A novel sesquiterpene lactone fraction from Eupatorium chinense L. suppresses hepatocellular carcinoma growth by triggering ferritinophagy and mitochondrial damage.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive tumor with limited treatment options, and it is the third leading cause of cancer-related deaths. Hence, novel therapeutic strategies are required to treat HCC. Eupatorium chinense L. is a traditional Chinese medicine (TCM) that can effectively neutralize heat and smoothen the flow of "Qi" through the liver. However, the anti-HCC effects of Eupatorium chinense L. remain unknown. PURPOSE: The present study investigated the anti-HCC effects and the underlying mechanisms of the electrophilic sesquiterpenes isolated from E. chinense L. (EChLESs) in the regulation of ferroptosis and apoptosis in HCC cells. STUDY DESIGN/METHODS: Cell viability was assessed by the MTT assay. Cell apoptosis was confirmed by flow cytometry and western blotting assay. Ferroptosis was assessed by flow cytometry, transmission electron microscopy, and western blotting assay. Ferritinophagy was detected by acridine orange staining and western blotting assay. Small interfering RNA of nuclear receptor coactivator 4 (NCOA4) was used to confirm the role of ferritinophagy in the therapeutic effect of EChLESs on HCC cells. A mouse xenograft model was constructed to determine the inhibitory effect of EChLESs on HCC in vivo. RESULTS: EChLESs induced apoptosis by disrupting mitochondrial membrane potential depolarization and mitochondrial reactive oxygen species. EChLESs induced ferroptosis as noted by a significant increase in mitochondrial disruption, lipid peroxidation, and intracellular iron level and decreased glutathione level. The apoptosis inhibitor Z-VAD-FMK and lipid reactive oxygen species scavenger ferrostatin 1 attenuated EChLESs-induced cell death. NCOA4-mediated ferritinophagy through autophagic flux was the crucial pathway for ferroptosis induced by EChLESs. NCOA4 knockdown alleviated EChLESs-induced cell death. EChLESs controlled the expression of NCOA4 at the transcriptional and post-transcriptional levels. In the in vivo experiment, EChLESs suppressed HCC growth in the xenograft tumor mouse model. CONCLUSION: EChLESs enhances cell apoptosis through mitochondrial dysfunction and ferroptosis through NCOA4-mediated ferritinophagy. Thus, Eupatorium chinense L. could be a potential TCM for treating HCC.

A Novel Classifier Based on Urinary Proteomics for Distinguishing Between Benign and Malignant Ovarian Tumors.

BACKGROUND: Preoperative differentiation of benign and malignant tumor types is critical for providing individualized treatment interventions to improve prognosis of patients with ovarian cancer. High-throughput proteomics analysis of urine samples was performed to identify reliable and non-invasive biomarkers that could effectively discriminate between the two ovarian tumor types. METHODS: In total, 132 urine samples from 73 malignant and 59 benign cases of ovarian carcinoma were divided into C1 (training and test datasets) and C2 (validation dataset) cohorts. Mass spectrometry (MS) data of all samples were acquired in data-independent acquisition (DIA) mode with an Orbitrap mass spectrometer and analyzed using DIA-NN software. The generated classifier was trained with Random Forest algorithm from the training dataset and validated in the test and validation datasets. Serum CA125 and HE4 levels were additionally determined in all patients. Finally, classification accuracy of the classifier, serum CA125 and serum HE4 in all samples were evaluated and plotted via receiver operating characteristic (ROC) analysis. RESULTS: In total, 2,199 proteins were quantified and 69 identified with differential expression in benign and malignant groups of the C1 cohort. A classifier incorporating five proteins (WFDC2, PTMA, PVRL4, FIBA, and PVRL2) was trained and validated in this study. Evaluation of the performance of the classifier revealed AUC values of 0.970 and 0.952 in the test and validation datasets, respectively. In all 132 patients, AUCs of 0.966, 0.947, and 0.979 were achieved with the classifier, serum CA125, and serum HE4, respectively. Among eight patients with early stage malignancy, 7, 6, and 4 were accurately diagnosed based on classifier, serum CA125, and serum HE4, respectively. CONCLUSION: The novel classifier incorporating a urinary protein panel presents a promising non-invasive diagnostic biomarker for classifying benign and malignant ovarian tumors.

Eucannabinolide, a novel sesquiterpene lactone, suppresses the growth, metastasis and BCSCS-like traits of TNBC via inactivation of STAT3.

Signal transducer and activator of transcription 3 (STAT3) is an important therapeutic target to triple negative breast cancer (TNBC) treatment. In the present study, we aim to investigate the potential activity of Eucannabinolide (Euc), a novel sesquiterpene lactone separated from Eupatorium cannabinum Linn. against TNBC by targeting STAT3 and expect that Euc will be developed as an inhibitor of STAT3 in the treatment of TNBC. We found that Euc effectively suppressed STAT3 activation at tyrosine 705, inhibited its translocation to nucleus, and decreased its DNA binding capacity. Moreover, introduction of STAT3-short hairpin RNAs or STAT3 inhibitor S3I-201 attenuates the Euc-induced inhibition of cell viability. And, Euc inhibited cell viability, proliferation, metastasis and breast cancer stem cell-like traits but did not induce cytotoxicity in human mammary epithelial cells. The in vivo study similarly demonstrated that administration of Euc inhibited the growth of xenograft tumors and impaired tumor metastasis of a lung metastasis model. The above phenomena were associated with STAT3 dysfunction induced by Euc. In conclusion, Euc elicits the effects of anti-proliferation, anti-metastasis and anti-breast cancer stem cell-like traits in TNBC via targeting STAT3. These data highlight that development of Euc as a STAT3 inhibitor may offer a promising therapeutic strategy for TNBC.

The Treatment of Mid-shaft Clavicle Fractures.

OBJECTIVE: Through reviewing the relevant literature from the past decades, to summarize the assessment and management of fractures of the clavicle, and provide an overview of the clinical results of a range of treatment options. DATA SOURCES: The data analyzed in this review are mainly from articles included in PubMed and EMBASE, published from 1960 to 2015. STUDY SELECTION: Studies involving assessment of fractures of the clavicle were reviewed. Further literatures were gathered regarding the conservative and surgical treatment of these fractures, including the methods of fixation and the surgical approaches used. Both conservative and surgical treatments were then compared and contrasted. RESULTS: Through retrieving and reading the abstract, a total of 42 representative articles were selected, which covered all aspects of the conservative treatment and surgical treatment, and compared the advantages and disadvantages of different treatment options. CONCLUSIONS: Although the majority of recent data suggest that surgery may be more appropriate as it improves functional outcome and reduces the risk of complications, we recommend that the treatment should be individually assessed.

Genetic variant near TERC influencing the risk of gliomas with older age at diagnosis in a Chinese population.

A recent genome-wide association study has identified an association between rs1920116 near TERC and high-grade glioma in populations of European ancestry. In order to evaluate the effect of the SNP rs1920116 near TERC in the Chinese population, we examined associations of this candidate SNP with glioma in a sample of 1970 Chinese Han individuals. SNP genotype data were available for 980 Chinese glioma patients and 990 healthy controls. Logistic regression analyses were performed to evaluate the association between rs1920116 and glioma risk adjusted for age, gender and stratified by tumor grade where appropriate. The allele G at TERC rs1920116 are risk factors for gliomas, and its association with glioma risk was consistent across tumor subgroups in the Chinese Han population (OR = 1.18-1.21). In order to assess variation in SNP effect size at different patient ages, glioma cases and controls were divided into 3 age strata, in years: <50, 50-59, and 60+. The results of multiple logistic regression analyses indicate that the SNP has age-specific effects on the risk of developing glioma. Our report confirmed the effects of rs1920116 near TERC on glioma occurring in older peoples in the Chinese Han population for the first time. As TERC is a candidate for inter-individual variation in telomere length, our study supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life.