Geniposidic Acid from Eucommia ulmoides Oliver Staminate Flower Tea Mitigates Cellular Oxidative Stress via Activating AKT/NRF2 Signaling

Cheng, Shuo; Jia, Huiling; Zhang, Yisen; Zhou, Juanjuan; Chen, Xue; Wu, Lifang; Wang, Jun

doi:10.3390/molecules27238568

Cited by 11 publications

(6 citation statements)

References 53 publications

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“…It possesses multiple pharmacological activities, with main activity being anticancer. 61 A recent article reports its antiviral activity against white spot syndrome virus via reducing STAT (signal transducer and activator of transcription) gene expression, thereby reducing viral replication. 62 Compound 11 has been studied as tool molecule for white spot syndrome virus replication inhibition.…”

Section: Resultsmentioning

confidence: 99%

Peptide Mold: A Novel Strategy for Mapping Potential Binding Sites in Protein Targets

Bagwe,

Jagtap,

Ghegade

et al. 2024

Preprint

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A novel concept titled ‘Peptide Mold’ for mapping potential binding sites in protein targets is presented. A large multiconformer tetrapeptide library comprising of 32 million conformations of all possible combinations of naturally-occurring amino acids was constructed and used for molecular docking analysis in the substrate-binding site of SARS-CoV-2 PLpro enzyme. The top-ranking, structurally-diverse tetrapeptide docked conformations (symbolizing peptide mold, analogous to a clay mold) were used then for elucidating a five-point pharmacophore. Ligand-based virtual screening of a large, multiconformer library of phytoconstituents using the derived five-point pharmacophore led to identification of potential binders for SARS-CoV-2 PLpro at its substrate-binding site. The approach is based on generating the imprint of a macromolecular binding site (cavity) using tetrapeptides (clay), thereby generating a reverse mold (with definitive shape and size), which can further be used for identifying small-molecule ligands matching the captured features of the target binding site. The approach is based on the fact that the individual amino acids in the tetrapeptide represent all possible drug-receptor interaction features (electrostatic, H-bonding, van der Waals, dispersion and hydrophobic among others). The ‘peptide mold’ approach can be extended to any protein target for mapping the binding site(s), and further use of the generated pharmacophore model for virtual screening of potential binders. The peptide mold approach is a robust, hybrid computational screening strategy, overcoming the present limitations of structure-based methods, e.g., molecular docking and the ligand-based methods such as pharmacophore search. Exploration of the peptide mold strategy is expected to yield high-quality, reliable and interesting virtual hits in the computational screening campaigns during the hit and lead identification stages.

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Section: Resultsmentioning

confidence: 99%

Peptide Mold: A Novel Strategy for Mapping Potential Binding Sites in Protein Targets

Bagwe,

Jagtap,

Ghegade

et al. 2024

Preprint

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show abstract

“…Previous studies have found that phosphorylation of Akt had the ability to reduce cellular apoptosis and ease neuroinflammation in diverse pathophysiological conditions [ 47 – 49 ]. On the other hand, Akt signaling has been reported to regulate the Nrf2 transcription factors, which aid in suppressing oxidative stress and negatively modulating the inflammatory response [ 27 – 29 , 50 ]. Numerous studies have indicated that Nrf2 contributed to modulating the functional phenotype of microglia and enhancing microglial phagocytosis in brain injury [ 26 , 51 – 54 ].…”

Section: Discussionmentioning

confidence: 99%

“…Disruptions to the Akt signaling pathway are associated with multiple human diseases, such as cancer, cardiovascular disease, and neurological disorders [ 24 , 25 ]. And it’s reported that phosphorylated Akt could upregulate the expression of nuclear factor E2-related factor 2 (Nrf2), which was involved in antioxidant and cytoprotective functions, inhibition of inflammation, and modulation of microglial functional phenotype [ 26 – 29 ]. Given the close relationship between the aforementioned proteins and Nrf2’s pivotal regulatory function, it is plausible that Mas receptor activation could mediate hematoma clearance and neuroprotection partially via the Akt/Nrf2 pathway in ICH.…”

Section: Introductionmentioning

confidence: 99%

Mas receptor activation facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice

Deng,

Ren,

Chen

et al. 2024

J Neuroinflammation

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Background Intracerebral hemorrhage (ICH) is a devastating neurological disease causing severe sensorimotor dysfunction and cognitive decline, yet there is no effective treatment strategy to alleviate outcomes of these patients. The Mas axis-mediated neuroprotection is involved in the pathology of various neurological diseases, however, the role of the Mas receptor in the setting of ICH remains to be elucidated. Methods C57BL/6 mice were used to establish the ICH model by injection of collagenase into mice striatum. The Mas receptor agonist AVE0991 was administered intranasally (0.9 mg/kg) after ICH. Using a combination of behavioral tests, Western blots, immunofluorescence staining, hematoma volume, brain edema, quantitative-PCR, TUNEL staining, Fluoro-Jade C staining, Nissl staining, and pharmacological methods, we examined the impact of intranasal application of AVE0991 on hematoma absorption and neurological outcomes following ICH and investigated the underlying mechanism. Results Mas receptor was found to be significantly expressed in activated microglia/macrophages, and the peak expression of Mas receptor in microglia/macrophages was observed at approximately 3–5 days, followed by a subsequent decline. Activation of Mas by AVE0991 post-treatment promoted hematoma absorption, reduced brain edema, and improved both short- and long-term neurological functions in ICH mice. Moreover, AVE0991 treatment effectively attenuated neuronal apoptosis, inhibited neutrophil infiltration, and reduced the release of inflammatory cytokines in perihematomal areas after ICH. Mechanistically, AVE0991 post-treatment significantly promoted the transformation of microglia/macrophages towards an anti-inflammatory, phagocytic, and reparative phenotype, and this functional phenotypic transition of microglia/macrophages by Mas activation was abolished by both Mas inhibitor A779 and Nrf2 inhibitor ML385. Furthermore, hematoma clearance and neuroprotective effects of AVE0991 treatment were reversed after microglia depletion in ICH. Conclusions Mas activation can promote hematoma absorption, ameliorate neurological deficits, alleviate neuron apoptosis, reduced neuroinflammation, and regulate the function and phenotype of microglia/macrophages via Akt/Nrf2 signaling pathway after ICH. Thus, intranasal application of Mas agonist ACE0991 may provide promising strategy for clinical treatment of ICH patients.

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“…NRF2 is an important regulator of cellular oxidative status. As well as DNJ, various natural products have been found to stimulate the NRF2 antioxidative response, such as chlorogenic acid, geniposidic acid, and glucoraphanin [36][37][38], which were thought to be of value to health. HO-1 is a well-known downstream target of NRF2.…”

Section: Discussionmentioning

confidence: 99%

1-Deoxynojirimycin Attenuates High-Glucose-Induced Oxidative DNA Damage via Activating NRF2/OGG1 Signaling

Chen,

Wang

2024

Applied Sciences

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1-Deoxynojirimycin (DNJ) is a type of alkaloid that mainly exists in mulberry fruit and leaves. DNJ inhibits α-glucosidase, reduces the absorption of sugar, and suppresses after-meal hyperglycemia. It was reported that DNJ functions in attenuating cellular oxidative stress. However, the mechanisms remain largely unknown. In this study, we firstly confirmed that 5 µmol/L DNJ treatment mitigated the oxidative DNA damage and cell senescence in human umbilical vein endothelial cells (HUVEC) cultured in medium containing 50 mmol/L glucose. Next, we found that DNJ treatment stimulates the expression of anti-oxidative response regulator, Nuclear factor (erythroid-derived 2)-like 2 (NRF2) by around 50% in cells cultured with high glucose. In addition, 8-oxoguanine DNA glycosylase (OGG1) was upregulated by over 15% after DNJ treatment to mitigate high-glucose-induced oxidative DNA damage, and it was identified as a downstream target of NRF2. Further, DNJ treatment promoted the phosphorylation and activation of AKT (ser473) by around 50% in cells cultured with high glucose, and AKT inhibitor treatment abrogated DNJ-induced upregulation of NRF2 and OGG1. Taken together, our results indicate that DNJ is an effective natural antioxidant in mitigating high-glucose-induced oxidative stress in HUVEC via activating the AKT-NRF2-OGG1 anti-oxidative response.

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Geniposidic Acid from Eucommia ulmoides Oliver Staminate Flower Tea Mitigates Cellular Oxidative Stress via Activating AKT/NRF2 Signaling

Cited by 11 publications

References 53 publications

Peptide Mold: A Novel Strategy for Mapping Potential Binding Sites in Protein Targets

Peptide Mold: A Novel Strategy for Mapping Potential Binding Sites in Protein Targets

Mas receptor activation facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice

1-Deoxynojirimycin Attenuates High-Glucose-Induced Oxidative DNA Damage via Activating NRF2/OGG1 Signaling

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