Natural products-based polypharmacological modulation of the peripheral immune system for the treatment of neuropsychiatric disorders

Mok, Simon Wing-Fai; Lo, Hang Hong; Dias, Ivo Ricardo de Seabra Rodrigues; Leung, Elaine Lai‐Han; Law, Betty Yuen‐Kwan; Liu, Liang

doi:10.1016/j.pharmthera.2020.107480

Cited by 27 publications

(14 citation statements)

References 323 publications

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“…Notably, natural products show a promising role in the development of novel agents for PD treatment due to their pharmacological properties linked to neuroprotection [ [12] , [13] , [14] ]. Celastrol, a pentacyclic triterpene, is an active component of tripterygium wilfordi (thunder god vine).…”

Section: Introductionmentioning

confidence: 99%

The Nrf2-NLRP3-caspase-1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease

et al. 2021

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Parkinson's disease (PD) is a chronic neurodegenerative disorder that is characterized by motor symptoms as a result of a loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), accompanied by chronic neuroinflammation, oxidative stress, formation of α-synuclein aggregates. Celastrol, a potent anti-inflammatory and anti-oxidative pentacyclic triterpene, has emerged as a neuroprotective agent. However, the mechanisms by which celastrol is neuroprotective in PD remain elusive. Here we show that celastrol protects against dopamine neuron loss, mitigates neuroinflammation, and relieves motor deficits in MPTP-induced PD mouse model and AAV-mediated human α-synuclein overexpression PD model. Whole-genome deep sequencing analysis revealed that Nrf2, NLRP3 and caspase-1 in SNc may be associated with the neuroprotective actions of celastrol in PD. By using multiple genetically modified mice (Nrf2-KO, NLRP3-KO and Caspase-1-KO), we identified that celastrol inhibits NLRP3 inflammasome activation, relieves motor deficits and nigrostriatal dopaminergic degeneration through Nrf2-NLRP3-caspase-1 pathway. Taken together, these findings suggest that Nrf2-NLRP3-caspase-1 axis may serve as a key target of celastrol in PD treatment, and highlight the favorable properties of celastrol for neuroprotection, making celastrol as a promising disease-modifying agent for PD.

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Section: Introductionmentioning

confidence: 99%

The Nrf2-NLRP3-caspase-1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease

et al. 2021

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“…In particular, the targeted therapy of Salvianolic acid A, Liquiritigenin, and Isoliquiritigenin could be further investigated. There are even more naturally derived compounds that are either in clinical trials or have shown potential in pre-clinical studies which merit further investigation [71]. In the present study, we used four methods to verify the multi-target therapeutic effect of NCMC extraction.…”

Section: Discussionmentioning

confidence: 99%

Polypharmacology-based Approach for Screening of Traditional Chinese Medicinal extract and Multi-dimensional Targeting Verification

Xia

Wang

et al. 2021

Preprint

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Background: Natural products and their unique polypharmacology offer significant advantages for finding novel therapeutics particularly for the treatment of complex diseases. Meanwhile, natural products in traditional Chinese medicine possess drug-like properties. In this study, we used the previously established co-infection model of Mycoplasma gallisepticum and Escherichia coli as a representative of complex diseases. The multi-omics joint analysis was used to reverse screen TCMs from the Chinese medicinal database and then targeted verification was conducted from multiple dimensions. Results: The results showed that the Chinese herbal compound screened by the target network played a good therapeutic effect in the case of co-infection. Furthermore, the four methods were performed at gene, protein, and metabolite levels, as well as molecular docking in vitro respectively, which were used to verify the multi-target therapeutic effect. Conclusions: These data suggest that we may provide a new method to validate target combinations of natural products that can be used to optimize their multiple structure-activity relationships to obtain drug-like natural product derivatives. Furthermore, the study could establish a new methodology for the research of Chinese herbal medicinal extract and provide a new multi-target treatment method for the occurrence of co-infection.

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“…Neuroinflammation is well documented as the common pathological characteristic of PD. Notably, the neuroinflammatory phenotypes of PD can be modulated by peripheral immunoreactions through the molecular crosstalk between resident and blood-derived cellular components, suggesting that peripheral immunity is an active participant in the neuroinflammatory and neurodegenerative progression of PD [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Chicoric Acid Prevents Neuroinflammation and Neurodegeneration in a Mouse Parkinson’s Disease Model: Immune Response and Transcriptome Profile of the Spleen and Colon

Wang

Feng

et al. 2022

IJMS

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Chicoric acid (CA), a polyphenolic acid compound extracted from chicory and echinacea, possesses antiviral, antioxidative and anti-inflammatory activities. Growing evidence supports the pivotal roles of brain–spleen and brain–gut axes in neurodegenerative diseases, including Parkinson’s disease (PD), and the immune response of the spleen and colon is always the active participant in the pathogenesis and development of PD. In this study, we observe that CA prevented dopaminergic neuronal lesions, motor deficits and glial activation in PD mice, along with the increment in striatal brain-derived neurotrophic factor (BDNF), dopamine (DA) and 5-hydroxyindoleacetic acid (5-HT). Furthermore, CA reversed the level of interleukin-17(IL-17), interferon-gamma (IFN-γ) and transforming growth factor-beta (TGF-β) of PD mice, implicating its regulatory effect on the immunological response of spleen and colon. Transcriptome analysis revealed that 22 genes in the spleen (21 upregulated and 1 downregulated) and 306 genes (190 upregulated and 116 downregulated) in the colon were significantly differentially expressed in CA-pretreated mice. These genes were functionally annotated with GSEA, GO and KEGG pathway enrichment, providing the potential target genes and molecular biological mechanisms for the modulation of CA on the spleen and gut in PD. Remarkably, CA restored some gene expressions to normal level. Our results highlighted that the neuroprotection of CA might be associated with the manipulation of CA on brain–spleen and brain–gut axes in PD.

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Natural products-based polypharmacological modulation of the peripheral immune system for the treatment of neuropsychiatric disorders

Cited by 27 publications

References 323 publications

The Nrf2-NLRP3-caspase-1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease

The Nrf2-NLRP3-caspase-1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease

Polypharmacology-based Approach for Screening of Traditional Chinese Medicinal extract and Multi-dimensional Targeting Verification

Chicoric Acid Prevents Neuroinflammation and Neurodegeneration in a Mouse Parkinson’s Disease Model: Immune Response and Transcriptome Profile of the Spleen and Colon

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