Rhein Relieves Oxidative Stress in an Aβ1-42 Oligomer-Burdened Neuron Model by Activating the SIRT1/PGC-1α-Regulated Mitochondrial Biogenesis

Yin, Zhihui; Geng, Xinyue; Zhang, Zhengyi; Wang, Ying; Gao, Xiaoyan

doi:10.3389/fphar.2021.746711

Cited by 21 publications

(21 citation statements)

References 67 publications

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“…The elevated NOX2 and NOX4 protein levels after Ang II stimulation in the CMs and CFs were obviously reversed by rhein. Consistent with these findings, rhein significantly suppressed neuronal oxidative stress in Alzheimer disease [ 40 ], hydrogen peroxide-induced oxidative stress in intestinal epithelial cells [ 41 ], and ATP-triggered inflammatory responses in rheumatoid rat fibroblast-like synoviocytes [ 18 ]. Further research is needed to examine whether rhein has similar effects on ROS derived from the mitochondria or other sources.…”

Section: Discussionmentioning

confidence: 68%

Rhein attenuates angiotensin II-induced cardiac remodeling by modulating AMPK–FGF23 signaling

Zhu

et al. 2022

J Transl Med

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Background Increasing evidence indicates that myocardial oxidative injury plays a crucial role in the pathophysiology of cardiac hypertrophy (CH) and heart failure (HF). The active component of rhubarb, rhein exerts significant actions on oxidative stress and inflammation. Nonetheless, its role in cardiac remodeling remains unclear. Methods CH was induced by angiotensin II (Ang II, 1.4 mg/kg/d for 4 weeks) in male C57BL/6 J mice. Then, rhein (50 and 100 mg/kg) was injected intraperitoneally for 28 days. CH, fibrosis, oxidative stress, and cardiac function in the mice were examined. In vitro, neonatal rat cardiomyocytes (CMs) and cardiac fibroblasts (CFs) pre-treated with rhein (5 and 25 μM) were challenged with Ang II. We performed RNA sequencing to determine the mechanistic role of rhein in the heart. Results Rhein significantly suppressed Ang II-induced CH, fibrosis, and reactive oxygen species production and improved cardiac systolic dysfunction in vivo. In vitro, rhein significantly attenuated Ang II-induced CM hypertrophy and CF collagen expression. In addition, rhein obviously alleviated the increased production of superoxide induced by Ang II. Mechanistically, rhein inhibited FGF23 expression significantly. Furthermore, FGF23 overexpression abolished the protective effects of rhein on CMs, CFs, and cardiac remodeling. Rhein reduced FGF23 expression, mostly through the activation of AMPK (AMP-activated protein kinase). AMPK activity inhibition suppressed Ang II-induced CM hypertrophy and CF phenotypic transformation. Conclusion Rhein inhibited Ang II-induced CH, fibrosis, and oxidative stress during cardiac remodeling through the AMPK–FGF23 axis. These findings suggested that rhein could serve as a potential therapy in cardiac remodeling and HF.

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Section: Discussionmentioning

confidence: 68%

Rhein attenuates angiotensin II-induced cardiac remodeling by modulating AMPK–FGF23 signaling

Zhu

et al. 2022

J Transl Med

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“…Our previous research has proven that rhein relieves oxidative stress by activating the SIRT1/PGC-1 α -regulated mitochondrial biogenesis in vitro [ 29 ]. Thus, western blot was employed to detect the protein expression of SIRT1, PGC-1 α , and NRF1 in the hippocampal tissues.…”

Section: Resultsmentioning

confidence: 99%

“…A growing body of evidence demonstrates that neuronal oxidative stress contributes significantly to the pathogenesis and progression of AD, and activating the endogenous antioxidant pathway represents a great promising target to modulate AD pathology [ 46 , 47 ]. Previous research conducted in our group unveils that rhein effectively relieves mitochondrial oxidative stress in primary neurons induced by A β 42 oligomers, and mitochondrial biogenesis regulated by the SIRT1/PGC-1 α pathway is a potential antioxidant pathway involved [ 29 ]. While impressive in vitro antioxidant activity and neuroprotection were obtained, pharmacodynamics evaluation of rhein for AD in vivo still needs to be carried out.…”

Section: Discussionmentioning

confidence: 99%

“…Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid), a type of anthraquinone compound derived from rhubarb, is identified as a potent antioxidant for multiple diseases, such as cerebral ischemic/reperfusion [ 26 ], hyperglycemia [ 27 ], and traumatic brain injury [ 28 ]. By establishing an A β 42 oligomer-burdened neuron model, our previous work has proven that rhein notably mitigated intracellular ROS levels, reversed the depletion of mitochondrial membrane potential in neurons, and protected neurons from mitochondrial oxidative damage-associated apoptosis [ 29 ]. Moreover, activation of the SIRT1/PGC-1 α -regulated mitochondrial biogenesis is an essential mechanism of rhein for mobilizing the mitochondrial antioxidant defense system.…”

Section: Introductionmentioning

confidence: 99%

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Rhein Ameliorates Cognitive Impairment in an APP/PS1 Transgenic Mouse Model of Alzheimer’s Disease by Relieving Oxidative Stress through Activating the SIRT1/PGC-1α Pathway

Yin

Gao

et al. 2022

Oxidative Medicine and Cellular Longevity

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Mitochondrial oxidative stress plays an important role in the pathogenesis of Alzheimer’s disease (AD). Recently, antioxidant therapy has been considered an effective strategy for the treatment of AD. Our previous work discovered that rhein relieved mitochondrial oxidative stress in β-amyloid (Aβ) oligomer-induced primary neurons by improving the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha- (PGC-1α-) regulated mitochondrial biogenesis. While encouraging results have been provided, mechanisms underlying the beneficial effect of rhein on AD are yet to be elucidated in vivo. In this study, we evaluated the therapeutic effect of rhein on an APP/PS1 transgenic (APP/PS1) mouse model of AD and explored its antioxidant mechanisms. As a result, rhein significantly reduced Aβ burden and neuroinflammation and eventually ameliorated cognitive impairment in APP/PS1 mice. Moreover, rhein reversed oxidative stress in the brain of APP/PS1 mice and protected neurons from oxidative stress-associated apoptosis. Further study revealed that rhein promoted mitochondrial biogenesis against oxidative stress by upregulating SIRT1 and its downstream PGC-1α as well as nuclear respiratory factor 1. Improved mitochondrial biogenesis not only increased the activity of superoxide dismutase to scavenge excess reactive oxygen species (ROS) but also repaired mitochondria by mitochondrial fusion to inhibit the production of ROS from the electron transport chain. Notably, the exposure of rhein in the brain analyzed by tissue distribution study indicated that rhein could permeate into the brain to exert its therapeutic effects. In conclusion, these findings drive rhein to serve as a promising therapeutic antioxidant for the treatment of AD. Our research highlights the therapeutic efficacy for AD through regulating mitochondrial biogenesis via the SIRT1/PGC-1α pathway.

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“…During the occurrence of DE, the brain is more susceptible to oxidative stress than other organs. Most of the components of neurons (lipid, protein, and nucleic acid) may be oxidized, thereby promoting the apoptosis of related neurons [ 12 ]. The brain-derived neurotrophic factor (BDNF) is the most prominent neurotrophic factor in the human body, and it plays an important role in neuronal development, survival, and synaptic plasticity [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Explore the Mechanism of β-Asarone on Improving Cognitive Dysfunction in Rats with Diabetic Encephalopathy

Cai

Xia

et al. 2022

ADR

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Background: The number of people with diabetes is increasing, and many patients have significantly impaired cognitive function. For patients with diabetic encephalopathy (DE), simply lowering blood sugar does not improve learning and memory. Studies have shown that β-asarone can significantly improve cognitive impairment in patients with DE, but the specific mechanism of action is unclear. Objective: This experiment hopes to use a variety of experimental methods to clarify the protective effect and mechanism of β-asarone on brain neurons during the development of DE disease. Methods: A high-sugar and high-fat diet and streptozotocin injection-induced DE rat model was used. β-asarone was administered for four weeks. The experiment used the Morris water maze test, biochemical index detection, and many methods to evaluate the neuroprotective effect of β-asarone on DE rats from various aspects and understand its mechanism. Results: β-asarone reduced neuronal cell damage and significantly improved the learning and memory ability of DE rats. In addition, β-asarone can reduce the oxidative stress response and amyloid-β accumulation in the brain of DE model rats and increase the content of brain-derived neurotrophic factor (BDNF) in the brain tissue, thereby reducing neuronal cell apoptosis and playing a protective role. Conclusion: β-asarone can reduce the accumulation of oxidative stress and amyloid-β in the brain, increase the content of BDNF, reduce the apoptosis of neuronal cells, and exert neuronal protection, thereby improving the learning and memory ability of DE model rats.

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Rhein Relieves Oxidative Stress in an Aβ1-42 Oligomer-Burdened Neuron Model by Activating the SIRT1/PGC-1α-Regulated Mitochondrial Biogenesis

Cited by 21 publications

References 67 publications

Rhein attenuates angiotensin II-induced cardiac remodeling by modulating AMPK–FGF23 signaling

Rhein attenuates angiotensin II-induced cardiac remodeling by modulating AMPK–FGF23 signaling

Rhein Ameliorates Cognitive Impairment in an APP/PS1 Transgenic Mouse Model of Alzheimer’s Disease by Relieving Oxidative Stress through Activating the SIRT1/PGC-1α Pathway

Explore the Mechanism of β-Asarone on Improving Cognitive Dysfunction in Rats with Diabetic Encephalopathy

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