Cross-talk between hepatic stellate cells and T lymphocytes in liver fibrosis.

BACKGROUND: Fibrosis results from inflammation and healing following injury. The imbalance between extracellular matrix (ECM) secretion and degradation leads to the ECM accumulation and liver fibrosis. This process is regulated by immune cells. T lymphocytes, including alpha beta (αß) T cells, which have adaptive immune functions, and gamma delta (γδ) T cells, which have innate immune functions, are considered regulators of liver fibrosis. This review aimed to present the current understanding of the cross-talk between T lymphocytes and hepatic stellate cells (HSCs), which are the key cells in liver fibrosis. DATA SOURCES: The keywords "liver fibrosis", "immune", and "T cells" were used to retrieve articles published in PubMed database before January 31, 2020. RESULTS: The ratio of CD8+ (suppressor) T cells to CD4+ (helper) T cells is significantly higher in the liver than in the peripheral blood. T cells secrete a series of cytokines and chemokines to regulate the inflammation in the liver and the activation of HSCs to influence the course of liver fibrosis. In addition, HSCs also regulate the differentiation and proliferation of T cells. CONCLUSIONS: The cross-talk between T cells and HSCs regulates liver fibrosis progression. The elucidation of this communication process will help us to understand the pathological process of liver fibrosis.

Human cytomegalovirus IE1 downregulates Hes1 in neural progenitor cells as a potential E3 ubiquitin ligase.

Congenital human cytomegalovirus (HCMV) infection is the leading cause of neurological disabilities in children worldwide, but the mechanisms underlying these disorders are far from well-defined. HCMV infection has been shown to dysregulate the Notch signaling pathway in human neural progenitor cells (NPCs). As an important downstream effector of Notch signaling, the transcriptional regulator Hairy and Enhancer of Split 1 (Hes1) is essential for governing NPC fate and fetal brain development. In the present study, we report that HCMV infection downregulates Hes1 protein levels in infected NPCs. The HCMV 72-kDa immediate-early 1 protein (IE1) is involved in Hes1 degradation by assembling a ubiquitination complex and promoting Hes1 ubiquitination as a potential E3 ubiquitin ligase, followed by proteasomal degradation of Hes1. Sp100A, an important component of PML nuclear bodies, is identified to be another target of IE1-mediated ubiquitination. A C-terminal acidic region in IE1, spanning amino acids 451 to 475, is required for IE1/Hes1 physical interaction and IE1-mediated Hes1 ubiquitination, but is dispensable for IE1/Sp100A interaction and ubiquitination. Our study suggests a novel mechanism linking downregulation of Hes1 protein to neurodevelopmental disorders caused by HCMV infection. Our findings also complement the current knowledge of herpesviruses by identifying IE1 as the first potential HCMV-encoded E3 ubiquitin ligase.

The effects of the location of cancer stem cell marker CD133 on the prognosis of hepatocellular carcinoma patients.

BACKGROUND: CD133 (prominin-1) is widely believed to be a cancer stem cell marker in various solid tumor types, and CD133 has been correlated with tumor-initiating capacity. Recently, the nuclear location of CD133 expression in tumors has been discussed, but hepatocellular carcinoma (HCC) has not been included in these discussions. The goal of this study was to investigate the location of CD133 expression in HCC and this location's potential value as a prognostic indicator of survival in patients with HCC. METHODS: We enrolled 119 cancerous tissues and pair-matched adjacent normal liver tissue from HCC patients. These tissues were obtained immediately after operation, and tissue microarrays were subsequently constructed. The expression of CD133 was measured by immunohistochemistry (IHC), and the correlations between this expression and clinical characteristics and prognosis was estimated using statistical analysis. RESULTS: The results showed that the CD133 protein expression levels of HCC in both the cytoplasm and nucleus were significantly higher than adjacent normal liver tissue. Kaplan-Meier survival and Cox regression analyses revealed that high CD133 expression in the cytoplasm was an independent predictor of poor prognosis for the overall survival (OS) and relapse-free survival (RFS) rates of HCC patients (P = 0.028 and P = 0.046, respectively). Surprisingly, high nuclear CD133 expression of HCC was an independent predictor of the good prognosis of the OS and RFS rates of HCC patients (P = 0.023 and P = 0.012, respectively). CONCLUSIONS: The clinical evidence that revealed cytoplasmic CD133 expression was correlated with poor prognosis, while nuclear CD133 expression was significantly correlated with favorable prognosis.

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients.

The highly variable pharmacokinetics and narrow therapeutic window of tacrolimus (TAC) has hampered its clinical use. Genetic polymorphisms may contribute to the variable response, but the evidence is not compelling, and the explanation is unclear. In this study we attempted to find previously unknown genetic factors that may influence the TAC dose requirements. The association of 105 pathway-related single nucleotide polymorphisms (SNPs) with TAC dose-adjusted concentrations (C0/D) was examined at 7, 30 and 90 d post-operation in 382 Chinese kidney transplant recipients. In CYP3A5 non-expressers, the patients carrying the IL-3 rs181781 AA genotype showed a significantly higher TAC logC0/D than those with the AG genotype at 30 and 90 d post-operation (AA vs AG, 2.21±0.06 vs 2.01±0.03, P=0.004; and 2.17±0.06 vs 2.03±0.03, P=0.033, respectively), and than those with the GG genotype at 30 d (AA vs GG, 2.21±0.06 vs 2.04±0.03, P =0.011). At 30 d, the TAC logC0/D in the grouped AG+GG genotypes of CTLA4 rs4553808 was significantly lower than that in the AA genotype (P =0.041) in CYP3A5 expressers, but it was higher (P=0.008) in the non-expressers. We further validated the influence of CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437 on the TAC C0/D; other candidate SNPs were not associated with the differences in TAC C0/D. In conclusion, genetic polymorphisms in the immune genes IL-3 rs181781 and CTLA4 rs4553808 may influence the TAC C0/D. They may, together with CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437, contribute to the variation in TAC dose requirements. When conducting individualized therapy with tacrolimus, these genetic factors should be taken into account.

Tacrolimus decreases insulin sensitivity without reducing fasting insulin concentration: a 2-year follow-up study in kidney transplant recipients.

New Onset Diabetes after Transplantation (NODAT) is defined as sustained hyperglycemia developing in patients without diabetes history before transplantation. A cohort study was performed to access the effects of tacrolimus on insulin secretion and insulin sensitivity and consequently in the development of NODAT in kidney transplant recipients. Then, we further investigated the association between NODAT and single-nucleotide polymorphisms of IRS-1 and IRS-2 in renal allograft recipients. One hundred and fifty-eight kidney transplant patients, receiving tacrolimus as the base immunosuppressant, were divided into two groups: with or without NODAT. Plasma levels of fasting insulin concentration (FINS) and C-peptide were determined by enhanced chemiluminescence immunoassay and ADVIA Centaur C peptide assay, respectively. The genotypes of Gly1057Asp in IRS-2 and Gly972Arg in IRS-1 were detected through polymerase chain reaction fragment length polymorphism in NODAT and non-NODAT patients. It was found that the concentrations of fasting plasma insulin and C-peptide in NODAT and non-NODAT patients treated with tacrolimus were higher than that in healthy volunteers (p < 0.05). Fasting plasma insulin concentration in NODAT was significantly elevated compared with than that in non-NODAT group (p < 0.05). But there are no statistical differences in fasting plasma C-peptide concentrations between NODAT and non-NODAT groups. The allele and genotype frequencies of IRS-2 Gly1057Asp and IRS-1 Gly972Arg in NODAT patients were not significantly different from non-NODAT patients (p > 0.05). In conclusion, insulin resistance is the primary cause of tacrolimus-induced NODAT. The IRS-2 Gly1057Asp and IRS-1 Gly972Arg genotypes are not related to NODAT.

miR-24 promotes the proliferation and invasion of HCC cells by targeting SOX7.

Accumulating evidence shows that microRNAs (miRNAs) are involved in the development and progression of multiple tumors, including hepatocellular carcinoma (HCC). Recent studies have found that miR-24 acts as an oncogene in several tumors; however, the function of miR-24 in HCC remains unclear. In this study, we found that miR-24 was increased in HCC tissues and cell lines. Inhibition of miR-24 by inhibitor significantly suppressed HCC cells proliferation, migration, and invasion. Furthermore, the sex-determining region Y (SRY)-box 7 (SOX7), a putative tumor suppressor, was found to be a target of miR-24 in HCC cells. Forced expression of SOX7 substantially attenuated the oncogenic effects of miR-24. Those results strongly suggest that miR-24 plays important role in HCC development partially by targeting SOX7.

Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis.

OBJECTIVE: Tacrolimus is used clinically for the long-term treatment of antirejection of transplanted organs in liver and kidney transplant recipients, although dose optimization is poorly managed. The aim of this study was to examine the association between tacrolimus pharmacokinetic variability and CYP3A4 and CYP3A5 genotypes by a population pharmacokinetic analysis based on routine drug monitoring data in adult renal transplant recipients. MATERIALS AND METHODS: Trough tacrolimus concentrations were obtained from 161 adult kidney transplant recipients after transplantation. The population pharmacokinetic analysis was carried out using the nonlinear mixed-effect modeling software NONMEM version 7.2. The CYP3A4*1G and CYP3A5*3 genetic polymorphisms from the patients studied were determined by direct sequencing using a validated automated genetic analyzer. RESULTS: A one-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of tacrolimus. Covariates including CYP3A5*3 and CYP3A4*1G alleles and hematocrit were retained in the final model. The apparent clearance of tacrolimus was about two-fold higher in kidney transplant patients with higher enzymatic activity of CYP3A5*1 and CYP3A4*1G (with the CYP3A5*1/*1 or *1/*3 and CYP3A4*1/*1G or CYP3A4*1G/*1G) compared with those with lower enzymatic activity (CYP3A5*3/*3 and CYP3A4*1/*1). CONCLUSION: This is the first study to extensively determine the effect of CYP3A4*1G and CYP3A5*3 genetic polymorphisms and hematocrit value on tacrolimus pharmacokinetics in Chinese renal transplant recipients. The findings suggest that CYP3A5*3 and CYP3A4*1G polymorphisms and hematocrit are determinant factors in the apparent clearance of tacrolimus. The initial dose design is mainly based on CYP3A5 and CYP3A4 genotypes as well as hematocrit. This result may also be useful for maintenance tacrolimus dose optimization and may help to avoid fluctuating tacrolimus levels and improve the efficacy and tolerability of tacrolimus in kidney transplant recipients.

Hepatic veins anatomy and piggy-back liver transplantation.

BACKGROUND: The piggy-back caval anastomosis technique is widely used in orthotopic liver transplantation although it carries an increased risk of complications, including outflow obstruction and Budd-Chiari syndrome. The aim of this study is to clarify the anatomy and variations of hepatic veins (HVs) draining into the inferior vena cava (IVC), and to classify the surgical techniques of piggy-back liver transplantation (PBLT) based on the anatomy of HVs which can reduce the occurrence of complications. METHODS: PBLT was performed in 248 consecutive cases at our hospital from January 2004 to August 2011. The anatomy of recipients' HVs was determined when removing the native diseased livers. Both anatomy of HVs and short HVs draining into the IVC were recorded. These data were collected and analyzed. RESULTS: We classified anatomic variations of HVs in the 248 livers into five types according to the way of drainage into the IVC: type I (trunk type of left and middle HVs), 142 (57.3%) patients; type II (trunk type of right and middle HVs), 54 (21.8%); type III (trunk type of left, middle and right HVs), 14 (5.6%); type IV (non-trunk type of left, middle and right HVs), of which, type IVa, 16 (6.5%), in the same horizontal plane; type IVb, 18 (7.3%), in different horizontal planes; and type V (segment type), 4 (1.6%). The patients whose HVs anatomy belonged to types I, II and III underwent classical piggy-back liver transplantation. Type IVa patients had classical PBLT via HV venoplasty prior to piggy-back anastomosis, while type IVb patients and type V patients could only have modified PBLT. CONCLUSION: This study demonstrates that HVs can be classified according to the anatomy of their drainage into the IVC and we can use this classification to choose the best operative approach to PBLT.

[Evaluation of the renal replacement therapy on the liver transplant patients with acute renal failure].

OBJECTIVE: To analyze the preoperative risk factors on liver transplant recipients with acute renal failure(ARF), and to evaluate renal replacement therapy (RRT) as a transitonary therapy before liver transplantation. METHODS: Liver transplant recipients with acute renal failure treated with renal replacement therapy between January 1st, 2001 and January 1st, 2008 in our center were retrospected. Clinical characteristics, the kinds of RRT and prognosis were analyzed; Logistic regression was applied to analyze the parameters that can forecast the motality of the liver transplant recipients with acute renal failure. RESULTS: Of the patients who received RRT, 30% survived to liver transplantation, 67.5% died while waiting for liver transplantation. The dead had a higher multiple organ dysfunction score (MODS), and lower mean arterial pressure than those survived to liver transplantation. There was no significant difference in the duration of RRT between continuous renal replacement therapy (CRRT) patients and hemodialysis patients. CRRT patients had a higher MODS, lower mean arterial pressure, lower serum creatinine than hemodialysis patients. Lower mean arterial pressure was statistically associated with higher risk of mortality. CONCLUSION: Though mortality was high, RRT helps part (30%) of patients survive to liver transplantation. Therefore, considering the high mortality without transplantation, RRT is acceptable for liver transplant recipients with ARF.

Incorporation of Gene-Environment Interaction Terms Improved the Predictive Accuracy of Tacrolimus Stable Dose Algorithms in Chinese Adult Renal Transplant Recipients.

The narrow therapeutic window of tacrolimus necessitates daily monitoring and predictive algorithms based on genetic and nongenetic factors. In this study, we constructed predictive algorithms for tacrolimus stable dose in a retrospective cohort of 1045 Chinese renal transplant recipients. All patients were genotyped for CYP3A4 20230T>C (rs2242480), CYP3A4 T>C (rs4646437), CYP3A5*3 6898A>G (rs776746), ABCB1 129T>C (rs3213619); ABCB1 c.1236C>T (rs01128503), ABCB1 c.2677G>T/A (rs2032582) and ABCB1 c.3435C>T (rs1045642) polymorphisms, and the effects of gene-gene and gene-environment interactions on the predictive accuracy of algorithm were evaluated. In wild-type CYP3A4 rs2242480 (TT) carriers, patients who took calcium channel blockers had lower tacrolimus stable doses than those without the concomitant medications (P < 1 × 10-4 ). In contrast, there was no significant difference in mutant type patients. Similarly, the tacrolimus stable doses in wild-type CYP3A5 rs776746 carriers who had hypertension were higher than those without hypertension (P = 4.10 × 10-3 ). More importantly, dose-predictive algorithms with interaction terms showed higher accuracy and better performance than those without interaction terms. Our finding suggested that wild-type CYP3A4 rs2242480 (TT) carriers should be more cautious to take tacrolimus when they are coadministrated with calcium channel blockers, and CYP3A5 rs776746 (AA) carriers may need higher tacrolimus dosage when they are in combination with hypertension.

[Piggy-back liver transplantation in treating acute liver failure patients: a report of 15 cases].

OBJECTIVE: To study the clinical significance of piggy-back liver transplantation in treating acute liver failure (ALF). METHODS: Fifteen ALF patients (13 caused by HBV and 2 with acute Wilson disease) had piggy-back liver transplantations (PBLT) in our hospital from Sept 1999 to Feb 2006. The outcomes of these patients were retrospectively analyzed. RESULTS: One year survival rate of the 15 patients was 87% (13/15). Excellent outcome was achieved in the 2 acute Wilson disease cases: their corneal Kayser-Fleischer rings disappeared and serum ceruloplasmin levels returned to normal. Among the 15 cases, one died of severe pulmonary infection and another died of multiple organ system failure on the 6th and 11th postoperative days. HBsAg positivity was observed in 13 cases before liver transplantation. Eleven patients survived and later received anti-HBV treatment recommended by the American Association for the Study of Liver Diseases. Their HBsAg became negative. CONCLUSION: Liver transplantation is an effective therapy for ALF and can improve survival rate significantly.

Corrigendum: Application of Machine-Learning Models to Predict Tacrolimus Stable Dose in Renal Transplant Recipients.

This corrects the article DOI: 10.1038/srep42192.

Pedicled greater omentum flap for preventing bile leak in liver transplantation patients with poor biliary tract conditions.

BACKGROUND: Bile leak remains a main complication in liver transplantation patients with poor biliary tract conditions, mainly caused by an insufficient blood supply or dysplasia of the biliary tract. Although Roux-en-Y modus operandi can be adopted, the risk of other complications of the biliary tract such as infection increases. Using pedicled greater omentum flaps to wrap the anastomotic stoma, which increases the biliary tract blood supply, may reduce the incidence of bile leak. METHODS: Fourteen patients undergoing piggy-back liver transplantation and having poor biliary tract conditions were treated with pedicled greater omentum flaps to wrap the anastomotic stoma of the biliary tract. Their clinical data were analyzed retrospectively. RESULTS: Of the 14 patients, only one (7.1%) had a mild bile leak on the 8th day post-operation and fully recovered after symptomatic treatment. The other patients had no biliary complications. CONCLUSIONS: Using pedicled greater omentum flaps to wrap the anastomotic stoma of the biliary tract is an effective way to prevent bile leak in liver transplantation patients, especially those with poor biliary tract conditions. However, experience with this surgical technique still needs to be further explored.

[Effect of extract of ginkgo biloba leaves on the precondition of liver graft in rat liver transplantation].

OBJECTIVE: To explore the effect of extract of ginkgo biloba leaves on the precondition of liver graft in rat liver transplantation. METHODS: Male Sprague-Dawley rats were used as donors and recipients of orthotopic liver transplantation (OLT), and were randomly divided into extract of ginkgo biloba leaves group (Egb), NS control group (NS), and sham operation group (SO) according to whether the extract of ginkgo biloba leaves was injected by the venous (40 mg/kg) 1 h before the liver grafts harvesting. The rats were killed at 2 h, 6 h, and 24 h after the ischemia/reperfusion. The serum concentrations of ALT and AST were determined and the liver tissue were sampled to observe the expression of TNF-alpha and IL-1. RESULTS: After the ischemia/reperfusion the serum concentration of ALT and AST and expressions of TNF-alpha and IL-1 in the hepatic tissue in the NS group significantly increased (p<0.01), and the hepatocytic morphologic change was obvious compared with the SO group. The treatment of ginkgo biloba extract significantly decreased the serum concentration of ALT and AST and the expressions of TNF-alpha and IL-1 in the hepatic tissue in EGb group compared with the NS group (p<0.01), and relieved the hepatocyte swelling and necrosis. CONCLUSION: Ginkgo bilobA extract may decrease the release of TNF-alpha and IL-1 by inhibiting activation of kuffer cells and regulate the cell factors to protect the live.

Phosphorylated AKT expression in tumor-adjacent normal tissue is associated with poor prognosis in patients with hepatocellular carcinoma.

The AKT pathway serves important roles in tumor cell growth. Its overexpression is associated with poor prognosis in a number of types of cancer; however, the role of AKT in the role of the pathogenesis of hepatocellular carcinoma (HCC) remains unclear. The present study was undertaken to explore the clinical relevance of phosphorylated AKT (p-AKT) in HCC. The level of p-AKT in tumor (TU) and paired adjacent normal liver (AN) tissue from 202 HCC patients was evaluated with immunohistochemistry. The results demonstrated that p-AKT was more highly expressed in TU than in AN tissue. Kaplan-Meier curves and Cox regression revealed that patients with a high expression of p-AKT (AN) exhibited reduced overall and relapse-free survival times; this was not observed at a statistically significant level in p-AKT (TU). Additionally, the high expression of p-AKT (AN) was positively correlated with hepatitis C virus (HCV) infection in HCC patients. These results support the hypothesis that AKT activation is a mechanism of HCV-induced hepatocarcinogenesis, suggesting that AKT can be a therapeutic target for the treatment of recurrent HCC subsequent to surgical resection.

A Follow-Up Study on the Renal Protective Efficacy of Telbivudine for Hepatitis B Virus-Infected Taiwanese Patients After Living Donor Liver Transplant.

OBJECTIVES: Preservation of renal function is an important issue after living donor liver transplant. We aimed to examine the renal protective efficacy of telbivudine in hepatitis B virus-infected patients after living donor liver transplant. MATERIALS AND METHODS: In this retrospective study, we compared 18 patients who received telbivudine 600 mg once per day and 23 patients who received entecavir 1 mg once per day after living donor liver transplant. Clinical data were obtained through chart review and included Model for End-Stage Liver Disease score and pre- and postoperative aspartate aminotransferase, alanine aminotransferase, and creatinine levels and estimated glomerular filtration rate. RESULTS: Posttransplant estimated glomerular filtration rates and creatinine levels were calculated, and improvement of renal function was found in the group of patients who received telbivudine. Significant improvements were shown in estimated glomerular filtration rates started after 9 months of administration and creatinine levels after 12 months compared with patients who received entecavir. CONCLUSIONS: In our study, long-term telbivudine therapy is associated with a sustained improvement of renal function in patients with hepatitis B virus infection after living donor liver transplant.