Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells.

Background & Aims: Reactive oxygen species (ROS) act as modulators triggering cellular dysfunctions and organ damage including liver fibrosis in which hepatic stellate cell (HSC) activation plays a key role. Previous studies suggest that microRNA-144 (miR-144) acts as a pro-oxidant molecule; however, whether and how miR-144 affects HSC activation and liver fibrosis remain unknown. Methods: Carbon tetrachloride (CCl4) and bile duct ligation (BDL)-induced experimental liver fibrosis models were used. Hepatic miR-144 expression was analyzed by miRNA in situ hybridization with RNAscope probe. The in vivo effects of silencing or overexpressing miR-144 were examined with an adeno-associated virus 6 (AAV6) carrying miR-144 inhibitor or mimics in fibrotic mouse experimental models. Results: In this study, we demonstrated that ROS treatment significantly upregulated miR-144 in HSCs, which further promoted HSC activation in vitro. Interestingly, miR-144 was preferentially elevated in HSCs of experimental liver fibrosis in mice and in human liver fibrotic tissues. Furthermore, in vivo loss or gain-of-function experiments via AAV6 carrying miR-144 antagomir or agomir revealed that blockade of miR-144 in HSCs mitigated, while overexpression of miR-144 in HSCs accelerated the development of experimental liver fibrosis. Mechanistically, SIN3 transcription regulator family member A (SIN3A), a transcriptional repressor, was identified to be the target of miR-144 in HSCs. MiR-144 downregulated Sin3A, and in line with this result, specific knockdown of Sin3a in HSCs remarkedly activated p38 MAPK signaling pathway to promote HSC activation, eventually exacerbating liver fibrosis. Conclusions: Oxidative stress-driven miR-144 fuels HSC activation and liver fibrogenesis by limiting the SIN3A-p38 axis. Thus, a specific inhibition of miR-144 in HSCs could be a novel therapeutic strategy for the treatment of liver fibrosis.

LSAM: L2-norm self-attention and latent space feature interaction for automatic 3D multi-modal head and neck tumor segmentation.

Objective.Head and neck (H&N) cancers are prevalent globally, and early and accurate detection is absolutely crucial for timely and effective treatment. However, the segmentation of H&N tumors is challenging due to the similar density of the tumors and surrounding tissues in CT images. While positron emission computed tomography (PET) images provide information about the metabolic activity of the tissue and can distinguish between lesion regions and normal tissue. But they are limited by their low spatial resolution. To fully leverage the complementary information from PET and CT images, we propose a novel and innovative multi-modal tumor segmentation method specifically designed for H&N tumor segmentation.Approach.The proposed novel and innovative multi-modal tumor segmentation network (LSAM) consists of two key learning modules, namely L2-Norm self-attention and latent space feature interaction, which exploit the high sensitivity of PET images and the anatomical information of CT images. These two advanced modules contribute to a powerful 3D segmentation network based on a U-shaped structure. The well-designed segmentation method can integrate complementary features from different modalities at multiple scales, thereby improving the feature interaction between modalities.Main results.We evaluated the proposed method on the public HECKTOR PET-CT dataset, and the experimental results demonstrate that the proposed method convincingly outperforms existing H&N tumor segmentation methods in terms of key evaluation metrics, including DSC (0.8457), Jaccard (0.7756), RVD (0.0938), and HD95 (11.75).Significance.The innovative Self-Attention mechanism based on L2-Norm offers scalability and is effective in reducing the impact of outliers on the performance of the model. And the novel method for multi-scale feature interaction based on Latent Space utilizes the learning process in the encoder phase to achieve the best complementary effects among different modalities.

Atractylenolide III ameliorates Non-Alcoholic Fatty Liver Disease by activating Hepatic Adiponectin Receptor 1-Mediated AMPK Pathway.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver diseases worldwide. At present, there are no effective pharmacological therapies for NAFLD except lifestyle intervention-mediated weight loss. Atractylenolide III (ATL III), the major bioactive component found in Atractylode smacrocephala Koidz, has been shown to exert anti-oxidant, anti-tumor, anti-allergic response, anti-bacterial effects and cognitive protection. Here we investigate the therapeutic potential and underlying mechanisms of ATL III for the treatment of NAFLD. Methods: Male C57BL/6J mice were fed a high-fat diet (HFD) and treated with ATL III. Lipid accumulation was analyzed by Oil Red O staining in liver tissues and free fatty acids (FFAs)-treated hepatocytes. AMP-activated protein (AMPK) and sirtuin 1(SIRT1) signaling pathways were inhibited by Compound C and EX527 in vitro, respectively. Small-interfering RNA (siRNA) was used to knockdown adiponectin receptor 1 (AdipoR1) expression in HepG2 cells. Results: ATL III treatment ameliorated liver injury and hepatic lipid accumulation in the HFD-induced NAFLD mouse model as demonstrated by that ATL III administration significantly reduced serum levels of alanine aminotransferase, glutamic oxaloacetic transaminase, triglycerides, total cholesterol and low-density lipoprotein. Furthermore, treatment with ATL III alleviated hepatic oxidative stress, inflammation and fibrosis in the HFD feeding model. To study the underlying mechanisms, we performed Computer Aided Design assay and found that open-formed AdipoR1 and adiponectin receptor 2 were the potential receptors targeted by ATL III. Interestingly, HFD feeding or FFAs treatment only reduced hepatic AdipoR1 expression, while such reduction was abolished by ATL III administration. In addition, in vitro treatment with ATL III activated the AdipoR1 downstream AMPK /SIRT1 signaling pathway and reduced lipid deposition in HepG2 cells, which was diminished by silencing AdipoR1. Finally, inhibition of AMPK or SIRT1, the AdipoR1 downstream signaling, abolished the protective effects of ATL III on lipid deposition and oxidative stress in FFAs-treated HepG2 cells. Conclusion: Our findings suggest that ATL III is a therapeutic drug for the treatment of NAFLD and such protective effect is mediated by activating hepatic AdipoR1-mediated AMPK/SIRT1 signaling pathway.

Cross-sectional study of the educational background and trauma knowledge of trainees in the "China trauma care training" program.

BACKGROUND: Since the trauma knowledge of trauma providers correlates with the outcomes of injured patients, this study aims to assess the socio-demographic characteristics and levels of trauma knowledge of trainees in the China trauma care training (CTCT) program in addition to their post-course test results to provide support for the development of trauma care training programs and trauma systems in China. METHODS: A cross-sectional study was conducted by collecting demographic information, hospital-related information and trauma knowledge of the trainees from 19 regions in China. All participants were assessed by questionnaires collecting the socio-demographic data, the trauma care knowledge levels and the information of the hospitals. RESULTS: There were 955 males (78.9%) and 256 females (21.1%) enrolled. Among them, 854 were physicians (70.5%), 357 were registered nurses (29.5%). In addition, 64 of them also played an administrative role in the hospitals (5.3%). The score of the trainees who were members of the emergency department staff (72.59 ± 14.13) was the highest among the scores of all the personnel surveyed, followed by those of the trainees from the intensive care unit (ICU) (71.17 ± 12.72), trauma surgery department (67.26 ± 13.81), orthopedics department (70.36 ± 14.48), general surgery department (69.91 ± 14.79) and other departments (69.93 ± 16.91), P = 0.031. The score of the professors (73.09 ± 15.05) was higher than those of the associate professors (72.40 ± 14.71), lecturers (70.07 ± 14.25) and teaching assistants (67.58 ± 15.16), P < 0.0001. The score of the individuals who attended experts' trauma lectures (72.22 ± 14.45) was higher than that of individuals who did not attend the lectures (69.33 ± 15.17), P = 0.001. The mean scores before and after the training were 71.02 ± 14.82 and 84.24 ± 13.77, respectively, P < 0.001. The mean score of trauma knowledge after the training of trainees from different provinces and with different educational backgrounds was higher than that before the training, with a statistically significant difference (P < 0.05). CONCLUSIONS: The level of trauma knowledge of trauma care providers was associated with their department, professional position and previous participation in related academic conferences. Trauma care experience and participation in academic lectures and training program including CTCT may effectively improve individuals' level of trauma knowledge.

MicroRNA-216b-5p Functions as a Tumor-suppressive RNA by Targeting TPT1 in Pancreatic Cancer Cells.

MicroRNAs (miRNAs) are increasingly recognized as being involved in pancreatic cancer progression by directly regulating the expression of their targets. In this study, we showed that miR-216b-5p expression was significantly decreased in pancreatic cancer tissues and cell lines. In addition, low miR-216b-5p expression was significantly associated with large tumor size and advanced TNM stage. Meanwhile, both Kaplan-Meier and multivariate survival analysis showed that decreased miR-216b-5p expression was associated with overall survival. miR-216b-5p over-expression repressed pancreatic cancer cell proliferation and induced cell cycle arrest and cell apoptosis in vitro and inhibited tumorigenesis in vivo. The translationally controlled tumor protein (TPT1) was identified as a novel direct target of miR-216b-5p. miR-216b-5p up-regulation suppressed TPT1 expression. Moreover, TPT1 mRNA expression levels were increased in pancreatic cancer tissues, and were inversely correlated with miR-216b-5p expression. TPT1 down-regulation had similar effects as miR-216b-5p up-regulation on pancreatic cancer cell progression. The restoration of TPT1 reversed the effect of miR-216b-5p on pancreatic cancer cell progression. Furthermore, we found that miR-216b-5p up-regulation suppressed Pim-3, Cyclin B1, p-Bad and Bcl-xL protein expression. However, the effect of miR-216b-5p up-regulation was partly reversed by TPT1 up-regulation in vitro. Taken together, our findings suggested that miR-216b-5p functions as a potential tumor suppressor by regulating TPT1 in pancreatic cancer cells, and it may represent a potential therapeutic target for patients with pancreatic cancer.

Association of elevated risk of pancreatic cancer in diabetic patients: A systematic review and meta-analysis.

Pancreatic cancer has a five-year overall survival rate <5%, a situation that has not improved since for 40 years. Diabetes mellitus including type 2 diabetes mellitus (T2D) is a suspected risk factor for the development of pancreatic cancer and nearly 45% of the pancreatic cancer cases are likely to present as new onset diabetes cases; however, the nature of association between T2D and pancreatic cancer is still controversial. In this meta-analysis, we examined the association specifically of T2D with pancreatic cancer and the influence of insulin therapy. PubMed, EMBASE, Scholar, Web of Science and Scopus databases were searched to identify clinical and patient oriented studies that examined the incidence of diabetes in pancreatic cancer patients and vice versa, over the last 10 years. All the authors independently screened the articles, and a collective decision was reached about the studies included in the meta-analysis. Parameters analyzed included, the Incidence of diabetes in pancreatic cancer patients; duration history of T2D in pancreatic cancer patients; influence of insulin therapy in T2D patients on pancreatic cancer incidence. Eleven studies with a total of 14,399 patients, of whom 4,080 were T2D-positive and 9,721 were non-diabetic were included in this meta-analysis. T2D duration history was significantly related to pancreatic cancer incidence and insulin therapy effects. In conclusion, recent-onset T2D is probably a manifestation of pancreatic cancer whereas long-term T2D is likely a risk factor for this cancer. Insulin therapy appears to decrease the incidence of pancreatic cancer.

MiRNA-22 inhibits oncogene galectin-1 in hepatocellular carcinoma.

Hepatic stellate cells (HSCs) induce immune privilege and promote hepatocellular carcinoma (HCC) by suppressing the immune system. On the other hand, galectin-1 and miRNA-22 (miR-22) are dysregulated in HCC and serve as prognostic indicators for patients. In this study, therefore, we measured galectin-1 and miR-22 expression in HSCs isolated from HCC tissues (Ca-HSCs), and in normal liver tissues (N-HSCs) as a control. We also investigated the apoptosis rate among T cells and the production of cytokines (IFN-γ and IL-10) in HSCs co-cultured with T cells. And we used immunohistochemical staining to tested for correlation between galectin-1 expression, CD3 expression and clinicopathological features in 162 HCC patients. Our results showed that galectin-1 expression was much higher in Ca-HSCs than in N-HSCs. Overexpression of galectin-1 promoted HSC-induced T cell apoptosis and cytokine production (IFN-γ and IL-10), while miR-22 expression inhibited it. Galectin-1 expression correlated negatively with miR-22 expression in HSCs. High galectin-1 and low CD3 expression levels were associated with poor prognosis in HCC patients. These results suggest that the immunosuppressive microenvironment promoted by HSC-derived galectin-1 in HCC can be inhibited by miR-22. Galectin-1 and miR-22 could potentially serve as prognostic markers and therapeutic targets in HCC.

Effects of Raf kinase inhibitor protein expression on pancreatic cancer cell growth and motility: an in vivo and in vitro study.

PURPOSE: Raf kinase inhibitor protein (RKIP) is a tumor suppressor that inhibits cell growth and metastasis of malignant tumors. Pancreatic cancer is a leading cause of cancer death with a low survival rate. RKIP expression and its role in tumorigenesis and metastasis in pancreatic cancer are poorly understood. The aims of our study were to assess the effects of RKIP on pancreatic carcinoma cells in vitro and in tumor tissues in vivo. METHODS: This study included 84 patients with histologically confirmed pancreatic adenocarcinoma. The expression levels of RKIP were measured in pancreatic cancer tissues and adjacent normal tissues using real-time PCR and immunohistochemistry. Overexpression plasmid of RKIP was transfected into SW1990 and AsPC-1 cell lines, and the effects on cell proliferation were studied using a Cell Counting Kit-8 assay. MEK1/2 and ERK1/2 were detected by Western blot and immunofluorescence assay. RESULTS: Results showed a reduced expression of RKIP in pancreatic carcinoma tissues compared with adjacent normal tissues, which closely correlated with patient outcomes. Overexpression of RKIP suppressed cell proliferation and promoted apoptosis in cultured SW1990 and AsPC-1 cell lines. Transwell assay showed RKIP can inhibit cell migration and invasion, and in vivo RKIP can suppress tumorigenesis by diminishing the volume of the tumors. CONCLUSIONS: In conclusion, expression of RKIP is closely correlated with the survival of pancreatic cancer patients. RKIP can inhibit pancreatic adenocarcinoma cells proliferation, activities of migration and invasion, through downregulating Raf-1-MEK1/2-ERK1/2 signaling pathway.

Par-4 downregulation confers cisplatin resistance in pancreatic cancer cells via PI3K/Akt pathway-dependent EMT.

Cisplatin (CDDP) efficiency in pancreatic cancer therapy is limited due to development of drug resistance. However, the comprehensive mechanisms remain largely unclear. In this study, we first established a CDDP-resistant pancreatic cancer cell line-BXPC-3/CDDP from its parental cell line-BXPC-3. The results showed that CDDP resistance in BXPC-3/CDDP cells correlates with changes in cellular EMT phenotypes. Prostate apoptosis response-4 (Par-4) expression at both mRNA and protein levels were reduced in CDDP-resistant BXPC-3/CDDP cells compared with that in BXPC-3 cells. Ectopic expression of Par-4 reversed EMT and CDDP resistance in BXPC-3/CDDP cells. In BXPC-3 cells, knockdown of Par-4 expression induces EMT and CDDP insensitivity, however, these effects were blocked by inhibition of PI3K/Akt pathway using LY294002. Furthermore, Par-4 knockdown could significantly stimulate PI3K/Akt signaling in BXPC-3 cells. In vivo studies, xenograft BXPC-3 tumors were sensitive to CDDP treatment. Treatment with CDDP alone had little effect on the growth of Par-4 siRNA-transfected BXPC-3 tumors in nude mice and the survival rate compared with control. Inhibition of PI3K/Akt pathway using LY294002 reversed CDDP resistance in Par-4 siRNA-transfected BXPC-3 tumors. In conclusion, these results indicate that Par-4 downregulation confers CDDP resistance via PI3K/Akt pathway-dependent EMT in BXPC-3 cells. Therefore, Par-4 may be a potential target for overcoming CDDP resistance in pancreatic cancer.