Hibiscus sabdariffa extract protects HT-22 cells from glutamate-induced neurodegeneration by upregulating glutamate transporters and exerts lifespan extension in C. elegans via DAF-16 mediated pathway

BACKGROUND: Glutamate toxicity is involved in several neurodegenerative conditions, including Alzheimer’s disease. OBJECTIVE: The study aims to investigate the neuroprotective efficacy of ethanol extract of Hibiscus sabdariffa calyces (HS) against glutamate-induced toxicity in HT-22 cells and induce anti-aging property in Caenorhabditis elegans. METHODS: HT-22 cells were pre-treated with HS followed by glutamate and evaluated for the neuroprotective effect using cell viability assay, confocal microscopic analysis, qPCR, Western blot, and docking analysis. Induction of anti-aging property in C. elegans with HS extract was analyzed through physiological assays and qPCR analysis. RESULTS: GC-MS analysis of the HS extract showed the presence of 19 compounds with antioxidant properties including oleamide,2-(diethoxymethyl)furan and 5-methylfurfural. In vitro studies reveal that glutamate exerted toxicity in HT-22 cells by inducing oxidative stress, depleting glutathione, downregulating glutamate transporters, antioxidant genes, inducing autophagy (Beclin-1, Atg-5, Atg-7, LC3-II) by the activation of MAPK (p38, JNK) pathway, and causing apoptosis. However, pre-treatment with HS extract (5, 10μg/ml) reversed the effect and offered neuroprotection. In silico studies showed that the compounds of HS extract can bind effectively and inhibit the activity of NMDAR, calpain-1 and GSK-3β. In C. elegans, HS extended lifespan, reduced the accumulation of lipofuscin, modulated healthspan-related genes and downregulated the expression of daf-2. CONCLUSION: Our results indicate that HS with its bioactive components exhibits neuroprotective activity by upregulating glutamate transporters, inhibiting autophagy and exerts anti-aging property through DAF-16 dependent mechanism.

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Enhancement of the Neuroprotective Effect of Fermented Spirulina maxima Associated with Antioxidant Activities by Ultrasonic Extraction

Applied Sciences ◽

10.3390/app8122469 ◽

2018 ◽

Vol 8 (12) ◽

pp. 2469 ◽

Cited By ~ 4

Author(s):

Woon Choi ◽

Do Kang ◽

Soo-Jin Heo ◽

Hyeon Lee

Keyword(s):

Antioxidant Activities ◽

Neuroprotective Effect ◽

Antioxidant Properties ◽

Radical Scavenging ◽

Ultrasonic Extraction ◽

Biologically Active ◽

Water Extraction ◽

Neuroprotective Activity ◽

Spirulina Maxima ◽

Β Carotene

This study is the first demonstration of the neuroprotective activity of the marine alga, Spirulina maxima, fermented by Lactobacillus plantarum HY-08, which was freshly isolated from fermented vegetables. The combined process of the fermentation with ultrasonic extraction at 40 kHz for 4 hr greatly increased the amounts of β-carotene in the extract up to 1.62 mg/g, along with a high extraction yield of 18.26%, compared to 1.03 mg/g and 12.8% from ultrasonic extraction itself, and even much higher than 0.81 mg/g and 10.6% from conventional water extraction. It was also proved that the neuroprotective activities of the extract were enhanced possibly by higher contents of β-carotene in the extract, compared to those from water extraction or ultrasonic extraction itself. This extract was found to have strong antioxidant properties, with 49.01% 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, which resulted in 90.30% neuroprotective activity. Specifically, the fermented extract markedly enhanced the brain-derived neurotrophic factor (BDNF)/p-CREB signaling pathways, which can effectively prevent memory impairment in mice caused by oxidative stress. β-Carotene also increased the expression of p-CREB and BDNF, and a mechanism of their upregulation by β-carotene is first proposed in this study. It can be concluded that the strong neuroprotective effect of the extract was markedly influenced by the antioxidant activities, due to the synergistic effects of high amounts of β-carotene and other biologically active substances in the extract that can be obtained by lactic acid fermentation, combined with ultrasonic processing.

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Neuroprotective γ-Pyrones from Fusarium Solani JS-0169: Cell-Based Identification of Active Compounds and an Informatics Approach to Predict the Mechanism of Action

Biomolecules ◽

10.3390/biom10010091 ◽

2020 ◽

Vol 10 (1) ◽

pp. 91 ◽

Cited By ~ 3

Author(s):

Hyun Gyu Choi ◽

Ji Hoon Song ◽

Musun Park ◽

Soonok Kim ◽

Chang-Eop Kim ◽

...

Keyword(s):

Cell Death ◽

Fusarium Solani ◽

Neuroprotective Effect ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Neuroprotective Activity ◽

Glutamate Toxicity ◽

Protective Effects ◽

Cns Injury ◽

Ht22 Cells

Glutamate toxicity has been implicated in neuronal cell death in both acute CNS injury and in chronic diseases. In our search for neuroprotective agents obtained from natural sources that inhibit glutamate toxicity, an endophytic fungus, Fusarium solani JS-0169 isolated from the leaves of Morus alba, was found to show potent inhibitory activity. Chemical investigation of the cultures of the fungus JS-0169 afforded isolation of six compounds, including one new γ-pyrone (1), a known γ-pyrone, fusarester D (2), and four known naphthoquinones: karuquinone B (3), javanicin (4), solaniol (5), and fusarubin (6). To identify the protective effects of the isolated compounds (1–6), we assessed their inhibitory effect against glutamate-induced cytotoxicity in HT22 cells. Among the isolates, compound 6 showed significant neuroprotective activity on glutamate-mediated HT22 cell death. In addition, the informatics approach using in silico systems pharmacology identified that compound 6 may exert its neuroprotective effect by controlling the amount of ubiquinone. The results suggest that the metabolites produced by the endophyte Fusarium solani JS-0169 might be related to the neuroprotective activity of its host plant, M. alba.

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Neuroprotective Effects of Extracts from Tiger Milk Mushroom Lignosus rhinocerus Against Glutamate-Induced Toxicity in HT22 Hippocampal Neuronal Cells and Neurodegenerative Diseases in Caenorhabditis elegans

Biology ◽

10.3390/biology10010030 ◽

2021 ◽

Vol 10 (1) ◽

pp. 30

Author(s):

Parinee Kittimongkolsuk ◽

Nattaporn Pattarachotanant ◽

Siriporn Chuchawankul ◽

Michael Wink ◽

Tewin Tencomnao

Keyword(s):

Oxidative Stress ◽

Neuroprotective Effect ◽

Water Extract ◽

Neuroprotective Effects ◽

Ht22 Cells ◽

Antioxidant Genes ◽

C Elegans ◽

Intracellular Ros

Despite the Tiger Milk Mushroom Lignosus rhinocerus (LR) having been used as a traditional medicine, little is known about the neuroprotective effects of LR extracts. This study aims to investigate the neuroprotective effect of three extracts of LR against glutamate-induced oxidative stress in mouse hippocampal (HT22) cells as well as to determine their effect in Caenorhabditis elegans. In vitro, we assessed the toxicity of three LR extracts (ethanol extract (LRE), cold-water extract (LRC) and hot-water extract (LRH)) and their protective activity by MTT assay, Annexin V-FITC/propidium iodide staining, Mitochondrial Membrane Potential (MMP) and intracellular ROS accumulation. Furthermore, we determined the expression of antioxidant genes (catalase (CAT), superoxide dismutase (SOD1 and SOD2) and glutathione peroxidase (GPx)) by qRT-PCR. In vivo, we investigated the neuroprotective effect of LRE, not only against an Aβ-induced deficit in chemotaxis behavior (Alzheimer model) but also against PolyQ40 formation (model for Morbus Huntington) in transgenic C. elegans. Only LRE significantly reduced both apoptosis and intracellular ROS levels and significantly increased the expression of antioxidant genes after glutamate-induced oxidative stress in HT22 cells. In addition, LRE significantly improved the Chemotaxis Index (CI) in C. elegans and significantly decreased PolyQ40 aggregation. Altogether, the LRE exhibited neuroprotective properties both in vitro and in vivo.

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Bioisosteric Analogues of Cinnamic Acid as Effective Neuroprotectors

Biomedical Chemistry Research and Methods ◽

10.18097/bmcrm00052 ◽

2018 ◽

Vol 1 (3) ◽

pp. e00052

Author(s):

M.E. Neganova ◽

V. Semenov ◽

M. Semenova ◽

O.M. Redkozubova ◽

Yu.R. Aleksandrova ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Cinnamic Acid ◽

Biological Activities ◽

Neuroprotective Effect ◽

Antioxidant Properties ◽

Neuroprotective Activity ◽

Age Related ◽

Mitochondrial Functions ◽

Wide Range ◽

The Creation

Compounds that act on mitochondrial functions are considered as promising drugs for the treatment of neurodegenerative diseases and age-related dementias. As a basis for the creation of such potential drugs, bioisosteric cinnamic acid analogs and polymethoxybenzene derivatives were selected. Derivatives of cinnamic acid have a wide range of biological activities, which can be important for drugs aimed at the treatment of neurodegenerative diseases, in particular Alzheimer′s disease. In this work, the neuroprotective activity of bioisosteric cinnamic acid analogs and polymethoxybenzene derivatives was studied. Among the compounds studied, lead substances 3, 4, and 7 have been identified. These compounds show no intrinsic toxicity and have a neuroprotective effect on the cellular model of neurodegeneration associated with calcium stress. The mechanism of their cytoprotective activity is probably due to the influence on mitochondrial functions, because these compounds effectively suppress the calcium-induced process of mitochondrial permeability jump. In addition, one of the substances investigated (7) has antioxidant properties, showing the ability to inhibit lipid peroxidation (LPO) of rat brain homogenate, which may be an additional mechanism of neuroprotective effect. The data obtained make it possible to recommend the investigated substances as a basis for the creation of effective neuroprotective drugs capable of influencing early stages of the development of neurodegenerative diseases.

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Neuroprotective Activity of Methanolic Extract of Lysimachia christinae against Glutamate Toxicity in HT22 Cell and Its Protective Mechanisms

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/5352034 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Gahee Ryu ◽

Choong Je Ma

Keyword(s):

Oxidative Stress ◽

Cell Viability ◽

Cell Damage ◽

Neuroprotective Effect ◽

Neuronal Cell ◽

Neuroprotective Activity ◽

Glutamate Toxicity ◽

Protective Mechanisms ◽

Ht22 Cells ◽

Ht22 Cell

Purpose. Excessive glutamate amount can give oxidative stress to neuronal cells, and the accumulation of cell death can trigger the neurodegenerative disorders. In this study, we discovered the neuroprotective effect of Lysimachia christinae Hance in the mouse hippocampal HT22 cell line. Method. Overnight incubated HT22 cells were pretreated with L. christinae extract dose dependently (1, 10, and 100 μg/ml). Followed by then, glutamate was treated. These treated cells were incubated several times again, and cell viability, accumulation of reactive oxygen species (ROS) and Ca2+, mitochondrial membrane potential (MMP), and glutathione-related enzyme amount were measured. Results. As a result, L. christinae increases the cell viability by inhibiting the ROS and Ca2+ formation, recovering the level of MMP and enhancing the activity of glutathione production compared with only vehicle-treated groups. Conclusion. These draw that L. christinae may remarkably decelerate the neurodegeneration by minimizing neuronal cell damage via oxidative stress.

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Bioactive Alkaloids from Genus Aspergillus: Mechanistic Interpretation of Their Antimicrobial and Potential SARS-CoV-2 Inhibitory Activity Using Molecular Modelling

International Journal of Molecular Sciences ◽

10.3390/ijms22041866 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1866

Author(s):

Fadia S. Youssef ◽

Elham Alshammari ◽

Mohamed L. Ashour

Keyword(s):

Active Sites ◽

Biological Activities ◽

Antioxidant Properties ◽

Marine Organisms ◽

Topoisomerase Iv ◽

Angiotensin Converting Enzyme 2 ◽

Nucleotidyl Transferase ◽

In Silico Studies ◽

Best Fitting ◽

Inhibitory Potential

Genus Aspergillus represents a widely spread genus of fungi that is highly popular for possessing potent medicinal potential comprising mainly antimicrobial, cytotoxic and antioxidant properties. They are highly attributed to its richness by alkaloids, terpenes, steroids and polyketons. This review aimed to comprehensively explore the diverse alkaloids isolated and identified from different species of genus Aspergillus that were found to be associated with different marine organisms regarding their chemistry and biology. Around 174 alkaloid metabolites were reported, 66 of which showed important biological activities with respect to the tested biological activities mainly comprising antiviral, antibacterial, antifungal, cytotoxic, antioxidant and antifouling activities. Besides, in silico studies on different microbial proteins comprising DNA-gyrase, topoisomerase IV, dihydrofolate reductase, transcriptional regulator TcaR (protein), and aminoglycoside nucleotidyl transferase were done for sixteen alkaloids that showed anti-infective potential for better mechanistic interpretation of their probable mode of action. The inhibitory potential of compounds vs. Angiotensin-Converting Enzyme 2 (ACE2) as an important therapeutic target combating COVID-19 infection and its complication was also examined using molecular docking. Fumigatoside E showed the best fitting within the active sites of all the examined proteins. Thus, Aspergillus species isolated from marine organisms could afford bioactive entities combating infectious diseases.

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The Potential Effects of Phytoestrogens: The Role in Neuroprotection

Molecules ◽

10.3390/molecules26102954 ◽

2021 ◽

Vol 26 (10) ◽

pp. 2954

Author(s):

Justyna Gorzkiewicz ◽

Grzegorz Bartosz ◽

Izabela Sadowska-Bartosz

Keyword(s):

Neuroprotective Effect ◽

Antioxidant Properties ◽

Estrogen Therapy ◽

Neuroprotective Effects ◽

Potential Health ◽

Naturally Occurring ◽

Epigenetic Effects ◽

Estrogen Synthesis ◽

Health Promoting ◽

The Brain

Phytoestrogens are naturally occurring non-steroidal phenolic plant compounds. Their structure is similar to 17-β-estradiol, the main female sex hormone. This review offers a concise summary of the current literature on several potential health benefits of phytoestrogens, mainly their neuroprotective effect. Phytoestrogens lower the risk of menopausal symptoms and osteoporosis, as well as cardiovascular disease. They also reduce the risk of brain disease. The effects of phytoestrogens and their derivatives on cancer are mainly due to the inhibition of estrogen synthesis and metabolism, leading to antiangiogenic, antimetastatic, and epigenetic effects. The brain controls the secretion of estrogen (hypothalamus-pituitary-gonads axis). However, it has not been unequivocally established whether estrogen therapy has a neuroprotective effect on brain function. The neuroprotective effects of phytoestrogens seem to be related to both their antioxidant properties and interaction with the estrogen receptor. The possible effects of phytoestrogens on the thyroid cause some concern; nevertheless, generally, no serious side effects have been reported, and these compounds can be recommended as health-promoting food components or supplements.

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Protective Effect of Osmundacetone against Neurological Cell Death Caused by Oxidative Glutamate Toxicity

Biomolecules ◽

10.3390/biom11020328 ◽

2021 ◽

Vol 11 (2) ◽

pp. 328

Author(s):

Tuy An Trinh ◽

Young Hye Seo ◽

Sungyoul Choi ◽

Jun Lee ◽

Ki Sung Kang

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Defense Mechanism ◽

Neuroprotective Effect ◽

Glutamate Release ◽

Chromatin Condensation ◽

Critical Role ◽

Glutamate Toxicity ◽

Heme Oxygenase 1 ◽

Brain Functions

Oxidative stress is one of the main causes of brain cell death in neurological disorders. The use of natural antioxidants to maintain redox homeostasis contributes to alleviating neurodegeneration. Glutamate is an excitatory neurotransmitter that plays a critical role in many brain functions. However, excessive glutamate release induces excitotoxicity and oxidative stress, leading to programmed cell death. Our study aimed to evaluate the effect of osmundacetone (OAC), isolated from Elsholtzia ciliata (Thunb.) Hylander, against glutamate-induced oxidative toxicity in HT22 hippocampal cells. The effect of OAC treatment on excess reactive oxygen species (ROS), intracellular calcium levels, chromatin condensation, apoptosis, and the expression level of oxidative stress-related proteins was evaluated. OAC showed a neuroprotective effect against glutamate toxicity at a concentration of 2 μM. By diminishing the accumulation of ROS, as well as stimulating the expression of heat shock protein 70 (HSP70) and heme oxygenase-1 (HO-1), OAC triggered the self-defense mechanism in neuronal cells. The anti-apoptotic effect of OAC was demonstrated through its inhibition of chromatin condensation, calcium accumulation, and reduction of apoptotic cells. OAC significantly suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), including c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 kinases. Thus, OAC could be a potential agent for supportive treatment of neurodegenerative diseases.

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Molecular and Biochemical Pathways of Catalpol in Alleviating Diabetes Mellitus and Its Complications

Biomolecules ◽

10.3390/biom11020323 ◽

2021 ◽

Vol 11 (2) ◽

pp. 323

Author(s):

Subrat Kumar Bhattamisra ◽

Hui Min Koh ◽

Shin Yean Lim ◽

Hira Choudhury ◽

Manisha Pandey

Keyword(s):

Diabetes Mellitus ◽

Diabetic Complications ◽

Inflammatory Markers ◽

Phosphoenolpyruvate Carboxykinase ◽

Neuroprotective Effect ◽

Antioxidant Properties ◽

Beneficial Effects ◽

Ppar Γ ◽

High Glucose Condition ◽

Anti Inflammatory

Catalpol isolated from Rehmannia glutinosa is a potent antioxidant and investigated against many disorders. This review appraises the key molecular pathways of catalpol against diabetes mellitus and its complications. Multiple search engines including Google Scholar, PubMed, and Science Direct were used to retrieve publications containing the keywords “Catalpol”, “Type 1 diabetes mellitus”, “Type 2 diabetes mellitus”, and “diabetic complications”. Catalpol promotes IRS-1/PI3K/AKT/GLUT2 activity and suppresses Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose 6-phosphatase (G6Pase) expression in the liver. Catalpol induces myogenesis by increasing MyoD/MyoG/MHC expression and improves mitochondria function through the AMPK/PGC-1α/PPAR-γ and TFAM signaling in skeletal muscles. Catalpol downregulates the pro-inflammatory markers and upregulates the anti-inflammatory markers in adipose tissues. Catalpol exerts antioxidant properties through increasing superoxide dismutase (sod), catalase (cat), and glutathione peroxidase (gsh-px) activity in the pancreas and liver. Catalpol has been shown to have anti-oxidative, anti-inflammatory, anti-apoptosis, and anti-fibrosis properties that in turn bring beneficial effects in diabetic complications. Its nephroprotective effect is related to the modulation of the AGE/RAGE/NF-κB and TGF-β/smad2/3 pathways. Catalpol produces a neuroprotective effect by increasing the expression of protein Kinase-C (PKC) and Cav-1. Furthermore, catalpol exhibits a cardioprotective effect through the apelin/APJ and ROS/NF-κB/Neat1 pathway. Catalpol stimulates proliferation and differentiation of osteoblast cells in high glucose condition. Lastly, catalpol shows its potential in preventing neurodegeneration in the retina with NF-κB downregulation. Overall, catalpol exhibits numerous beneficial effects on diabetes mellitus and diabetic complications.

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Quercetin attenuates the reduction of parvalbumin in middle cerebral artery occlusion animal model

Laboratory Animal Research ◽

10.1186/s42826-021-00086-0 ◽

2021 ◽

Vol 37 (1) ◽

Author(s):

Dong-Ju Park ◽

Ju-Bin Kang ◽

Fawad-Ali Shah ◽

Phil-Ok Koh

Keyword(s):

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Cerebral Artery ◽

Neuroprotective Effect ◽

Neuronal Cell ◽

Artery Occlusion ◽

Male Rats ◽

Neurological Deficits ◽

Glutamate Toxicity ◽

Cerebral Artery Occlusion

Abstract Background Calcium is a critical factor involved in modulation of essential cellular functions. Parvalbumin is a calcium buffering protein that regulates intracellular calcium concentrations. It prevents rises in calcium concentrations and inhibits apoptotic processes during ischemic injury. Quercetin exerts potent antioxidant and anti-apoptotic effects during brain ischemia. We investigated whether quercetin can regulate parvalbumin expression in cerebral ischemia and glutamate toxicity-induced neuronal cell death. Adult male rats were treated with vehicle or quercetin (10 mg/kg) 30 min prior to middle cerebral artery occlusion (MCAO) and cerebral cortical tissues were collected 24 h after MCAO. We used various techniques including Western blot, reverse transcription-PCR, and immunohistochemical staining to elucidate the changes of parvalbumin expression. Results Quercetin ameliorated MCAO-induced neurological deficits and behavioral changes. Moreover, quercetin prevented MCAO-induced a decrease in parvalbumin expression. Conclusions These findings suggest that quercetin exerts a neuroprotective effect through regulation of parvalbumin expression.

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