Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis.

BACKGROUND: Acute liver failure (ALF) has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis. The silent information regulator sirtuin 1 (SIRT1)-mediated deacetylation affects multiple biological processes, including cellular senescence, apoptosis, sugar and lipid metabolism, oxidative stress, and inflammation. AIM: To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms. METHODS: This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) testing. C57BL/6 mice were also intraperitoneally pretreated with SIRT1, p53, or glutathione peroxidase 4 (GPX4) inducers and inhibitors and injected with lipopolysaccharide (LPS)/D-galactosamine (D-GalN) to induce ALF. Gasdermin D (GSDMD)-/- mice were used as an experimental group. Histological changes in liver tissue were monitored by hematoxylin and eosin staining. ALT, AST, glutathione, reactive oxygen species, and iron levels were measured using commercial kits. Ferroptosis- and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction. SIRT1, p53, and GSDMD were assessed by immunofluorescence analysis. RESULTS: Serum AST and ALT levels were elevated in patients with ALF. SIRT1, solute carrier family 7a member 11 (SLC7A11), and GPX4 protein expression was decreased and acetylated p5, p53, GSDMD, and acyl-CoA synthetase long-chain family member 4 (ACSL4) protein levels were elevated in human ALF liver tissue. In the p53 and ferroptosis inhibitor-treated and GSDMD-/- groups, serum interleukin (IL)-1ß, tumour necrosis factor alpha, IL-6, IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated. In mice with GSDMD knockout, p53 was reduced, GPX4 was increased, and ferroptotic events (depletion of SLC7A11, elevation of ACSL4, and iron accumulation) were detected. In vitro, knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels, the cytostatic rate, and GSDMD expression, restoring SLC7A11 depletion. Moreover, SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group, accompanied by reduced p53, GSDMD, and ACSL4, and increased SLC7A11 and GPX4. Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalN-induced in vitro and in vivo models. CONCLUSION: SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.

Autoimmune hepatitis-primary biliary cholangitis overlap syndrome complicated by various autoimmune diseases: A case report.

BACKGROUND: Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are two common clinical autoimmune liver diseases, and some patients have both diseases; this feature is called AIH-PBC overlap syndrome. Autoimmune thyroid disease (AITD) is the most frequently overlapping extrahepatic autoimmune disease. Immunoglobulin (IgG) 4-related disease is an autoimmune disease recognized in recent years, characterized by elevated serum IgG4 levels and infiltration of IgG4-positive plasma cells in tissues. CASE SUMMARY: A 68-year-old female patient was admitted with a history of right upper quadrant pain, anorexia, and jaundice on physical examination. Laboratory examination revealed elevated liver enzymes, multiple positive autoantibodies associated with liver and thyroid disease, and imaging and biopsy suggestive of pancreatitis, hepatitis, and PBC. A diagnosis was made of a rare and complex overlap syndrome of AIH, PBC, AITD, and IgG4-related disease. Laboratory features improved on treatment with ursodeoxycholic acid, methylprednisolone, and azathioprine. CONCLUSION: This case highlights the importance of screening patients with autoimmune diseases for related conditions.

ABCB4 gene mutation-associated cirrhosis with systemic amyloidosis: A case report.

BACKGROUND: Gene mutations in ATP-binding cassette, subfamily B (ABCB4) lead to autosomal recessive disorders. Primary light amyloidosis is a rare and incurable disease. Here, we report a rare case of liver cirrhosis caused by ABCB4 gene mutation combined with primary light amyloidosis. CASE SUMMARY: We report a case of a 25-year-old female who was hospitalized due to recurrent abdominal pain caused by calculous cholecystitis and underwent cholecystectomy. Pathological examination of the liver tissue suggested liver cirrhosis with bile duct injury. Exon analyses of the whole genome from the patient's peripheral blood revealed the presence of a heterozygous mutation in the ABCB4 gene. Bone marrow biopsy tissues, renal puncture examination, and liver mass spectrometry confirmed the diagnosis of a rare progressive familial intrahepatic cholestasis type 3 with systemic light chain type κ amyloidosis, which resulted in cirrhosis. Ursodeoxycholic acid and the cluster of differentiation 38 monoclonal antibody daretozumab were administered for treatment. Following treatment, the patient demonstrated significant improvement. Urinary protein became negative, peripheral blood-free light chain and urine-free light chain levels returned to normal, and the electrocardiogram showed no abnormalities. Additionally, the patient's lower limb numbness resolved, and her condition remained stable. CONCLUSION: This report presents the diagnosis and treatment of liver cirrhosis, a rare disease that is easily misdiagnosed or missed.

Establishment and Comparison of Two Different Animal Models of Graves' Orbitopathy.

Purpose: The purpose of this study was to construct an animal model of Graves' ophthalmopathy (GO) by comparing recombinant adenovirus expressing human thyrotropin receptor A subunit (Ad-TSHR A) gene immunization and dendritic cell (DC) immunization. We evaluated the animal models that are closer to the pathology of human GO, and laid the foundation for the study of GO. Materials and Methods: Ad-TSHR A was injected intramuscularly into female BALB/c mice to induce the GO animal model. A GO animal model was constructed using TSHR combined with IFN-γ-modified primary DC immunized female BALB/c. The animal models constructed by the above two methods were evaluated in terms of ocular appearance, serology, pathology, and imaging to assess the modeling rate of the animal models, respectively. Results: Both modeled mice exhibited increased serological indexes of free thyroxine (FT4) and TSH receptor antibodies (TRAbs) levels and decreased TSH (P < 0.01). Thyroid pathology analysis revealed the number of thyroid follicles increases, the size varies, and the follicular epithelial cells proliferate to varying degrees in a cuboidal or tall columnar pattern, with a small amount of lymphocytic infiltration visible. Adipose tissue behind the eyeball was accumulated, the muscle outside the eyeball was broken and fibrotic, and hyaluronic acid (HA) behind the eyeball was increased. The animal model of GO constructed by immunization of TSHR with IFN-γ-modified DC had a modeling rate of 60%, whereas that of Ad-TSHR A gene immunization was 72%. Conclusions: Both gene immunization and cellular immunization can be used to construct GO models, and the modeling rate of gene immunization is higher than that of cellular immunization. Translational Relevance: In this study, two innovative methods, cellular immunity and gene immunity, were used to establish GO animal models, which improved the success rate to a certain extent. To our knowledge, this study presents the first cellular immunity modeling idea of TSHR combined with IFN-γ for the GO animal model, which provides an animal model basis for understanding the pathogenesis of GO and developing new treatment methods.

Improved cathodic oxygen reduction and bioelectricity generation of electrochemical reactor based on reduced graphene oxide decorated with titanium-based composites.

A kind of reduced graphene oxide decorated with titanium-based (RGO/TiO2) composites are successfully synthesized and employed in this current study as a novel nonprecious metal catalyst for enhancing bioelectricity generation and cathodic oxygen reduction reaction (ORR) in single chamber microbial fuel cells (MFCs). Compared with commercial Pt/C, RGO/TiO2 shows obviously enhanced oxygen reduction reaction activity due to the appropriately-permeated, large electrochemical active area, enough exposure of electrocatalytic active sites of RGO/TiO2. The air-cathode MFC with RGO/TiO2-1 cathode achieves 1786.7 mW m-3 of power density, 86.7% ±â€¯1.2% of COD removal and 31.6% ±â€¯1.1% of CE, which are higher than commercial Pt/C. Moreover, RGO/TiO2-1 cathode exhibits high-effective electrocatalytic activity, and the power density of RGO/TiO2-1 can keep a stable level and only has a minor decline (5.35%) during 30-cycles operation. These results indicate that RGO/TiO2-1 is a potential cathode catalyst, markedly enhancing cathode ORR, wastewater treatment efficiency, and bioelectricity generation of MFC.

[ANAMMOX Reactor with Two Kinds of Inoculated Sludge: Start-up and Kinetics Characteristics].

Two different mixed sludges (aerobic nitrifying sludge and ANAMMOX-denitrification sludge:R1, and anaerobic digestion flocculent sludge and ANAMMOX-denitrification sludge:R2), were used as inocula in two UBF reactors to enrich Anammox bacteria. Both kinds of mixed sludge set up the Anammox process successfully. It took 36 days for R1, while R2 required 53 days. Nitrogen removal rates of R1 and R2 were high during the whole operation. During the stable operation stage, the removal rates of NH4+-N, NO2--N, and TN were about 99.92%, 96.64%, and 81.87% for R1; and 97.54%, 94.91%, and 80.98% for R2. Illumina High-throughput Sequencing revealed Candidatus Kuenenia was in the top six taxa in the two reactors with 3.22% relative abundance in R1 and 2.35% in R2 after the successful start-up. Simulation results indicated that the Modified Stover-Kincannon model and the second-order model were appropriate models. It was deduced that the N-removal potential of R1 was a little greater than that of R2 after comparing the projected maximum substrate removal rate Umax of the two reactors.

[Nitrogen Removal Characteristics and Diversity of Microbial Community in ANAMMOX Reactor].

The volume loading of upflow blanket filter increased from 0.52 kg·(m3·d)-1to 2.75 kg·(m3·d)-1 by improving the influent NH4+-N and NO2--N concentrations. The removal efficiency of NH4+-N, NO2--N and TN increased from 76.18%, 53.47%, 55.66% to 94.04%, 86.97%, 82.96% respectively. Meanwhile, the microbial community of UBF ANAMMOX reactor was analyzed by Illumina high-throughput sequencing during the initial and later operational process. The results indicated that the denitrifying bacteria coexisted in the reactor. The percentages of Planctomycetes, Proteobacteria and Nitrospirae in the sludge were 27.9%-39.9%, 1.1%-26.4% and 0.035%-0.188%, respectively. The proportions of Planctomycetes and Proteobacteria increased from 1.1%, 27.9% in the enrichment stage to 26.4%, 39.9% in the stable operation stage respectively. In addition, Planctomycetes increased significantly. The proportion of Brocadiacea reached 24.57%. Therefore, Brocadiacea became the dominant bacteria in the phylum Planctomycete, which contained Candidatus brocadia. The alpha diversity index and relative abundance of clustering figure indicated that the diversity of microbial community decreased gradually and the structure of microbial community changed obviously.

[Microecology of the anaerobic ammonium oxidation reactor].

The microbial community structure and biodiversity in the ANAMMOX system were studied by applying the methods of microtechnic, separation and purification technology of microorganisms, and molecular biotechnology. The ANAMMOX microbial population in an upflow anaerobic sludge blanket (UASB) bioreactor and a UASB-biofilm bioreactor was successfully enriched in the laboratory with inorganic and dark condition. The removal efficiencies of NH4+-N and NO2(-)-N in UASB reactor were 99.99% and 99.9% respectively. For the UASB- biofilm, they were 99.3% and 97.4% respectively in an optimal condition in which the temperature was 30-34 degrees C and the pH was 7-8. In traditional methods of identifying microorganism, the population of bacteria, actinomycete and fungi were researched and the species in the two reactors were basically identical. Most of the microorganisms were anaerobic and anoxic bacteria. The size of the preponderant bacteria was (0.6-0.8) microm x (0.9-1.2) microm from the scanning electron micrographs of sludge cultivated in the two reactors, and the shape was oval. The rate of this preponderant bacteria was above 90%. The result of the denaturing gradient gel electrophoresis(DGGE) and 16S rDNA digested reveals that there was one predominant species and the biodiversity was not high.