Glaucocalyxin A alleviates LPS-mediated septic shock and inflammation via inhibiting NLRP3 inflammasome activation.

Glaucocalyxin A (GLA) is a bioactive ent-kauranoid diterpenoid derived from the herbal medicine, Rabdosia japonica var. glaucocalyx, and it has been reported to possess marked anti-inflammatory properties. However, the underlying mechanisms are not fully understood. Here, we reported that GLA dramatically inhibited canonical and non-canonical NLRP3 inflammasome activation induced by multiple agonists. In addition, GLA also blocked NLRC4 inflammasome activation but had no effect on AIM2 inflammasome. Furthermore, we found that GLA inhibited NLRP3 or NLRC4 agonists-induced ASC oligomerization, which is an upstream event of the inflammasomes assembly. Most importantly, administration of GLA significantly reduced lipopolysaccharide (LPS)-induced mortality in septic-shock mouse model. Additionally, GLA dose-dependently inhibited the production of interleukin (IL)-1ß, but had no effect on NLRP3-independent TNF-α production induced by LPS in vivo. In conclusion, our study suggests that GLA alleviates LPS-induced septic shock and inflammation via inhibiting NLRP3 inflammasome activation and provides a promising candidate drug for the treatment of NLRP3-driven diseases.

Oridonin inhibits IL-1ß-induced inflammation in human osteoarthritis chondrocytes by activating PPAR-γ.

Osteoarthritis (OA), a progressive disease of the joints, affects millions of people worldwide. In the present study, we investigated the effects of oridonin, a diterpenoid isolated from Rabdosia rubescens, on IL-1ß-induced inflammation using human osteoarthritis chondrocytes. The results showed that oridonin significantly suppressed IL-1ß-induced MMP1, MMP3, and MMP13 production. IL-1ß-induced NO and PGE2 production, as well as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression were also attenuated by oridonin. Western blot analysis demonstrated IL-1ß-induced NF-κB activation was reduced by oridonin. Furthermore, the expression of PPAR-γ was increased by oridonin in a concentration-dependent manner. PPAR-γ antagonist could reverse the anti-inflammatory activity of oridonin. The results suggested that oridonin could be a candidate agent for the treatment of OA.

Oridonin protects against the inflammatory response in diabetic nephropathy by inhibiting the TLR4/p38-MAPK and TLR4/NF-κB signaling pathways.

Inflammation plays a pivotal role in the development and progression of diabetic nephropathy (DN). Oridonin (Ori), a component isolated from Rabdosia rubescens, possesses remarkable anti-inflammatory, immunoregulatory and antitumor properties. However, the renoprotective effects of Ori and the underlying molecular mechanisms have not been explored in DN. In this study, we aimed to investigate the protective effects and potential mechanisms responsible for the anti-inflammatory effects of Ori in diabetes-induced renal injury in vivo and in vitro. Our results showed that Ori significantly attenuated diabetes-induced renal injury and markedly decreased urinary protein excretion levels, serum creatinine concentrations and blood urea nitrogen concentrations in rats. Ori also significantly alleviated infiltration of inflammatory cells (cluster of differentiation (CD)68) in kidney tissues and reduced the levels of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1ß and monocyte chemotactic protein 1 (MCP-1), both in vivo and in vitro. TLR4 is a principal mediator of innate immune and inflammatory responses and participates in the development of DN. Our molecular studies indicated that Ori administration significantly down-regulated TLR4 overexpression in DN. Additional studies were conducted to investigate the effect of Ori on the p38-mitogen-activated protein kinase (p38-MAPK) and nuclear factor (NF)-κB pathways. The results showed that Ori inhibited IκBα, p65, and p38 phosphorylation, as well as NF-κB DNA-binding activity. In conclusion, these results demonstrated that Ori exerts protective effects in diabetes-induced renal injury in vivo and in vitro. These effects may be ascribed to its anti-inflammatory and modulatory effects on the TLR4/p38-MAPK and TLR4/NF-κB signaling pathways.

Diterpenos en infl amación: las Labiadas como paradigma / Diterpenes in inflammation: Labiatae as paradigm

Esta revisión trata esencialmente sobre los diterpenos antiinflamatorios procedentes de especies de Labiadas. Se estudian las publicaciones posteriores a 2002 referentes a los cuatro tipos estructurales más importantes en esa familia: labdano, abietano, pimarano y kaurano. Además se incluyen algunas moléculas interesantes obtenidas de especies de diferente origen taxonómico. De entre los mecanismos implicados destaca la inhibición del metabolismo del ácido araquidónico a través de ciclooxigenasas y lipoxigenasas, así como el freno a la producción de NO o citocinas. Adicionalmente se ha descrito para algunos principios el aumento de la expresión de hemo-oxigenasa 1. Algunos de los géneros botánicos mejor representados son Lavandula, Isodon, Rosmarinus y Sideritis (AU)

This review is devoted to the antiinflammatory diterpenoids obtained from species of Labiatae. Basically, we study the post-2002 publications concerning the four major structural types in the family: labdane, abietane, pimarane and kaurane. Certain interesting diterpenes derived from plants of different taxonomic origin are also reported. Among the mechanisms involved in the pharmacological effect, we should highlight the inhibition of arachidonic acid metabolism through cyclo-oxygenases and lipoxygenases, and the decrease in the production of NO or cytokines. Additionally, some principles are described as enhancers of the expression of heme oxygenase 1. Some of the botanical genera best represented are Lavandula, Isodon, Rosmarinus or Sideritis (AU)