Table 1.

The regulations of rhein on inflammatory signaling pathways and cellular processes

Signaling pathway	Abbreviations	Action mechanisms	References
Nuclear transcription factor-kB signaling pathway	NF-kB	Rhein inhibits NF-κB activation and suppresses the transcription of downstream genes and inhibits NO and IL-6 levels by inhibiting IKKβ in LPS-activated macrophages. It also elevates the activity of Caspase-1 by inhibiting intracellular IKKβ, thereby increasing the release of IL-1β and HMGB1	[35]
		Rhein inhibits the degradation of the inhibitor of nuclear factor kB-α (IkBα) and regulates the translocation of the protein p65	[36]
Mitogen-activated protein kinase signaling pathway	MAPK	Rhein can regulate multiple sites of MAPK signaling pathways, and its targets are mainly involved in three signaling cascades, including ERK1/2, JNK, and p38 MAPK	[39]
Vascular endothelial growth factor signaling pathway	VEGF	Rhein can down regulate the expression of VEGFA and receptor KDR(VEGFR-2) to inhibit angiogenesis and cell migration	[41]
		In the downstream of VEGF signaling pathway, rhein inhibits Hsp90α activity to induce the degradation of its client protein COX-2 and to promote the production of PGI2	[42]
Peroxisome proliferators-activated receptors signaling pathway	PPARs	Rhein increases the level of PPARγ in a dose-dependent manner, which can be explained by the fact that the inhibition of TNF-α mediated by rhein leads to the increasing of PPARγ and, consequently, inhibits the release of inflammatory mediators	[43]
Cellular processes		Rhein inhibits ATP-induced cytosolic calcium concentration ([Ca(2 +)]c) elevation and pore formation of the plasma membrane in a dose-dependent manner. It also offsets macrophage phagocytosis and suppresses the production of ROS	[44]