Protective Effect and Mechanism of Fruit Extract of Aegle marmelos Against Amyloid-β Toxicity in a Transgenic Caenorhabditis elegans

Alzheimer’s disease (AD) is the most common form of dementia found in the elderly. AD is caused by the accumulation of toxic proteins including amyloid-β (Aβ). The purpose of this study was to investigate the effect of fruit extract of Aegle marmelos against Aβ toxicity in Caenorhabditis elegans. The fruit of A. marmelos has been used in a traditional Thai herb formula in fatigue patients recovering from illnesses such as fever and diarrhea. We used a transgenic C. elegans strain CL4176, which expresses the human Aβ42, to investigate the effects and the mechanisms of action of the extracts against Aβ toxicity. The extract of A. marmelos significantly delayed Aβ-induced paralysis. Aegle marmelos lost the ability to delay Aβ-induced paralysis in worms fed with daf-16 ribonucleic acid interference (RNAi) bacteria, but not in worms fed with hsf-1 and skin-1 RNAi bacteria. These results indicated that daf-16 transcription factor was required for A. marmelos-mediated delayed paralysis. Aegle marmelos enhanced the level of daf-16 gene. Taken together, these results indicated that A. marmelos reduced Aβ toxicity via the DAF-16-mediated cell signaling pathway. In addition, A. marmelos reduced toxic Aβ oligomers. Aegle marmelos also displayed antioxidative effect in in vivo as it enhanced resistance to paraquat-induced oxidative stress in wild type worms. All of the results suggested that A. marmelos can protect against Aβ-induced toxicity and can be a potential candidate for the prevention or treatment of AD.

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Neuroprotective Effects of Palmatine via the Enhancement of Antioxidant Defense and Small Heat Shock Protein Expression in Aβ-Transgenic Caenorhabditis elegans

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/9966223 ◽

2021 ◽

Vol 2021 ◽

pp. 1-18

Author(s):

Weizhang Jia ◽

Qina Su ◽

Qiong Cheng ◽

Qiong Peng ◽

Aimin Qiao ◽

...

Keyword(s):

Lipid Metabolism ◽

Caenorhabditis Elegans ◽

Radical Scavenging ◽

Amyloid Β ◽

Small Heat Shock Protein ◽

Isoquinoline Alkaloid ◽

Neuroprotective Effects ◽

C Elegans ◽

Aβ Aggregation

Palmatine is a naturally occurring isoquinoline alkaloid that has been reported to display neuroprotective effects against amyloid-β- (Aβ-) induced neurotoxicity. However, the mechanisms underlying the neuroprotective activities of palmatine remain poorly characterized in vivo. We employed transgenic Caenorhabditis elegans models containing human Aβ1-42 to investigate the effects and possible mechanisms of palmatine-mediated neuroprotection. Treatment with palmatine significantly delayed the paralytic process and reduced the elevated reactive oxygen species levels in Aβ-transgenic C. elegans. In addition, it increased oxidative stress resistance without affecting the lifespan of wild-type C. elegans. Pathway analysis suggested that the differentially expressed genes were related mainly to aging, detoxification, and lipid metabolism. Real-time PCR indicated that resistance-related genes such as sod-3 and shsp were significantly upregulated, while the lipid metabolism-related gene fat-5 was downregulated. Further studies demonstrated that the inhibitory effects of palmatine on Aβ toxicity were attributable to the free radical-scavenging capacity and that the upregulated expression of resistance-related genes, especially shsp, whose expression was regulated by HSF-1, played crucial roles in protecting cells from Aβ-induced toxicity. The research showed that there were significantly fewer Aβ deposits in transgenic CL2006 nematodes treated with palmatine than in control nematodes. In addition, our study found that Aβ-induced toxicity was accompanied by dysregulation of lipid metabolism, leading to excessive fat accumulation in Aβ-transgenic CL4176 nematodes. The alleviation of lipid disorder by palmatine should be attributed not only to the reduction in fat synthesis but also to the inhibition of Aβ aggregation and toxicity, which jointly maintained metabolic homeostasis. This study provides new insights into the in vivo neuroprotective effects of palmatine against Aβ aggregation and toxicity and provides valuable targets for the prevention and treatment of AD.

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In Vivo and In Vitro Antioxidant Activities of Methanol Extracts from Olive Leaves on Caenorhabditis elegans

Molecules ◽

10.3390/molecules24040704 ◽

2019 ◽

Vol 24 (4) ◽

pp. 704 ◽

Cited By ~ 8

Author(s):

Siyuan Luo ◽

Xuelian Jiang ◽

Liping Jia ◽

Chengyue Tan ◽

Min Li ◽

...

Keyword(s):

Antioxidant Enzymes ◽

Caenorhabditis Elegans ◽

Antioxidant Activities ◽

Control Group ◽

Potential Candidate ◽

Olive Leaves ◽

C Elegans ◽

Main Component

The aim of this study was to evaluate the antioxidant activities of extracts from olive leaves (EOL). The main contents of EOL were determined by colorimetric methods. The antioxidant activities were assessed by measuring the scavenging free radicals in vitro. To investigate the antioxidant activity in vivo, we detected the survival of Caenorhabditis elegans, under thermal stress. Subsequently the reactive oxygen species (ROS) level, activities of antioxidant enzymes, the expression of HSP-16.2 and the translocation of daf-16 were measured. The results showed that, polyphenols was the main component. EOL could well scavenge DPPH and superoxide anion radicals in vitro. Compared to the control group, the survival rate of C. elegans treated with EOL was extended by 10.43%, under heat stress. The ROS level was reduced, while the expression of hsp-16.2 was increased to protect the organism against the increasing ROS. The level of malondialdehyde (MDA) also decreased sharply. The activities of inner antioxidant enzymes, such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) were potentiated, which might have had a correlation with the DAF-16 transcription factor that was induced-turned into the nuclear. Therefore, EOL showed a strong antioxidant ability in vitro and in vivo. Hence, it could be a potential candidate when it came to medicinal and edible plants.

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Heat Stress Reduces the Susceptibility of Caenorhabditis elegans to Orsay Virus Infection

Genes ◽

10.3390/genes12081161 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1161

Author(s):

Yuqing Huang ◽

Mark G. Sterken ◽

Koen van Zwet ◽

Lisa van Sluijs ◽

Gorben P. Pijlman ◽

...

Keyword(s):

Heat Stress ◽

Caenorhabditis Elegans ◽

Virus Infection ◽

Intracellular Pathogen ◽

Potential Candidate ◽

Molecular Responses ◽

C Elegans ◽

Pathogen Response ◽

Orsay Virus ◽

Natural Virus

The nematode Caenorhabditis elegans has been a versatile model for understanding the molecular responses to abiotic stress and pathogens. In particular, the response to heat stress and virus infection has been studied in detail. The Orsay virus (OrV) is a natural virus of C. elegans and infection leads to intracellular infection and proteostatic stress, which activates the intracellular pathogen response (IPR). IPR related gene expression is regulated by the genes pals-22 and pals-25, which also control thermotolerance and immunity against other natural pathogens. So far, we have a limited understanding of the molecular responses upon the combined exposure to heat stress and virus infection. We test the hypothesis that the response of C. elegans to OrV infection and heat stress are co-regulated and may affect each other. We conducted a combined heat-stress-virus infection assay and found that after applying heat stress, the susceptibility of C. elegans to OrV was decreased. This difference was found across different wild types of C. elegans. Transcriptome analysis revealed a list of potential candidate genes associated with heat stress and OrV infection. Subsequent mutant screens suggest that pals-22 provides a link between viral response and heat stress, leading to enhanced OrV tolerance of C. elegans after heat stress.

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Caenorhabditis elegans as an in vivo Model to Assess Amphetamine Tolerance

Brain Behavior and Evolution ◽

10.1159/000514858 ◽

2021 ◽

pp. 1-9

Author(s):

Dayana Torres Valladares ◽

Sirisha Kudumala ◽

Murad Hossain ◽

Lucia Carvelli

Keyword(s):

Caenorhabditis Elegans ◽

Molecular Mechanisms ◽

Drugs Of Abuse ◽

Genetic Model ◽

In Vivo Model ◽

C Elegans ◽

Hyperactivity Disorder ◽

In Vitro Data

Amphetamine is a potent psychostimulant also used to treat attention deficit/hyperactivity disorder and narcolepsy. In vivo and in vitro data have demonstrated that amphetamine increases the amount of extra synaptic dopamine by both inhibiting reuptake and promoting efflux of dopamine through the dopamine transporter. Previous studies have shown that chronic use of amphetamine causes tolerance to the drug. Thus, since the molecular mechanisms underlying tolerance to amphetamine are still unknown, an animal model to identify the neurochemical mechanisms associated with drug tolerance is greatly needed. Here we took advantage of a unique behavior caused by amphetamine in <i>Caenorhabditis elegans</i> to investigate whether this simple, but powerful, genetic model develops tolerance following repeated exposure to amphetamine. We found that at least 3 treatments with 0.5 mM amphetamine were necessary to see a reduction in the amphetamine-induced behavior and, thus, to promote tolerance. Moreover, we found that, after intervals of 60/90 minutes between treatments, animals were more likely to exhibit tolerance than animals that underwent 10-minute intervals between treatments. Taken together, our results show that <i>C. elegans</i> is a suitable system to study tolerance to drugs of abuse such as amphetamines.

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Transfer and tissue-specific accumulation of components in embryos of Caenorhabditis elegans and dolichura: in vivo analysis with a low-cost signal

Development ◽

10.1242/dev.114.2.317 ◽

1992 ◽

Vol 114 (2) ◽

pp. 317-330 ◽

Cited By ~ 4

Author(s):

O. Bossinger ◽

E. Schierenberg

Keyword(s):

Caenorhabditis Elegans ◽

Low Cost ◽

Free Living ◽

Tissue Specific ◽

C Elegans ◽

Specific Accumulation ◽

In Vivo Analysis

The pattern of autofluorescence in the two free-living namatodes Rhabditis dolichura and Caenorhabditis compared. In C. elegans, during later embryogenesis cells develop a typical bluish autofluorescence as illumination, while in Rh. dolichura a strong already present in the unfertilized egg. Using a new,

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Edible Flowers of Tagetes erecta L. as Functional Ingredients: Phenolic Composition, Antioxidant and Protective Effects on Caenorhabditis elegans

Nutrients ◽

10.3390/nu10122002 ◽

2018 ◽

Vol 10 (12) ◽

pp. 2002 ◽

Cited By ~ 7

Author(s):

Cristina Moliner ◽

Lillian Barros ◽

Maria Dias ◽

Víctor López ◽

Elisa Langa ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

In Vivo Model ◽

Tagetes Erecta ◽

Protective Effects ◽

Phenolic Composition ◽

C Elegans ◽

Amyloid Toxicity ◽

Phenolic Profiles ◽

Tagetes Erecta L

Tagetes erecta L. has long been consumed for culinary and medicinal purposes in different countries. The aim of this study was to explore the potential benefits from two cultivars of T. erecta related to its polyphenolic profile as well as antioxidant and anti-aging properties. The phenolic composition was analyzed by LC-DAD-ESI/MSn. Folin-Ciocalteu, DPPH·, and FRAP assays were performed in order to evaluate reducing antiradical properties. The neuroprotective potential was evaluated using the enzymes acetylcholinesterase and monoamine oxidase. Caenorhabditis elegans was used as an in vivo model to assess extract toxicity, antioxidant activity, delayed aging, and reduced β-amyloid toxicity. Both extracts showed similar phenolic profiles and bioactivities. The main polyphenols found were laricitin and its glycosides. No acute toxicity was detected for extracts in the C. elegans model. T. erecta flower extracts showed promising antioxidant and neuroprotective properties in the different tested models. Hence, these results may add some information supporting the possibilities of using these plants as functional foods and/or as nutraceutical ingredients.

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Identification of gmhA, a Yersinia pestis Gene Required for Flea Blockage, by Using a Caenorhabditis elegans Biofilm System

Infection and Immunity ◽

10.1128/iai.73.11.7236-7242.2005 ◽

2005 ◽

Vol 73 (11) ◽

pp. 7236-7242 ◽

Cited By ~ 55

Author(s):

Creg Darby ◽

Sandya L. Ananth ◽

Li Tan ◽

B. Joseph Hinnebusch

Keyword(s):

Caenorhabditis Elegans ◽

Yersinia Pestis ◽

Biofilm Formation ◽

Yersinia Pseudotuberculosis ◽

C Elegans ◽

Transposon Insertion ◽

Insertion Mutants ◽

Random Screening

ABSTRACT Yersinia pestis, the cause of bubonic plague, blocks feeding by its vector, the flea. Recent evidence indicates that blockage is mediated by an in vivo biofilm. Y. pestis and the closely related Yersinia pseudotuberculosis also make biofilms on the cuticle of the nematode Caenorhabditis elegans, which block this laboratory animal's feeding. Random screening of Y. pseudotuberculosis transposon insertion mutants with a C. elegans biofilm assay identified gmhA as a gene required for normal biofilms. gmhA encodes phosphoheptose isomerase, an enzyme required for synthesis of heptose, a conserved component of lipopolysaccharide and lipooligosaccharide. A Y. pestis gmhA mutant was constructed and was severely defective for C. elegans biofilm formation and for flea blockage but only moderately defective in an in vitro biofilm assay. These results validate use of the C. elegans biofilm system to identify genes and pathways involved in Y. pestis flea blockage.

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Withanone Ameliorates Stress Symptoms in Caenorhabditis Elegans by Acting through Serotonin Receptors

Pharmacopsychiatry ◽

10.1055/a-1349-3870 ◽

2021 ◽

Author(s):

Janine Naß ◽

Thomas Efferth

Keyword(s):

Caenorhabditis Elegans ◽

In Silico ◽

Serotonin Receptors ◽

New Drugs ◽

Potential Candidate ◽

Human Beings ◽

Wild Type ◽

C Elegans ◽

Stress Symptoms ◽

Serotonin System

Abstract Introduction Depression is responsible for 800 000 deaths worldwide, a number that will rise significantly due to the COVID-19 pandemic. Affordable novel drugs with less severe side effects are urgently required. We investigated the effect of withanone (WN) from Withania somnifera on the serotonin system of wild-type and knockout Caenorhabditis elegans strains using in silico, in vitro, and in vivo methods. Methods WN or fluoxetine (as positive control drug) was administered to wild-type (N2) and knockout C. elegans strains (AQ866, DA1814, DA2100, DA2109, and MT9772) to determine their effect on oxidative stress (Trolox, H2DCFDA, and juglone assays) on osmotic stress and heat stress and lifespan. Quantitative real-time RT-PCR was applied to investigate the effect of WN or fluoxetine on the expression of serotonin receptors (ser-1, ser-4, ser-7) and serotonin transporter (mod-5). The binding affinity of WN to serotonin receptors and transporter was analyzed in silico using AutoDock 4.2.6. Results WN scavenged ROS in wild-type and knockout C. elegans and prolonged their lifespan. WN upregulated the expression of serotonin receptor and transporter genes. In silico analyses revealed high binding affinities of WN to Ser-1, Ser-4, Ser-7, and Mod-5. Limitations Further studies are needed to prove whether the results from C. elegans are transferrable to mammals and human beings. Conclusion WN ameliorated depressive-associated stress symptoms by activating the serotonin system. WN may serve as potential candidate in developing new drugs to treat depression.

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The inhibition of cellular toxicity of amyloid-β by dissociated transthyretin

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013440 ◽

2020 ◽

Vol 295 (41) ◽

pp. 14015-14024 ◽

Cited By ~ 1

Author(s):

Qin Cao ◽

Daniel H. Anderson ◽

Wilson Y. Liang ◽

Joshua Chou ◽

Lorena Saelices

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protective Effect ◽

Amyloid Β ◽

Inhibitory Effect ◽

Aβ Oligomers ◽

Cellular Toxicity ◽

Computational Docking

The protective effect of transthyretin (TTR) on cellular toxicity of β-amyloid (Aβ) has been previously reported. TTR is a tetrameric carrier of thyroxine in blood and cerebrospinal fluid, the pathogenic aggregation of which causes systemic amyloidosis. However, studies have documented a protective effect of TTR against cellular toxicity of pathogenic Aβ, a protein associated with Alzheimer's disease. TTR binds Aβ, alters its aggregation, and inhibits its toxicity both in vitro and in vivo. In this study, we investigate whether the amyloidogenic ability of TTR and its antiamyloid inhibitory effect are associated. Using protein aggregation and cytotoxicity assays, we found that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from Aβ oligomers. These findings suggest that the Aβ-binding site of TTR may be hidden in its tetrameric form. Aided by computational docking and peptide screening, we identified a TTR segment that is capable of altering Aβ aggregation and toxicity, mimicking TTR cellular protection. EM, immune detection analysis, and assessment of aggregation and cytotoxicity revealed that the TTR segment inhibits Aβ oligomer formation and also promotes the formation of nontoxic, nonamyloid amorphous aggregates, which are more sensitive to protease digestion. Finally, this segment also inhibits seeding of Aβ catalyzed by Aβ fibrils extracted from the brain of an Alzheimer's patient. Together, these findings suggest that mimicking the inhibitory effect of TTR with peptide-based therapeutics represents an additional avenue to explore for the treatment of Alzheimer's disease.

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Antioxidant Activities and Reduced Amyloid-β Toxicity of 7-Hydroxycalamenene Isolated from the Essential Oil of Zelkova serrata Heartwood

Natural Product Communications ◽

10.1177/1934578x1601100943 ◽

2016 ◽

Vol 11 (9) ◽

pp. 1934578X1601100

Author(s):

Pei-Ling Yen ◽

Sen-Sung Cheng ◽

Chia-Cheng Wei ◽

Huan-You Lin ◽

Vivian Hsiu-Chuan Liao ◽

...

Keyword(s):

Essential Oil ◽

Antioxidant Activities ◽

Radical Scavenging ◽

Amyloid Β ◽

Total Phenolic ◽

C Elegans ◽

In Vivo Assays ◽

Zelkova Serrata

The in vitro and in vivo antioxidant activities and its potential to protect against amyloid-β toxicity of essential oils from Zelkova serrata (Thunb.) Makino were investigated in the model organism Caenorhabditis elegans. The results revealed that the essential oil of Z. serrata heartwood exhibited great radical scavenging activities and high total phenolic content. In vivo assays showed significant inhibition of oxidative damage in wild-type C. elegans under juglone-induced oxidative stress and heat shock. Based on results from both in vitro and in vivo assays, the major compound in essential oil of heartwood, (-)-(1 S, 4 S)-7-hydroxycalamenene (1 S, 4 S-7HC), may contribute significantly to the observed antioxidant activity. Further evidence showed that 1 S, 4 S-7HC significantly delayed the paralysis phenotype in amyloid beta-expressing transgenic C. elegans. These findings suggest that 1 S, 4 S-7HC from the essential oil of Z. serrata heartwood has potential as a source for antioxidant or Alzheimer's disease treatment.

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