Interplay among Oxidative Stress, Autophagy, and the Endocannabinoid System in Neurodegenerative Diseases: Role of the Nrf2- p62/SQSTM1 Pathway and Nutraceutical Activation
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsTe manuscript is sufficent The conclusion is precise, just a little short. The bibliography is well done.
Comments on the Quality of English LanguageThe quality of English is sufficient.
Author Response
Comment 1: Te manuscript is sufficent The conclusion is precise, just a little short. The bibliography is well done.
Response1: We thank the referee for his comments according to his suggestions we have extended the conclusions. introducing new perspectives for the use bioactive molecules obtained from plants.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe high points of this review are about the potential interplay between misfolded cargo aggregation, oxidative stress, and autophagy process in neurodegenerative diseases.
Most importantly, the author discusses how the Nrf2 signaling pathway regulates and maintains age-related degenerative disease (AD) to prevent mitochondrial damage and oxidative stress.
In addition, the author also stated the importance of plant-based derivates for Nrf2 activators (i.e Caffeic acid, curcumin, resveratrol, etc.), which would be a great advancement approach for neurodegenerative disease.
Potentially this review manuscript could be appropriate for the readership of CIMB.
Author Response
We thank the referee for his valuable comments and for taken the time to review our paper.
Reviewer 3 Report
Comments and Suggestions for AuthorsIt is an amazing review paper where the authors have attempted to discuss the complex relationship between oxidative stress and autophagy in neurodegenerative diseases. It highlights the importance of the Nrf2 pathway in combating oxidative stress and maintaining cellular balance through autophagy. This is a comprehensive review discussing the key mechanisms involved in neurodegenerative diseases. It offers effective treatment options targeting oxidative stress, autophagy, and the endocannabinoid system. Comments :
>> Provide specific examples of nutraceuticals that target the Nrf2-p62/SQSTM1 pathway for neuroprotection. It will provide practical insights for potential therapeutic applications.
>>It would be great if case studies or experiments were included to show the application of Nrf2 activators in preclinical or clinical settings. It could strengthen the evidence supporting the therapeutic potential of targeting this pathway.
>> Any current challenges or limitations in targeting the Nrf2-p62/SQSTM1 pathway for neuroprotection can be explored. It may provide a holistic view of the topic.
Comments on the Quality of English LanguageGood, though minor corrections are required.
Author Response
It is an amazing review paper where the authors have attempted to discuss the complex relationship between oxidative stress and autophagy in neurodegenerative diseases. It highlights the importance of the Nrf2 pathway in combating oxidative stress and maintaining cellular balance through autophagy. This is a comprehensive review discussing the key mechanisms involved in neurodegenerative diseases. It offers effective treatment options targeting oxidative stress, autophagy, and the endocannabinoid system. Comments :
>> Provide specific examples of nutraceuticals that target the Nrf2-p62/SQSTM1 pathway for neuroprotection. It will provide practical insights for potential therapeutic applications.
Response 1: We thank the reviewer for his valuable comments. We added:
reference #111 reporting experiments on ELAV-SCA3tr-Q78 transgenic Drosophila flies that show that Caffeic acid and resveratrol treatment increased levels of antioxidant and autophagy protein expression with lower levels of reactive oxygen species through increased Nrf2 transcriptional activity that upregulates p62/SQSTM1 autophagy gene expression.
Reference #114 showing that treatment with thonningianin A, a polyphenolic compound found in natural plant-derived foods, significantly facilitated Nrf2 nuclear translocation by promoting p62/SQSTM1 interaction in zebrafish with 6-OHDA-induced ferroptosis and in dopaminergic neurons.
>>It would be great if case studies or experiments were included to show the application of Nrf2 activators in preclinical or clinical settings. It could strengthen the evidence supporting the therapeutic potential of targeting this pathway.
According to the suggestions of the reviewer we added references #115-121 dealing with preclinical and clinical studies. It should be noted that while there is a bulk of studies identifying the role of Nrf2 in counteracting oxidative stress, there are very few studies analyzing the role of plant extracts targeting Nrf2-p62/SQSTM1. We reported several preclinical studies and only few cliical studies , as detailed below:
Rats injected with Aβ into the CA1 region of the hippocampus and prefrontal cortex fed Salvia macilenta showed an increase in Nrf2 protein expression compared with the group injected with Aβ alone [115].
The role of nutraceuticals has been evaluated in several preclinical studies and a few clinical trials. A randomized, triple-blind, placebo-controlled trial showed that ellagic acid supplementation to Multiple Sclerosis patients was able to restore the Nrf2 decrease observed in these patients [116].
In Chinese AD patients, taking curcumin for 6 months a slowing of neuronal loss and improvement in cognitive function compared with the placebo group was detected [117]. Preclinical studies have demonstrated the neuroprotective effects of gypenosides in neurological disorders such as depression, PD, and AD by modulating important signaling pathways including NF-κB, AKT, ERK1/2, through activation of the Nrf2/KEAP1/ARE/HO-1 pathway [118]. Epigallocatechin-3-gallate has been shown to exhibit antioxidant, neuroprotective, and pro-autophagy properties by modulating the Nrf2/HO-1 antioxidant pathway [119]. Epigallocatechin-3-gallate-rich green tea has been associated with improved cognitive function in the elderly population [120]. However, it is important to note that the beneficial effects are carried out not by the single component but by the synergy of the combined components in green or black tea (epigallocatechin-3-gallate, theanine, or caffeine), thus showing a holistic effect [119]. Evidence from clinical studies on resveratrol supplementation has shown significant improvement in cognitive functions in healthy older adults and improvement in the integrity of the blood-brain barrier through enhancement of the antioxidant system through activation of the Nrf2 signaling pathway. Many studies confirm that resveratrol could positively modulate autophagy by reducing oxidative stress [119,121].
>> Any current challenges or limitations in targeting the Nrf2-p62/SQSTM1 pathway for neuroprotection can be explored. It may provide a holistic view of the topic.
We thank the reviewer for his valuable comments. We have detailed possible limitations in stimulating Nrf2 pathway and new possible perspectives to use nutraceuticals inserted into nanocarriers:
. Currently, the nasal route of administration is at the center of research in the field of nanocarriers for the treatment of neurodegenerative diseases. Encapsulating the drug in the nanocarrier and administering it intranasally can improve its absorption and facilitate its transport. It has been found that liposomes encapsulating flavonoids, improve the solubility and bioavailability of drugs, better penetrate the blood brain barrier, counteracting oxidative stress by activating Nrf2 [122]. Generally, Nrf2 activation provides protection to cells and maintains their function. In contrast, prolonged Nrf2 activation appears to be detrimental, causing tissue damage, inflammation, and resistance to chemotherapy. Nrf2 inhibitors could be used to suppress prolonged Nrf2 activation due to defects in autophagy. The p62/SQSTM1-Nrf2 pathway has revealed the mechanistic basis of prolonged Nrf2 signaling. When autophagy is impaired, p62/SQSTM1 sequesters Keap1, causing upregulation of Nrf2-controlled genes, this leads to prolonged Nrf2-ARE activation [40]. This review also opens the debate on the possibility that Nrf2 activation may enhance cannabinoid signalling through CB2R, amplifying the neuroprotective effects of ECBS on microglia reactivity and polarization. Although some details have yet to be clarified, these studies have provided new scenarios for the treatment of neurodegeneration. More insights into the mechanism of the interaction between the Nrf2-Keap1-ARE axis and autophagy are needed to facilitate the discovery of new therapies.
