Parthenolide induces gallbladder cancer cell apoptosis via MAPK signalling.

Objective: Parthenolide (PTL) has a wide range of clinical applications owing to its anti-inflammatory and antitumor effects. To date, the antitumor effect of PTL on gallbladder cancer (GBC) remains largely unknown. Therefore, we aimed to investigate the biological effects of PTL on GBC. Methods: The cellular viability and proliferation of GBC-SD and NOZ cell lines after treatment with different concentrations of PTL were analyzed using the Cell Counting Kit-8 (CCK8)assay and colony formation assay. Apoptosis analysis was performed using flow cytometry. Hoechst staining was performed. RNA sequencing (RNA-seq) was performed to identify PTL-related genes and signalling pathways. Furthermore, we confirmed the involvement of these signalling pathways by qRT-PCR and western blotting. For the in-vivo experiments, a xenograft model was used to evaluate the effects of PTL on the proliferation of NOZ cells. Results: PTL significantly inhibited GBC cell growth in vitro and induced apoptosis in the GBC-SD and NOZ cell lines in a dose-dependent manner. RNA sequencing data showed that the immune response and mitogen-activated protein kinase (MAPK) signalling pathways are closely associated with PTL-induced gallbladder cancer cell apoptosis. PTL upregulated BAX, cleaved PARP-1, cleaved caspase-3, cleaved caspase-9, P53 and decreased the expression of BCL-2, phosphorylated ERK, and phosphorylated MEK in vitro. Tumour volume and weight were also suppressed by PTL in vivo. Moreover, the effects of PTL on GBC cells might be mediated by the MAPK pathway. Conclusion: PTL significantly inhibits gallbladder cancer cell proliferation and induces apoptosis through the MAPK pathway, which is a potential molecular reagent for treating GBC. However, further exploration is needed to verify the antitumor effects of PTL and its intracellular signalling mechanism.

Sphingosine kinase 2 regulates insulin receptor trafficking in hepatocytes.

Disturbed insulin receptor (InsR) trafficking is associated with impaired insulin signaling and the development of diabetes. Sphingosine kinase (SphK), including SphK1 and SphK2, is a key enzyme of sphingolipid metabolism, which has been implicated in the regulation of membrane trafficking. More recently, we have reported that SphK2 is a key regulator of hepatic insulin signaling and glucose homeostasis. However, the role of SphK in InsR trafficking is still undefined. Huh7 cells were treated with specific SphK1 and SphK2 inhibitors or SphK1- and SphK2-specific small interfering RNA (siRNA) in the presence or absence of insulin. Flow cytometry and immunofluorescence assays were carried out to investigate the role of SphK in InsR trafficking. InsR endocytosis, recycling, and insulin signaling were analyzed. Inhibition of SphK2, but not SphK1, by either specific pharmaceutic inhibitors or siRNA, significantly suppressed InsR endocytosis and recycling following insulin stimulation. Consequently, the insulin-stimulated Akt activation was significantly attenuated by SphK2 inhibition in hepatocytes. Moreover, the effect of SphK2 on InsR trafficking was mediated via the clathrin-dependent mechanism. Thus, our results show that SphK2 is able to regulate InsR trafficking. These findings suggest that SphK2 may impinge on hepatic insulin signaling by regulating InsR trafficking, providing further mechanistic evidence that SphK2 could serve as a potential intervention target against insulin resistance and T2D (type 2 diabetes).

Current research status of biliary stents / 临床肝胆病杂志

Biliary tract diseases are a common type of hepatobiliary diseases in China and have a relatively high incidence rate， and related complications are important influencing factors for the health of Chinese patients. Biliary stents are mainly used to alleviate and relieve benign or malignant biliary stricture and obstruction， with the features of little trauma， high safety， and in line with the physiological and anatomical structure of biliary tract， and it has become the preferred palliative treatment method for biliary obstruction caused by unresectable pancreaticobiliary tumors. However， there is still a lack of satisfactory treatment outcomes since commonly used biliary stents have the shortcomings such as bacterial adhesion， cholestasis， stent obstruction， and stent migration. In recent years， scholars have conducted extensive and in－depth studies on the causes of biliary stent obstruction， the improvement of stent design， and the extension of drainage duration and have made certain progress. This article reviews the types， advantages and disadvantages， and development history of biliary stents and proposes the future research directions and application value of biliary stents.

Neoadjuvant chemoradiotherapy followed by liver transplantation is a promising treatment for patients with unresectable hilar cholangiocarcinoma: A case report.

Hilar cholangiocarcinoma is a highly malignant tumor and is currently treated by surgical resection or liver transplantation; however, these treatments result in poor patient prognosis accompanied with high recurrence and low patient mortality rates. Neoadjuvant therapy with liver transplantation is a novel treatment that exhibits promising clinical application, with a reported 5-year survival rate of 82%. However, transplantation centers conducting research into this treatment are limited due to its length and complexity. In the current study, the effects of brachytherapy and chemoradiotherapy followed by orthotopic liver transplantation (OLT) were investigated in a patient with unresectable hilar cholangiocarcinoma. Following treatment, the liver function of the patient normalized and physical status significantly improved. Furthermore, tomographic evaluation demonstrated no sign of recurrence 8 months later following continued adjunct chemotherapy. Therefore, neoadjuvant therapy followed by OLT may be an effective novel therapeutic strategy to treat patients with unresectable hilar cholangiocarcinoma.

BM­MSCs protect against liver ischemia/reperfusion injury via HO­1 mediated autophagy.

Ischemia/reperfusion (I/R) injury is considered to be a contributing factor in liver injury following major hepatic resection or liver transplantation. Bone marrow mesenchymal stem cells (BM­MSCs) have the potential to protect against liver I/R injury; however, the precise mechanisms have not been completely elucidated. Autophagy serves an important role in protecting against various injuries, including I/R injury. The present study aimed to determine the role of autophagy and its potential regulatory mechanism in BM­MSC­mediated protection against liver I/R injury in rats. The results demonstrated that BM­MSCs mitigated I/R injury and enhanced autophagy in vivo. In addition, inhibition of autophagy by 3­methyladenine reversed the positive effects of BM­MSCs. Furthermore, heme oxygenase­1 (HO­1) expression was promoted by BM­MSCs. Using zinc protoporphyrin IX to inhibit HO­1 demonstrated that HO­1 was important for the promotion of autophagy. In conclusion, the present study revealed that BM­MSCs protected against liver I/R injury via the promotion of HO­1­mediated autophagy.

Podoplanin is an important stromal prognostic marker in perihilar cholangiocarcinoma.

Cancer-associated fibroblasts (CAFs) exhibit various phenotypes and serve an important role in tumor progression. However, research on podoplanin expression in CAFs is limited, and its role in the cholangiocarcinoma microenvironment remains unclear. The present study analyzed the clinical and pathological records of 42 patients diagnosed with perihilar cholangiocarcinoma (pCCA) in The Affiliated Drum Tower Hospital of Nanjing University Medical School (Nanjing, China). Immunohistochemical staining was performed to evaluate the expression of podoplanin in CAFs in order to determine its association with clinicopathological parameters and survival rate. Podoplanin expression in the CAFs was associated with the tumor-node-metastasis staging system, and lymph node metastasis in pCCA. Tumor tissue demonstrated an increase in lymphatic vessel density (LVD) compared with para-tumor tissue. Podoplanin expression in CAFs was associated with LVD in tumor and para-tumor tissues. To examine the effect of podoplanin expression in CAFs on tumor progression, CAFs were isolated from tumor xenografts. Following transfection with an expression plasmid encoding podoplanin, the migratory ability of CAFs was significantly increased. Therefore, CAF-associated podoplanin expression in pCCA may serve as a potential biomarker to evaluate prognosis and provide a valuable target for anticancer therapy.

Malignant fibrous histiocytoma of visceral organs: clinicopathologic features and diagnostic value of ezrin and HMG-CoA reductase.

Malignant fibrous histiocytoma (MFH) of the breast and visceral organs is extremely rare. There is an incomplete understanding of the clinical pathology of the primary MFH originating from the breast and visceral organs, especially in comparison with other soft tissue sarcomas. As a consequence we searched and analyzed the clinical and pathological records of all the nine patients with diagnosed breast and visceral MFH in our hospital. Immunohistochemical staining was performed for ezrin and HMG-CoA reductase in these MFH cases and relevant mesenchymal sarcomas. The 9 MFH cases presented with nonspecific symptoms and imaging manifestations. 6 cases were classified as storiform-pleomorphic MFH, 2 cases as inflammatory MFH, and the remaining 1 case as giant cell MFH. The results showed that ezrin expression, as well as HMG-CoA reductase expression, was significantly stronger in MFH cases than other non-MFH sarcomas. Poor prognosis seemed to be associated with younger age. Certain characteristics and clinicopathologic features can help us making the diagnosis of MFH. In conclusion, our study provided the potential value of ezrin and HMG-CoA reductase for diagnosis and differential diagnosis of MFH located in the breast and visceral organs. More accurate prognostic information of this rare disease needed to be further investigated.