Cynanchi atrati and Its Phenolic Constituent Sinapic Acid Target Regulator of Calcineurin 1 (RCAN1) to Control Skin Inflammation

Abstract

Atopic dermatitis (AD) is a common inflammatory skin disorder, and numerous pharmacological approaches are employed to reduce symptoms. Natural products of plant-derived materials have been accepted as complementary therapy for the treatment of a wide range of inflammatory diseases. Cynanchi atrati (CA) is an oriental medicinal herb used in the treatment of acute urinary infection, febrile diseases, and laryngopharyngitis. However, the role of CA root extract in skin inflammation such as AD has not been explored yet. In this study, we examined the possible effect of CA root extract on skin inflammation and evaluated the underlying signaling mechanism using in vitro and in vivo modeling systems. Raw264.7 macrophages were used for in vitro experiments, and an oxazolone-induced AD mouse model was used to evaluate in vivo effects. CA extract significantly inhibited the expression levels of lipopolysaccharide (LPS)-induced pro-inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-1β (IL-1β) in RAW264.7 macrophages. The CA root extract mediated suppression of pro-inflammatory cytokine expression and was associated with the decreased nuclear factor kappa B (NF-κB) gene transcriptional activation. Moreover, CA root extract attenuated the in vivo expression of IL-6 and tumor necrosis factor-α (TNF-α) and ear swelling in the AD mouse models. We also observed that the inhibitory effect of CA root extract on skin inflammation was accompanied by the upregulation of calcineurin 1 (RCAN1) expression, which functions in the inflammatory pathways by suppressing NF-κB signaling. We consistently observed that the immunosuppressive effect of CA root extract in AD was significantly perturbed in the RCAN1 knockout mice. In addition, we isolated a phenolic acid compound, sinapic acid (SA), from the CA root extract and found that SA consistently exerted an immunosuppressive effect in RAW264.7 macrophages by inducing RCAN1 expression. Our results provide the first evidence that CA root extract and its phenolic acid constituent, SA, modulate NF-κB signaling pathways by inducing RCAN1 expression in the skin inflammation process. Thus, we suggest that CA root extract has a therapeutic value for the treatment of AD by targeting endogenous immune regulators.

N-Acetylcysteine, an ROS Inhibitor, Alleviates the Pathophysiology of Hyperthyroidism-Induced Cardiomyopathy via the ROS/Ca2+ Pathway

“…Combining these results, the animal and cell model simulated the process of heart disease caused by hyperthyroidism, which could be applied to investigate the molecular mechanism. As shown in Figure 11 , an increase in Cav1.3 induces an increase in the cytosolic Ca 2+ concentration of H9c2 cells, thereby increasing the activation of Ca 2+ -dependent signalling, Rcan1, calcineurin, and calpain, which subsequently upregulates the gene expression of hypertrophy markers and upregulates the gene expression of inflammatory cytokines by activating the NF-κB/p65-dependent signalling pathway [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ], causing cardiac hypertrophy and inflammation. Meanwhile, the elevation of Gal-3, RhoA, and Rock further increased ROS [ 27 , 28 , 29 , 30 , 31 , 32 ], subsequently regulating the Bcl-2/caspase-3-dependent apoptotic signalling pathway [ 33 , 34 ], thereby leading to cell rupture and fibrosis.…”

Cynanoside F Controls Skin Inflammation by Suppressing Mitogen-Activated Protein Kinase Activation

“…At present, more than 400 compounds have been isolated from diverse members of the Asclepiadaceae family, including steroids, acetophenones, saponins, alkaloids, flavonoids, terpenes, polysaccharides, and other compounds [ 18 , 19 , 30 ]. Pharmacological research has revealed that Cynanchum atratum , including its isolated components, possesses anti-inflammatory, cytotoxic, antitumor, and even acetylcholinesterase inhibitory properties [ 14 , 17 ]. Although Cynanchum atratum has been shown to have immunosuppressive effects, it is uncertain whether CF has comparable effects and what its intrinsic molecular mechanisms are.…”

“…We found that CF markedly suppressed LPS-induced phosphorylation of MAPKs, such as p38, JNK, and ERK, and subsequent AP-1 transcriptional activation in a dose-dependent manner. In our previous study, crude extracts of Cynanchum atratum and one of the isolated compounds, sinapic acid, exerted an anti-inflammatory function by inhibiting NF-κB signaling [ 17 ]. In addition to this report, our current study suggests that CF suppresses LPS-induced inflammatory signaling by inhibiting the MAPK/AP-1 signaling axis.…”

“…It belongs to the Asclepiadaceae family and has traditionally been used to treat fever, urinary tract infections, edema, and rheumatic arthralgia [ 14 , 15 ]. Pharmacological investigations have reported that Cynanchum atratum has antitumor, anti-amnesic, and anti-acetylcholinesterase activities as well as anti-inflammatory activities [ 15 , 16 , 17 ].…”

Changes in miroRNA‐103 expression in wound margin tissue are related to wound healing of diabetes foot ulcers

“…Knockout of the RCAN1 gene can aggravate proteinuria and podocyte injury in mice with adriamycinnephropathy 29 . Recent studies have revealed that RCAN1 can regulate the NF‐κB signalling pathway, thereby participating in the process of skin inflammation 30 . The up‐regulated expression of RCAN1 in vascular endothelial cells can promote the integrity of the vascular endothelial barrier and reduce vascular permeability 31 .…”