IL-36 family members are highly expressed in hyperproliferative keratinocytes and play an important role in the pathogenesis of skin diseases such as psoriasis. However, whether and how IL-36 cytokines are induced to promote wound healing remains unknown. Here we showed that skin injury increased the expression of IL-36γ to promote wound healing. Mechanistically, the expression of IL-36γ was induced by RNAs from damaged cells via the activation of toll-like receptor 3 (TLR3) and TIR-domain-containing adapter-inducing IFN-β (TRIF) followed by the induction of a zinc finger protein SLUG to abrogate the inhibitory effect of vitamin D receptor (VDR) on the promoter of IL-36γ gene. IL-36γ acted back on keratinocytes to induce REG3A, which regulated keratinocyte proliferation and differentiation, thus promoting wound re-epithelialization. These observations show that skin injury increases IL-36γ via the activation of TLR3-SLUG-VDR axis and that IL-36γ induces REG3A to promote wound healing. These findings also provide insights into pathways contributing to wound repair.
Agonist-dependent activation of G protein-coupled receptors induces diversified receptor cellular and signaling properties. Norepinephrine (NE) and epinephrine (Epi) are two endogenous ligands that activate adrenoceptor (AR) signals in a variety of physiological stress responses in animals. Here we use cardiomyocyte contraction rate response to analyze the endogenous  2 AR signaling induced by Epi or NE in cardiac tissue. The Epi-activated  2 AR induced a rapid contraction rate increase that peaked at 4 min after stimulation. In contrast, the NE-activated  2 AR induced a much slower contraction rate increase that peaked at 10 min after stimulation. Whereas both drugs activated  2 AR coupling to G s proteins, only Epi-activated receptors were capable of coupling to G i proteins. Subsequent studies showed that the Epi-activated  2 AR underwent a rapid phosphorylation by G protein-coupled receptor kinase 2 (GRK2) and subsequent dephosphorylation on serine residues 355 and 356, which was critical for sufficient receptor recycling and G i coupling. In contrast, the NE-activated  2 ARs underwent slow GRK2 phosphorylation, receptor internalization and recycling, and failed to couple to G i . Moreover, inhibiting  2 AR phosphorylation by ARK C terminus or dephosphorylation by okadaic acid prevented sufficient recycling and G i coupling. Together, our data revealed that distinct temporal phosphorylation of  2 AR on serine 355 and 356 by GRK2 plays a critical role for dictating receptor cellular events and signaling properties induced by Epi or NE in cardiomyocytes. This study not only helps us understand the endogenous agonist-dependent  2 AR signaling in animal heart but also offers an example of how G protein-coupled receptor signaling may be finely regulated by GRK in physiological settings.GPCRs 3 comprise the largest known family of cell-surface receptors and are fundamentally involved in mammalian physiology (1, 2). This receptor superfamily represents the largest single target for modern drug therapy. A growing body of evidence indicates that divergent efficacies of an activated GPCR are both agonist-and tissue-dependent (3-5), which presents a great challenge on clinical application when a specific receptor is targeted with drugs. Many of the drug-dependent effects have been attributed to the distinct receptor conformational changes induced by different ligands, leading to different subsequent cellular events and signaling properties (5, 6). Thus, there is great interest in elucidating the mechanisms underlying the drug-dependent cellular events in physiologically relevant contexts.Interestingly, ARs, a family of prototypical GPCRs, can be activated by two endogenous ligands NE and Epi. The receptors play critical roles in the regulation of cardiovascular (7) and pulmonary function (8), as well as other physiological processes. NE is primarily released from sympathetic nerve terminal on the innervated tissues, whereas Epi is primarily released from adrenal gland to the circulating plasma. The distinct ...
Oxidative stress and inflammatory response are well known to be involved in the pathogenesis of acute liver injury. This study was performed to examine the hepatoprotective effect of ginsenoside Rg1 (Rg1) against CCl -induced acute liver injury, and further to elucidate the involvement of Nrf2 signaling pathway in vivo and in vitro. Mice were orally administered Rg1 (15, 30, and 60 mg/kg) or sulforaphane (SFN) once daily for 1 week prior to 750 μL/kg CCl injection. The results showed that Rg1 markedly altered relative liver weights, promoted liver repair, increased the serum level of TP and decreased the serum levels of ALT, AST and ALP. Hepatic oxidative stress was inhibited by Rg1, as evidenced by the decrease in MDA, and increases in GSH, SOD, and CAT in the liver. Further research demonstrated that Rg1 suppressed liver inflammation response through repressing the expression levels of inflammation-related genes including TNF-α, IL-1β, IL-6, COX-2, and iNOS. In addition, Rg1 enhanced antioxidative stress and liver detoxification abilities by up-regulating Nrf2 and its target-genes such as GCLC, GCLM, HO-1, NQO1, Besp, Mrp2, Mrp3, Mrp4, and down-regulating Cyp2e1. However, the changes in Nrf2 target-genes, as well as ameliorative liver histology induced by Rg1 were abrogated by Nrf2 antagonist all-transretinoic acid in vivo and Nrf2 siRNA in vitro. Overall, the findings indicated that Rg1 might be an effective approach for the prevention against acute liver injury by activating Nrf2 signaling pathway.
Hepatic fibrosis is a pathological process that eventually leads to the development of cirrhosis and liver cancer by various types of chronic liver disease. To date, there is no standard treatment for the progression of liver fibrosis. This study aims to investigate the hepatoprotection of auraptene (AUR), a simple coumarin contained in the peels of citrus fruits such as grapefruit, against thioacetamide (TAA)-induced hepatic fibrosis in mice. The involvement of farnesoid X receptor (FXR) in the anti-fibrotic effect of AUR was further elucidated using in vivo and in vitro experiments. AUR was found to remarkably protect against liver injury induced by TAA in mice and maintain the homeostasis of bile acids via the regulation of FXR-target genes including Bsep, Mrp2, Ntcp, Cyp7a1 and Cyp8b1. Masson and Sirius red staining indicated a reduction of the collagen content in the liver of AUR treated mice. Furthermore, AUR inhibited the activation of hepatic stellate cells (HSCs) by down-regulating the expression of TGF-β1 and α-SMA and expressed anti-inflammatory effects by reducing the expression of NF-κB, TNF-α and IL-1β. However, the changes in these genes and protein as well as ameliorative liver histology induced by AUR were abrogated by FXR antagonist guggulsterone in vivo and FXR siRNA in vitro. Overall, AUR protects against TAA-induced hepatic fibrosis due to the reduction of toxic bile acids and inhibition of hepatic stellate cell (HSC) activation and inflammation, which were all in association with FXR activation. AUR might be efficacious for the prevention and treatment of hepatic fibrosis in mice.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.