Ursolic acid ameliorates amyloid β-induced pathological symptoms in Caenorhabditis elegans by activating the proteasome

Wang, Ningbo; Wang, Enhui; Wang, Ruyue; Muhammad, Fahim; Li, Ting; Yue, Jun; Zhou, Yanjun; Zhi, Dejuan; Li, Hongyu

doi:10.1016/j.neuro.2021.12.004

Cited by 12 publications

(14 citation statements)

References 49 publications

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“…It also exerts anti-apoptotic effect that results in the alleviation of inflammation and oxidative stress associated neurodegeneration as observed in a model for Parkinson's disease (Lv et al, 2020). Consistently UA also hindered the deposition of Aβ and lowered the levels of its oligomers and monomers in an Aβ-induced Caenorhabditis elegans transgenic model (Wang et al, 2022). These results are indicative of the potential of UA and RA in the reduction of Aβ plaques which constitute a hallmark feature of AD.…”

Section: Discussionmentioning

confidence: 60%

Ursolic acid and rosmarinic acid ameliorate alterations in hippocampal neurogenesis and social memory induced by amyloid beta in mouse model of Alzheimer’s disease

Mirza

Zahid

2022

Front. Pharmacol.

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Alzheimer’s disease (AD) is a multifaceted neurodegenerative disorder characterized by substantial neuronal damage which manifests in the form of deficits in memory and cognition. In spite of the debilitating nature of Alzheimer’s disease (AD), a dearth of treatment strategies calls for the need to develop therapeutic agents that stimulate neurogenesis and alleviate the associated cognitive deficits. The present study investigates the therapeutic potential of two major phytochemicals, rosmarinic acid (RA) and ursolic acid (UA) in an amyloid beta1–42 (Aβ1–42)-induced model of AD. UA, a natural pentacyclic triterpenoid and RA, a phenolic ester are major bioactive constituents of Rosmarinus officinalis, which is a medicinal herb belonging to family Lamiaceae and exhibiting significant biological properties including neuroprotection. Donepezil, a second generation cholinesterase inhibitor approved for the treatment of mild, moderate and severe Alzheimer’s disease (AD) is used as control. Out of eight groups of male BALB/c mice, stereotaxic surgery was performed on four groups (n = 6 each) to introduce Aβ1–42 in the hippocampus followed by treatment with vehicle (phosphate-buffered saline (PBS)), donepezil, UA or RA. The other four groups were given vehicle, donepezil, UA and RA only. Behavior analysis for social interaction was performed which constitutes the social affiliation and the social novelty preference test. Presence of Aβ plaques and expression of neurogenesis markers i.e., doublecortin (DCX) and Ki-67 were also assessed. Results revealed the neuroprotective effect of UA and RA observed through substantial reduction in Aβ plaques as compared to the Aβ1-42- and donepezil-treated groups. The neuronal density was also restored as evident via DCX and Ki-67 immunoreactivity in Aβ1–42 + RA and Aβ1–42+UA-treated groups in comparison to Aβ1–42-treated and Aβ1–42+donepezil-treated groups. The social affiliation was reestablished in the Aβ1–42 administered groups treated with UA and RA. Molecular docking studies further validated the comparable binding of UA and RA with Ki-67 and DCX to that of donepezil. Our findings suggest that UA and RA are potential neuroprotective compounds that reverses the histological hallmarks of AD and ameliorate impaired social memory and hippocampal neurogenesis.

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Section: Discussionmentioning

confidence: 60%

Ursolic acid and rosmarinic acid ameliorate alterations in hippocampal neurogenesis and social memory induced by amyloid beta in mouse model of Alzheimer’s disease

Mirza

Zahid

2022

Front. Pharmacol.

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“…UA has been reported to be an inducer of proteasome activity in the brain [ 19 ]. To determine whether UA activates proteasome activity in the heart, we treated WT mice with two doses (40 or 80 mg/kg) of UA for 24 h. Compared with the vehicle control, UA treatment at both 40 and 80 mg/kg had no cardiotoxic effect, as reflected by the measurement of LDH activity ( Figure 1 B).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, UA has recently been reported to alleviate apoptosis in hypoxia/reoxygenation (H/R)-induced cardiomyocytes in vitro [ 17 ] and ameliorates I/R-mediated myocardial injury in isolated rat heart [ 18 ]. Interestingly, a recent study suggests that UA can induce the proteasome activity in Caenorhabditis elegans [ 19 ]. However, whether UA could increase proteasome activity in the heart to protect against cardiac I/R-related dysfunction and its underlying mechanism are unclear.…”

Section: Introductionmentioning

confidence: 99%

Ursolic Acid Ameliorates Myocardial Ischaemia/Reperfusion Injury by Improving Mitochondrial Function via Immunoproteasome-PP2A-AMPK Signalling

et al. 2023

Nutrients

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Cardiac ischaemia/reperfusion (I/R) injury causes cardiomyocyte apoptosis and mitochondrial dysfunction. Ursolic acid (UA), as a pentacyclic triterpenoid carboxylic acid, exerts several bioactivities in animal models of different diseases, but the preventive role of UA in I/R-induced myocardial dysfunction remains largely unknown. Male wild-type mice were pre-administered with UA at a dosage of 80 mg/kg i.p. and then subjected to cardiac I/R injury for 24 h. Cardiac function and pathological changes were examined by echocardiography and histological staining. The protein and mRNA levels of the genes were determined using qPCR and immunoblotting analysis. Our results revealed that UA administration in mice significantly attenuated the I/R-induced decline in cardiac function, infarct size, myocyte apoptosis, and oxidative stress. Mechanistically, UA increased three immunoproteasome catalytic subunit expressions and activities, which promoted ubiquitinated PP2A degradation and activated AMPK-PGC1α signalling, leading to improved mitochondrial biosynthesis and dynamic balance. In vitro experiments confirmed that UA treatment prevented hypoxia/reperfusion (H/R)-induced cardiomyocyte apoptosis and mitochondrial dysfunction through activation of AMPK signalling. In summary, our findings identify UA as a new activator of the immunoproteasome that exerts a protective role in I/R-induced myocardial dysfunction and suggest that UA supplementation could be beneficial for the prevention of cardiac ischaemic disease.

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“…In a similar vein, ginsenosides have previously been reported to reduce the oligomeric levels of Aβ proteins by activating the HSF-1 molecular signaling pathway, while inhibiting the expression of the Q40::YFP protein in AM141 nematodes [ 38 ]. Wang et al found that ursolic acid reduced β-amyloid levels by upregulating the proteasome activity of AD nematodes, while it also had an inhibitory effect on human-derived α-synuclein transferred in OW13 nematodes [ 39 ]. HSPs play a key role in preventing the formation of toxic aggregates of abnormal proteins and assisting in their degradation [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Cryptotanshinone Alleviates Oxidative Stress and Reduces the Level of Abnormally Aggregated Protein in Caenorhabditis elegans AD Models

Cui

Zhang

Bai

et al. 2022

IJMS

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Alzheimer’s disease (AD) is one of the leading causes of dementia. As the first common neurodegenerative disease, there are no effective drugs that can reverse the progression. The present study is to report the anti-AD effect of cryptotanshinone (CTS), a natural product isolated from Salvia castanea. It is found that it can alleviate AD-like features associated with Aβ1-42 toxicity in muscle cells as well as neuronal cells of Caenorhabditis elegans (C. elegans). Further studies showed that CTS reduced the level of reactive oxygen species (ROS) in nematodes, up-regulated the expression of sod-3, and enhanced superoxide dismutase activity. Cryptotanshinone reduced the level of Aβ monomers and highly toxic oligomers in C. elegans while inhibiting the abnormal aggregation of polyglutamine protein. In addition, CTS upregulated the expression of hsp-16.2 and downregulated the expression of ace-2. These results suggested that CTS could alleviate oxidative stress and reduce the level of abnormally aggregated proteins and has the potential to be developed as an anti-AD drug candidate.

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Ursolic acid ameliorates amyloid β-induced pathological symptoms in Caenorhabditis elegans by activating the proteasome

Cited by 12 publications

References 49 publications

Ursolic acid and rosmarinic acid ameliorate alterations in hippocampal neurogenesis and social memory induced by amyloid beta in mouse model of Alzheimer’s disease

Ursolic acid and rosmarinic acid ameliorate alterations in hippocampal neurogenesis and social memory induced by amyloid beta in mouse model of Alzheimer’s disease

Ursolic Acid Ameliorates Myocardial Ischaemia/Reperfusion Injury by Improving Mitochondrial Function via Immunoproteasome-PP2A-AMPK Signalling

Cryptotanshinone Alleviates Oxidative Stress and Reduces the Level of Abnormally Aggregated Protein in Caenorhabditis elegans AD Models

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