As the central organ of metabolism, the liver plays a pivotal role in the regulation of the synthesis and metabolism of various nutrients within the body. Ferroptosis, as a newly discovered type of programmed cell death caused by the accumulation of iron-dependent lipid peroxides, is involved in the physiological and pathological processes of a variety of acute and chronic liver diseases. Ferroptosis can accelerate the pathogenetic process of acute liver injury, metabolic associated fatty liver disease, alcoholic liver disease, viral hepatitis, and autoimmune hepatitis; while it can slower disease progression in advanced liver fibrosis and hepatocellular carcinoma. This suggests that targeted regulation of ferroptosis may impact the occurrence and development of various liver diseases. This article reviews the latest research progress of ferroptosis in various liver diseases, including acute liver injury, metabolic associated fatty liver disease, alcoholic liver disease, viral hepatitis, autoimmune hepatitis, liver fibrosis and hepatocellular carcinoma. It aims to provide insights for the prevention and treatment of acute and chronic liver diseases through targeting ferroptosis.
Humans ; Liver Diseases/etiology* ; Ferroptosis/physiology* ; Liver Neoplasms/pathology* ; Carcinoma, Hepatocellular/pathology* ; Liver Cirrhosis/etiology* ; Liver/pathology* ; Hepatitis, Autoimmune/metabolism* ; Liver Diseases, Alcoholic/metabolism*

The orphan nuclear receptor Nur77 is emerging as an attractive target for cancer therapy, and activating Nur77's non-genotypic anticancer function has demonstrated strong therapeutic potential. However, few Nur77 site B ligands have been identified as excellent anticancer compounds. There are no co-crystal structures of effective anticancer agents at Nur77 site B, which greatly limits the development of novel Nur77 site B ligands. Moreover, the lack of pharmaceutical ligands restricts Nur77's therapeutic proof of concept. Herein, we developed a first-in-class Nur77 site B ligand (NB1) that significantly inhibited cancer cells by mediating the Nur77/Bcl-2-related apoptotic effect at mitochondria. The X-ray crystallography suggests that NB1 is bound to the Nur77 site B with a distinct binding mode. Importantly, NB1 showed favorable pharmacokinetic profiles and safety, as evidenced by its good oral bioavailability in rats and lack of mortality, bodyweight loss, and pathological damage at the 512.0 mg/kg dose in mice. Furthermore, oral administration of NB1 demonstrated remarkable in vivo anticancer efficacy in an MDA-MB-231 xenograft model. Together, our work discovers NB1 as a new generation Nur77 ligand that activates the Nur77/Bcl-2 apoptotic pathway with a safe and effective cancer therapeutic potency.

Objective:To analyze the clinical characteristics and genetic variants of children with hepatic Wilson disease (WD).Methods:The clinical data and genetic test results of 35 children, who were diagnosed as WD with primary hepatic manifestation in the Department of Gastroenterology, Children′s Hospital of Capital Institute of Pediatrics from March 2018 to March 2022, were retrospectively analyzed. The relationship between phenotype and genotype of patients was analyzed.Results:Among 35 children, there were 24 males and 11 females with a median age at diagnosis of 5.5 (4.0, 7.5) years. All patients had elevated transaminases. The elevated transaminases was found during routine physical examination in 33 cases (94.3%), in whom there was no fever, cough, recurrent vomiting, abdominal pain, diarrhea, jaundice, limb tremor, gait instability and other discomfort 2 weeks before admission, except 1 case with nausea; abdominal ultrasonography showed that 5 cases (15.2%) had no abnormality, and others had different degrees of hepatomegaly, splenomegaly, and echo enhancement in liver parenchyma. Among the remaining 2 cases, one 11-year-old child presented with edema, and had cirrhosis portal hypertension with esophageal varices; another 7-year-old child was diagnosed as acute liver failure manifested with nausea and jaundice. Thirty three patients(94.3%)had decreased serum ceruloplasmin levels (<100 mg/L); 24-h urinary copper concentration was>100 μg in 16 cases (45.7%) and<40 μg in 2 cases (5.7%). The tests of hepatitis B virus, hepatitis C virus, cytomegalovirus and EB virus were all negative in 35 children, and the autoimmune hepatitis antibodies were also negative. A total of 34 different ATP7B gene mutations were detected; the most frequent mutation was c.2333G>T (P.R778L) at exon 8, followed by c.2621C>T(p.A874V)at exon 11 and c.2621C>T(p.A874V)at exon 13. There was no significant difference in clinical phenotype between patients with nonsense mutation, frameshift mutation or splicing mutation and those with only missense mutations( Z=-1.00, t=-0.16, Z=-1.14, Z=-1.03,all P>0.05). Conclusions:The onset of WD in children is obscure, and clinicians should consider this disease in patients presenting with elevated transaminase. Ceruloplasmin and urine copper should be tested timely, the early diagnosis and treatment can improve the prognosis. And there is no significant correlation between genotype and clinical phenotype.

Objective:To investigate the etiology, incidence and clinical characteristics of pediatric prolonged and chronic diarrhea.Methods:The clinical data of children with prolonged and chronic diarrhea were collected and analyzed, which were hospitalized in the Department of Gastroenterology of the Children′s Hospital Affiliated to the Capital Institute of Pediatrics from January 2017 to June 2020.Results:A total of 190 children with prolonged and chronic diarrhea were collected, with a male-to-female ratio of 1.64∶1(118/72) and a median age of 11.2(5.0, 48.0)months.Among them, 74.3%(141/190) were infants aged 0-3 years, and 54.3%(103/190) were infants aged 0-1 years.The overall cure and improvement rate was 83.7%(159/190). Gastrointestinal concomitant symptoms were dominated by abdominal pain, and vomiting, bloating, and extraintestinal concomitant symptoms were mainly fever, weight loss, and growth and development disorders.Common comorbidities included malnutrition (46.3%), anemia (35.3%), and electrolyte abnormalities (20.5%). The lesion detection rate of electronic gastrointestinal endoscopy and capsule endoscopy reached 93.1%(122/131). The detection rate of genetic testing was 60.0%(9/15). In this group of studies, 169 patients had a clear cause, and the confirmed diagnosis rate was 88.9%.The main causes of childhood prolonged and chronic diarrhea were food allergy(36.8%), inflammatory bowel disease(12.6%), and irritable bowel syndrome(9.5%), but 11.1% of the children did not identify the cause after comprehensive examination.Conclusion:Children with prolonged and chronic diarrhea are mainly infants and young children, especially infants, with diverse etiology, mainly non-infectious factors, food allergy and inflammatory bowel disease are important causes.Malnutrition, anemia and other complications are easy to occur.Endoscopy is helpful in diagnosing and differentiating the cause, if necessary, genetic testing could help to determine the cause.

OBJECTIVE: To explore the characteristics of SLC25A13 gene variants in 16 infants with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). METHODS: The infants were subjected to high-throughput DNA sequencing for coding exons and flanking regions of the target genes. Suspected variants were verified by Sanger sequencing and bioinformatic analysis. RESULTS: Among the 16 NICCD cases, 15 were found to harbor pathogenic variants. Among these, IVS14-9A>G, c.1640G>A, c.762T>A, c.736delG, c.1098Tdel and c.851G>A were previously unreported. CONCLUSION Six novel SLC25A13 variants were found by high-throughput sequencing, which has enriched the spectrum of SLC25A13 gene variants and provided a basis for genetic counseling and prenatal diagnosis.
Calcium-Binding Proteins/genetics* ; Cholestasis, Intrahepatic/genetics* ; Citrullinemia/genetics* ; Humans ; Infant ; Infant, Newborn ; Mitochondrial Membrane Transport Proteins/genetics* ; Mutation ; Organic Anion Transporters/genetics* ; Protein Deficiency

Objective:To investigate the clinical and genetic characteristics of genetic and metabolic infantile cholestatic hepatopathy (ICH), and to provide evidence for its diagnosis and treatment.Methods:Clinical data and follow-up outcomes of hospitalized children diagnosed with ICH in the Department of Gastroenterology, Children′s Hospital, Capital Institute of Pediatrics from January 2014 to December 2019 were retrospectively analyzed.Among the 80 children, 27 were female and 53 were male, with a mean age of onset of (39±18) days old.Children with confirmed etiology by high-throughput sequencing analysis were included in the genetic metabolic group (44 cases), and those with idiopathic neonatal cholestasis(INC) of unknown etiology after the systematic examination were included in the INC group (36 cases). The t-test or independent sample rank sum test was used to compare the laboratory test results and biochemical indexes.The infection rate of cytomegalovirus was compared by the Chi- square test. Results:(1) A total of 80 cases were included, and 44 cases (55.0%)were confirmed as INC by high-throughput sequencing.Among those with a positive molecular diagnosis, there were 23 cases of citrin deficiency (CD), 10 cases of Alagille syndrome (ALGS), 6 cases of progressive familial intrahepatic cholestasis (PFIC), 2 cases of congenital bile acid synthesis defect, 2 cases of Nieman Pick disease, and 1 case of cystic fibrosis.(2) Serum total bile acid (TBA) and activated partial prothrombin time (APTT) levels in the genetic metabolic group were significantly higher than those in the INC group (all P<0.05). TBA and APTT levels in genetic metabolites were 180.6 (115.5, 271.6) μmol/L and 40.6 (37.1, 45.2) s, respectively, which were 123.3 (98.8, 163.4) μmol/L and 34.8 (31.7, 40.1) s in INC group, respectively.There was no significant difference in the cytomegalovirus infection rate between the 2 groups ( P>0.05). (3)The pathological examination of liver tissue in the genetic metabolic group was worse than that in the INC group, with spot-like and fusion focal-like necrosis, and 5 cases (4 cases of ALGS and 1 case of CD) showed a reduced number of bile ducts in the portal area and lumen stenosis. Conclusions:CD, ALGS and PFIC are the common causes of genetic and metabolic ICH.Fundamental cause of cholestasis should be actively examined in children with cytomegalovirus infection.High-throughput sequencing is of great significance in the accurate diagnosis of ICH.

Objective:To investigate the clinical characteristics of hepatitis-associated aplastic anaemia(HAAA)in children.Methods:A retrospective analysis was performed on the clinical manifestations, laboratory examinations, treatments and other clinical data of five children with aplastic anemia(AA)diagnosed by bone marrow examination after admission with acute liver dysfunction admitted to the Department of Gastroenterology, Children′s Hospital Affiliated to Capital Institute of Pediatrics from January 2016 to December 2020.Results:All five children were boys and the onset age of these children ranged from 2 to 13 years.All of the five cases were acute onset and presented with jaundice.The time frame of the diagnosis of HAAA was 0 to 12 weeks from the presentation of the liver disease.One patient had simultaneous onset of hepatitis and aplastic anemia.The liver function was significantly improved at the diagnosis of HAAA in three patients and worsen in one patient.Only one patient showed CMV-DNA positive and the pathogen results of other patients were negative.Lymphocyte immunity disorders were found in all five patients, and the proportion of inhibitory/cytotoxic T lymphocytes(CD3 + CD8 + ) increased.Two children received hematopoietic stem cell transplantation, of which one died and one improved after transplantation.One child improved after treated with antithymocyteglobulin and cyclosporin.One child died due to severe infection.There was no significant improvement in one child treated with cyclosporine. Conclusion:HAAA should be alerted in acute hepatitis patients.Blood routine should be monitored even if liver function improves.Bone marrow tests are needed if patients have peripheral cytopenia in two or more lineages.Early and timely treatments with immunosuppressive therapy and hematopoietic stem cell transplantation can improve the prognosis.

Objective: To explore the high expression level of serum heat shock protein 90α(HSP90α) and gene HSP90 AA1 in cancer tissue, and to discover the prognosis of lung cancer. Methods: A total of 109 cases of lung cancer were collected as the experimental group; 38 lung inflammation groups as the reference group; and 30 healthy controls. The serum HSP90α levels between the three groups were compared; the correlation between HSP90α and clinical parameters were analyzed. The TCGA data were used to analyze the correlation between the expression level of HSP90 AA1 and various pathological features, as well as its influence on the prognosis of lung cancers. Results: The serum HSP90α concentrations in the experimental group were higher than those of the reference group and the control group(P<0.05). The ROC curve area of HSP90α in the diagnosis of lung cancer was 0.898(P<0.05); the expression of HSP90α in the lung squamous cell carcinoma group(LUSC) and the small cell lung cancer group(SCLC) were higher than those in lung adenocarcinoma group(LUAD)(P<0.05); the level of HSP90α decreased when condition alleviated, while increased significantly when disease progressed(P<0.05); Further TCGA database showed that the expression of HSP90 AA1 in cancer tissues was higher than that of adjacent cancer tissues(P<0.05),meanwhile, remarkably increased in LUSC compared with in LUAD(P<0.05). The expression of HSP90 AA1 has no significant correlation with the age, gender, clinical stage, and tumor residue of lung cancer patients. Survival analysis and Cox regression analysis showed that high expression of HSP90 AA1 reduced the overall survival(OS) of lung cancer patients; HSP90 AA1 was an independent prognostic factor for lung cancer patients. Conclusion Serum HSP90α and HSPAA1 in cancer tissues are elevated in patients with lung cancer, which should be used as an auxiliary diagnosis method for lung cancer. Meanwhile they should be used for therapeutic effect observation and survival status prediction.

ObjectiveTo investigate the clinical features and gene mutation characteristics of neonatal intrahepatic cholestasis caused citrin deficiency (NICCD) in northern China. MethodsA total of 23 pediatric patients in northern China who were diagnosed with NICCD by blood tandem mass spectrometry and/or gene detection in Department of Gastroenterology, Children’s Hospital Affiliated to Capital Institute of Pediatrics, from January 2015 to December 2018 were enrolled as NICCD group, and 36 pediatric patients with idiopathic neonatal cholestasis (INC) who had unclarified etiology after a series of examinations during the same period of time were enrolled as INC group. A retrospective analysis was performed for the clinical manifestation, laboratory examination, pathology, blood/urine metabolic screening, and gene sequencing results of the pediatric patients in the NICCD group, and follow-up was performed to observe their outcome; biochemical parameters were compared between the two groups. The independent samples t-test was used for comparison of normally distributed continuous data, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data; the chi-square test was used for comparison of categorical data between groups. ResultsAmong the 23 patients in the NICCD group, 10 had hypoglycemia, 13 had hypoalbuminemia, 17 had hyperammonemia, and 15 had hyperlactacidemia; 15 had an increase in low-density lipoprotein, 6 had an increase in cholesterol, and 7 had an increase in triglyceride; 17 had prolonged prothrombin time, and 16 had prolonged activated partial thromboplastin time (APTT). Compared with the INC group, the NICCD group had significantly higher gamma-glutamyl transpeptidase (GGT), total bile acid (TBA), and APTT and a significantly lower albumin (Alb) level (Z=-2.487, Z=-3.528, t=3.532, t=-2.24, all P＜0.05). For the patients with NICCD, blood tandem mass spectrometry showed that the most common abnormalities were the increased levels of arginine, citrulline, methionine, free carnitine, and long-chain acylcarnitine, while urinary gas chromatography showed the increased levels of 4-hydroxyphenyllactic acid, galactose, galactitol, and galactonic acid. Gene detection was performed for all 23 patients and identified 16 pathogenic mutations, among which 7 were newly discovered, namely ivs14-9a＞G, c1640 G＞A, c.762T＞A, c.736delG, c.1098 T del, c.851G＞A, and c.550G＞A. Except for the 2 patients who were lost to follow-up, the levels of aminotransferases and bilirubin gradually returned to normal in 21 patients after 2-6 months of treatment; none of them showed delayed growth and development after being followed up to the age of 1 year, and 2 of them developed dietary preference (they liked fish and meat and did not like staple food). ConclusionAbnormalities of blood GGT, TBA, Alb, and APTT may provide ideas for the differential diagnosis of NICCD and INC. NICCD gene mutations in northern China are heterogeneous and most patients tend to have a good prognosis.

Objective:To investigate the clinical characteristics and non-infective etiological characteristics of children with lower gastrointestinal bleeding(LGIB), and to explore the application value of electronic colonoscopy in diagnosis and treatment of LGIB.Methods:A total of 311 cases of children with LGIB admitted to our hospital from June 2016 to June 2020 were analyzed retrospectively, and the relevant clinical data were summarized.Results:The ratio of boys to girls was 1.46∶1.The average age was(4.67±3.99)years old.Preschool children account for 67.85%.A total of 97.75% of the children had bloody stool with naked eyes, mainly with simple bloody stool.The main accompanying symptoms were abdominal pain(31.19%)and diarrhea(24.11%). The positive rate of occult blood test was 55.26%, and the positive rate of colonoscopy was 86.49%.The common causes of LGIB in children were intestinal polyps, colitis, inflammatory bowel disease, allergic colitis, allergic purpura and Meckel′s diverticulum.There were statistical differences in the number of cases of some etiology at different age stages, including colon polyps( P<0.001), colitis( P=0.020), ulcerative colitis( P<0.001), allergic colitis( P<0.001), Henoch-Schonlein purpura( P=0.031)and Behcet′s disease( P=0.033). Allergic colitis was more common in 1~6 months old, and the incidence rate gradually decreased with age.Inflammatory bowel disease was the primary cause of children aged 11~16 years.All children′s bleeding symptoms disappeared after treatment and the occult blood test was negative.The cure rate was 41.80% (130 cases) and the improvement rate was 58.20% (181 cases). Conclusion:The etiology of LGIB in children is complex, and the etiology is related to the age of onset.Intestinal polyps and colitis are the main causes of the disease, which are common in all ages.Colonoscopy is safe and efficient, playing an important role in the diagnosis and treatment of children with LGIB.