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Zn-Based Multi-Active Framework Nanoparticles TSA-CAN-Zn Inhibit Skin Glycation via Dual Blockade of HMGB1/RAGE and
Cheng Yao1,2, Heqi Wang3, Jingxia Han3
1Cheermore Cosmetic Dermatology Laboratory, Shanghai, China.
Abstract:
Receptor for advanced glycation end products (RAGE) plays an important role in skin glycation damage. High-mobility group 1B protein (HMGB1) and advanced glycation end products (AGEs) are key RAGE ligands. Simultaneous inhibition of HMGB1/RAGE and AGEs/RAGE pathways maybe an effective strategy to alleviate glycation induced skin damage. In this work, Theasinensin A (TSA) is identified as the active molecule inhibiting HMGB1-RAGE interaction through molecular docking. To simultaneously suppress HMGB1/RAGE and AGEs/RAGE pathways, Zn-based multi-active framework nanoparticles TSA-CAN-Zn are designed, which contain TSA and the active molecule L-carnosine (CAN) that inhibits AGEs production. In vitro studies demonstrated that TSA-CAN-Zn have radical scavenging activity and AGEs formation inhibition activity. TSA-CAN-Zn can not only inhibit ROS accumulation, cell apoptosis, and inflammatory factors production induced by glycation in HaCaT cells but also enhanced the lysosomal degradation of AGEs. TSA-CAN-Zn also mitigated the damage caused by glycation in mouse skin glycation model. Single-cell RNA sequencing results revealed the impact of TSA-CAN-Zn on different cell types of skin tissue, especially the basal cells of the epidermal layer and inflammation-related macrophages. And pathway analysis revealed that TSA-CAN-Zn mainly influences the downstream pathways of RAGE. Collectively, TSA-CAN-Zn is a promising therapeutic candidate for ameliorating glycation-induced skin damage.
Insights
This study introduces TSA-CAN-Zn nanoparticles to combat skin damage from advanced glycation end products (AGEs). These nanoparticles inhibit key pathways, reducing inflammation and AGEs accumulation for healthier skin.
Area of Science:
- Biochemistry
- Dermatology
- Nanotechnology
Background:
- Receptor for advanced glycation end products (RAGE) is crucial in skin damage caused by glycation.
- High-mobility group 1B protein (HMGB1) and advanced glycation end products (AGEs) are primary RAGE ligands.
- Simultaneously blocking HMGB1/RAGE and AGEs/RAGE pathways offers a strategy to reduce glycation-induced skin damage.
Purpose of the Study:
- To design and evaluate Zn-based nanoparticles (TSA-CAN-Zn) for simultaneous inhibition of HMGB1/RAGE and AGEs/RAGE pathways.
- To investigate the therapeutic potential of TSA-CAN-Zn in mitigating glycation-induced skin damage.
- To elucidate the molecular mechanisms underlying TSA-CAN-Zn's effects on skin cells and pathways.
Main Methods:
- Molecular docking identified Theasinensin A (TSA) as an inhibitor of HMGB1-RAGE interaction.
- TSA-CAN-Zn nanoparticles were synthesized, incorporating TSA and L-carnosine (CAN).
- In vitro assays (HaCaT cells, mouse skin models) and single-cell RNA sequencing were employed to assess efficacy and mechanisms.
Main Results:
- TSA-CAN-Zn exhibited radical scavenging and AGEs formation inhibition.
- The nanoparticles reduced glycation-induced ROS, apoptosis, and inflammation in HaCaT cells.
- TSA-CAN-Zn enhanced lysosomal AGEs degradation and improved skin damage in a mouse model, primarily affecting RAGE downstream pathways.
Conclusions:
- TSA-CAN-Zn nanoparticles effectively inhibit both HMGB1/RAGE and AGEs/RAGE pathways.
- These nanoparticles demonstrate therapeutic potential for ameliorating glycation-induced skin damage.
- TSA-CAN-Zn represents a promising candidate for treating skin aging and glycation-related conditions.
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