Yanping Yang

Molecular mechanisms of Polyphyllin I-induced apoptosis and reversal of the epithelial-mesenchymal transition in human osteosarcoma cells.

Osteosarcoma is a most common highly malignant bone tumor in children and adolescents. Polyphyllin I (PPI) is an ethanol extraction from Paris polyphylla Smith var.yunnanensis (Franch.) Hand.-Mazz, which belongs to antipyretic-detoxicate family and has been used as a natural medicine in the treatment of infectious disease and cancer in China for centuries. The proteasome activity inhibitory and anti-osteosarcoma effects of PPI have not been known. Here we found PPI exhibited a selective inhibitory effect on proteasomal chymotrypsin (CT)-like activity, both in purified human proteasome and in cultured osteosarcoma cellular proteasome, and caused an accumulation of ubiquitinated proteins. PPI also inhibited viability, proliferation, migration, and invasion of MG-63, Saos-2, and U-2 OS osteosarcoma cells and resulted in S phase arrest and apoptosis. Furthermore, we explored the molecular targets involved. Exposure of osteosarcoma cells to PPI caused an inactivation of the intrinsic nuclear factor κB (NF-κB) and activation of unfolded protein response (UPR)/endoplasmic reticulum (ER) stress signaling cascade in osteosarcoma cells, followed by down-regulation of anti-apoptotic proteins, with up-regulation of pro-apoptotic proteins. We also demonstrated down-regulation of c-Myc, Cyclin B1, Cyclin D1, and CDK1, which are involved in the cell cycle and growth. Finally, we identified down-regulation of Vimentin, Snail, Slug, and up-regulation of E-cadherin, which are integral proteins involved in epithelial-mesenchymal transition (EMT). Taken together, our data provide insights into the mechanism underlying the anticancer activity of PPI in human osteosarcoma cells.

Chinese Herbal Medicine for Myelosuppression Induced by Chemotherapy or Radiotherapy: A Systematic Review of Randomized Controlled Trials

Background. Myelosuppression is one of the major side effects of chemo- and radiotherapy in cancer patients and there are no effective interventions to prevent it currently. Chinese herbal medicine (CHM) may be helpful due to its multidrug targets. Objectives. This study was designed to evaluate effectiveness of CHM on preventing patients from experiencing myelosuppression by chemo- or radiotherapy. Search Methods. Randomized controlled trials (RCTs) were retrieved from seven different databases from the date of database creation to April 2014. We assessed all included studies using Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 and performed statistical analysis using RevMan 5.2.1. Results. Eight RCTs were included (818 patients). Pooled data showed that increase of white blood cells (WBCs) is higher with CHM plus chemotherapy/radiotherapy than with chemotherapy/radiotherapy only. Both CHM compared to placebo and CHM combined with chemotherapy/radiotherapy compared to chemotherapy/radiotherapy lacked significant differences in the peripheral platelets, red blood cells (RBCs), and hemoglobin changes. Conclusions. Our results demonstrated that CHM significantly protected peripheral blood WBCs from a decrease caused by chemotherapy or radiotherapy. There were no significant protective effects on peripheral RBCs, hemoglobin, or platelets, which may be related to low quality and small sample of included studies.

Polyphyllin I suppresses human osteosarcoma growth by inactivation of Wnt/β-catenin pathway in vitro and in vivo

Osteosarcoma is the most common primary bone cancer in children and adolescents. In spite of aggressive treatment, osteosarcoma has a high mortality rate with minimal improvements in survival over past few decades. Polyphyllin I (PPI), a component in the traditional Chinese medicinal herb Paris polyphylla Smith, has been shown to have anti-tumor properties. However, its mechanism as an anti-osteosarcoma agent has not been well elucidated. In this study, we found that PPI suppressed osteosarcoma cell viability, arrested cell cycle in G2/M phase, induced apoptosis and inhibited invasion and migration of osteosarcoma cells. Moreover, PPI significantly suppressed intratibial primary tumor growth in xenograft orthotopic mouse model without any obvious side effects. These therapeutic efficacies were associated with inactivation of Wnt/β-catenin pathway, as PPI treatment decreased the amount of p-GSK-3β, leading to down-regulated levels of active β-catenin. PPI induced inhibition of osteosarcoma cell viability was abolished upon addition of GSK-3β specific inhibitor, CHIR99021, while PPI induced inhibition of osteosarcoma cell viability and migration were potentiated by β-catenin silencing. These findings suggested that, in vitro and in vivo, PPI treatment inhibited osteosarcoma, at least in part, via the inactivation of Wnt/β-catenin pathway. Thus, PPI could serve a novel therapeutic option for osteosarcoma patients.

Cyclophosphamide causes osteoporosis in C57BL/6 male mice: suppressive effects of cyclophosphamide on osteoblastogenesis and osteoclastogenesis

The clinical evidence indicated that cyclophosphamide (CPD), one of the chemotherapy drugs, caused severe deteriorations in bones of cancer patients. However, the exact mechanisms by which CPD exerts effects on bone remodeling is not yet fully elucidated. Therefore, this study was performed to investigate the role and potential mechanism of CPD in osteoblastogenesis and osteoclastogenesis. Here it was found that CPD treatment (100mg/kg/day) for 7 days led to osteoporosis phenotype in male mice. CPD inhibited osteoblastogenesis as shown by decreasing the number and differentiation of bone mesenchymal stem cells (MSCs) and reducing the formation and activity of osteoblasts. Moreover, CPD suppressed the osteoclastogenesis mediated by receptor activator for nuclear factor-κ B ligand (RANKL) as shown by reducing the maturation and activity of osteoclasts. At the molecular level, CPD exerted inhibitory effect on the expression of components (Cyclin D1, β-catenin, Wnt 1, Wnt10b) of Wnt/β-catenin signaling pathway in MSCs and osteoblasts-specific factors (alkaline phosphatase, Runx2, and osteocalcin). CPD also down-regulated the expression of the components (tumor necrosis factor receptor-associated factor 6, nuclear factor of activated T-cells cytoplasm 1, c-Fos and NF-κB) of RANKL signaling pathway and the factors (matrix metalloproteinase 9, cathepsin K, tartrate-resistant acid phosphates and carbonic anhydrase II) for osteoclastic activity. Taken together, this study demonstrated that the short-term treatment of CPD induced osteoporosis in mice and the underlying mechanism might be attributed to its marked suppression on osteoblastogenesis and osteoclastogenesis, especially the effect of CPD on bone formation might play a dominant role in its detrimental effects on bone remodeling.

Matrine inhibits prostate cancer via activation of the unfolded protein response/endoplasmic reticulum stress signaling and reversal of epithelial to mesenchymal transition

Prostate cancer is the second most commonly diagnosed malignancy and the sixth global primary cause of malignancy-associated fatality. Increased invasiveness and motility in prostate cancer cells are associated with ubiquitin proteasome system-regulated epithelial to mesenchymal transition (EMT). Impairment of the endoplasmic reticulum (ER) causes ER stress due to the accumulation of unfolded proteins and altered cell survival. In the current study, the effect and mechanism of matrine on cell apoptosis, viability, migration and invasion of human prostate cancer cells in vivo and in vitro through the unfolded protein response (UPR)/ER stress pathway were investigated. Matrine inhibited proteasomal chymotrypsin-like (CT-like) activity in the prostate carcinoma cellular proteasome. Upregulated vimentin and N-cadherin and downregulated E-cadherin were also observed in vitro and in vivo. In vitro analyses showed that matrine repressed cell motility, viability and invasion, arrested the cell cycle at the G0/G1 phase and induced prostate cancer cell apoptosis. Furthermore, matrine activated the UPR/ER stress signaling cascade in prostate cancer cells and tumor tissues of xenograft-bearing nude mice. Results also demonstrated that the anti-apoptotic protein Bcl-2 was downregulated, the pro-apoptotic protein Bak was upregulated and the cell growth and cell cycle-related proteins c-Myc, Cyclin B1, Cyclin D1 and CDK1 were downregulated. Moreover, matrine inhibited tumor growth and Ki-67 expression in xenograft-bearing nude mice. To the best of our knowledge, the present study indicated for the first time that matrine exerted marked anticancer functions in human prostate carcinoma in vivo and in vitro through activation of the proteasomal CT-like activity inhibition mediated by the UPR/ER stress signaling pathway.

Down-Regulated microRNA-34a Expression as a Prognostic Marker for Poor Osteosarcoma in Mice: A Systematic Review and Meta-Analysis

Background: In children and adolescents, osteosarcomais the most common malignant bone tumor with a high mortality rate. New therapeutic strategies are urgent to be explored. Studies have proven that microRNAs (miRNAs) in malignant tumors often appear dysregulation, this provides a direction for exploring the new therapeutic strategies for cancers. The aim of this meta-analysis is to summarize and analyze whethermicroRNA-34a(miRNA-34a) could be a prognostic marker for osteosarcoma in mice. Methods: We searched PubMed, Web of Science, Embase, Wan Fang Database, China Knowledge Resource Integrated Database, VIP Database, and SinoMed since their initiation date to January 24, 2018. After screening based on inclusion and exclusion criteria, eight articles were included for the final analysis. Results: Our results showed that tumor volume and tumor weight were inhibited by restoring the down-regulated expression of miRNA-34a in the xenograft mouse models. Conclusions: Down-regulated miRNA-34a expression is a prognostic marker for poor osteosarcoma. We should be more committed to investigate the clinical significance of miRNA-34a in osteosarcoma patients.

Long non-coding RNAs for osteosarcoma in the mouse: a meta-analysis

Osteosarcoma, one of the most common primary bone malignances, is a leading cause of cancer death among children and adolescents. Recently, growing studies have found that long non-coding RNAs (lncRNAs) can interfere with the expression of various genes, and participate in the occurrence and development of malignancies. The purpose of this study is to evaluate the potential functions of lncRNAs as diagnostic biomarkers and therapeutic targets for osteosarcoma in mice, thus to direct the strict design for the future preclinical experiments and clinical trials. We systematically searched PubMed, Web of Science, Embase, China Knowledge Resource Integrated Database, VIP, Chinese BioMedical and Wan Fang Database from their initiation date to June 20, 2017. Two researchers independently screened the literatures and withdrew the data, which used the tumor volume and tumor weight as the outcome measures. A total of 10 studies were included, and the results of this meta-analysis revealed that lncRNAs could serve as the diagnostic biomarkers and therapeutic targets for osteosarcoma; and progression of osteosarcoma in mice could be inhibited via rescuing the abnormally expressed lncRNAs. It is necessary to carry out more rigorous basic experiments before lncRNAs can be further investigated in the clinical trials and used in future clinical practices.

MicroRNAs for osteosarcoma in the mouse: a meta-analysis.

Osteosarcoma (OS) is the most common primary malignant bone carcinoma with high morbidity that happens mainly in children and young adults. As the key components of gene-regulatory networks, microRNAs (miRNAs) control many critical pathophysiological processes, including initiation and progression of cancers. The objective of this study is to summarize and evaluate the potential of miRNAs as targets for prevention and treatment of OS in mouse models, and to explore the methodological quality of current studies. We searched PubMed, Web of Science, Embase, Wan Fang Database, VIP Database, China Knowledge Resource Integrated Database, and Chinese BioMedical since their beginning date to 10 May 2016. Two reviewers separately screened the controlled studies, which estimate the effects of miRNAs on osteosarcoma in mice. A pair-wise analysis was performed. Thirty six studies with enough randomization were selected and included in the meta-analysis. We found that blocking oncogenic or restoring decreased miRNAs in cancer cells could significantly suppress the progression of OS in vivo, as assessed by tumor volume and tumor weight. This meta-analysis suggests that miRNAs are potential therapeutic targets for OS and correction of the altered expression of miRNAs significantly suppresses the progression of OS in mouse models, however, the overall methodological quality of studies included here was low, and more animal studies with the rigourous design must be carried out before a miRNA-based treatment could be translated from animal studies to clinical trials.