Novel Method to Remove Bilirubin from the Blood of Jaundiced Rats: A Preliminary Study

BACKGROUND The removal of bilirubin from serum is the primary method for treating hyperbilirubinemia. However, currently used treatment methods have several limitations.AIMTo introduce a novel method to remove bilirubin from the blood of jaundiced rats.METHODS This novel therapy involved cross-circulation of blood between a rat liver preserved in vitro and a rat with hyperbilirubinemia. The liver was perfused with blood from the model animal, resulting in the clearance of serum bilirubin. Twenty rats with jaundice caused by acute liver failure induced using D-galactosamine were treated. All model animals were randomly divided into two groups based on whether they received the novel therapy. Serum samples were collected before modelling, at the beginning of treatment, and 2 hours after treatment. The levels of serum transaminase and bilirubin were detected and compared between different time points. Histological examination of the liver in vitro was also performed after the treatment. Long-term survival was compared by Kaplan-Meier analysis between rats who did and did not receive the novel treatment.RESULTSIn vitro, the liver could be perfused with the blood from the model animal through the portal vein. The bile produced by the liver after 1 hour of therapy was darker than the bile produced while harvesting. Across different hyperbilirubinemia models, serum total bilirubin level was significantly improved (24.8 ± 1.2 vs. 17.4 ± 1.2 μmol/L, P<0.05), despite a rise serum transaminase levels after treatment (AST: 4612 ± 382 vs. 5144 ± 390 U/L, P＞0.05; ALT: 5051 ± 722 vs. 5488 ± 707 U/L, P＜0.05). No necrosis was found in the preserved liver tissue after treatment, and the hepatic lobule structure was normal. Hepatocyte necrosis was not found on histological examination. This novel treatment significantly raised the long-term survival rates of jaundiced rats (P <0.05).CONCLUSIONThis novel method could safely and effectively help eliminate bilirubin from the blood of jaundiced rats.

Dapagliflozin, as Add-on Therapy in Type 2 Diabetes Patients, Is Associated With a Reduction in Albuminuria and Serum Transaminase Levels

IntroductionSGLT-2 inhibitors are shown to be nephroprotective, slowing progression of nonalcoholic steatohepatitis (NASH) in addition to improving glycemic control in patients with type 2 diabetes (T2D). To date, no real-life clinical data is available on the effect of SGLT-2 inhibitors on urine albumin-creatinine ratio (ACR) and liver enzymes in a Middle Eastern population. Therefore, we evaluated the effect of dapagliflozin (DAPA) on urine ACR, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) when added to standard therapy for T2D.MethodsThis is an observational study of 40 patients with T2D in whom DAPA was added to their existing anti-diabetic regimen to improve glycemic control. The primary outcomes were changes in serum transaminase level and urine albumin-to-creatinine ratio (ACR). Secondary outcomes include changes in glycosylated hemoglobin (HbA1C), body mass index (BMI), oral hypoglycemic agents and insulin dose.ResultsWhole group analysis showed a reduction in ALT (p&lt;0.0001), (AST) (p=0.009), ACR (p=0.009) and BMI (p&lt;0.0001) following DAPA treatment. Further sub-group analysis showed that patients on insulin and DAPA combination had a reduction in ACR (p=0.0090), ALT (p=0.0312), BMI (p=0.0007) and HbA1c (p&lt;0.0001) compared to the sulfonylurea and DAPA combination group. In the sulfonylurea and DAPA combination group, there was a reduction in the sulfonylurea requirement following DAPA therapy (p=0.0116), with reductions in ALT (p=0.0122), AST (p=0.0362), BMI (p=0.0026) and HbA1c (p&lt;0.0001) but with no change in ACR (p=0.814).ConclusionIn routine clinical practice, the addition of DAPA to standard medical therapy is well tolerated and beneficial for T2D patients and is associated with a reduction of ALT and ACR.

Chlorogenic Acid Improves NAFLD by Regulating gut Microbiota and GLP-1

Our previous studies have shown that chlorogenic acid (CGA) could significantly improve acute and chronic liver injury through antioxidant and anti-inflammatory activities. However, its effect on non-alcoholic fatty liver disease (NAFLD) are not entirely clear. This study aims to explore the effect of CGA on NAFLD induced by high-fat diet (HFD) and whether it regulates the gut microbiota and Glucagon-like peptide-1 (GLP-1). NAFLD mice were established by HFD and treated with or without CGA. Serum transaminase, fasting blood glucose (FBG), blood lipids, insulin, GLP-1 and lipopolysaccharide (LPS) were detected. Liver histology was evaluated with Hematoxylin-eosin staining. Toll like receptor 4 (TLR4) signaling pathway was analyzed with western blot and inflammatory cytokines were detected with real-time PCR. The content of gut microbiota were determined with real-time PCR of the bacterial 16S rRNA gene. Expressions of intestine tight junctional protein were examined with immunohistochemistry. CGA could alleviate HFD-induced hepatic steatosis and inflammation, reduce serum transaminase, FBG and blood lipids, increase insulin sensitivity. CGA also could reverse HFD-induced activation of TLR4 signaling pathway and expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in liver. Meanwhile, CGA increased the content of Bifidobacterium and reduced the content of Escherichia coli in feces. Furthermore, CGA could increase the expression of tight junction proteins Occludin and zonula occludens-1 (ZO-1) in intestinal tissue. Moreover, CGA could the level of LPS and increased the level of GLP-1 in portal vein. These results indicated that CGA protected against HFD-induced hepatic steatosis and inflammation probably through its anti-inflammatory effects associated with regulation of gut microbiota and an increase of GLP-1 secretion and thus could be used as a potential drug for prevention and treatment of NAFLD.

MAN1B1-CDG: novel patients and novel variant

Objectives Congenital disorders of glycosylation (CDGs) are a group of genetic disorders due to hypoglycosylation of proteins and lipids. A type I pattern is associated with defects in glycan assembly and transfer (CDG-I; cytosol; and endoplasmic reticulum defects), a type II pattern is seen in processing defects of the Golgi apparatus. MAN1B1-CDG is an autosomal recessive CDG-II due to mutations in the α 1,2-mannosidase gene (MAN1B1), mainly characterized by psychomotor disability, facial dysmorphism, truncal obesity, and hypotonia. Case presentation Three patients (two males and one female), with MAN1B1-CDG who had elevated transaminase levels are presented. All patients had presented due to dysmorphic and neurological findings and hypertransaminasemia was remarkable. A type 2 pattern was found on serum transferrin isoelectrofocusing analysis of the presented cases. MAN1B1-CDG was confirmed by genetic analysis. Conclusions Although the cause of the increased serum transaminase levels in the present patients is not clear, no evidence for an infection or underlying liver pathology could be identified. In order to know if this is a consistent feature, we suggest measuring serum transaminase levels regularly in MAN1B1-CDG patients.

High Mobility Group Box 1 Contributes to the Acute Rejection of Liver Allografts by Activating Dendritic Cells

Acute rejection induced by the recognition of donor alloantigens by recipient T cells leads to graft failure in liver transplant recipients. The role of high mobility group box 1 (HMGB1), an inflammatory mediator, in the acute allograft rejection of liver transplants is unknown. Here, rat orthotopic liver transplantation was successfully established to analyze the expression pattern of HMGB1 in liver allografts and its potential role in promoting the maturation of dendritic cells (DCs) to promote T cell proliferation and differentiation. Five and 10 days after transplantation, allografts showed a marked upregulation of HMGB1 expression accompanied by elevated levels of serum transaminase and CD3+ and CD86+ inflammatory cell infiltration. Furthermore, in vitro experiments showed HMGB1 increased the expressions of co-stimulatory molecules (CD80, CD83, and MHC class II) on bone marrow-derived DCs. HMGB1-pulsed DCs induced naive CD4+ T cells to differentiate to Th1 and Th17 subsets secreting IFN-γ and IL-17, respectively. Further in vivo experiments confirmed the administration of glycyrrhizic acid, a natural HMGB1 inhibitor, during donor liver preservation had therapeutic effects by reducing inflammation and hepatocyte damage reflected by a decline in serum transaminase and prolonged allograft survival time. These results suggest the involvement of HMBG1 in acute liver allograft rejection and that it might be a candidate therapeutic target to avoid acute rejection after liver transplantation.