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Jiabin Wang,1,2,* Zhonghang Xu,3,* Xiaoqing Hu,1 Yimeng Yang,1,2 Jing Su,1 Yanan Liu,1 Li Zhou,4 Jianchun Qin,5 Dawei Zhang,6 Huimei Yu1,6 1Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, People’s Republic of China; 2Department of Microbiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, People’s Republic of China; 3Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital, Jilin University, Changchun 130033, People’s Republic of China; 4Department of Obstetrics & Gynecology, The First Hospital of Jilin University, Changchun 130021, People’s Republic of China; 5College of Plant Sciences, Jilin University, Changchun, Jilin 130062, People’s Republic of China; 6Center of Animal Experiment, College of Basic Medical Sciences, Jilin University, Changchun 130021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dawei Zhang; Huimei YuCollege of Basic Medical Sciences, Jilin University, Changchun 130021, People’s Republic of ChinaEmail 13019225999@126.com; yuhuimei@jlu.edu.cnBackground: Natural compounds extracted from plants have been reported to have antitumor activity. A fungal metabolite from Phomopsis, identified as epoxycytochalasin H and isolated from the flowering plant Polygonatum sibiricum, was found to have significant antitumor activity. In this study, we report the antitumor effects and mechanism of action of epoxycytochalasin H in the ovarian cancer cell line A2780. Our data suggest that epoxycytochalasin H markedly reduces cell proliferation and induces apoptosis in ovarian cancer cells.Materials and Methods: The viability, apoptosis and colony formation of A2780 cells, treated with epoxycytochalasin H, were detected by MTT assay, nuclear staining, flow cytometry, and clone formation assay. MitoROS and mitochondrial membrane potentials were detected by MitoSOX staining and flow cytometry. The expression of proteins associated with apoptosis, autophagy, and endoplasmic reticulum stress, in A2780 cells treated with epoxycytochalasin H, was detected by Western blot. Effects of mitophagy were detected in Parkin-overexpressing 293T cells.Results: Our data suggested that epoxycytochalasin H could strongly reduce cell proliferation and induce apoptosis in ovarian cancer cell line A2780. Epoxycytochalasin H induced apoptosis through mitochondrial injury, mitophagy, and endoplasmic reticulum stress. Specifically, epoxycytochalasin H increased ROS level in cells, and in mitochondria, it decreased mitochondrial membrane potential, caused mitochondrial injury, activated macroautophagy and mitophagy, and subsequently induced apoptosis via the mitochondrial pathway. Additionally, it was discovered that epoxycytochalasin H could induce apoptosis more significantly in 293T cells overexpressing Parkin than in the parental cells. Thus, the mitophagy activated by epoxycytochalasin H could promote apoptosis. In addition, epoxycytochalasin H mediated endoplasmic reticulum stress-related apoptosis.Conclusion: Epoxycytochalasin H could promote apoptosis of human ovarian cancer A2780 cells by activating mitochondrial and endoplasmic reticulum stress-related apoptotic pathways.Keywords: natural compound, human ovarian cancer, apoptosis, mitochondrial damage, endoplasmic reticulum stress

Based on the results acquired in Part I of this paper, analysis is made of the theoretical mechanism of thermal forcing multiple equilibrium states (MES) and their stability. The results are as follows: 1) nonlinear effect and external forcing are determinative factors for MES formation; 2) under proper “environmental conditions” the forcing can excite stable MES, particularly three types of solutions, two of which, with larger amplitude of resonance, are not sensitive to the change in the forcing intensity; while the other, i. e. the one of small amplitude, dependent significantly on it; 3) in general, the domain of parameter values for the MES existence increases, but the stability decreases, with increasing thermal forcing; 4) steady thermal forced waves are always unstable for the most part; 5) thermal driving and orographic effect act equally as dynamical triggers; 6) friction has significant influence upon the behavior of MES solutions. Analysis shows that the changes in the “environmental parameters”, such as the alteration of the shear of a basic current and intensity of the forcing, induce the transition between different equilibria.