Jolkinolide B inhibits the progression of hepatocellular carcinoma by regulating Musashi-2 protein.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. However, the HCC treatment is still challenging. Herein, we aimed to reveal the anti-tumor effect of Jolkinolide B in HCC cell lines Huh-7 and SK-Hep-1. The results showed that Jolkinolide B inhibited the migration, invasion, and epithelial-to-mesenchymal transition(EMT) of HCC cells. In addition, Jolkinolide B induced HCC cell apoptosis by upregulating Bax and downregulating BCL-2 expressions. Furthermore, we demonstrated that Jolkinolide B inactivated the ß-catenin signaling and reduced Musashi-2 expression. Finally, we revealed that Musashi-2 overexpression reversed the Jolkinolide B-induced anti-HCC effect. Overall, we proved that Jolkinolide B is a potential candidate for treating HCC.

Isolongifolene alleviates liver ischemia/reperfusion injury by regulating AMPK-PGC1α signaling pathway-mediated inflammation, apoptosis, and oxidative stress.

Isolongifolene (ISO) has antioxidant, anti-inflammatory, anticancer, and neuroprotective effects; however, it is unclear whether ISO has a protective effects against liver ischemia/reperfusion (I/R) injury. In this study, a mouse liver I/R injury model and a mouse AML12 cell Hypoxia reoxygenation (H/R) model were established after pretreatment with different concentrations of ISO. Serum transaminase levels, necrotic liver area, cell viability, inflammation response, oxidative stress, and apoptosis were used to evaluate the effect of ISO on liver I/R or cell H/R injury. Western blotting was used to detect Bax, Bcl-2, C-Caspase3, AMPK, P-AMPK, and PGC1α protein expression levels. The AMPK inhibitor, compound C, was used to inhibit the AMPK expression. The results showed that ISO reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, liver necrosis, inflammatory factors IL-1ß, IL-6, MCP-1, and TNF-α expression, MPO+ inflammatory cell infiltration, MDA content, TUNEL-positive cell number, cell apoptosis rate, and the expression of pro-apoptotic proteins Bax and C-Caspase3, while increasing cell viability, SOD and GSH activity, and the expression of anti-apoptotic protein Bcl-2. Moreover, Western blotting results showed that ISO could increase the protein expression of P-AMPK and PGC1α. Following the addition of compound C, the protective effect of ISO was significantly weakened. Therefore, our results suggest that ISO alleviates liver I/R injury by regulating AMPK-PGC1α signaling pathway-mediated anti-inflammatory, and antioxidant and anti-apoptotic effects.

Early outcomes of implanting larger-sized grafts in deceased donor liver transplantation.

BACKGROUND: The outcomes of large-sized graft mismatch in deceased donor liver transplantation (LT) have been rarely studied. The aim of this study was to determine whether a large-sized graft for recipient influenced the post-transplant outcomes. METHODS: A total of 273 patients undergoing LT were enrolled and divided into a large and a normal-sized graft group by graft weight to recipient weight (GWRW) >2.5% (n = 76) or GWRW ≤2.5% (n = 197). Post-operative complications and outcomes were retrospectively analysed. RESULTS: The two groups were comparable in demographic characteristics. The rate of complications was significantly higher in the large-sized graft group including early allograft dysfunction (36.8% versus 17.8%, P = 0.001), hepatic necrosis (26.3% versus 13.7%, P = 0.01) and massive hydrothorax (25% versus 14.7%, P = 0.04). The large-sized graft group suffered higher early mortality compared with the normal-sized graft group (30 days: 14.5% versus 5.6%, P = 0.02, 90 days: 21.1% versus 9.6%, P = 0.01). The primary causes of early death were multiple organ failure (10.5% versus 2%, P = 0.002) and sepsis (2.6% versus 1.5%, P = 0.54). Four parameters including donor alanine transaminase, GWRW, estimated blood loss and model for end-stage liver disease score were significant on multivariate analysis, and indicated significant risk factors for the early mortality of recipients. CONCLUSION: In deceased donor LT, GWRW >2.5% is associated with increased liver injury, risk of early mortality and other adverse outcomes. Thus, donor livers should be allocated to recipients with GWRW ≤2.5%.

Laparoscopic hepatectomy assisted by a flexible 915 MHz microwave antenna: A safe and innovative device for hepatectomy.

BACKGROUND: The objective of the present study was to elaborate a flexible 915 MHz microwave antenna (F915 MMA) and to evaluate the safety and feasibility in laparoscopic hepatecyomy (LH). METHODS: The F915 MMA was redesigned based on the experiences in clinical practice. Ten porcine LHs were divided into a 'flexible' group and a control group, with 5 porcine LHs in each group. The F915 MMA was used in the flexible group. The data for 48 patients who underwent LH were analyzed; 12 patients underwent F915 MMA-assisted LH and were regarded as the flexible group, and the others were considered as controls. RESULTS: The F915 MMA bends freely and rotates flexibly. In the porcine LH in vivo, the flexible group had less intraoperative blood loss (54.00 ±â€¯27.02 ml vs 230.00 ±â€¯83.67 ml, P = 0.002), and the mean duration of hepatic parenchyma transection in the flexible group was significantly shorter than that in the control group (17.3 ±â€¯7.8min vs 37.9 ±â€¯6.4min). Among th patients, compared to the control group, the flexible group had less intraoperative blood loss (154.17 ±â€¯68.95 ml vs 284.86 ±â€¯294.68 ml, P = 0.018), less frequency and duration of the first porta hepatic occlusion (1.50 ±â€¯0.52times vs 2.35 ±â€¯1.14times, P = 0.021 and 22.50 ±â€¯7.83min vs 35.95 ±â€¯17.23min, P = 0.017, respectively) and lower accumulative complications (33.3% vs 80.5%, P = 0.008). CONCLUSIONS: Laparoscopic F915 MMA is an innovative device that can assist LH in a safe, feasible and flexible manner.

Pretransplant renal function evaluated by serum cystatin C was associated with mortality after liver transplantation: a single-center experience.

BACKGROUND: In the model for end-stage liver disease (MELD) score, renal function was well thought to be associated with the prognosis of liver recipients. Serum cystatin C (CystC)-based equations were considered more accurate for calculating estimated glomerular filtration rate (eGFR) than creatinine (Pcr) based equations. Thus, we aimed to assess the association between eGFR estimated by chronic kidney disease epidemiology collaboration (CKD-EPI)-CystC equation and post-transplantation mortality. METHODS: From January 2015 to January 2018, prior to liver transplantation (LT) and other clinical parameters, CystC was collected in all 307 consecutive patients who underwent LT at our center. Patients were divided into four groups according to the Kidney Disease Outcomes Quality Initiative (KDOQI) classification. RESULTS: Based on CKD-EPI-CystC and the KDOQI classification, 117 patients (38.1%) were stage I, 76 (24.8%) were stage II, 85 (27.7%) were stage III, and 29 (9.4%) were stage IV-V. After univariate and multivariate analysis, MELD score [hazard ratio (HR) =1.035; 95% confidence interval (CI), 1.006-1.066; P=0.018], associated HCC (HR =2.314; 95% CI, 1.253-4.273; P=0.007), and KDOQI stage III (HR =1.850; 95% CI, 1.001-3.419; P=0.049), and stage IV-V (HR =3.915; 95% CI, 1.843-8.316; P<0.001) according to CKD-EPI-CystC equation were confirmed to be independent prognostic factors for post-LT survival. CONCLUSIONS: The pretransplant renal function evaluated by serum CystC was associated with mortality after LT and could be used for predicting post-transplant survival.

Graft-Versus-Tumor Effect in Major Histocompatibility Complex-Mismatched Mouse Liver Transplantation.

Liver transplantation (LT) is currently considered an important method in treating hepatocellular carcinoma (HCC) and an alternative treatment for other liver malignancies. Here, we demonstrated that the graft-versus-tumor (GVT) effect exists in allogeneic liver transplantation (allo LT). Recipient-derived T cells played a critical role in the GVT process of allo LT, as demonstrated by extensive infiltration and significant activation of recipient T cells in the tumor after surgery. Moreover, this process was related to donor-derived T/B cells by improving the immune microenvironment in the tumor, as demonstrated by elevated levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-6, IL-16, chemokine (C-X-C motif) ligand 10 (CXCL10), and CXCL11 and decreased levels of IL-10 and IL-4 at tumor sites. Additionally, tacrolimus (FK506) treatment inhibited the GVT effect on allo LT. Donor liver-derived T/B cells infiltrate extrahepatic tumors to trigger a strong T-cell-mediated immune response and thus improve the tumor immune microenvironment.

Albumin Based Nanomedicine for Enhancing Tacrolimus Safety and Lymphatic Targeting Efficiency.

The increasing demand of organ transplantation and the frequent occurrence of transplant rejection necessitate the development of new therapies. Immunosuppressant marks an effective therapeutic strategy but is usually impeded by its toxicity, untargeted delivery to draining lymph node. The emergence of nanoformulations provides a possibly way to address these challenges. In this work, we prepared a novel human serum albumin (HSA) nanoformulation loaded with a well-known immunosuppressant tacrolimus (TAC) (termed TAC-HSA-NPs), via a simple self-assembly procedure of albumin in aqueous solution to enhance the solubility of TAC. By adjusting the molar ratio of HSA to TAC, we were able to take control of several key parameters of the obtained nanoparticles, such as loading capacity and particle size. Under the molar ratio of HSA:TAC = 1:10, TAC-HSA-NPs showed a mean size of 164 ± 51 nm with reliable pharmacokinetic stability, prolonged blood circulation time as well as decreased renal toxicity. More importantly, in vivo mice allo-heart transplantation verified the efficient lymphatic targeting of TAC-HSA-NPs, which is of crucial significance for immunosuppression in heart transplant recipients. Overall, our study proposed a new nanoformulation of TAC-HSA-NPs and confirmed the potential application in organ transplantation.

915-MHz microwave-assisted laparoscopic hepatectomy: a new technique for liver resection.

BACKGROUND: Hemorrhage during the liver transection is the major hazard for laparoscopic hepatectomy (LH). We aimed to evaluate the feasibility and safety of a 915-MHz microwave device used in LH. METHODS: Data were retrospectively analyzed regarding 60 patients who underwent LH with or without 915-MHz microwave coagulation at our center from January 2016 to June 2016. 30 patients underwent the 915-MHz microwave-assisted LH (MW group), and 30 patients otherwise were considered as control group. RESULTS: No perioperative mortality was observed. Intraoperative blood loss amounts in microwave group and control group were 26.83 ml and 186.33 ml, respectively (P < 0.001). The durations of parenchyma transaction (55.17 vs. 70.83 min, P < 0.001), blood occlusion (2.17 vs. 25.33 min, P < 0.001), and operation (120.67 vs. 148.00 min, P < 0.001) were much shorter in microwave group compared with control group. Lower incidence of postoperative complications (0.0 vs. 14.3%, P = 0.038) and shorter length of postoperative hospital stay (6.00 vs. 7.23 days, P = 0.027) were also noted in the microwave group, compared with the control group. CONCLUSION: 915-MHz microwave-assisted LH was found to be safe and efficient.

Strategy for discriminating cholesterol and premalignancy in polypoid lesions of the gallbladder: a single-centre, retrospective cohort study.

BACKGROUND: The present study aimed to assess the risk factors of cholesterol and premalignancy in polypoid lesions of the gallbladder (PLGs) and to establish an appropriate treatment strategy. METHODS: Data from patients who underwent cholecystectomy at the First Affiliated Hospital, School of Medicine, Zhejiang University, between January 2011 and July 2017, were collected retrospectively. RESULTS: A total of 1561 patients were included in the present study. The cohort comprised of 636 (40.7%) males and 925 (59.3%) females, with a mean age of 49.5 (range 16-88) years; 65.6% (1024/1561) demonstrated cholesterol lesions in this cohort, among which cholesterol polyps accounted for 81.0%. Age younger than 50 years and multiple number of polyps were found to be independent predictive variables for cholesterol lesions (odds ratio (OR) 3.461, 95% confidence interval (CI) 2.058-5.820, P < 0.001 and OR 3.321, 95% CI 1.988-5.547, P < 0.001, respectively). The presence of polyp growth was associated with premalignancy (OR 5.366, 95% CI 1.466-19.637, P = 0.011), and the presence of clinical symptoms indicated benign non-cholesterol lesions (OR 0.368, 95% CI 0.153-0.885, P = 0.026). CONCLUSION: In the case of patients ≥50 years old with single asymptomatic polyp, cholecystectomy was recommended if the polyp presented growth at a rate above 3-4 mm within 6 months. If not, trimonthly ultrasound follow up was recommended, and clinicians should carefully assess the risk factors for premalignancy in PLGs.

Natural product pectolinarigenin inhibits proliferation, induces apoptosis, and causes G2/M phase arrest of HCC via PI3K/AKT/mTOR/ERK signaling pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by considerable phenotypic and molecular heterogeneity, but the overall survival of HCC patients remains extremely poor. Thus, novel and efficient alternatives to antitumor agents are urgently needed. Pectolinarigenin, a flavonoid compound extract, has been previously reported for the treatment of nasopharyngeal cancer. However, the potential antitumor roles of pectolinarigenin in HCC have not been clearly elaborated. In the present study, we investigated its role in HCC treatment and explored the potential molecular mechanism(s). MATERIALS AND METHODS: HCC cell lines SMMC7721 and PLC5 were cultured and treated with indicated concentrations of pectolinarigenin. For the HCC cell proliferation, after HCC cells were stimulated with indicated concentrations of pectolinarigenin, the cell viability was detected in CCK-8 and colony-forming assays. HCC cell invasion/migration assay was performed by Transwell and wound scratch methods. Additionally, cellular apoptosis and cell cycle arrest analysis was performed with flow cytometric analysis. Finally, the involved underlying signaling pathway, the PI3K/AKT/mTOR/ERK signaling-related molecular markers were detected through Western blot methods with indicated antibodies. Meanwhile, antitumor activity of pectolinarigenin was also assessed in tumor-bearing mice. RESULTS: The results indicated that the treatment with pectolinarigenin significantly inhibited cell proliferation and migratory and invasive abilities of SMMC7721 and PLC5 cells in concentration- and time-dependent manner. Meanwhile, pectolinarigenin markedly induced cell apoptosis and G2/M phase arrest in SMMC7721 and PLC5 cells, which was associated with apoptosis- and cell cycle-related protein levels, respectively. Furthermore, pectolinarigenin inhibited PI3K/AKT/mTOR/ERK signaling pathway. It also significantly suppressed HCC tumor growth in vivo. CONCLUSION: Pectolinarigenin could suppress the viability and motility and cause apoptosis and G2/M phase arrest in HCC cell lines by inhibiting the PI3K/AKT/mTOR/ERK signaling pathway. This might be an appealing potential therapeutic agent for HCC treatment.

Elevated expression of neuropilin-2 associated with unfavorable prognosis in hepatocellular carcinoma.

Neuropilin-2 (NRP2) is a single-pass transmembrane glycoprotein and has recently been detected in several human cancer cells. However, its clinical relevance in hepatocellular carcinoma (HCC) remains unclear. This study aimed at evaluating NRP2 expression and clinicopathological significance in HCC patients. Tissue microarray of 190 HCC patients from the First Affiliated Hospital of Zhejiang University was established, and immunohistochemical staining was performed for NRP2. The Kaplan-Meier analysis and Cox proportional hazard model were used to analyze the survival rate. We found that NRP2 expression in HCC was significantly associated with tumor histological degree (P=0.023) and cirrhosis (P=0.040). Furthermore, NRP2-positive HCC patients demonstrated shorter disease-free survival (DFS) and overall survival (OS) than those of NRP2-negative patients. Then, the multivariate Cox analysis showed that hazard ratios of NRP2-positive patients with DFS and OS were 2.167 (95% CI: 1.626, 2.889) and 2.317 (95% CI: 1.548, 3.469), respectively. Our results suggested that NRP2 expression was considered as an independent factor for the prediction of unfavorable prognosis in HCC patients, and we believe that NRP2 could serve as a biomarker of poor prognosis and a novel target in treating HCC tumors.