A Silver Nanoparticle Method for Ameliorating Biliary Atresia Syndrome in Mice

Biliary atresia (BA) is a severe type of cholangitis with high mortality in children of which the etiology is still not fully understood. Viral infections ...

A Mouse Model of Chronic Liver Fibrosis for the Study of Biliary Atresia

Biliary atresia (BA) is a fatal disease involving obstructive jaundice, and it is the most common indication for liver transplantation in children. Due to ...

Guangzhou Medical University

Guangzhou Women and Children’s Medical Center

Biliary atresia (BA) is a neonatal biliary system disease closely associated with viral infection and bile duct inflammation. Silver nanoparticles (AgNps) have previously revealed antiviral and anti-inflammatory properties. In this study, we have investigated the effects of AgNps in the treatment of the Rhesus rotavirus inoculation induced BA in mice. The morphology, liver histopathology, clinical biochemistry examination, and inflammatory cells were analyzed in BA mice. Results indicated that AgNps could significantly increase the survival rate of BA mice, and reduce jaundice and weight lost and the liver enzymes and bilirubin metabolism clinical parameters were close to the normal levels. Diminished numbers of NK cells were observed by flow cytometry analysis and immunohistochemical staining. Furthermore, the viral load was reduced and transcripts for TGF-β mRNA were augmented after AgNps treatment. Collectively, our results suggest that AgNps treatment has beneficial effects on the BA mouse model partially through upregulation of TGF-β.

Silver nanoparticle treatment ameliorates biliary atresia syndrome in rhesus rotavirus inoculated mice.

Knee osteoarthritis (KOA) is reported to have characteristic kinematics during walking. However, the relationship between Kellgren-Lawrence (K/L) score and the 3D kinematic gait of patients with medial KOA remains unclear. Here, ninety-seven patients with medial KOA and thirty-eight asymptomatic participants were involved. Patients with medial KOA were divided into early, moderate, and severe KOA based on the K/L score. Through kinematic gait analysis, we found a relationship between K/L score and 3D kinematic gait for patients. All KOA knees had a significantly reduced range of motion. As the K/L score was increasing, the knee flexion at the heel strike and 50% of the stance phase increased while the peak knee flexion in the swing phase decreased. In addition, the adduction and femoral rotation increased internally at the heel strike, 50% of the stance phase, and maximum angle of the swing phase. Femoral translation increased anteriorly and distally at the heel strike and 50% of the stance phase. The severe group had more medial translation than the asymptomatic groups. Significant alterations of three-dimensional joint kinematics were identified in subjects suffering various severities in Chinese patients. This study provides an important reference for the treatment options, therapy assessment, and rehabilitation of KOA.

Relationship between Kellgren-Lawrence score and 3D kinematic gait analysis of patients with medial knee osteoarthritis using a new gait system.

At present, there few studies on the kinematic features of lateral discoid meniscus injury. In this study, a motion capture system was used to investigate the motion characteristics of knees with lateral discoid meniscus after injury, and the differences between the knees with lateral meniscus and intact knees were compared. Fourteen patients diagnosed with unilateral lateral discoid meniscus injury, fourteen patients diagnosed with unilateral lateral meniscus injury, and fourteen normal subjects with healthy knees were recruited and grouped. Through kinematic gait analysis, it was found that the subjects in the two groups with meniscus injuries exhibited significantly smaller ranges of rotation and translation than those with healthy knees on the sagittal, coronal, and horizontal planes, but not in proximal-distal translation. Maximum lateral tibial translation and maximum internal tibial rotation in the knees with lateral discoid meniscus injury were significantly decreased compared to those with lateral meniscus injury. The results show that the kinematic features of knees with lateral discoid meniscus injury are statistically different than those of healthy knees and knees with lateral meniscus injury. This study provides an important reference for the dynamic function of knees with lateral discoid meniscus injury.

Kinematic features in patients with lateral discoid meniscus injury during walking.

Activation of innate immunity together with cholangiocyte damage occurs in biliary atresia (BA). However, detailed information on the inflammatory cells involved is lacking. This study investigates both the pathophysiology of CD11bGr-1 cells in a mouse model of BA and their presence in BA patients. CD11bGr-1 cells were targeted by an anti-Ly6G antibody in murine BA induced by inoculation with rhesus rotavirus. Expression of the Ly6G homolog CD177 was examined in biopsies from BA patients. The symptoms of BA were ameliorated, and survival was prolonged in those mice receiving 5 to 10 μg of antibody per mouse every 3 days for four times compared with the mice treated with virus alone. However, the mice later developed chronic BA with persistent low body weight and jaundice. Hepatic inflammatory cells were reduced compared with acute BA. Blockade of extrahepatic bile ducts occurred, whereas intrahepatic ductules were partially preserved, and a progressive increase in liver fibrosis was observed. High levels of CD11bGr-1 cells were present in these mice. The administration of an anti-Ly6G antibody again in those chronic BA mice reduced jaundice and restored body weight. In BA patients CD177 cells were highly expressed in the liver. Our data suggest that the chronic mouse BA model shares key characteristics with clinical BA and indicates the importance of CD11bGr-1 cells in the initiation and progression of BA.

The Role of Neonatal Gr-1 Myeloid Cells in a Murine Model of Rhesus-Rotavirus-Induced Biliary Atresia.

Wilms' tumor is one of the most prevalent pediatric malignancies, ranking fourth in childhood cancer worldwide.  is a critical tumor suppressor gene, which encodes a 53 kDa protein, p53. The p53 functions to protect against cancer by regulating cell cycle and apoptosis and maintaining DNA integrity.  gene is highly polymorphic. Several  gene polymorphisms have been considered to be associated with cancer risk. Of them, a nonsynonymous polymorphism, Arg72Pro (rs1042522 C>G), has been most extensively studied for the association with cancer risk; however, few studies have investigated its effect on Wilms' tumor. Because of the central role of p53 in cell cycle control, the  gene Arg72Pro polymorphism is also a good potential candidate predisposition locus for this pediatric cancer. We genotyped this polymorphism in 145 patients and 531 cancer-free controls recruited from Chinese children by Taqman methodology. Overall, our result suggested a lack of association between the  gene Arg72Pro polymorphism and Wilms' tumor. In the stratified analysis, we found that carriers of CG/GG genotypes had a significantly increased Wilms' tumor risk in children not older than 18 months (adjusted odds ratio =2.04, 95% confidence interval =1.003-4.13, =0.049) compared with CC genotype carriers. Our study indicated that the  gene Arg72Pro polymorphism may have a weak, age-related effect on Wilms' tumor risk in Chinese children. These findings need further validations in other populations with larger sample size.

Association between  gene Arg72Pro polymorphism and Wilms' tumor risk in a Chinese population.

To analyze the expression and function of the Notch signaling target gene Hes1 in a rhesus rotavirus-induced mouse biliary atresia model.

Downregulation of Hes1 expression in experimental biliary atresia and its effects on bile duct structure.

Biliary atresia (BA) is the most common cause of endstage liver disease in infants with poor prognosis and high mortality. The etiology of BA is still unknown, but the genetic factors have been considered as an important player in BA. We investigated the association of two cis-regulated variants in CD14 (rs2569190) and NOTCH2 (rs835576) with BA susceptibility, using the largest case-control cohort, totaling 506 BA patients and 1,473 healthy controls in a Southern Chinese population. Significant epistatic interaction between the two variants in our samples was observed (p = 8.1E-03; OR = 2.78; 95% CI: 1.32-5.88). The expression of CD14 and NOTCH2 in the BA group was consistently lower than that in the control (CC) group (0.31 ± 0.02 versus 1.00 ± 0.14; p < 0.001), which might be related to the genetic susceptibility of the genes awaiting further validation.

Epistatic Association of CD14 and NOTCH2 Genetic Polymorphisms with Biliary Atresia in a Southern Chinese Population.

Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA profiling, we observed macrophage hypo-inflammation, Kupffer cell scavenger function defects, cytotoxic T cell expansion, and deficiency of CX3CR1effector T and natural killer (NK) cells in infants with BA. More importantly, we discovered that hepatic B cell lymphopoiesis did not cease after birth and that tolerance defects contributed to immunoglobulin G (IgG)-autoantibody accumulation in BA. In a rhesus-rotavirus induced BA model, depleting B cells or blocking antigen presentation ameliorated liver damage. In a pilot clinical study, we demonstrated that rituximab was effective in depleting hepatic B cells and restoring the functions of macrophages, Kupffer cells, and T cells to levels comparable to those of control subjects. In summary, our comprehensive immune profiling in infants with BA had educed that B-cell-modifying therapies may alleviate liver pathology.

Liver Immune Profiling Reveals Pathogenesis and Therapeutics for Biliary Atresia.

Biliary atresia (BA) is an immune-related disorder and signal transducer and activator of transcription 3 (STAT3) is a key signalling molecule in inflammation. The present study was designed to clarify the function of STAT3 in BA. STAT3 expression was examined in patients and a mouse BA model in which STAT3 levels were further altered with a specific inhibitor or activator. Neutrophil accumulation and the levels of the neutrophil chemoattractants (C-X-C motif) ligand 1 (CXCL1) and IL-8 were determined. The effects of STAT3 inhibition on IL-8 expression were examined in human biliary epithelial cell (BEC) cultures. Functional changes in liver STAT3+ neutrophils in the mouse model were analysed with 10× single cell RNA-seq methods. Results showed STAT3 and p-STAT3 expression was reduced in BA liver tissue compared with control samples. Administration of a STAT3 inhibitor increased jaundice and mortality and reduced body weight in BA mice. In contrast, the STAT3 activator ameliorated BA symptoms. Extensive neutrophil accumulation together with CXCL1 up-regulation, both of which were suppressed by an anti-CXCL1 antibody, were observed in the STAT3 inhibitor-treated group. Recombinant IL-8 administration increased disease severity in BA mice, and the STAT3 activator had the reverse effect. Inhibiting STAT3 increased apoptosis of human BECs together with up-regulated IL-8 expression. RNA-seq analysis revealed reduced the numbers of STAT3 expressing neutrophil in BA which was accompanied by marked enhanced interferon-related antiviral activities. In conclusion, STAT3 reduction, enhanced IL-8 and CXCL1 expression and promoted the accumulation of interferon-responsive neutrophils resulting in BEC damage in BA.

Down-regulation of STAT3 enhanced chemokine expression and neutrophil recruitment in biliary atresia.

We have previously reported on the potential pathogenic role of neutrophils in biliary atresia (BA). Herein, we aimed to delineate the role of CD177+ neutrophils in the pathogenesis of BA.

Zefeng Lin

Department of Pediatric Surgery,
Guangzhou Women & Children's Medical Center,
Department of Pediatric Surgery, Guangzhou Women & Children's Medical Center

Guangzhou Medical University

A Silver Nanoparticle Method for Ameliorating Biliary Atresia Syndrome in Mice

A Mouse Model of Chronic Liver Fibrosis for the Study of Biliary Atresia

Zefeng Lin

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Pediatric Surgery,Guangzhou Women & Children's Medical Center,Department of Pediatric Surgery, Guangzhou Women & Children's Medical Center

Guangzhou Medical University

A Silver Nanoparticle Method for Ameliorating Biliary Atresia Syndrome in Mice

A Mouse Model of Chronic Liver Fibrosis for the Study of Biliary Atresia

Department of Pediatric Surgery,
Guangzhou Women & Children's Medical Center,
Department of Pediatric Surgery, Guangzhou Women & Children's Medical Center