Overexpression of pressure-responsive miRNA-5703 inhibits pressure-induced growth and metastasis of liver cancer.

A vast majority of liver cancers coexist with cirrhosis and/or portal hypertension. A high-pressure tumour microenvironment may lead to malignant progression of liver cancer. Through quantitative reverse transcription-polymerase chain reaction, we found that miRNA-5703 was expressed at low levels in HepG2 and Huh-7 cells and pressure-treated MHCC97H implanted mouse cancer tissues, while its potential target gene, sarcoma gene (SRC), was highly expressed. The expression of miRNA-5703 was higher in liver cancer tissues from Barcelona Clinic Liver Cancer (BCLC) stage A1 patients than those from BCLC stage A2-D patients, whereas SRC showed the opposite expression pattern. Bioinformatics analysis, luciferase reporter assay, and western blotting were performed to verify the relationship between miRNA-5703 and its potential target SRC. Using intravital imaging and immunohistochemistry, we demonstrated that pressure promotes tumour growth in subcutaneous tumourigenesis nude mice, and overexpression of miRNA-5703 significantly downregulated Ki67 and upregulated NM23 in tumour tissues of mice, implying the blockage of tumour growth and metastasis. The activation of proliferation, migration, and invasion of HepG2 and Huh-7 cells by pressure, and inhibition by overexpressing miRNA-5703 were observed by cell counting kit-8 assay, flow cycle assay, transwell assay, and wound healing assay. After the intervention of pressure, inhibitor, and lentivirus to hepatoma cells, SRC, focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3K), serum/glucocorticoid regulated kinase-3 (SGK3), phosphoinositide dependent protein kinase 1 (PDK1), and paxillin were upregulated, and forkhead box O1 (FOXO1) and cyclin dependent kinase inhibitor 1B (P27Kip1) were downregulated in pressure-loaded hepatoma cells, which could be reversed by overexpression of miRNA-5703 or SRC knockdown. In conclusion, upregulation of miRNA-5703 inhibited pressure-induced growth and metastasis by suppressing the SRC-FAK-FOXO1 axis and SRC-paxillin axis. This novel perspective may be conducive to the mechano-inspired anticancer drugs of liver cancer.

Timing of endoscopic intervention in patients with cirrhosis with acute variceal haemorrhage (TEACH trial): protocol for a randomised clinical trial (RCT).

INTRODUCTION: Acute variceal haemorrhage (AVH) in patients with cirrhosis remains a topic of great interest. Although several guidelines recommend endoscopy within 24 hours after AVH, there is no consensus on the most appropriate time to perform this intervention. The purpose of this study is to identify whether urgent endoscopy (within 6 hours after gastroenterological consultation) is superior to non-urgent endoscopy (between 6 hours and 24 hours after gastroenterological consultation) in reducing the rebleeding rate of these patients. METHODS AND ANALYSIS: This is a single-centred, prospective, randomised clinical trial. Between March 2021 and December 2023, an estimated 400 patients will be randomised in a 1:1 ratio to receive endoscopic intervention either within 6 hours or between 6 and 24 hours after gastroenterological consultation. Randomisation will be conducted by permuted block randomisation, with stratification by age, systolic blood pressure and pulse rate. The primary efficacy endpoint is rebleeding within 42 days after control of AVH. The secondary efficacy endpoints mainly include all-cause mortality within 42 days after randomisation, persistent bleeding, length of hospitalisation, etc. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethical Committees of Jinling Hospital (authorised ethics no. DZQH-KYLL-21-01). This trial will provide valuable insights into the timing of endoscopic intervention for AVH in patients with cirrhosis. Furthermore, the trial results and conclusions could provide high-quality evidence to guide clinical research and treatment. TRIAL REGISTRATION NUMBER: NCT04786743.

Dissolved oxygen responses to tropical cyclones "Wind Pump" on pre-existing cyclonic and anticyclonic eddies in the Bay of Bengal.

This study examines how dissolved oxygen (DO) responds to tropical cyclones (TCs) "Wind Pump" in a pre-existing cyclonic and an anticyclonic eddy over the Bay of Bengal (BoB) based on Argo and satellite data. Both TCs induced DO temporal decreases in the subsurface waters (Deep Depression BOB 04 with a pre-existing cyclonic eddy and cyclonic storm Roanu with a pre-existing anticyclonic eddy) owing mainly to the storm-induced upwelling. The deeper oxycline caused by the pre-existing anticyclonic eddy relieved the storm-induced shallow of oxycline during Roanu. On the contrary, the pre-existing cyclonic eddy shoaled the oxycline, intensifying the storm-induced shallow of oxycline during BOB 04. Furthermore, the pre-existing cyclonic eddy induced a long time of DO decrease after BOB 04. This study suggests that the subsurface DO concentrations in the BoB are affected mainly by storm-induced physical processes, and the mesoscale eddies also play an important role.

Study of dissolved oxygen responses to tropical cyclones in the Bay of Bengal based on Argo and satellite observations.

Effects of tropical cyclones (TCs) on dissolved oxygen (DO) in subsurface waters (20-200 m) over the Oxygen Minimum Zones (OMZs) in the Bay of Bengal (BoB) are examined based on Argo and satellite data. Five TCs (Hudhud, Five, Vardah, Maarutha and Mora) during 2013-2018 are considered. Analyses reveal three types of DO temporal variability caused by the storm-induced mixing and upwelling. The first type features temporal DO increases in subsurface waters (37-70 m) caused mainly by intense vertical mixing and downwelling. The second type features DO reductions in subsurface waters after the storms attributed to storm-induced upwelling. The third type features temporal DO increases at depths between 40 and 79 m and decreases at depths between 80 and 150 m due to the combined effect of strong vertical mixing and upwelling. These three types of DO responses can occur in different areas, depending on TC intensity, translational speed and Ekman pumping. The temporal DO variability is also influenced by the shallow oxycline (58.3 ±â€¯16.7 m), mesoscale eddies and biochemical processes. Due to TC intensification, a pre-existing oceanic cyclonic eddy produced a large upwelling and induced a long time of DO decrease in the subsurface layer. This study suggests three different types of DO responses along the TC track in the OMZ, which is useful to evaluate the influence of TCs on the OMZ.

Effect of Huagantongluofang, a Chinese Traditional Medicine, in Hepatic Fibrogenesis in a Mouse Model of Biliary Cirrhosis.

BACKGROUND: Biliary cirrhosis (BC) is a chronic cholestatic liver disease, in which hepatic fibrosis is an early symptom. This study aimed to identify the biological function and the therapeutic effect of a Chinese traditional medicine, HuaGanTongLuoFang (HGTLF), in a mouse model of BC. METHODS: The mice (n = 72) were randomly divided into a sham group (n =12) and BC group (n = 60). The animals in the BC group were then randomly divided into five groups (n = 12 in each) and treated with three different doses of HGTLF, ureodeoxycholic acid (UDCA), or normal saline (the model group). Four weeks later, serum and liver tissues were obtained from all the animals for analyses. Hematoxylin and eosin (H&E) staining was used to quantify the hepatic morphology, while real-time PCR and Enzyme-linked immunosorbent assay (ELISA) were used to determine the level of hepatic fibrosis-related genes. RESULTS: Compared with the model group, all three doses of HGTLF improved hepatic function, as well as reducing inflammation and fibrogenesis. The best therapeutic effect was observed in the high-dose HGTLF group. Furthermore, HGTLF contributed to down-regulation of hepatic fibrosis-related genes (platelet-derived growth factor [PDGF], transforming growth factor-ß [TGF-ß], p38, nuclear factor-κB [NF-kB], intercellular adhesion molecular-1 [ICAM-1], and tissue inhibitor of metalloproteinase-1 [TIMP-1]). CONCLUSION: The data suggested that HGTLF effectively improved liver function and the morphology of the liver tissue in a mouse model of BC, possibly via suppression of hepatic fibrosis-related signals.

MiR-29a and miR-652 Attenuate Liver Fibrosis by Inhibiting the Differentiation of CD4+ T Cells.

BACKGROUND: Liver fibrosis is the response of liver diseases that puzzles patients. MiRNAs were involved in the regulating processes of liver fibrosis. This study aims to investigate the effects of ARRB1 mediated by miR-29a and miR-652 on liver fibrosis and its possible mechanism. METHODS: Liver fibrosis of mice was induced by intraperitoneal injection of CCl4. Liver function was observed by the levels of alanine transaminase (ALT) and aspartate transaminase (AST). Flow cytometry was used to detect the percent of T helper17 (Th17). ELISA (Enzyme linked immunoassay) was used to detect the levels of Interleukin-17 (IL-17) and Interleukin-22 (IL-22). Real-time PCR was used to detect the expression of IL-17A, IL-22, miR-29a, miR-652 and ß-Arrestin 1 Gene (ARRB1). Western blot was used to detect the protein expression of ARRB1. RESULTS: CCl4 supplementation significantly increased the level of ALT and AST, the percent of Th17, the level of IL-17A, IL-22, miR-29a and miR-652, but decreased ARRB1. Overexpression of miR-29a/miR-652 prominently decreased Th17, IL-17A, IL-22 and ARRB1 in the normal CD4+ T cells. Both miR-29a and miR-652 targeted ARRB1 to regulate its expression. The effects of miR-29a/miR-652 overexpression on CD4+ T cells were reversed by ARRB1 overexpression. In vivo experiments demonstrated the protective role of miR-29a/miR-652 overexpression on liver fibrosis. CONCLUSION: ARRB1 mediated by miR-29a and miR-652 probably involved in the CD4+ T cells differentiation in patients with liver fibrosis, and functioned as a biomarker of fibrosis liver.Key words: liver fibrosis, miR-29a, miR-652, ARRB1, CD4+ T cells.

Anti-TGFß-1 receptor inhibitor mediates the efficacy of the human umbilical cord mesenchymal stem cells against liver fibrosis through TGFß-1/Smad pathway.

The aim of the current investigation was to evaluate the anti-fibrosis potential of human umbilical cord mesenchymal stem cells (hUC-MSCs) and further to explore some of its underlying mechanisms. Hepatic fibrosis mice model was induced by CCl4. Liver function parameters in serum and fibrosis-associated markers in tissues were detected. Moreover, SB-431542, an anti-TGFß-1 receptor inhibitor, was employed in vitro to reveal the underlying mechanism of TGFß-1/Smad pathway on hUC-MSCs against liver fibrosis. In the present study, we illustrated that hUC-MSCs could differentiate into osteogenic, adipogenic, and cartilage. Liver fibrosis was attenuated with hUC-MSCs treatment, determined by reductions of AST, ALT. and fibrosis area, along with some critical parameters including TGFß-1, α-SMA, and TIMP-1. However, TGFß-1 receptor antagonist SB-431542 reduced the paracrine TGFß-1 expression of hUC-MSCs and blunted the activation of downstream target genes. Furthermore, the restrained hUC-MSCs proliferation and migration induced by SB-431542 could be reversed by si-TGFß-1. These results demonstrated that TGFß-1 receptor inhibitor improved the repair potential of hUC-MSCs against hepatic injury through TGFß-1/Smad pathway, which contributed to improving the therapeutic efficiency of liver fibrosis.

The diagnostic performance of serum MUC5AC for cholangiocarcinoma: A systematic review and meta-analysis.

Specific diagnostic biomarker for cholangiocarcinoma (CCA) has been lacking. This systematic review and meta-analysis was performed aiming to investigate serum MUC5AC's diagnostic performance on CCA.Studies investigating serum MUC5AC's diagnostic value on CCA were retrieved from Pubmed, Embase, and Cochrane Library. The methodology quality of included studies was assessed according to QUADAS-2. Diagnostic 2 × 2 table was extracted from each eligible study, Meta-disc 1.4 was used for statistical analysis, data synthesis was done using a random-effects model. Subgroup analyses were conducted according to region and array method.Six eligible studies were identified, a total of 1213 patients were involved in the meta-analysis. The AUC on SROC was 0.9138, and the Q* was 8463. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio (DOR) were 0.69 (95% CI: 0.65-0.73), 0.93 (95% CI: 0.91-0.95), 8.99 (95% CI: 5.65-14.30), 0.33 (95% CI: 0.24-0.46), and 33.98 (95% CI: 20.12-57.40), respectively. Targeting MUC5AC's epitope has a higher pooled sensitivity than targeting MUC5AC protein (0.77 vs 0.63). There was substantial cross-study heterogeneity.Serum MUC5AC might be potentially used as a surrogate marker in the diagnosis of CCA. However, the appropriate array method and the optimum cut-off value are yet to be decided.