Anti-Oxidant and Anti-Aging Effects of Phlorizin Are Mediated by DAF-16-Induced Stress Response and Autophagy in Caenorhabditis elegans

Park, Suhyeon; Park, Sang-Kyu

doi:10.3390/antiox11101996

Cited by 16 publications

(13 citation statements)

References 62 publications

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“…The IIS pathway, which regulates signal factors and activates a series of genes in the nucleus that mediate oxidative stress, is the most typical life-extending mechanism in C. elegans (Hesp et al 2015), with the daf-2, age-1, ak-1 and daf-16 genes playing a crucial role (Altintas et al 2016). The results suggested that phlorizin improved C. elegans survival by regulating daf-16 in the IIS pathway, and Suhyeon Park found similar results (Park and Park 2022). Mutations with decreased daf-2 activity have been found to more than double the longevity of animals (Zhang et al 2015), and the extension of lifespan is determined by the nuclear translocation of DAF-16 (Kitaoka et al 2016).…”

Section: Discussionmentioning

confidence: 75%

Phlorizin Prolongs the Lifespan of Caenorhabditis elegans by insulin/SIR-2.1 Regulation

Zhang

Wang

Yang

et al. 2023

Preprint

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Phlorizin, a natural compound, was studied using C. elegans to explore its potential mechanism for extending lifespan. Results showed that phlorizin mitigated the harmful effects of high temperatures and hydrogen peroxide, reduced oxidative stress, increased antioxidant enzyme activity, and reduced MDA levels. Through network pharmacological analysis, it was determined that the AKT1, INSR and SOD2 signaling pathway plays a key role in the anti-aging effects of phlorizin. Experiments with mutants and transgenic C. elegans showed that phlorizin lifespan extension and antioxidant effects are mainly mediated by insulin and SIR-2.1 pathways that regulate DAF-16 and SKN-1 nuclear translocation and its downstream targets SOD-3 and HSP-16.2. These findings were supported by molecular docking experiments. Overall, this study provides insight into the potential use of phlorizin as an anti-aging agent and highlights the importance of the DAF-16/SOD-3 signaling pathway in mediating its action.

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Section: Discussionmentioning

confidence: 75%

Phlorizin Prolongs the Lifespan of Caenorhabditis elegans by insulin/SIR-2.1 Regulation

Zhang

Wang

Yang

et al. 2023

Preprint

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“…The treatment with DHA-TG specially enhanced the activity and expression of the SOD enzyme family. Since the effect of DHA-TG is lost in DAF-16 deficient strain, and the expression of sod-3 is very dependent on the factor DAF-16/FOXO [67], it might be hypothesized that healthspan-promoting effects of DHA-TG are closely related to the antioxidant response using DAF-16 as an intermediary, as stated in similar research [68,69].…”

Section: Discussionmentioning

confidence: 87%

Structured Docosahexaenoic Acid (DHA) Enhances Motility and Promotes the Antioxidant Capacity of Aged C. elegans

Mora,

Pérez-Santamaria,

Tortajada-Pérez

et al. 2023

Cells

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The human lifespan has increased over the past century; however, healthspans have not kept up with this trend, especially cognitive health. Among nutrients for brain function maintenance, long-chain omega-3 polyunsaturated fatty acids (ω-3 LCPUFA): DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) must be highlighted, particularly structured forms of EPA and DHA which were developed to improve bioavailability and bioactivity in comparison with conventional ω-3 supplements. This study aims to elucidate the effect of a structured triglyceride form of DHA (DHA-TG) on the healthspan of aged C. elegans. Using a thrashing assay, the nematodes were monitored at 4, 8, and 12 days of adulthood, and DHA-TG improved its motility at every age without affecting lifespan. In addition, the treatment promoted antioxidant capacity by enhancing the activity and expression of SOD (superoxide dismutase) in the nematodes. Lastly, as the effect of DHA-TG was lost in the DAF-16 mutant strain, it might be hypothesized that the effects of DHA need DAF-16/FOXO as an intermediary. In brief, DHA-TG exerted a healthspan-promoting effect resulting in both enhanced physical fitness and increased antioxidant defense in aged C. elegans. For the first time, an improvement in locomotive function in aged wild-type nematodes is described following DHA-TG treatment.

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“…Decreased hormone levels also significantly impact metabolism and cell death in post-trauma periods, which makes us hypothesize that restoring hormonal control of brain functions with exogenous hormones can serve as a pharmacological treatment to reduce the mortality of neurons and other brain cells, such as astrocytes and microglia. Although both compounds (phlorizin and phloretin) investigated here have demonstrated decisive anti-inflammatory actions [ 39 , 41 , 42 , 43 , 44 ], their possible molecular actions have not been studied in TBI. Our goal was to decipher which proteins regulated by phlorizin and phloretin, two natural compounds with estrogenic activity, can potentially regulate pro-oxidative and inflammatory mechanisms, which are the main hallmarks of TBI.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Antioxidant Capacity and Network Pharmacology of Phloretin and Phlorizin against Neuroinflammation in Traumatic Brain Injury

2023

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Neuroinflammation is a hallmark of traumatic brain injury (TBI)’s acute and chronic phases. Despite the medical and scientific advances in recent years, there is still no effective treatment that mitigates the oxidative and inflammatory damage that affects neurons and glial cells. Therefore, searching for compounds with a broader spectrum of action that can regulate various inflammatory signaling pathways is of clinical interest. In this study, we determined not only the in vitro antioxidant capacity of apple pomace phenolics, namely, phlorizin and its metabolite, phloretin, but we also hypothesize that the use of these bioactive molecules may have potential use in TBI. We explored the antioxidant effects of both compounds in vitro (DPPH, iron-reducing capacity (IRC), and Folin–Ciocalteu reducing capacity (FCRC)), and using network pharmacology, we investigated the proteins involved in their protective effects in TBI. Our results showed that the antioxidant properties of phloretin were superior to those of phlorizin in the DPPH (12.95 vs. 3.52 mg ascorbic acid equivalent (AAE)/L), FCRC (86.73 vs. 73.69 mg gallic acid equivalent (GAE)/L), and iron-reducing capacity (1.15 vs. 0.88 mg GAE/L) assays. Next, we examined the molecular signature of both compounds and found 11 proteins in common to be regulated by them and involved in TBI. Meta-analysis and GO functional enrichment demonstrated their implication in matrix metalloproteinases, p53 signaling, and cell secretion/transport. Using MCODE and Pearson’s correlation analysis, a subcluster was generated. We identified ESR1 (estrogen receptor alpha) as a critical cellular hub being regulated by both compounds and with potential therapeutic use in TBI. In conclusion, our study suggests that because of their vast antioxidant effects, probably acting on estrogen receptors, phloretin and phlorizin may be repurposed for TBI treatment due to their ease of obtaining and low cost.

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Anti-Oxidant and Anti-Aging Effects of Phlorizin Are Mediated by DAF-16-Induced Stress Response and Autophagy in Caenorhabditis elegans

Cited by 16 publications

References 62 publications

Phlorizin Prolongs the Lifespan of Caenorhabditis elegans by insulin/SIR-2.1 Regulation

Phlorizin Prolongs the Lifespan of Caenorhabditis elegans by insulin/SIR-2.1 Regulation

Structured Docosahexaenoic Acid (DHA) Enhances Motility and Promotes the Antioxidant Capacity of Aged C. elegans

Comparison of Antioxidant Capacity and Network Pharmacology of Phloretin and Phlorizin against Neuroinflammation in Traumatic Brain Injury

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