The skin serves as the primary defensive barrier of the human body against external stimuli and damage. Keratinocytes, which are the predominant cell type in the human epidermis, undergo a differentiation process that is crucial for the formation of the skin barrier. Myricetin, a dietary flavonoid present in various fruits and vegetables, is known to play a significant role in maintaining intestinal barrier function; however, its impact on the skin barrier remains inadequately understood. Consequently, this study investigates the effects of myricetin on the differentiation of epidermal keratinocytes and the integrity of the skin barrier. Differentiation of primary mouse keratinocytes was induced using 1.8 mM CaCl2. tudy demonstrated that myricetin effectively suppresses cell proliferation and induces both cell cycle arrest and calcium ion (Ca2+) influx, without influencing apoptosis. Concurrently, myricetin enhances the expression of differentiation markers, including K10, TGase1, Filaggrin, and Involucrin, and facilitates the formation of tight junctions. Upon examining the underlying mechanisms, we discovered that myricetin activates the TRPV4 channel, and the promotion of keratinocyte differentiation by myricetin is contingent upon the activation of this channel. In summary, these findings suggested that myricetin could promote keratinocytes differentiation and have well-established skin barrier protective function.
Remifentanil-induced hyperalgesia (RIH) represents a significant clinical challenge due to the widespread use of opioids in pain management. However, the molecular and cellular mechanisms underlying RIH remain elusive. This study aimed to unravel the role of spinal cord microglia, focusing on the Nrf2/HO-1 signaling pathway and TRPV4 channels in the development of RIH. We used both in vivo and in vitro models to investigate the activation state of spinal cord microglia, the expression of TRPV4 channels, and the modulation of the Nrf2/HO-1 pathway under remifentanil exposure. In addition, we evaluated the potential therapeutic effects of dexmedetomidine, a perioperative α2-adrenergic agonist, on RIH and its related molecular pathways. Our results revealed a prominent role of spinal cord microglia in RIH, demonstrating an apparent microglial M1 polarization and increased TRPV4 channel expression. A notable observation was the downregulation of the Nrf2/HO-1 pathway, which was associated with increased neuroinflammation and mechanical allodynia. By upregulating or overexpressing Nrf2, we confirmed its ability to inhibit TRPV4 and thereby attenuate RIH-associated mechanical allodynia, M1 polarization, and neuroinflammation. Encouragingly, dexmedetomidine demonstrated therapeutic potential by positively modulating the Nrf2-TRPV4 nexus, attenuating mechanical allodynia, and reducing microglial inflammation. Our research highlights the critical role of spinal cord microglia in RIH mediated by the Nrf2-TRPV4 axis. The ability of dexmedetomidine to modulate this axis suggests its potential as an adjunctive therapy to remifentanil in mitigating RIH. Further studies are imperative to explore the broader implications and practical applicability of our findings.
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