Autophagy in Triptolide-Mediated Cytotoxicity in Hepatic Cells.

Triptolide is a major active ingredient isolated from the traditional Chinese herb Tripterygium wilfordii Hook F. However, its use in clinical practice is limited due to its severe hepatotoxicity. Autophagy, a highly conserved intracellular process, is essential for maintaining cytoplasmic homeostasis. Considering that abnormalities in autophagy are closely associated with drug-mediated hepatotoxicity, we applied human normal liver HL7702 cells to elucidate the roles of autophagy in triptolide-induced hepatotoxicity. Our study revealed that triptolide was cytotoxic to HL7702 cells. It markedly increased autophagosome formation and expression of autophagy-related proteins, namely Beclin1 and microtubule-associated protein 1 light chain 3II, and induced oxidative stress. These proautophagic effects were counteracted by pretreatment with N-acetylcysteine, a reactive oxygen species scavenger. Moreover, the pharmacological suppression of autophagy further exacerbated triptolide-elicited decrease in cell viability, increase in lactate dehydrogenase leakage, and activation of apoptosis proteases (caspase 3 and caspase 9). Our findings suggest that triptolide-induced oxidative stress consequently enhances autophagic activity, and autophagy is a cytoprotective mechanism against triptolide-induced cytotoxicity in HL7702 cells.

[Protective effects of hydroxysafflower yellow A on pulmonary fibrosis in mice].

OBJECTIVE: To investigate the effect of hydroxysafflower yellow A (HSYA) on pulmonary fibrosis induced by bleomycin in mice and transforming growth factor ß 1(TGF-ß1) /Smad signal transduction pathway regulation. METHODS: The pulmonary fibrosis model was prepared by intranasal injection of bleomycin 50 µl (15 mg/kg). ICR mice were randomly divided into control group, model group, HSYA group(6 mg/kg) and dexamethasone (Dex) group(3 mg/kg), with 15 mice in each group. From the next day of modeling, HSYA and Dex groups were intraperitoneally injected with corresponding drugs, while the control group and model group were intraperitoneally injected with the same volume of normal saline, once a day, for 28 consecutive days. After 4 weeks, the mice were sacrificed and the lungs were collected. HE and Masson staining were used to observe the pathological damage of lung tissue; Immunohistochemistry, RT-qPCR and Western blot were used to detect the expressions of TGF-ß1/Smad signaling pathway in lung tissues. RESULTS: Compared with the control group, the model group showed severe alveolitis and pulmonary fibrosis. The mRNA and protein expressions of TGF-ß1 and Smad3 in lung tissues were increased significantly (P＜0.01), while the mRNA and protein expressions of Smad7 were decreased significantly (P＜0.01). Compared with the model group, the degree of alveolitis and pulmonary fibrosis in the HSYA and Dex groups was reduced significantly. The mRNA and protein expressions of TGF-ß1 and Smad3 in lung tissues of HSYA and Dex groups were decreased significantly (P＜0.01), while the mRNA and protein expressions of Smad7 were increased significantly(P＜0.01). CONCLUSION: HSYA can alleviate the pathogenesis of pulmonary fibrosis, and its mechanism may be related to the regulation of TGF-ß1/Smad signaling pathway.

Triptolide, A Potential Autophagy Modulator.

As a major active component extracted from traditional Chinese herb Tripterygium wilfordii Hook F, triptolide exhibits multiple pharmacological effects. Autophagy is an evolutionary conserved intracellular catabolic process involved in cytoplasmic materials degradation. Autophagic dysfunction contributes to the pathologies of many human diseases, which makes it a promising therapeutic target. Recent studies have shown that triptolide exerts neuroprotection, anti-tumor activities, organ toxicity, and podocyte protection by modulating autophagy. This article highlights the current information on triptolide-modulated autophagy, analyzes the possible pathways involved, and describes the crosstalk between autophagy and apoptosis modulated by triptolide, in hope of providing implications for the roles of autophagy in pharmacological effects of triptolide and expanding its novel usage as an autophagy modulator.