Astaxanthin Alleviates Autoimmune Hepatitis by Modulating CD8+ T Cells: Insights From Mass Cytometry and Single-Cell RNA Sequencing Analyses.

Astaxanthin (ASX) is an oxygen-containing non-vitamin A carotenoid pigment. However, the role of ASX in autoimmune hepatitis (AIH) remains unclear. In this study, a mouse model of AIH is established induced by concanavalin A (ConA). Mass cytometry and single-cell RNA sequencing (scRNA-seq) are used to analyze the potential role of ASX in regulating the immune microenvironment of AIH. ASX treatment effectively alleviated liver damage induced by ConA and downregulated pro-inflammatory cytokines production in mice. Mass cytometry and scRNA-seq analyses revealed a significant increase in the number of CD8+ T cells following ASX treatment. Functional markers of CD8+ T cells, such as CD69, MHC II, and PD-1, are significantly downregulated. Additionally, specific CD8+ T cell subclusters (subclusters 4, 13, 24, and 27) are identified, each displaying distinct changes in marker gene expression after ASX treatment. This finding suggests a modulation of CD8+ T cell function by ASX. Finally, the key transcription factors for four subclusters of CD8+ T cells are predicted and constructed a cell-to-cell communication network based on receptor-ligand interactions probability. In conclusion, ASX holds the potential to ameliorate liver damage by regulating the number and function of CD8+ T cells.

Modulation of host lipid metabolism by virus infection leads to exoskeleton damage in shrimp.

The arthropod exoskeleton provides protection and support and is vital for survival and adaption. The integrity and mechanical properties of the exoskeleton are often impaired after pathogenic infection; however, the detailed mechanism by which infection affects the exoskeleton remains largely unknown. Here, we report that the damage to the shrimp exoskeleton is caused by modulation of host lipid profiles after infection with white spot syndrome virus (WSSV). WSSV infection disrupts the mechanical performance of the exoskeleton by inducing the expression of a chitinase (Chi2) in the sub-cuticle epidermis and decreasing the cuticle chitin content. The induction of Chi2 expression is mediated by a nuclear receptor that can be activated by certain enriched long-chain saturated fatty acids after infection. The damage to the exoskeleton, an aftereffect of the induction of host lipogenesis by WSSV, significantly impairs the motor ability of shrimp. Blocking the WSSV-caused lipogenesis restored the mechanical performance of the cuticle and improved the motor ability of infected shrimp. Therefore, this study reveals a mechanism by which WSSV infection modulates shrimp internal metabolism resulting in phenotypic impairment, and provides new insights into the interactions between the arthropod host and virus.

NFKBIZ regulates NFκB signaling pathway to mediate tumorigenesis and metastasis of hepatocellular carcinoma by direct interaction with TRIM16.

Hepatocellular carcinoma (HCC) is a malignant tumor with high incidence and mortality rates. NFKBIZ, a member of the nuclear factor kappa B inhibitory family, is closely related to tumor progression. However, the precise role of NFKBIZ in HCC remains unclear. To explore this, we conducted a series of experiments from clinic to cells. Western blot and qPCR revealed a significant downregulation of NFKBIZ in human HCC tissues. Clinical character analysis showed that the patients with lower NFKBIZ expression had poorer prognosis and higher clinical stage. By using CCK-8, wound healing, transwell invasion and migration assay, we discovered that NFKBIZ expression was reversely associated with the proliferation, invasion, and migration ability of HCC cells in vitro. Additionally, the results obtained from xenograft assay and lung metastasis models showed that NFKBIZ overexpression inhibited the growth and metastasis of HCC cells in vivo. Western blot and immunofluorescence assay further revealed that NFKBIZ mediated HCC cell growth and migration by regulating NFκB signaling transduction. Finally, flow cytometry, protein degradation assay and Co-immunoprecipitation indicated that TRIM16 can enhance NFKBIZ ubiquitination by direct interactions at its K48 site, which may thereby alleviate HCC cell apoptosis to induce the insensitivity to sorafenib. In conclusion, our study demonstrated that NFKBIZ regulated HCC tumorigenesis and metastasis by mediating NFκB signal transduction and TRIM16/NFKBIZ/NFκB axis may be the underlying mechanism of sorafenib insensitivity in HCC.

Pectolinarigenin attenuates hepatic ischemia/reperfusion injury via activation of the PI3K/AKT/Nrf2 signaling pathway.

Hepatic ischemia/reperfusion (I/R) injury is an unavoidable complication of liver hepatectomy, transplantation, and systemic shock. Pectolinarigenin (Pec) is a flavonoid with many biological activities, which include anti-inflammatory, anti-apoptotic, and antioxidant stress. This study explored whether Pec pretreatment could reduce hepatic I/R injury and the potential mechanisms at play. After pretreatment of mice and AML12 cells with Pec, I/R and hypoxia/reoxygenation (H/R) models were established. By examining markers related to liver injury, cell viability, oxidative stress, inflammatory response, and apoptosis, the effect of Pec on important processes involved in hepatic I/R injury was assessed. Protein levels associated with the PI3K/AKT/Nrf2 pathway were analyzed by relative quantification to investigate possible pathways through which Pec plays a role in the I/R process. Pec treatment corrected abnormal transaminase levels resulting from I/R injury, improved liver injury, and increased AML12 cell viability. Moreover, Pec treatment inhibited oxidative stress, inflammation and apoptosis and could activate the PI3K/AKT/Nrf2 pathway during I/R and H/R. Further studies found that LY294002 (PI3K inhibitor) suppressed the protective effect of Pec on hepatic I/R injury. In summary, our results show that Pec inhibits oxidative stress, inflammatory responses, and apoptosis, thereby attenuating I/R-induced liver injury and H/R-induced cell damage via activation of the PI3K/AKT/Nrf2 pathway.

Regulator of G-protein signaling 14 protects the liver from ischemia-reperfusion injury by suppressing TGF-ß-activated kinase 1 activation.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion injury (IRI) is a common complication of hepatectomy and liver transplantation. However, the mechanisms underlying hepatic IRI have not been fully elucidated. Regulator of G-protein signaling 14 (RGS14) is a multifunctional scaffolding protein that integrates the G-protein and mitogen-activated protein kinase (MAPK) signaling pathways. However, the role of RGS14 in hepatic IRI remains unclear. APPROACH AND RESULTS: We found that RGS14 expression increased in mice subjected to hepatic ischemia-reperfusion (IR) surgery and during hypoxia reoxygenation in hepatocytes. We constructed global RGS14 knockout (RGS14-KO) and hepatocyte-specific RGS14 transgenic (RGS14-TG) mice to establish 70% hepatic IRI models. Histological hematoxylin and eosin staining, levels of alanine aminotransferase and aspartate aminotransferase, expression of inflammatory factors, and apoptosis were used to assess liver damage and function in these models. We found that RGS14 deficiency significantly aggravated IR-induced liver injury and activated hepatic inflammatory responses and apoptosis in vivo and in vitro. Conversely, RGS14 overexpression exerted the opposite effect of the RGS14-deficient models. Phosphorylation of TGF-ß-activated kinase 1 (TAK1) and its downstream effectors c-Jun N-terminal kinase (JNK) and p38 increased in the liver tissues of RGS14-KO mice but was repressed in those of RGS14-TG mice. Furthermore, inhibition of TAK1 phosphorylation rescued the effect of RGS14 deficiency on JNK and p38 activation, thus blocking the inflammatory responses and apoptosis. CONCLUSIONS: RGS14 plays a protective role in hepatic IR by inhibiting activation of the TAK1-JNK/p38 signaling pathway. This may be a potential therapeutic strategy for reducing incidences of hepatic IRI in the future.

E3 ubiquitin ligase ring finger protein 5 protects against hepatic ischemia reperfusion injury by mediating phosphoglycerate mutase family member 5 ubiquitination.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion (HIR) injury, a common clinical complication of liver transplantation and resection, affects patient prognosis. Ring finger protein 5 (RNF5) is an E3 ubiquitin ligase that plays important roles in endoplasmic reticulum stress, unfolded protein reactions, and inflammatory responses; however, its role in HIR is unclear. APPROACH AND RESULTS: RNF5 expression was significantly down-regulated during HIR in mice and hepatocytes. Subsequently, RNF5 knockdown and overexpression of cell lines were subjected to hypoxia-reoxygenation challenge. Results showed that RNF5 knockdown significantly increased hepatocyte inflammation and apoptosis, whereas RNF5 overexpression had the opposite effect. Furthermore, hepatocyte-specific RNF5 knockout and transgenic mice were established and subjected to HIR, and RNF5 deficiency markedly aggravated liver damage and cell apoptosis and activated hepatic inflammatory responses, whereas hepatic RNF5 transgenic mice had the opposite effect compared with RNF5 knockout mice. Mechanistically, RNF5 interacted with phosphoglycerate mutase family member 5 (PGAM5) and mediated the degradation of PGAM5 through K48-linked ubiquitination, thereby inhibiting the activation of apoptosis-regulating kinase 1 (ASK1) and its downstream c-Jun N-terminal kinase (JNK)/p38. This eventually suppresses the inflammatory response and cell apoptosis in HIR. CONCLUSIONS: We revealed that RNF5 protected against HIR through its interaction with PGAM5 to inhibit the activation of ASK1 and the downstream JNK/p38 signaling cascade. Our findings indicate that the RNF5-PGAM5 axis may be a promising therapeutic target for HIR.

Recent Advances in Costimulatory Blockade to Induce Immune Tolerance in Liver Transplantation.

Liver transplantation is an effective therapy for end-stage liver disease. However, most postoperative patients must take immunosuppressive drugs to prevent organ rejection. Interestingly, some transplant recipients have normal liver function and do not experience organ rejection after the withdrawal of immunosuppressive agents. This phenomenon, called immune tolerance, is the ultimate goal in clinical transplantation. Costimulatory molecules play important roles in T cell-mediated immune responses and the maintenance of T cell tolerance. Blocking costimulatory pathways can alter T cell responses and prolong graft survival. Better understanding of the roles of costimulatory molecules has facilitated the use of costimulatory blockade to effectively induce immune tolerance in animal transplantation models. In this article, we review the state of the art in costimulatory pathway blockade for the induction of immune tolerance in transplantation and its potential application prospects for liver transplantation.

Impact of Al2O3 doping on Bi active center photobleaching in Bi/Er-codoped fibers.

In this Letter, the impact of Al2O3 doping on the Bi active center (BAC) photobleaching is investigated in Bi/Er-codoped fibers (BEDFs). By measuring the evolution of emission attributed to the BAC associated with silica (BAC-Si) at ∼1400nm, the linear relationship between the ratio of unbleached/bleached part (γUB/γB) and 830 nm irradiation intensity (P830) was revealed in the log-log plot. The experimental results demonstrate that Al2O3 doping or its induced defects could be one key factor exaggerating the BAC photobleaching in BEDFs.

Association between Body Mass Index Status and Childhood Asthma Control.

Background: The association between body mass index (BMI) status and childhood asthma control is not well understood. The aim of this study was to explore the association between BMI status and childhood asthma control. Methods: Two hundred forty-two children, aged 6-11 years, with asthma were included. The outcome variables were asthma control levels assessed by the Chinese version of the childhood asthma control test (C-ACT), asthma-related hospitalizations or emergency department (ED) visits in the past 12 months, and forced expiratory volume in 1 second (FEV1) as a percentage of the predicted value. The associations between BMI status (underweight, overweight, or obese, relative to normal weight) and the three outcome variables were estimated by ordinal logistic regression, binary logistic regression, and multiple linear regression analyses. Results: No significant association was found between BMI status and asthma control levels assessed by C-ACT, and between BMI status and asthma-related hospitalizations or ED visits in the past 12 months, after adjustment for age, sex, father's education level, mother's education level, per capita family monthly income, medical insurance, passive smoking, allergic rhinitis, course of disease, and medication compliance. A significant association between underweight and FEV1 as a percentage of the predicted value was found after adjustment for the above covariates. However, no significant association between overweight or obese and FEV1 as a percentage of the predicted value was found. Conclusions: This study shows that BMI status may not be associated with childhood asthma control. Given the inconsistency in current evidence, more studies are needed in the future to investigate this association.

Atomically dispersed cobalt catalyst anchored on nitrogen-doped carbon nanosheets for lithium-oxygen batteries.

Developing single-site catalysts featuring maximum atom utilization efficiency is urgently desired to improve oxidation-reduction efficiency and cycling capability of lithium-oxygen batteries. Here, we report a green method to synthesize isolated cobalt atoms embedded ultrathin nitrogen-rich carbon as a dual-catalyst for lithium-oxygen batteries. The achieved electrode with maximized exposed atomic active sites is beneficial for tailoring formation/decomposition mechanisms of uniformly distributed nano-sized lithium peroxide during oxygen reduction/evolution reactions due to abundant cobalt-nitrogen coordinate catalytic sites, thus demonstrating greatly enhanced redox kinetics and efficiently ameliorated over-potentials. Critically, theoretical simulations disclose that rich cobalt-nitrogen moieties as the driving force centers can drastically enhance the intrinsic affinity of intermediate species and thus fundamentally tune the evolution mechanism of the size and distribution of final lithium peroxide. In the lithium-oxygen battery, the electrode affords remarkably decreased charge/discharge polarization (0.40 V) and long-term cyclability (260 cycles at 400 mA g-1).

Thermally aggravated photo-bleaching of BAC-Al in bismuth/erbium co-doped optical fiber.

The thermal effect upon the photo-bleaching of bismuth/erbium co-doped optical fiber (BEDF) containing Al has been investigated. The photo-bleaching effects of aluminum related bismuth active center (BAC-Al) in BEDF are studied from room temperature (RT) up to 350°C under the irradiation of a 980 nm laser. No visible bleaching of the luminescence associated with BAC-Al was observed at RT, but significant bleaching appeared at higher temperatures above 150°C under the same irradiation power. The underlying mechanism of significant thermal aggravation of photo-bleaching is discussed, and its impact needs to be considered in the design and application of optical amplifiers and lasers using Al-doped BEDF.

Synthesis of MnO2-CuO-Fe2O3/CNTs catalysts: low-temperature SCR activity and formation mechanism.

MnO2-CuO-Fe2O3/CNTs catalysts, as a low-dimensional material, were fabricated by a mild redox strategy and used in denitration reactions. A formation mechanism of the catalysts was proposed. NO conversions of 4% MnO2-CuO-Fe2O3/CNTs catalyst of 43.1-87.9% at 80-180 °C were achieved, which was ascribed to the generation of amorphous MnO2, CuO and Fe2O3, and a high surface-oxygen (Os) content.

Seroprevalence of diphtheria and pertussis immunoglobulin G among children with pneumonia in Ji'nan, China.

BACKGROUND: Vaccination is still one of the most important methods to control and prevent childhood infections including diphtheria and pertussis. This study evaluated the level of diphtheria (DT) and pertussis (PT)-related antibodies among children with pneumonia in Ji'nan, China. METHODS: A total of 484 sera of children from 1 day to 13 years of age were collected from 2014 to 2015 in Ji'nan. Children with recent history of pertussis were excluded from this study. Anti-DT and PT IgG concentrations were measured by ELISA (Euroimmun, Lübeck, Germany). RESULTS: Of the 484 subjects tested, the overall positivity rate of anti-DT IgG (≥0.1 IU/ml) was 48.97%, and the highest positivity rate of anti-DT IgG (68.55%) and proportion with long term protection (23.27%) were observed in children aged 6 m- < 3 y. For anti-PT IgG, 334 subjects (69.01%) had anti-PT IgG levels below the lower limit of detection (5 IU/ml). Even with detectable anti-PT antibodies, the majority (115/150, 76.67%) of them had antibody levels of 5- < 40 IU/ml. The highest proportion of subjects with detectable anti-PT IgG (≥5 IU/ml) was observed in children aged < 6 m (44.36%), then the proportion continually decreased to 15.0% at 3 y- < 6 y (χ2 = 24.05, p < 0.0001). The highest positivity rate (≥40 IU/ml) was only 8.27% in children aged < 6 m. Subjects with an anti-PT IgG ≥100 IU/ml were observed in all the groups and there were no significant differences in the proportions of subjects with a level ≥ 100 IU/ml among these age groups (χ2 = 2.572, p = 0.4624). A total of 5 subjects had anti-PT IgG ≥100 IU/ml (≥1 years post pertussis vaccination) which was considered to be indicative of a recent pertussis infection. CONCLUSIONS: We demonstrated low antibody levels and protection against pertussis in our study population. The anti-PT IgG maintained a low level throughout all age groups, and even no immune responses were observed after the basic immunization and booster. Our study supported the need to reevaluate the immune response of DTP vaccine which was used in Shandong province after 2010.

Antibiotic usage in Chinese children: a point prevalence survey.

BACKGROUND: Children as a population have high antimicrobial prescribing rates which may lead to high resistance of bacteria according to data from some single-center surveys of antibiotic prescribing rates in China. The acquirement of baseline data of antibiotic prescribing is the basis of developing intervention strategies on inappropriate antimicrobial prescriptions. Few studies show clearly the pattern and detailed information on classes of antibiotics and distribution of indications of antibiotic prescriptions in children in China. This study aims to assess the antibiotic prescribing patterns among children and neonates hospitalized in 18 hospitals in China. METHODS: A 24-hour point prevalence survey on antimicrobial prescribing was conducted in hospitalized neonates and children in China from December 1st, 2016 to February 28th, 2017. Information on the antibiotic use of patients under 18 years of age who were administered one or more on-going antibiotics in the selected wards over a 24-hour period was collected. These data were submitted to the GARPEC (Global Antimicrobial Resistance, Prescribing and Efficacy in Children and Neonates) web-based application ( https://pidrg-database.sgul.ac.uk/redcap/ ). For statistical analysis, Microsoft Excel 2007 and SPSS 22.0 were used. RESULTS: The antibiotic data were collected in 35 wards in 18 hospitals from 9 provinces. In total, 67.76% (975/1439) of the patients (n = 1439) were given at least one antibiotic, including 58.1% (173/298) of neonates (n = 298) and 70.3% (802/1141) of children (n = 1141). In neonates, the three most frequently prescribed antibiotics were third-generation cephalosporins (41.7%), penicillins plus enzyme inhibitor (23.8%), and carbapenems (11.2%). In children, the three most frequently prescribed antibiotics were third-generation cephalosporins (35.5%), macrolides (23.2%), and penicillins plus enzyme inhibitors (15.9%). The most common indication for antibiotics was proven or probable bacterial lower respiratory tract infection (30.9% in neonates and 66.6% in children). CONCLUSIONS: Antibiotics are commonly prescribed in the Chinese children population. It is likely that the third-generation cephalosporins and macrolides are currently overused in Chinese children. Efforts must be made to ensure safe and appropriate antibiotic prescribing to reduce and prevent the future development of antibiotic resistance.

Photo-bleaching mechanism of the BAC-Si in bismuth/erbium co-doped optical fibers.

Photo-bleaching of the silica-related bismuth active center (BAC-Si) in bismuth/erbium co-doped optical fibers is investigated. By analyzing dynamic spectral characteristics of BAC-Si, the photo-bleaching of the BAC-Si is found to be linked to the escape of an excited electron from the bismuth site in the BAC-Si. This mechanism of BAC-Si bleaching linked to an escaping excited electron is further confirmed with both photo-bleaching experiments by different laser pump wavelengths and a potential energy model describing the loss of an excited electron. Additionally, the temperature effect on the photo-bleaching, which is in good agreement with the above findings, is observed and discussed.

Reversible photo-bleaching effect in a bismuth/erbium co-doped optical fiber under 830 nm irradiation.

We observed photo-bleaching in a bismuth/erbium co-doped optical fiber (BEDF) under 830 nm irradiation. As a result of the photo-bleaching, the absorption at 814 nm and the near-infrared luminescence at 1420 nm are decreased, indicating that the silicon-based bismuth active center (BAC-Si) in a BEDF is bleached in the process. We further found that the photo-bleaching is reversible under room temperature. This is the first time that the BAC-Si could be bleached under 830 nm irradiation, and the photo-bleaching is reversible. The underlying mechanism of the reversible photo-bleaching effect is discussed.

γ irradiation induced effects on bismuth active centres and related photoluminescence properties of Bi/Er co-doped optical fibres.

We investigate the effects of γ irradiation on bismuth active centres (BACs) and related photoluminescence properties of bismuth/erbium co-doped silica fibre (BEDF), [Si] ~28, [Ge] ~1.60, [Al] ~0.10, [Er] ~ <0.10 and [Bi] ~0.10 atom%, fabricated by in-situ solution doping and Modified Chemical Vapor Deposition (MCVD). The samples were irradiated at 1 kGy, 5 kGy, 15 kGy, 30 kGy and 50 kGy doses, and dose rate of 5.5 kGy/h, at room temperature. The optical properties of BEDF samples are tested before and after γ irradiation. We found that high dose γ irradiation could significantly influence the formation and composition of BACs and their photoluminescence performance, as important changes in absorption and emission properties associated with the 830 nm pump produces the direct evidence of γ irradiation effects on BAC-Si. We notice that the saturable to unsaturable absorption ratio at pump wavelength could be increased with high dose γ irradiation, indicating that emission and pump efficiency could be increased by γ irradiation. Our experimental results also reveal good radiation survivability of the BEDF under low and moderate γ irradiation. Our investigation suggests the existence of irradiation related processing available for tailoring the photoluminescence properties and performance of bismuth doped/co-doped fibres.

Association between maternal smoking during pregnancy and recurrent wheezing in infancy: evidence from a meta-analysis.

BACKGROUND: Quantification of the association between the maternal smoking during pregnancy and recurrent wheezing in infancy is still conflicting. Thus, we performed a comprehensive meta-analysis to test the hypothesis that maternal smoking during pregnancy may increase the risk of recurrent wheezing in infancy. METHODS: Pertinent studies were identified by a search in PubMed and Web of Knowledge up to October 2014. Random-effect model (REM) or fixed effects model (FEM) was used to combine study-specific results. Publication bias was estimated using Egger's regression asymmetry test. RESULTS: Seven articles (3 cohort study and 4 cross-sectional studies) involving 8579 recurrent wheezing infant cases about maternal smoking during pregnancy and recurrent wheezing risk were used in this meta-analysis. The combined relative risks (RRs) of recurrent wheezing infants associated with maternal smoking during pregnancy was 1.491 (95% CIs = 1.329-1.672) overall. Significant associations were found both in Europe [RRs = 1.471, 95% CIs = 1.287-1.681] and other populations [RRs = 1.720, 95% CIs = 1.119-2.644] and cross-sectional studies [RRs = 1.474, 95% CIs = 1.306-1.663]. No publication bias was found. CONCLUSIONS: Our analysis indicated that maternal smoking during pregnancy could increase the risk of recurrent wheezing in infancy.