Metformin decreases IL-22 secretion to suppress tumor growth in an orthotopic mouse model of hepatocellular carcinoma.

Epidemiological, preclinical and cellular studies in the last 5 years have shown that metformin exerts anti-tumoral properties, but its mode of action in cancer remains unclear. Here, we investigated the effects of metformin on a mouse hepatocellular carcinoma (HCC) model and tumor-associated T cell immune responses. Oral metformin administration led to a significant reduction of tumor growth, which was accompanied by decreased interleukin-22 (IL-22). Meanwhile, IL-22-induced STAT3 phosphorylation and upregulation of downstream genes Bcl-2 and cyclin D1 were inhibited by metformin. At the cellular level, metformin attenuated Th1- and Th17-derived IL-22 production. Furthermore, metformin inhibited de novo generation of Th1 and Th17 cells from naive CD4(+) cells. These observations were further supported by the fact that metformin treatment inhibited CD3/CD28-induced IFN-γ and IL-17A expression along with the transcription factors that drive their expression (T-bet [Th1] and ROR-γt [Th17], respectively). The effects of metformin on T cell differentiation were mediated by downregulated STAT3 and STAT4 phosphorylation via the AMP-activated kinase-mammalian target of rapamycin complex 1 pathway. Notably, metformin led to a reduction in glucose transporter Glut1 expression, resulting in less glucose uptake, which is critical to regulate CD4(+) T cell fate. Taken together, these findings provide evidence for the growth-inhibitory and immune-modulatory effects of metformin in HCC and thus, broaden our understanding about the action of metformin in liver cancer treatment.

Extended hepatectomy with segments I and VII as resection remnant: a simple model for small-for-size injuries in pigs.

BACKGROUND: Small-for-size (SFS) syndrome is an important clinical problem after living donor liver transplantation, split liver transplantation or extended hepatectomy. The uncertainty of the mechanisms and treatments of SFS syndrome urges surgeons to establish effective models for SFS syndrome. METHODS: A new porcine model for SFS syndrome based on extended hepatectomy was established. Portal pressure gradient was observed before and after the surgery, and venous sampling for estimation of alanine aminotransferase, total bilirubin, and international normalized ratio was continued on a daily basis. RESULTS: Although the external morphology of the porcine liver differs from that of human being, segmental anatomy is remarkably similar in term of its vascularity and biliary tree. Extended hepatectomy with segments I and VII as resection remnant (about 20% of total liver volume) resulted in similar survival rates, blood liver function tests, and elevated portal pressure gradient as clinical SFS syndrome. CONCLUSIONS: The extended hepatectomy based new model can easily be reproduced, with few costs and surgical complications. Clinical SFS syndrome can easily be simulated by this new model, which is a useful tool for studying SFS syndrome-related liver injuries, especially portal overperfusion and hypertension.

Dual Effect of Hepatic Macrophages on Liver Ischemia and Reperfusion Injury during Liver Transplantation.

Ischemia-reperfusion injury (IRI) is a major complication in liver transplantation (LT) and it is closely related to the recovery of grafts' function. Researches has verified that both innate and adaptive immune system are involved in the development of IRI and Kupffer cell (KC), the resident macrophages in the liver, play a pivotal role both in triggering and sustaining the sterile inflammation. Damage-associated molecular patterns (DAMPs), released by the initial dead cell because of the ischemia insult, firstly activate the KC through pattern recognition receptors (PRRs) such as toll-like receptors. Activated KCs is the dominant players in the IRI as it can secret various pro-inflammatory cytokines to exacerbate the injury and recruit other types of immune cells from the circulation. On the other hand, KCs can also serve in a contrary way to ameliorate IRI by upregulating the anti-inflammatory factors. Moreover, new standpoint has been put forward that KCs and macrophages from the circulation may function in different way to influence the inflammation. Managements towards KCs are expected to be the effective way to improve the IRI.

Contrast-enhanced micro-computed tomography using ExiTron nano6000 for assessment of liver injury.

AIM: To explore the potential of contrast-enhanced computed tomography (CECT) using ExiTron nano6000 for assessment of liver lesions in mouse models. METHODS: Three mouse models of liver lesions were used: bile duct ligation (BDL), lipopolysaccharide (LPS)/D-galactosamine (D-GalN), and alcohol. After injection with the contrast agent ExiTron nano6000, the mice were scanned with micro-CT. Liver lesions were evaluated using CECT images, hematoxylin and eosin staining, and serum aminotransferase levels. Macrophage distribution in the injury models was shown by immunohistochemical staining of CD68. The in vitro studies measured the densities of RAW264.7 under different conditions by CECT. RESULTS: In the in vitro studies, CECT provided specific and strong contrast enhancement of liver in mice. CECT could present heterogeneous images and densities of injured livers induced by BDL, LPS/D-GalN, and alcohol. The liver histology and immunochemistry of CD68 demonstrated that both dilated biliary tracts and necrosis in the injured livers could lead to the heterogeneous distribution of macrophages. The in vitro study showed that the RAW264.7 cell masses had higher densities after LPS activation. CONCLUSION: Micro-CT with the contrast agent ExiTron nano6000 is feasible for detecting various liver lesions by emphasizing the heterogeneous textures and densities of CECT images.

Risk factors for new onset diabetes mellitus after liver transplantation: A meta-analysis.

AIM: To determine the risk factors for new-onset diabetes mellitus (NODM) after liver transplantation by conducting a systematic review and meta-analysis. METHODS: We electronically searched the databases of MEDLINE, EMBASE and the Cochrane Library from January 1980 to December 2013 to identify relevant studies reporting risk factors for NODM after liver transplantation. Two authors independently assessed the trials for inclusion and extracted the data. Discrepancies were resolved in consultation with a third reviewer. All statistical analyses were performed with the RevMan5.0 software (The Cochrane Collaboration, Oxford, United Kingdom). Pooled odds ratios (OR) or weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated using either a fixed effects or a random effects model, based on the presence (I (2) < 50%) or absence (I (2) > 50%) of significant heterogeneity. RESULTS: Twenty studies with 4580 patients were included in the meta-analysis, all of which were retrospective. The meta-analysis identified the following significant risk factors: hepatitis C virus (HCV) infection (OR = 2.68; 95%CI: 1.92-3.72); a family history of diabetes (OR = 1.69, 95%CI: 1.09-2.63, P < 0.00001); male gender (OR = 1.53; 95%CI: 1.24-1.90; P < 0.0001); impaired fasting glucose (IFG; OR = 3.27; 95%CI: 1.84-5.81; P < 0.0001); a family history of diabetes (OR = 1.69; 95%CI: 1.09-2.63; P = 0.02); use of tacrolimus (OR = 1.34; 95%CI: 1.03-1.76; P = 0.03) and body mass index (BMI)(WMD = 1.19, 95%CI: 0.69-1.68, P < 0.00001). Other factors, such as hepatitis B virus infection and alcoholism, were not found to be associated with the incidence of NODM. CONCLUSION: The study showed that HCV infection, IFG, a family history of diabetes, male gender, tacrolimus and BMI are risk factors for NODM after liver transplantation.

Liver transplantation for hepatocellular carcinoma: recent advances in China.

Orthotopic liver transplantation is currently the best treatment option for selected patients with hepatocellular carcinoma (HCC). From 1980 to 2011, 8874 patients with HCC in China underwent liver transplantation. The organ donation classification criteria of China (China criteria), which are established by the Government of China, are divided into three parts: China criteria I, donation after brain death; China criteria II, donation after cardiac death and China criteria III, donation after dual brain-cardiac death. Data from the China Liver Transplant Registry(CLTR) System shows that patients within the Milan criteria have higher survival rates than those who are beyond these criteria. Based on CLTR data, altogether 416 patients received living-donor liver transplantation(LDLT) in China. Their 1-year and 3-year survival rates were significantly higher than those of the non-LDLT recipients. The most common early stage(<30 days after liver transplantation) complications include pleural effusion, diabetes, peritoneal effusion or abscess, postoperative infection, hypertension and intraperitoneal hemorrhage; while the most common late stage (≥ 30 days after liver transplantation) complications were diabetes, hypertension, biliary complications,postoperative infection, tacrolimus toxicity and chronic graft rejection. The incidence of vascular complication, which is the main reason for acute graft failure and re-transplantation, was 2.4%. Liver transplantation is an effective treatment for patients with HCC in China.