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Background: Periplogenin (PPG), a natural compound isolated from traditional Chinese herb Cortex Periplocae, has been reported to possess anti-inflammatory and anti-cancer properties. Objective: The present study aims to investigate the antitumor effects of PPG and the underlying mechanism in human colorectal cancer cells. Methods: The inhibition of cell growth in vitro was assessed by MTT assay. The induction of apoptosis and the ROS production induced by PPG was investigated by flow cytometry analysis. Western blotting was applied to measure the protein expression. Small interference RNA (siRNA) and a specific pharmacological inhibitor were used to knock down or inhibit the expression of related genes. Results: PPG was able to cause the production of ROS, inhibit the cancer cell growth and induce apoptosis. Nacetylcysteine was able to inhibit ROS production and apoptosis. PPG up-regulated the protein levels of BIP, peIF2α and CHOP as well as IRE1α and p-JNK, and down-regulated the protein level of p-ASK1, all of which were reversed by N-acetylcysteine. Importantly, knockdown of CHOP or JNK protein level attenuated the PPGelicited apoptosis. Conclusion: PPG-induced apoptosis was regulated by ROS-mediated BIP/eIF2α/CHOP and BIP/ASK1/JNK signaling pathways in colon cancer cells, suggesting that PPG is a promising therapeutic agent for the treatment of human colon cancer.

Background/Aims: Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Levistolide A (LA), a natural compound isolated from the traditional Chinese herb Ligusticum chuanxiong Hort, is used for treating cancer. In this study, we investigated the anticancer effect of LA in HCT116 and its isogenic p53-/- colon cancer cells, as well as the underlying mechanisms. Methods: MTT assay was used to evaluate the effect of LA on the viability of cancer cells. Apoptosis and reactive oxygen species (ROS) production by the cells were determined by flow cytometry. Protein expression was detected by western blotting. Results: The results showed that LA inhibited viability and caused apoptosis of both wild-type and p53-/- HCT116 cells. LA was able to trigger production of ROS and endoplasmic reticulum (ER) stress. Inhibition of ROS using N-acetylcysteine abrogated LA-induced ER stress and apoptosis, as well as the reduction in cancer cell viability. Conclusion: Our results indicate that LA causes apoptosis of colon cancer cells via ROS-mediated ER stress pathway. It will be interesting to develop the natural compound for chemotherapy of cancers such as CRC.

Circular RNAs (circRNAs) are a new kind of endogenous non-coding RNAs, which have been discovered continuously. More and more studies have shown that circRNAs are related to the occurrence and development of human diseases. Identification of circRNAs associated with diseases can contribute to understand the pathogenesis, diagnosis and treatment of diseases. However, experimental methods of circRNA prediction remain expensive and time-consuming. Therefore, it is urgent to propose novel computational methods for the prediction of circRNA-disease associations. In this study, we develop a computational method called LLCDC that integrates the known circRNA-disease associations, circRNA semantic similarity network, disease semantic similarity network, reconstructed circRNA similarity network, and reconstructed disease similarity network to predict circRNAs related to human diseases. Specifically, the reconstructed similarity networks are obtained by using Locality-Constrained Linear Coding (LLC) on the known association matrix, cosine similarities of circRNAs and diseases. Then, the label propagation method is applied to the similarity networks, and four relevant score matrices are respectively obtained. Finally, we use 5-fold cross validation (5-fold CV) to evaluate the performance of LLCDC, and the AUC value of the method is 0.9177, indicating that our method performs better than the other three methods. In addition, case studies on gastric cancer, breast cancer and papillary thyroid carcinoma further verify the reliability of our method in predicting disease-associated circRNAs.

Accumulating biological experiments have shown that circRNAs are closely related to the occurrence and development of many complex human diseases. During recent years, the associations of circRNA with disease have caused more and more researchers to pay attention and to analyze their correlation mechanisms. However, experimental methods for determining the associations of circRNA with a particular disease are still expensive, difficult, and time consuming. Moreover, the available databases related to circRNA-disease correlations have only recently been updated, and only a few computational methods are constructed to predict potential circRNA-disease correlations. Taking into account the limitations of experimental studies, we develop a novel computational method, named IBNPKATZ, for predicting potential circRNA-disease associations, which integrates the bipartite network projection algorithm and KATZ measure. This model is based on the known circRNA-disease associations, combining circRNA similarity and disease similarity. Specifically, the circRNA similarity is derived from the average of the semantic similarity and the Gaussian interaction profile (GIP) kernel similarity of circRNA. Similarly, disease similarity is the mean of the semantic similarity and the GIP kernel similarity of disease. Furthermore, it is semi-supervised and does not require negative samples. Finally, IBNPKATZ achieves reliable AUC of 0.9352 in the leave-one-out cross validation, and case studies show that the circRNA-disease correlations predicted by our method can be successfully demonstrated by relevant experiments. The IBNPKATZ is expected to be a useful biomedical research tool for predicting potential circRNA-disease associations.

Pompe disease is due to a deficiency in acid-α-glucosidase (GAA) and results in debilitating skeletal muscle wasting, characterized by the accumulation of glycogen and autophagic vesicles. Given the role of lysosomes as a platform for mTORC1 activation, we examined mTORC1 activity in models of Pompe disease. GAA-knockdown C2C12 myoblasts and GAA-deficient human skin fibroblasts of infantile Pompe patients were found to have decreased mTORC1 activation. Treatment with the cell-permeable leucine analog l-leucyl-l-leucine methyl ester restored mTORC1 activation. In vivo, Pompe mice also displayed reduced basal and leucine-stimulated mTORC1 activation in skeletal muscle, whereas treatment with a combination of insulin and leucine normalized mTORC1 activation. Chronic leucine feeding restored basal and leucine-stimulated mTORC1 activation, while partially protecting Pompe mice from developing kyphosis and the decline in muscle mass. Leucine-treated Pompe mice showed increased spontaneous activity and running capacity, with reduced muscle protein breakdown and glycogen accumulation. Together, these data demonstrate that GAA deficiency results in reduced mTORC1 activation that is partly responsible for the skeletal muscle wasting phenotype. Moreover, mTORC1 stimulation by dietary leucine supplementation prevented some of the detrimental skeletal muscle dysfunction that occurs in the Pompe disease mouse model.