the ever-growing population of the elderly. The most known neurodegenerative diseases are Alzheimer's (AD) and Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, but some viral infections of the brain and traumatic brain injury may also cause NDD. Typical for NDD are the malfunctioning of neurons and their irreversible loss, which often progress irreversibly to dementia and ultimately to death. Numerous factors are involved in the pathogenesis of NDD: genetic variability, epigenetic changes, extent of oxidative/nitrosative stress, mitochondrial dysfunction, and DNA damage. The complex interplay of all the above-mentioned factors may be a fingerprint of neurodegeneration, with different diseases being affected to different extents by particular factors. There is a voluminous body of evidence showing the benefits of regular exercise to brain health and cognitive functions. Moreover, the importance of a healthy diet, balanced in macro- and micro-nutrients, in preventing neurodegeneration and slowing down a progression to full-blown disease is evident. Individuals affected by NDD almost inevitably have low-grade inflammation and anomalies in lipid metabolism. Metabolic and lipid profiles in NDD can be improved by the Mediterranean diet. Many studies have associated the Mediterranean diet with a decreased risk of dementia and AD, but a cause-and-effect relationship has not been deduced. Studies with caloric restriction showed neuroprotective effects in animal models, but the results in humans are inconsistent. The pathologies of NDD are complex and there is a great inter-individual (epi)genetic variance within any population. Furthermore, the gut microbiome, being deeply involved in nutrient uptake and lipid metabolism, also represents a pillar of the gut microbiome–brain axis and is linked with the pathogenesis of NDD. Numerous studies on the role of different micronutrients (omega-3 fatty acids, bioactive polyphenols from fruit and medicinal plants) in the prevention, prediction, and treatment of NDD have been conducted, but we are still far away from a personalized diet plan for individual NDD patients. For this to be realized, large-scale cohorts that would include the precise monitoring of food intake, mapping of genetic variants, epigenetic data, microbiome studies, and metabolome, lipidome, and transcriptome data are needed.

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Isomeric O-methyl cannabidiolquinones with dual BACH1/NRF2 activity

10.1101/2020.06.16.153981 ◽

2020 ◽

Author(s):

Laura Casares ◽

Juan Diego Unciti ◽

Maria Eugenia Prados ◽

Diego Caprioglio ◽

Maureen Higgins ◽

...

Keyword(s):

Oxidative Stress ◽

Multiple Sclerosis ◽

Neurodegenerative Diseases ◽

Cell Models ◽

Therapeutic Approaches ◽

Neuroprotective Effects ◽

Anti Oxidant ◽

Anti Inflammatory ◽

The Brain

ABSTRACTOxidative stress and inflammation in the brain are two key hallmarks of neurodegenerative diseases (NDs) such as Alzheimer’s, Parkinson’s, Huntington’s and multiple sclerosis. The axis NRF2-BACH1 has anti-inflammatory and anti-oxidant properties that could be exploited pharmacologically to obtain neuroprotective effects. Activation of NRF2 or inhibition of BACH1 are, individually, promising therapeutic approaches for NDs. Compounds with dual activity as NRF2 activators and BACH1 inhibitors, could therefore potentially provide a more robust antioxidant and anti-inflammatory effects, with an overall better neuroprotective outcome. The phytocannabinoid cannabidiol (CBD) inhibits BACH1 but lacks significant NRF2 activating properties. Based on this scaffold, we have developed a novel CBD derivative that is highly effective at both inhibiting BACH1 and activating NRF2. This new CBD derivative provides neuroprotection in cell models of relevance to Huntington’s disease, setting the basis for further developments in vivo.

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The Role of NADPH Oxidases and Oxidative Stress in Neurodegenerative Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms19123824 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3824 ◽

Cited By ~ 54

Author(s):

Anuradha Tarafdar ◽

Giordano Pula

Keyword(s):

Oxidative Stress ◽

Neurodegenerative Diseases ◽

Neurodegenerative Disorders ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Ros Generation ◽

Phagocytic Cells ◽

Nadph Oxidases ◽

Age Related ◽

Recent Developments ◽

Cerebrovascular Endothelial Cells

For a number of years, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) was synonymous with NOX2/gp91phox and was considered to be a peculiarity of professional phagocytic cells. Over the last decade, several more homologs have been identified and based on current research, the NOX family consists of NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2 enzymes. NOXs are electron transporting membrane proteins that are responsible for reactive oxygen species (ROS) generation—primarily superoxide anion (O2●−), although hydrogen peroxide (H2O2) can also be generated. Elevated ROS leads to oxidative stress (OS), which has been associated with a myriad of inflammatory and degenerative pathologies. Interestingly, OS is also the commonality in the pathophysiology of neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). NOX enzymes are expressed in neurons, glial cells and cerebrovascular endothelial cells. NOX-mediated OS is identified as one of the main causes of cerebrovascular damage in neurodegenerative diseases. In this review, we will discuss recent developments in our understanding of the mechanisms linking NOX activity, OS and neurodegenerative diseases, with particular focus on the neurovascular component of these conditions. We conclude highlighting current challenges and future opportunities to combat age-related neurodegenerative disorders by targeting NOXs.

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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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Neuroprotective Potential of GDF11: Myth or Reality?

International Journal of Molecular Sciences ◽

10.3390/ijms20143563 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3563 ◽

Cited By ~ 1

Author(s):

Luc Rochette ◽

Gabriel Malka

Keyword(s):

Neurodegenerative Diseases ◽

Blood Plasma ◽

Neurodegenerative Disorders ◽

Brain Aging ◽

Therapeutic Strategies ◽

Blood Concentrations ◽

Age Related ◽

Novel Therapeutic Strategies ◽

The Brain ◽

Novel Therapeutic

In the brain, aging is accompanied by cellular and functional deficiencies that promote vulnerability to neurodegenerative disorders. In blood plasma from young and old animals, various factors such as growth differentiation factor 11 (GDF11), whose levels are elevated in young animals, have been identified. The blood concentrations of these factors appear to be inversely correlated with the age-related decline of neurogenesis. The identification of GDF11 as a “rejuvenating factor” opens up perspectives for the treatment of neurodegenerative diseases. As a pro-neurogenic and pro-angiogenic agent, GDF11 may constitute a basis for novel therapeutic strategies.

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