The protective roles of Eugenol on type 1 diabetes mellitus through NRF2 mediated oxidative stress pathway
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eLife assessment
This valuable study partially succeeds in providing evidence to support the therapeutic potential of the plant-derived compound eugenol for ameliorating symptoms associated with Type 1 Diabetes, identifying Nuclear factor E2 - related factor (Nrf2) as a mediator of the effects induced by eugenol. Although the study provides some interesting data, the evidence for the proposed mechanism is currently incomplete.
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Abstract
Type 1 diabetes mellitus (T1DM), known as insulin-dependent diabetes mellitus, is characterized by persistent hyperglycemia resulting from damage to the pancreatic β cells and an absolute deficiency of insulin, leading to multi-organ involvement and a poor prognosis. The progression of T1DM is significantly influenced by oxidative stress and apoptosis. The natural compound eugenol (EUG) possesses anti-inflammatory, anti-oxidant, and anti-apoptotic properties. However, the potential effects of EUG on T1DM had not been investigated. In this study, we established the streptozotocin (STZ)-induced T1DM mouse model in vivo and STZ-induced pancreatic β cell MIN6 cell model in vitro to investigate the protective effects of EUG on T1DM, and tried to elucidate its potential mechanism. Our findings demonstrated that the intervention of EUG could effectively induce the activation of nuclear factor E2-related factor 2 (NRF2), leading to an up-regulation in the expressions of downstream proteins NQO-1 and HO-1, which are regulated by NRF2. Moreover, this intervention exhibited a significant amelioration in pancreatic β cell damage associated with T1DM, accompanied by an elevation in insulin secretion and a reduction in the expression levels of apoptosis and oxidative stress related markers. Furthermore, ML385, an NRF2 inhibitor, reversed these effects of EUG. The present study suggested that EUG exerted protective effects on pancreatic β cells in T1DM by attenuating apoptosis and oxidative stress through the activation of the NRF2 signaling pathway. Consequently, EUG holds great promise as a potential therapeutic candidate for T1DM.
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eLife assessment
This valuable study partially succeeds in providing evidence to support the therapeutic potential of the plant-derived compound eugenol for ameliorating symptoms associated with Type 1 Diabetes, identifying Nuclear factor E2 - related factor (Nrf2) as a mediator of the effects induced by eugenol. Although the study provides some interesting data, the evidence for the proposed mechanism is currently incomplete.
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Reviewer #1 (Public Review):
Summary
Type 1 diabetes mellitus (T1DM) progression is accelerated by oxidative stress and apoptosis. Eugenol (EUG) is a natural compound previously documented as anti-inflammatory, anti-oxidative, and anti-apoptotic. In this manuscript by Jiang et al., the authors study the effects of EUG on T1DM in MIN6 insulinoma cells and a mouse model of chemically induced T1DM. The authors show that EUG increases nuclear factor E2-related factor 2 (Nrf2) levels. This results in a reduction of pancreatic beta-cell damage, apoptosis, oxidative stress markers, and a recovery of insulin secretion. The authors highlight these effects as indicative of the therapeutic potential of EUG in managing T1DM.
Strengths
Relevant, timely, and addresses an interesting question in the field. The authors consistently observe enhanced …
Reviewer #1 (Public Review):
Summary
Type 1 diabetes mellitus (T1DM) progression is accelerated by oxidative stress and apoptosis. Eugenol (EUG) is a natural compound previously documented as anti-inflammatory, anti-oxidative, and anti-apoptotic. In this manuscript by Jiang et al., the authors study the effects of EUG on T1DM in MIN6 insulinoma cells and a mouse model of chemically induced T1DM. The authors show that EUG increases nuclear factor E2-related factor 2 (Nrf2) levels. This results in a reduction of pancreatic beta-cell damage, apoptosis, oxidative stress markers, and a recovery of insulin secretion. The authors highlight these effects as indicative of the therapeutic potential of EUG in managing T1DM.
Strengths
Relevant, timely, and addresses an interesting question in the field. The authors consistently observe enhanced beta cell functionality following EUG treatment, which makes the compound a promising candidate for T1DM therapy.
Weaknesses
The in vivo experiments have too few biological replicates. With an n=3 (as all figure legends indicate) in complex mouse studies such as these, drawing robust conclusions becomes challenging. It is important to reproduce these results in a larger cohort, to validate the conclusions of the authors. Another big concern is the lack of quantifications and statistical analysis throughout the manuscript. Although the authors claim statistical significance in various experiments, the limited information provided makes it difficult to verify. The authors use vague and minimal descriptions of their experiments, which further reduces the reader's comprehension and the reproducibility of the experiments. Finally, the use of Min6 cells as a model for pancreatic beta cells is a strong limitation of this study. Future studies should seek to reproduce these findings in a more translational model and use more relevant in vitro cell systems (eg. Islets).
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Reviewer #2 (Public Review):
Summary:
In this manuscript, the authors consider the effects of eugenol (EUG), a plant-produced substance known to reduce oxidative stress in various cellular contexts via Nrf2, in alleviating the effects of streptozotocin (STZ), a known rodent beta cell toxin. They claim that EUG treatment would be useful for T1D therapy.
Strengths:
The experiments shown are sufficiently clear and rather convincing in documenting that eugenol can revert the effects of streptozotocin on animal physiology as well as beta cell oxidative stress and cell death via activation of Nrf2.
Weaknesses:
In my view, there are major concerns with the basic premises of the manuscript.
(1) While oxidative stress may be implicated in T1D they are neither the primary nor the main reason for autoimmune beta cell destruction. In T1DM, ER …
Reviewer #2 (Public Review):
Summary:
In this manuscript, the authors consider the effects of eugenol (EUG), a plant-produced substance known to reduce oxidative stress in various cellular contexts via Nrf2, in alleviating the effects of streptozotocin (STZ), a known rodent beta cell toxin. They claim that EUG treatment would be useful for T1D therapy.
Strengths:
The experiments shown are sufficiently clear and rather convincing in documenting that eugenol can revert the effects of streptozotocin on animal physiology as well as beta cell oxidative stress and cell death via activation of Nrf2.
Weaknesses:
In my view, there are major concerns with the basic premises of the manuscript.
(1) While oxidative stress may be implicated in T1D they are neither the primary nor the main reason for autoimmune beta cell destruction. In T1DM, ER stress rather than oxidative stress is the main intracellular mediator of cell death. Thus, the abstract statement that 'oxidative stress plays a major role in T1D' is an exaggeration.
(2) Streptozotocin induces beta cell death through mechanisms that only partially overlap with autoimmune beta cell destruction. The main players ie beta cell / immune system crosstalk and T-cell mediated cell death are not present in the STZ model.
In short, because the interplay between the immune system and beta cell-intrinsic factors that trigger and accelerate the disease is completely missing, STZ treatment cannot be used as a T1DM model when beta cell demise mechanisms are concerned. The statement that STZ-treated mice are, in this context, a T1DM model, is misleading.
There are inconsistencies in the manuscript. Mechanistically, the manuscript remains at a rather superficial level demonstrating that the eugenol effects are mediated by Nrf2 upregulation and a downregulation of its partner inhibitor protein Keap1. How is eugenol penetrating the cell, is there a receptor that could be potentially targeted? Are there intermediary proteins that convey the effect to the Nrf2/Keap1 complex or is eugenol directly disrupting their interaction? What are direct downstream Nrf2 effectors? Besides, streptozotocin is also a powerful DNA alkylating agent. Are these effects mitigated by EUG?
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Reviewer #3 (Public Review):
Summary:
This study by Jiang et al. aims to establish the streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) mouse model in vivo and the STZ-induced pancreatic β cell MIN6 cell model in vitro to explore the protective effects of Eugenol (EUG) on T1DM. The authors tried to elucidate the potential mechanism by which EUG inhibits the NRF2-mediated anti-oxidative stress pathway. Overall, this study is well executed with solid data, offering an intriguing report from animal studies for a potential new treatment strategy for T1DM.
Strengths:
The in vivo efficacy study is comprehensive and solid. Given that STZ-induced T1DM is a devastating and harsh model, the in vivo efficacy of this compound is really impressive.
Weaknesses:
The Mechanism is linked with the anti-oxidant property of the compound, which …
Reviewer #3 (Public Review):
Summary:
This study by Jiang et al. aims to establish the streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) mouse model in vivo and the STZ-induced pancreatic β cell MIN6 cell model in vitro to explore the protective effects of Eugenol (EUG) on T1DM. The authors tried to elucidate the potential mechanism by which EUG inhibits the NRF2-mediated anti-oxidative stress pathway. Overall, this study is well executed with solid data, offering an intriguing report from animal studies for a potential new treatment strategy for T1DM.
Strengths:
The in vivo efficacy study is comprehensive and solid. Given that STZ-induced T1DM is a devastating and harsh model, the in vivo efficacy of this compound is really impressive.
Weaknesses:
The Mechanism is linked with the anti-oxidant property of the compound, which is common for many natural compounds, such as flavonoids and polyphenol. However, rarely, this kind of compound has been successfully developed into therapeutics in clinical usage. Indeed, if that is the case, Vitamin C or Vitamin E could be used here as the positive control.
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