Enhanced Nrf2 up‐regulation by extracellular basic pH in a human skin equivalent system

Park, Gunhyuk; Moon, Byeong Cheol; Oh, Dal‐Seok; Kim, Yong‐ung; Park, Moon‐Ki

doi:10.1111/jcmm.16472

Cited by 6 publications

(7 citation statements)

References 26 publications

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“…The main peak in TIC was evaluated by typical un-fragmented mass spectrometry pro le of melittin. This value was then con rmed with result of other studies [32,33]; subsequently, this speci c mass data is the indicator to detect melittin the analyzed samples.…”

Section: Mass Spectrometry Analysissupporting

confidence: 72%

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Prioritizing Nrf2/HO-1-Mediated Intrinsic Antioxidant Upregulation: The Foremost Neuroprotective Mechanism of Melittin in a Scopolamine-Induced Animal Model of Neural Stress, Preceding Anti- Inflammatory Effects

Yoo,

Nguyen,

Jeong

et al. 2024

Preprint

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Oxidative stress is a key driver of neurodegeneration, and the Nrf2/HO-1 pathway serves as a primary defense mechanism against this stress. Melittin, derived from bee venom, has shown promise in mitigating cognitive decline in mild cognitive impairment. This study for the first time investigates whether melittin can revive the compromised Nrf2/HO-1 pathway in neurodegenerative animals’ brains and whether this pathway is the initial target of melittin's action. In a scopolamine-induced neurodegeneration model in mice, melittin administration led to its significant accumulation in the hippocampus, indicating its direct interaction with neural tissues. Comprehensive analysis revealed that melittin's earliest effect was the restoration of the Nrf2/HO-1 system, reinforcing its role as an antioxidant defense against oxidative stress. In vitro studies with mouse hippocampus HT22 cells showed that melittin triggered the translocation of Nrf2 from the cytosol to the nucleus. Notably, the most significant inhibition of melittin's protective effects was observed with an HO-1 inhibitor, suggesting a close association between melittin's action and the HO-1 pathway. In summary, this study demonstrates for the first time melittin's ability to upregulate the compromised Nrf2/HO-1 pathway in neurodegenerative animals, with evidence pointing to its primary action through this pathway. The direct effect of melittin on the Keap-1/Nrf2/HO-1 pathway were further solidified with invitro evidences. These findings enhance our understanding of melittin's neuroprotective mechanisms and its potential as a therapeutic agent for neurodegenerative disorders, warranting further clinical exploration. This evidence strongly corroborates the prevailing trend of harnessing the activation of cellular antioxidation as a potent therapeutic strategy against neurodegeneration.

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Section: Mass Spectrometry Analysissupporting

confidence: 72%

“…While our earlier research showcased melittin's potential as a neuroprotective agent in mice [23,31,32], its impact on the compromised Nrf2/HO-1 pathway in animals undergoing neurodegeneration remains unexplored. Furthermore, the elucidation of the proposed mechanisms of action is essential for guiding future research endeavors.…”

Section: Introductionmentioning

confidence: 99%

Prioritizing Nrf2/HO-1-Mediated Intrinsic Antioxidant Upregulation: The Foremost Neuroprotective Mechanism of Melittin in a Scopolamine-Induced Animal Model of Neural Stress, Preceding Anti- Inflammatory Effects

Yoo,

Nguyen,

Jeong

et al. 2024

Preprint

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“…The cell culture system was established as per previous reports [ 14 , 15 ]. Human primary dermal fibroblast cells were purchased from TEGO Science (Seoul, Korea) and maintained in a fibroblast medium containing fibroblast growth supplement, 10% heat-inactivated FBS, and 1% penicillin-streptomycin.…”

Section: Methodsmentioning

confidence: 99%

Effects of the Higenamine, a Potent Compound from Aconitum, on UVB-Induced Photoaging in Hairless Mice

Lim

Jang

Park

2022

Evidence-Based Complementary and Alternative Medicine

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Aim. Higenamine [1-[(4-hydroxyphenyl) methyl]-1, 2, 3, 4-tetrahydroisoquinoline-6, 7-diol], a potent cardiotonic compound from Aconitum, contributes to vascular relaxation and bronchodilation. However, the effects and mechanisms of action of higenamine on skin aging remain poorly understood. In this study, the effects of higenamine on UVB-induced photoaging were examined in the hairless mouse model. Methods. The dorsal skin of hairless mice (CrlOri : SKH1) was exposed to chronic UVB irradiation (100–300 mJ/cm2 for 6 weeks), with subsequent administration of higenamine (1–20 mg/kg, p.o.) for 2 weeks. TGF-β, Smad3 DNA-binding phosphorylation, and COL1A1 levels were analyzed by immunohistochemistry, and histological analysis of the skin was performed via H&E and MT staining. Results. Higenamine increased TGF-β, Smad3 DNA-binding phosphorylation, and COL1A1 expression in primary human fibroblast cells and mouse skin. Higenamine suppressed UVB-induced photoaging via skin recovery, improved epidermal thickness, and prevented Smad3, DNA-binding phosphorylation, and COL1A1 depletion via TGF-β signaling. Conclusion. Higenamine enhances collagen production in the skin through TGF-β/Smad3 signaling and potentially suppresses UVB-induced skin aging.

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“…The hippocampus was speci cally chosen for its importance in the formation and recalling of memory, this organ is also the focus of Alzheimer's studies [32][33][34]. For in vivo experiment 1 (sections 3.1-3.3) mice were sacri ced on the 6th day after the Y maze test.…”

Section: Collection Of Brain Hippocampal Tissuementioning

confidence: 99%

Melittin - A Main Component of Bee Venom: A Promising Therapeutic Agent for Neuroprotection through Nrf2/HO-1 Pathway Activation

Yoo,

Nguyen,

et al. 2024

Preprint

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The Nrf2/HO-1 pathway, known for its significant role in regulating innate antioxidant defense mechanisms, is increasingly being recognized for its potential in neuroprotection studies. Derived from bee venom, melittin's neuroprotective effects are raising interest. This study confirms that melittin specificity upregulated the weaken Nrf2/HO-1 signaling in mice brain. Interestingly, we also revealed melittin’s efficient tactic, as the restored redox balance alone gradually stabilized other regulations of the mouse hippocampus. Using a scopolamine-induced, a common and effective neurodegeneration model in mice, chemical analysis revealed that melittin crosses the compromised blood-brain barrier, accumulates in the hippocampus, and significantly enhances neurogenesis and cognitive function in scopolamine-induced mice. Careful observation in mice showed: first signs of changes within 5 hours after melittin administration were the restoration of the Nrf2/HO-1 system and suppresses oxidative stress. After this event, from 7 to 12.5 hours after administration were the rebalancing of inflammation, apoptosis, neurotrophic factors, cholinergic function, and mitochondrial performance. This chain reaction underscores the redox balance's role in reviving multiple neuronal functions. Evidence of enhancement in mouse hippocampus led to further exploration with hippocampal cell line HT22. Immunofluorescence analysis showed melittin-induced Nrf2 translocation to the nucleus, which would initiating the translation of antioxidant genes like HO-1. Pathway inhibitors pinpointed melittin's direct influence on the Nrf2/HO-1 pathway. 3D docking models and pull-down assays suggested melittin's direct interaction with Keap1, Nrf2/HO-1’s activator. Overall, this study not only highlighted melittin specifically effect on Nrf2/HO-1, thus, rebalancing cellular redox, but also showed that this is a effective multi-effect therapeutic strategy against neurodegeneration.

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Enhanced Nrf2 up‐regulation by extracellular basic pH in a human skin equivalent system

Cited by 6 publications

References 26 publications

Prioritizing Nrf2/HO-1-Mediated Intrinsic Antioxidant Upregulation: The Foremost Neuroprotective Mechanism of Melittin in a Scopolamine-Induced Animal Model of Neural Stress, Preceding Anti- Inflammatory Effects

Prioritizing Nrf2/HO-1-Mediated Intrinsic Antioxidant Upregulation: The Foremost Neuroprotective Mechanism of Melittin in a Scopolamine-Induced Animal Model of Neural Stress, Preceding Anti- Inflammatory Effects

Effects of the Higenamine, a Potent Compound from Aconitum, on UVB-Induced Photoaging in Hairless Mice

Melittin - A Main Component of Bee Venom: A Promising Therapeutic Agent for Neuroprotection through Nrf2/HO-1 Pathway Activation

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