Nutraceutical based SIRT3 activators as therapeutic targets in Alzheimer's disease

Govindarajulu, Manoj; Ramesh, Sindhu; Neel, Logan; Fabbrini, Mary; Buabeid, Manal; Fujihashi, Ayaka; Dwyer, Darby; Lynd, Tyler; Shah, Karishma; Mohanakumar, Kochupurackal P.; Smith, Forrest; Moore, Timothy; Dhanasekaran, Muralikrishnan

doi:10.1016/j.neuint.2021.104958

Cited by 28 publications

(20 citation statements)

References 173 publications

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“…Sirtuin 3 (SIRT3), localized in the mitochondria, works as a deacetylase of mitochondrial protein [7][8][9]. SIRT3 maintains mitochondrial homeostasis by promoting mitochondrial dynamics, antioxidation, and mitophagy, as well as deacetylation of manganese superoxide dismutase (MnSOD), enhancing its biological activity in senescent NPCs and indicating that SIRT3 might play an important role in normal mitochondrial function in NPCs against oxidative stress [10].…”

Section: Introductionmentioning

confidence: 99%

Promoting Nrf2/Sirt3‐Dependent Mitophagy Suppresses Apoptosis in Nucleus Pulposus Cells and Protects against Intervertebral Disc Degeneration

Zhang

Qian

et al. 2021

Oxidative Medicine and Cellular Longevity

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One of the causes of intervertebral disc degeneration (IVDD) is nucleus pulposus cell (NPC) death, possibly apoptosis. In this study, we explored the role of the Nrf2/Sirt3 pathway and tert-butylhydroquinone (t-BHQ) in IVDD and elucidated the potential working mechanism. Reactive oxygen species (ROS) assay kits and malondialdehyde (MDA) assay kits were used to assess oxidative stress. Western blot and TUNEL staining were used to examine apoptosis. After siRNA against Nrf2 or lentivirus against Sirt3 was transfected into NPCs, the mechanism of the effect of the Nrf2/Sirt3 pathway on NPCs was assessed. The interaction between t-BHQ and its potential interacting protein NRF2 was further investigated through protein docking analysis. ChIP examined the binding affinity between Nrf2 and Sirt3 promoter. In vivo experiments, X-ray, hematoxylin-eosin (HE) staining, Safranin O staining, and immunohistochemistry were used to evaluate IVDD grades. The results demonstrated that activation of the Nrf2/Sirt3 pathway inhibited tert-butyl hydroperoxide- (TBHP-) induced apoptosis and mitochondrial dysfunction in vitro. In addition to apoptosis, upregulation of the Nrf2/Sirt3 pathway induced by t-BHQ restored TBHP-induced autophagic flux disturbances. However, its protective effect was reversed by chloroquine and Si-ATG5. Furthermore, t-BHQ ameliorated IVDD development in a rat model. In conclusion, our findings indicate that the Nrf2/Sirt3 pathway and its agonist represent a potential candidate for treating IVDD.

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Section: Introductionmentioning

confidence: 99%

Promoting Nrf2/Sirt3‐Dependent Mitophagy Suppresses Apoptosis in Nucleus Pulposus Cells and Protects against Intervertebral Disc Degeneration

Zhang

Qian

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…The excessive production of ROS can induce p53-mediated apoptosis ( 38 ). However, enhancing the expression of SIRT3 can eliminate ROS, while a deficiency in SIRT3 leads to oxidative damage and accelerates aging ( 39 , 40 ). SIRT3 weakens the binding between p53 and Bcl-2 associated athanogene 2 to activate the Bcl-2-mediated apoptosis-inhibiting pathway ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

Metformin attenuates H₂O₂‑induced osteoblast apoptosis by regulating SIRT3 via the PI3K/AKT pathway

et al. 2021

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Osteoporosis is a common metabolic disease that has a high incidence in postmenopausal women. Studies have indicated that oxidative damage plays an important role in the development of postmenopausal osteoporosis. Metformin has been showed to have the ability to relieve excessive oxidation. The aim of the present was to determine the therapeutic effect and potential mechanism of metformin in postmenopausal osteoporosis. Oxidative damage was stimulated in vitro by the addition of H 2 O 2 to MC3T3-E1 cells and a mouse menopausal model was also constructed. Cell viability and flow cytometry experiments were performed to determine the effects of H 2 O 2 and metformin treatment on apoptosis. Mitochondrial membrane potential was tested by JC-1 assays. Western blotting was used to detect the expression of mitochondrial apoptosis markers and antioxidant enzymes. Small interfering RNA was used to knockdown sirtuin3 (SIRT3), which was verified at the mRNA and protein levels. Bilateral ovariectomy was used to prepare menopausal mice, which were analyzed using micro-computed tomography. The results indicated that metformin is able to repair mitochondrial damage and inhibit the apoptosis of osteoblasts induced by H 2 O 2 , and also reverse bone mass loss in ovariectomized mice. Western blotting results demonstrated the involvement of SIRT3 in the production of antioxidant enzymes that are essential in protecting against mitochondrial injury. In addition, experiments with SIRT3 knockdown indicated that metformin reverses H 2 O 2 -induced osteoblast apoptosis by upregulating the expression of SIRT3 via the PI3K/AKT pathway. The results of the present reveal the pathogenesis of oxidative damage and the therapeutic effect of metformin in postmenopausal osteoporosis. They also suggest that SIRT3 is a potential drug target in the treatment of osteoporosis, with metformin being a candidate drug for modification and/or clinical application.

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“…By regulating IL-1 family cytokines, curcumin has been found to attenuate inflammatory reactions. [3,8,38] Vitamin C…”

Section: Curcuminmentioning

confidence: 99%

“…Neurological disorders are one of the major healthcare issues worldwide. [1][2][3] Lifestyle changes are associated with the risk of chronic illness. Nowadays, Alzheimer's is becoming a major puzzle in medicine.…”

Section: Introductionmentioning

confidence: 99%

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Exploring the potential of neuronutraceuticals as alternatives in the prevention of Alzheimer’s disease

Kumar¹,

Ali²,

Kumar³

et al. 2022

Pharmaspire

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Various chemical compounds with natural dietary origins have been shown to protect against age-related disorders, such as neurodegenerative diseases such as Alzheimer’s disease (AD). Such substances are known as nutraceuticals, and they differ structurally, function at distinct biochemical and metabolic levels, and have various neuroprotective characteristics. In this review, we analyzed the evidence from explanatory studies on the effects of selected nutritional supplements on age-related cognitive decline and dementia in humans, randomized clinical trials, and clinical trials. We provide findings from research on vitamins, flavonoids, and other natural compounds that have been researched in AD and may be useful for maintaining excellent cognitive function. In dementia-related therapy, nutraceuticals are not a choice due to a severe absence of high-quality research studies. Despite this, the significant potential for their neuroprotective effects discourages future research.

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Nutraceutical based SIRT3 activators as therapeutic targets in Alzheimer's disease

Cited by 28 publications

References 173 publications

Promoting Nrf2/Sirt3‐Dependent Mitophagy Suppresses Apoptosis in Nucleus Pulposus Cells and Protects against Intervertebral Disc Degeneration

Promoting Nrf2/Sirt3‐Dependent Mitophagy Suppresses Apoptosis in Nucleus Pulposus Cells and Protects against Intervertebral Disc Degeneration

Metformin attenuates H₂O₂‑induced osteoblast apoptosis by regulating SIRT3 via the PI3K/AKT pathway

Exploring the potential of neuronutraceuticals as alternatives in the prevention of Alzheimer’s disease

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Nutraceutical based SIRT3 activators as therapeutic targets in Alzheimer's disease

Cited by 28 publications

References 173 publications

Promoting Nrf2/Sirt3‐Dependent Mitophagy Suppresses Apoptosis in Nucleus Pulposus Cells and Protects against Intervertebral Disc Degeneration

Promoting Nrf2/Sirt3‐Dependent Mitophagy Suppresses Apoptosis in Nucleus Pulposus Cells and Protects against Intervertebral Disc Degeneration

Metformin attenuates H2O2‑induced osteoblast apoptosis by regulating SIRT3 via the PI3K/AKT pathway

Exploring the potential of neuronutraceuticals as alternatives in the prevention of Alzheimer’s disease

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Metformin attenuates H₂O₂‑induced osteoblast apoptosis by regulating SIRT3 via the PI3K/AKT pathway