Isoquinoline alkaloids reduce beta-amyloid peptide toxicity in <i>Caenorhabditis elegans</i>

Almeida, Wamberto Alristenio Moreira de; Andrade, Jean Paulo de; Chacon, Daisy Sotero; Lucas, Cecília Rodrigues; Mariana, Estela; Ferreira, Leandro de Santis; Guaratini, Thais; Barbosa, Euzébio Guimarães; Zuanazzi, José Ângelo Silveira; Hallwass, Fernando; Borges, Warley de Souza; Oliveira, Riva de Paula; Giordani, Raquel Brandt

doi:10.1080/14786419.2020.1727471

Cited by 10 publications

(7 citation statements)

References 14 publications

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“…It is currently recognized that the incidence of AD was caused by the aggregation of toxic amyloid-peptide A β protein, which leads to the decline of learning and memory ability [ 66 ]. The AD model of transgenic strain CL4176 could be induced to express human A β (1-42) when upshifted to the nonpermissive temperature of 23°C.…”

Section: Resultsmentioning

confidence: 99%

Para-Hydroxybenzyl Alcohol Delays the Progression of Neurodegenerative Diseases in Models of Caenorhabditis elegans through Activating Multiple Cellular Protective Pathways

Liu

Huang

et al. 2022

Oxidative Medicine and Cellular Longevity

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The traditional Chinese medicine Gastrodia elata (commonly called “Tianma” in Chinese) has been widely used in the treatment of rheumatism, epilepsy, paralysis, headache, and dizziness. Phenolic compounds, such as gastrodin, para-hydroxybenzyl alcohol (HBA), p-hydroxybenzaldehyde, and vanillin are the main bioactive components isolated from Gastrodia elata. These compounds not only are structurally related but also share similar pharmacological activities, such as antioxidative and anti-inflammatory activities, and effects on the treatment of aging-related diseases. Here, we investigated the effect of para-hydroxybenzyl alcohol (HBA) on neurodegenerative diseases and aging in models of Caenorhabditis elegans (C. elegans). Our results showed that HBA effectively delayed the progression of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease in models of C. elegans. In addition, HBA could increase the average lifespan of N2 worms by more than 25% and significantly improve the age-related physiological functions of worms. Moreover, HBA improved the survival rate of worms under stresses of oxidation, heat, and pathogenic bacteria. Further mechanistic investigation revealed that HBA could activate FOXO/DAF-16 and SKN-1 to regulate antioxidative and xenobiotic metabolism pathway. HBA could also activate HSF-1 to regulate proteostasis maintenance pathway, mitochondrial unfolded stress response, endoplasmic stress response and autophagy pathways. The above results suggest that HBA activated multiple cellular protective pathways to increase stress resistance and protect against aging and aging-related diseases. Overall, our study indicates that HBA is a potential candidate for future development of antiaging pharmaceutical application.

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Section: Resultsmentioning

confidence: 99%

Para-Hydroxybenzyl Alcohol Delays the Progression of Neurodegenerative Diseases in Models of Caenorhabditis elegans through Activating Multiple Cellular Protective Pathways

Liu

Huang

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Alkaloids are a kind of nitrogenous organic compounds derived from plants, fungi, and marine sponges, which have a complex nitrogen–heterocyclic structure and remarkable biological activity. They are generally considered an ongoing source of drugs for chronic diseases, such as cancer, diabetes, and neurodegenerative diseases. − Isoquinoline alkaloids are one of the most complex alkaloids that are widely distributed in different plants and have important biomedical significance and pharmacological potential. − Among them, berberine (BBR, Figure ) has received extensive attention because of its wide distribution and pharmacological effects. Recent studies on BBR mainly focus on its multitarget potential in neurodegenerative diseases, and BBR affected the biological functions of cholinesterase and monoamine oxidase, as well as the aggregation of amyloid-β (Aβ) associated with AD. − Previous studies have shown that patients with AD have a higher risk of developing T2DM. , The two disease-related proteins Aβ and hIAPP are structurally similar and have a coaggregation behavior, so they are frequently studied together to obtain high-quality dual inhibitors, such as flavonoids and artemisinins. , In addition, BBR is a major hypoglycemic component of Coptis chinensis alkaloids, which can promote the repair of islet β cells and improve the utilization of glucose by liver cells.…”

Section: Introductionmentioning

confidence: 99%

Exploration of Isoquinoline Alkaloids as Potential Inhibitors against Human Islet Amyloid Polypeptide

Wang

Zheng

Huo

et al. 2022

ACS Chem. Neurosci.

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Type-2 diabetes mellitus (T2DM) is one of the most concerning public health problems because of its high incidence, multiple complications, and difficult treatment. Human islet amyloid polypeptide (hIAPP) is closely linked to T2DM because its abnormal self-assembly causes membrane damage and cell dysfunction. The development of potential inhibitors to prevent hIAPP fibrillation is a promising strategy for the intervention and treatment of diabetes. Natural isoquinoline alkaloids are used as effective medication that targets different biomolecules. Although studies explored the efficacy of berberine, jatrorrhizine, and chelerythrine in diabetes, the underlying mechanism remains unclear. Herein, three isoquinoline alkaloids are selected to reveal their roles in hIAPP aggregation, disaggregation, and cell protection. All three compounds displayed good inhibitory effects on peptide fibrillation, scattered the preformed fibrils into small oligomers and most monomers, and upregulated cell viability by reducing hIAPP oligomerization. Moreover, combined biophysical analyses indicated that the compounds affected the β-sheet structure and hydrophobicity of polypeptides significantly, and the benzo[c]phenanthridine structure of chelerythrine was beneficial to the inhibition of hIAPP aggregation and their hydrophobic interaction, compared with that of berberine and jatrorrhizine. Our work elaborated the effects of these alkaloids on hIAPP fibrillation and reveals a possible mechanism for these compounds against T2DM.

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“…As of now, there is a good deal of toxicity models expressing normal or mutated Aβ in C. elegans. These models have made it possible to screen the potential natural compounds for reverse toxic effects, including nicotine, caffeic acid, n-butanol extract of Hedyotis diffusa Willd, erythraline, and erysodine, obtained from Fabaceae (DanQing et al, 2021;de Almeida et al, 2021;Li et al, 2021;Lu et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of Oligosaccharides in Rehmanniae Radix on Transgenic Caenorhabditis elegans Models for Alzheimer’s Disease

et al. 2022

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Rehmanniae Radix (RR, the dried tuberous roots of Rehmannia glutinosa (Gaertn.) DC.) is an important traditional Chinese medicine distributed in Henan, Hebei, Inner Mongolia, and Northeast in China. RR is frequently used to treat diabetes mellitus, cardiovascular disease, osteoporosis and aging-related diseases in a class of prescriptions. The oligosaccharides and catalpol in RR have been confirmed to have neuroprotective effects. However, there are few studies on the anti-Alzheimer’s disease (AD) effect of oligosaccharides in Rehmanniae Radix (ORR). The chemical components and pharmacological effects of dried Rehmannia Radix (DRR) and prepared Rehmannia Radix (PRR) are different because of the different processing methods. ORR has neuroprotective potential, such as improving learning and memory in rats. Therefore, this study aimed to prove the importance of oligosaccharides in DRR (ODRR) and PRR (OPRR) for AD based on the Caenorhabditis elegans (C. elegans) model and the different roles of ODRR and OPRR in the treatment of AD. In this study, we used paralysis assays, lifespan and stress resistance assays, bacterial growth curve, developmental and behavioral parameters, and ability of learning and memory to explore the effects of ODRR and OPRR on anti-AD and anti-aging. Furthermore, the accumulation of reactive oxygen species (ROS); deposition of Aβ; and expression of amy-1, sir-2.1, daf-16, sod-3, skn-1, and hsp-16.2 were analyzed to confirm the efficacy of ODRR and OPRR. OPRR was more effective than ODRR in delaying the paralysis, improving learning ability, and prolonging the lifespan of C. elegans. Further mechanism studies showed that the accumulation of ROS, aggregation, and toxicity of Aβ were reduced, suggesting that ORR alleviated Aβ-induced toxicity, in part, through antioxidant activity and Aβ aggregation inhibiting. The expression of amy-1 was downregulated, and sir-2.1, daf-16, sod-3, and hsp-16.2 were upregulated. Thus, ORR could have a possible therapeutic effect on AD by modulating the expression of amy-1, sir-2.1, daf-16, sod-3, and hsp-16.2. Furthermore, ORR promoted the nuclear localization of daf-16 and further increased the expression of sod-3 and hsp-16.2, which significantly contributed to inhibiting the Aβ toxicity and enhancing oxidative stress resistance. In summary, the study provided a new idea for the development of ORR.

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Isoquinoline alkaloids reduce beta-amyloid peptide toxicity in Caenorhabditis elegans

Cited by 10 publications

References 14 publications

Para-Hydroxybenzyl Alcohol Delays the Progression of Neurodegenerative Diseases in Models of Caenorhabditis elegans through Activating Multiple Cellular Protective Pathways

Para-Hydroxybenzyl Alcohol Delays the Progression of Neurodegenerative Diseases in Models of Caenorhabditis elegans through Activating Multiple Cellular Protective Pathways

Exploration of Isoquinoline Alkaloids as Potential Inhibitors against Human Islet Amyloid Polypeptide

Neuroprotective Effects of Oligosaccharides in Rehmanniae Radix on Transgenic Caenorhabditis elegans Models for Alzheimer’s Disease

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