Diterpenoid Lactones with Anti-Inflammatory Effects from the Aerial Parts of Andrographis paniculata.

Andrographis paniculata (AP) has been widely used in China for centuries to treat various diseases, and especially to treat inflammation. Diterpenoid lactones are the main anti-inflammatory components of AP. However, systematic chemical composition and biological activities, as well as key pharmacophores, of these diterpenoid lactones from AP have not yet been clearly understood. In this study, 17 diterpenoid lactones, including 2 new compounds, were identified by spectroscopic methods, and most of them attenuated the generation of TNF-α and IL-6 in LPS-induced RAW 274.7 cells examined by ELISA. Pharmacophores of diterpenoid lactones responsible for the anti-inflammatory activities were revealed based on the quantitative structure-activity relationship (QSAR) models. Moreover, new compounds (AP-1 and AP-4) exerted anti-inflammatory activity in LPS microinjection-induced zebrafish, which might be correlated with the inhibition of the translocation of NF-κB p65 from cytoplasm to nucleus. Our study provides guidelines for future structure modification and rational drug design of diterpenoid lactones with anti-inflammatory properties in medical chemistry.

Liang-Ge-San, a classic traditional Chinese medicine formula, protects against lipopolysaccharide-induced inflammation through cholinergic anti-inflammatory pathway.

Liang-Ge-San (LGS) is a classic formula in traditional Chinese medicine, which is widely used to treat acute lung injury (ALI), pharyngitis and amygdalitis in clinic. However, the underlying mechanisms remain poorly defined. In this study, we discovered that LGS exerted potent anti-inflammatory effects in lipopolysaccharide (LPS)-induced inflammation. We found that LGS significantly depressed the production of IL-6 and TNF-α in LPS-stimulated RAW 264.7 macrophage cells. The degradation and phosphorylation of IκBα and the nuclear translocation of NF-κB p65 were also inhibited. Moreover, LGS activated α7 nicotinic cholinergic receptor (α7nAchR). The blockage of α7nAchR by selective inhibitor methyllycaconitine (MLA) or α7nAchR siRNA attenuated the inhibitory effects of LGS on IκBα, NF-κB p65, IL-6 and TNF-α. Critically, LGS significantly inhibited inflammation in LPS-induced ALI rats through the activation of NF-κB signaling pathway. However, these protective effects could be counteracted by the treatment of MLA. Taken together, we first demonstrated anti-inflammatory effects of LGS both in vitro and in vivo through cholinergic anti-inflammatory pathway. The study provides a rationale for the clinical application of LGS as an anti-inflammatory agent and supports the critical role of cholinergic anti-inflammatory pathway in inflammation.

Giganteaside D induces ROS-mediated apoptosis in human hepatocellular carcinoma cells through the MAPK pathway.

PURPOSE: Every year, almost one million individuals are diagnosed with hepatocellular carcinoma (HCC) worldwide and more than 690,000 patients die of it. At present, most therapeutic anti-HCC agents are not effective, which is due to the appearance of chemo-resistance and/or toxic side effects. Therefore, it is imperative to find novel more effective anti-HCC agents. Here, we evaluated the effect of giganteaside D (GD), an oleanolic acid saponin from P. scabiosaefolia, on the growth and apoptosis of HCC cells. METHODS AND RESULTS: Using MTT and clonogenic assays, we found that GD exhibited a significant growth inhibitory effect on the HCC-derived cell lines HepG2 and Bel-7402. In addition, we found that GD induced mitochondria-mediated apoptosis in these HCC-derived cells, as indicated by a decreased mitochondrial potential, activation of Caspase-9 and Caspase-3, cleavage of PARP and release of Cytochrome C from the mitochondria. Besides, we found that GD stimulated the generation of reactive oxygen species (ROS) and that blockage of ROS attenuated the GD-induced mitochondria-mediated apoptosis. Additionally, we found that GD treatment led to a decrease in phosphorylated Erk (p-Erk) and triggered the generation of p-JNK, both components of the mitogen-activated protein kinase (MAPK) signaling pathway. Inhibition of Erk or JNK by specific inhibitors or siRNAs augmented or attenuated the cytotoxic and apoptotic effects of GD. CONCLUSIONS: From our results we conclude that GD can induce ROS-mediated apoptosis in HCC-derived cells through the MAPK pathway. This observation may open up avenues to explore the future use of GD as a HCC chemotherapeutic agent.