Crosstalk of cuproptosis-related subtypes, establishment of a prognostic signature, and immune infiltration characteristics in gastric cancer.

Background: Cuproptosis is a novel form of cellular demise that occurs through a unique pathway involving lipoylated proteins in the tricarboxylic acid (TCA) cycle and is closely linked to mitochondrial metabolism. Nevertheless, the comprehensive elucidation of the impact of carcinogenesis-associated genes (CRGs) on prognosis, tumor microenvironment (TME), and therapeutic response in patients with gastric cancer (GC) remains unclear. Methods: In total, 1374 GC samples were gathered from three Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas database. The samples were then stratified into different subtypes through unsupervised clustering of the 13 CRG profiles. The CRG_score was developed to quantify CRG patterns of individual tumors. Subsequently, we investigated the associations among the various groups and clinicopathological features, immune infiltration features, TME mutation status, and response to immunotherapy. Results: The GC samples were divided into two clusters based on their distinct clinicopathological features, prognosis, and immune characteristics. Using LASSO and Cox regression analyses, 9 genes were identified for constructing a prognostic signature related to cuproptosis. The novel signature displayed outstanding durability and prognostic capability for the overall lifespan of individuals. Additionally, the expression levels of signature genes in GC tissues and adjacent normal tissues were tested by qRT-PCR. Moreover, we developed a remarkably dependable nomogram to enhance the practicality of the CRG_score in clinical settings. High tumor mutation burden, increased microsatellite instability-high, immune activation, along with good survival probability and increased immunoreactivity to immune checkpoint inhibitors, were distinguishing features of low CRG_scores. Conclusions: The findings of this study revealed the possible impacts of CRGs on the TME, clinical and pathological characteristics, and outlook of patients with GC. This signature was strongly linked to the immune response against GC and has the potential to serve as a valuable tool for predicting patient prognosis.

[Administration of a single chain variable fragments chimeric protein (SD) of ovalbumin epitopes internalizing receptor DEC-205 antibody inhibits food allergy in mice].

Objective To investigate the preventive therapeutic effect and possible mechanism of single chain variable fragments chimeric protein (SD) of ovalbumin epitopes internalizing receptor DEC-205 antibody on food allergy in mice. Methods Mice were randomly divided to five groups (control, PBS, scFv DEC 100 µg, SD 50 µg, SD 100 µg) and treated for 24 hours before OVA administration. After challenge, the serum level of OVA-specific IgE, IgG1, IgG2a and IL-4 were detected by ELISA. Infiltration of eosinophils and mast cells in the jejunum was observed by HE staining and toluidine blue staining respectively. The bone marrow of tibia and femur was isolated and cultured to obtain immature dendritic cells(BMDCs), which were further treated with LPS (10 ng/mL), TSLP (50 ng/mL), scFv DEC protein (1000 ng/mL) and SD protein (10,100,1000)ng/mL for 24 hours, and the IL-10 level of supernatant was assayed by ELISA. Results Compared with PBS group, the number of SD-treated mice with diarrhea was markedly reduced. The difference in rectal temperature and the levels of serum OVA-specific IgE, IgG1, IgG2a and IL-4 decreased significantly after prophylactic administration of SD; The number of eosinophils and mast cells in jejunum also decreased significantly while the IL-10 level in the supernatant of BMDCs increased significantly after SD intervention. Conclusion SD mitigates experimental FA response by fosters the immune tolerance property of dendritic cells.

Post-synthetic Chemical Fixation of Fe2+ in MOF to Prepare Fe2 N-Embedded N-Doped Graphene Nanoribbons for Superior Oxygen Reduction Reaction.

The construction of efficient non-precious metal electrocatalysts for oxygen reduction reaction (ORR) with controlled structures and active sites is of fundamental importance for the wide utilization of hydrogen fuel cells. Herein, we report a controllable chemical fixation strategy that enables the simultaneous optimization in both of local and external structure of the Fe-N-C catalyst. The post-synthetic single-atomic chemical fixation of Fe2+ ions in coordinated-free bi-pyridine sites combined with the carbonation afford a Fe2 N-embedded N-doped graphene nanoribbon (Fe2 N/NGNR) with dispersing Fe2 N nanoparticles embedded in NGNR. When used as ORR electrocatalyst, Fe2 N/NGNR exhibits a half-wave potential of 0.87 V and 0.79 V vs. RHE in alkaline and acid medium, respectively, comparable to commercial Pt/C (20 wt%) catalysts. The prominent ORR activity of Fe2 N/NGNR is verified an H2 -O2 fuel cell which displayed a peak power density of 307.7 mW/cm2 when using the Fe2 N/NGNR as the catalyst in the cathode electrode.

Synergistic anti-inflammatory effect of gut microbiota and lithocholic acid on liver fibrosis.

BACKGROUND: Bile acids can regulate liver disease progression by affecting the functions of gut microbiota and immune cells. As the most potent natural agonist of G-protein coupled bile acid receptor 5 (TGR5) (expressed in macrophages, HSCs, and monocytes), lithocholic acid (LCA) has multiple functions, such as inhibiting inflammation and regulating metabolism. Therefore, this study aims to investigate the effects of LCA on immune cells and HSCs in liver fibrosis. METHODS: A liver fibrosis mouse model was induced by carbon tetrachloride followed by gavage of LCA, and the effects of LCA were evaluated by serum biochemical analysis, liver histology, and western bolt. Plasma cytokine levels and the number of immune cells were determined by cytometric bead array and flow cytometry, respectively. RESULTS: LCA could inhibit the activation of HSCs by inducing apoptosis and reducing the activation of transforming growth factor-ß (TGF-ß) Smad-dependent and Smad-independent pathways. Meanwhile, LCA inhibited glycolysis and promoted oxidative phosphorylation, leading to the differentiation of macrophages to M2 type and inhibiting their differentiation to M1 type. Furthermore, LCA increased the recruitment of NK cells and reduced the activation of NKT cells. However, these effects of LCA were attenuated after antibiotics reduced the diversity and abundance of the gut microbiota. CONCLUSIONS: Gut microbiota and LCA exerted synergistic anti-inflammatory effects on liver fibrosis. The combined intervention of gut microbiota and LCA will be a new strategy for treating liver fibrosis.

Co-interventions with Clostridium butyricum and soluble dietary fiber targeting the gut microbiota improve MAFLD via the Acly/Nrf2/NF-κB signaling pathway.

Purpose: The pathogenesis of metabolic associated fatty liver disease (MAFLD) is complex. Lipid metabolic disorder, chronic inflammation, and oxidative stress are the core events for MAFLD. Dietary intervention is an important treatment strategy for preventing the onset and progression of MAFLD. Clostridium butyricum (CB) and soluble dietary fiber (SDF) are often considered beneficial for health. We explored how two microbiota-targeted interventions (SDF and CB) influence the hepatic immune system, oxidative stress, and lipid metabolism in MAFLD mice. Methods: To explore the role of SDF and CB in MAFLD, we generated MAFLD mouse models by feeding C57BL/6 mice with a high-fat diet (HFD). After 8 weeks of intervention, we measured immune cell function, lipid metabolism, and oxidative stress levels in the livers of mice. Results: Single intervention with SDF or CB was not effective in improving MAFLD; however, co-interventions with SDF and CB increased microbiota diversity and decreased inflammation, oxidative stress, and lipid synthesis. Moreover, we determined that co-intervention with SDF and CB mediated fatty acid oxidation by activating the Acly/Nrf2/NF-κB signaling pathway. Most importantly, co-intervention exerted anti-inflammatory effects by inhibiting the differentiation of macrophages into pro-inflammatory M1 macrophages. Conclusion: This study show that co-intervention with SDF and CB can improve MAFLD, and co-intervention with  SDF and CB are suggested to be potential gut microbiota modulators and therapeutic substances for MAFLD.

Development of a Bile Acid-Related Gene Signature for Predicting Survival in Patients with Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most common diseases that threaten millions of lives annually. Evidence supports that bile acid (BA) affects HCC through inflammation, DNA damage, or other mechanisms. Methods: A total of 127 BA-associated genes were analyzed in HCC tumor and nontumor samples using The Cancer Genome Atlas data. Genes correlated to the prognosis of patients with HCC were identified using univariate and multivariate Cox regression analyses. Furthermore, a prediction model with identified genes was constructed to evaluate the risk of patients with HCC for prognosis. Results: Out of 26 genes with differential expressions between the HCC and nontumor samples, 19 and 7 genes showed upregulated and downregulated expressions, respectively. Three genes, NPC1, ABCC1, and SLC51B, were extrapolated to construct a prediction model for the prognosis of patients with HCC. Conclusion: The three-gene prediction model was more reliable than the pathological staging characters of the tumor for the prognosis and survival of patients with HCC. In addition, the upregulated genes facilitating the transport of BAs are associated with poor prognosis of patients with HCC, and genes of de novo synthesis of BAs benefit patients with HCC.

Effect of ORF7 of SARS-CoV-2 on the Chemotaxis of Monocytes and Neutrophils In Vitro.

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the most significant public health threat worldwide. Patients with severe COVID-19 usually have pneumonia concomitant with local inflammation and sometimes a cytokine storm. Specific components of the SARS-CoV-2 virus trigger lung inflammation, and recruitment of immune cells to the lungs exacerbates this process, although much remains unknown about the pathogenesis of COVID-19. Our study of lung type II pneumocyte cells (A549) demonstrated that ORF7, an open reading frame (ORF) in the genome of SARS-CoV-2, induced the production of CCL2, a chemokine that promotes the chemotaxis of monocytes, and decreased the expression of IL-8, a chemokine that recruits neutrophils. A549 cells also had an increased level of IL-6. The results of our chemotaxis Transwell assay suggested that ORF7 augmented monocyte infiltration and reduced the number of neutrophils. We conclude that the ORF7 of SARS-CoV-2 may have specific effects on the immunological changes in tissues after infection. These results suggest that the functions of other ORFs of SARS-CoV-2 should also be comprehensively examined.

Risk factors for mortality in patients over 70 years old with COVID-19 in Wuhan at the early break: retrospective case series.

BACKGROUND: Elderly patients with COVID-19 were shown to have a high case-fatality rate. We aimed to explore the risk factors associated with death in patients over 70 years old (yr). METHODS: In this retrospective study, we enrolled consecutively hospitalized patients over 70 yr with COVID-19 between January 20 and February 15, 2020 in Renmin Hospital of Wuhan University. Epidemiological, demographic, and clinical data were collected. Clinical subtypes, including mild, moderate, severe, and critical types, were used to evaluate the severity of disease. Patients were classified into two groups: survivor and non-survivor groups. Clinical data were compared between the two groups. Univariable and multivariable Cox regression methods were used to explore the risk factors. RESULTS: A total of 147 patients were enrolled. The case-fatality rate was 28.6%. Multivariable Cox proportional hazard regression showed that clinical subtypes, including the severe type (HR = 2.983, 95% CI: 1.231-7.226, P = 0.016) and the critical type (HR = 3.267, 95%CI: 1.009-10.576, P = 0.048), were associated with increasing risk of death when compared with the general type. Blood urea nitrogen greater than 9.5 mmol/L (HR = 2.805, 95% CI: 1.141-6.892, P = 0.025) on admission was an independent risk factor for death among laboratory findings. CONCLUSION: The patients over 70 yr with COVID-19 had a high case-fatality rate. The risk factors, including clinical subtypes and blood urea nitrogen greater than 9.5 mmol/L, could help physicians to identify elderly patients with poor clinical outcomes at an early stage.

Reduced Energy Metabolism Impairs T Cell-Dependent B Cell Responses in Patients With Advanced HBV-Related Cirrhosis.

Background and Aims: Patients with decompensated HBV-related liver cirrhosis (HBV D-LC) showed compromised immune responses, which manifested as a proneness to develop infections and hyporesponsiveness to vaccines, resulting in accelerated disease progression. The alterations in T cell-dependent B cell responses in this pathophysiological process were not well understood. This study aimed to investigate T cell-dependent B cell responses in this process and discuss the mechanism from the perspective of metabolism. Methods: Changes in phenotypes and subsets of peripheral B cells between HBV D-LC patients and healthy controls (HCs) were compared by flow cytometry. Isolated B cells were activated by coculture with circulating T follicular (cTfh) cells. After coculture, the frequencies of plasmablasts and plasma cells and immunoglobin levels were analyzed. Oxidative phosphorylation (OXPHOS) and glycolysis were analyzed by a Seahorse analyzer. Mitochondrial function and the AKT/mTOR pathway were analyzed by flow cytometry. Results: The proliferation and differentiation capacities of B cells after T cell stimulation were impaired in D-LC. Furthermore, we found that B cells from D-LC patients showed reductions in OXPHOS and glycolysis after activation, which may result from reduced glucose uptake, mitochondrial dysfunction and attenuated activation of the AKT/mTOR pathway. Conclusions: B cells from HBV D-LC patients showed dysfunctional energy metabolism after T cell-dependent activation. Understanding the regulations of B cell metabolic pathway and their changes may provide a new direction to rescue B cell hyporesponsiveness in patients with HBV D-LC, preventing these patients be infected and improving sensitivity to vaccines.

Role of bile acids in liver diseases mediated by the gut microbiome.

The intensive crosstalk between the liver and the intestine performs many essential functions. This crosstalk is important for natural immune surveillance, adaptive immune response regulation and nutrient metabolism and elimination of toxic bacterial metabolites. The interaction between the gut microbiome and bile acids is bidirectional. The gut microbiome regulates the synthesis of bile acids and their biological signaling activity and circulation via enzymes. Similarly, bile acids also shape the composition of the gut microbiome by modulating the host's natural antibacterial defense and the intestinal immune system. The interaction between bile acids and the gut microbiome has been implicated in the pathophysiology of many intestinal and extra intestinal diseases, especially liver diseases. As essential mediators of the gut-liver crosstalk, bile acids regulate specific host metabolic pathways and modulate the inflammatory responses through farnesoid X-activated receptor and G protein-coupled bile acid receptor 1. Several clinical trials have demonstrated the signaling effects of bile acids in the context of liver diseases. We hypothesize the existence of a gut microbiome-bile acids-liver triangle and explore the potential therapeutic strategies for liver diseases targeting the triangle.

Potential capacity of interferon-α to eliminate covalently closed circular DNA (cccDNA) in hepatocytes infected with hepatitis B virus.

Interferon-alpha (IFN-α) and nucleot(s)ide analogs (NAs) are first-line drugs for the treatment of chronic hepatitis B virus (HBV) infections. Generally, NAs target the reverse transcription of HBV pregenomic RNA, but they cannot eliminate covalently-closed-circular DNA (cccDNA). Although effective treatment with NAs can dramatically decrease HBV proteins and DNA loads, and even promote serological conversion, cccDNA persists in the nucleus of hepatocytes due to the lack of effective anti-cccDNA drugs. Of the medications currently available, only IFN-α can potentially target cccDNA. However, the clinical effects of eradicating cccDNA using IFN-α in the hepatocytes of patients with HBV are not proficient as well as expected and are not well understood. Herein, we review the anti-HBV mechanisms of IFN-α involving cccDNA modification as the most promising approaches to cure HBV infection. We expect to find indications of promising areas of research that require further study to eliminate cccDNA of HBV in patients.

Longitudinal associations between household solid fuel use and depression in middle-aged and older Chinese population: A cohort study.

BACKGROUND: Previous studies found that ambient air pollution was associated with a higher prevalence of depressive symptoms. However, the longitudinal associations between household solid fuel use, which is the main source of household air pollution, and depressive symptoms remain unclear. This cohort study aimed to explore the associations between household solid fuel use and incidence of depressive symptoms in China. METHODS: In total, 8637 participants were enrolled in this prospective cohort study. Depressive symptoms were assessed using the 10-item Center for Epidemiological Studies Depression Scale. The associations between baseline household solid fuel use and the incidence of depressive symptoms were examined using Cox proportional hazards regression models. RESULTS: During the 4-year of follow-up, 2074 of 8637 participants developed depressive symptoms. Compared with participants who used clean fuel for both heating and cooking, the multivariate-adjusted hazard ratio (HR) (95% confidence intervals [95% CI]) for depressive symptoms incidence in participants who used solid fuels for two purposes (cooking and heating) was 1.15 (1.01, 1.31). In the solid fuel use subgroup analysis, use of solid fuels for cooking (HR, 1.12; 95% CI, 1.02-1.24) was associated with a higher incidence of depressive symptoms after adjustments while use for heating (HR, 1.05; 95% CI, 0.93-1.18) was not. Moreover, compared with persistent solid fuel users, switching from solid to clean fuels for cooking resulted in a lower risk of depressive symptoms before adjustments (HR, 0.82; 95% CI, 0.71-0.95) and a non-significant association (HR, 0.90; 95% CI, 0.77-1.04) afterwards. CONCLUSIONS: The results suggest that household solid fuel use for cooking was associated with a higher incidence of depressive symptoms. Preventive strategies based on improving household cooking environment for depressive symptoms should be established.

Supraoptimal Cytokinin Content Inhibits Rice Seminal Root Growth by Reducing Root Meristem Size and Cell Length via Increased Ethylene Content.

Cytokinins (CKs), a class of phytohormone, regulate root growth in a dose-dependent manner. A certain threshold content of CK is required for rapid root growth, but supraoptimal CK content inhibits root growth, and the mechanism of this inhibition remains unclear in rice. In this study, treatments of lovastatin (an inhibitor of CK biosynthesis) and kinetin (KT; a synthetic CK) were found to inhibit rice seminal root growth in a dose-dependent manner, suggesting that endogenous CK content is optimal for rapid growth of the seminal root in rice. KT treatment strongly increased ethylene level by upregulating the transcription of ethylene biosynthesis genes. Ethylene produced in response to exogenous KT inhibited rice seminal root growth by reducing meristem size via upregulation of OsIAA3 transcription and reduced cell length by downregulating transcription of cell elongation-related genes. Moreover, the effects of KT treatment on rice seminal root growth, root meristem size and cell length were rescued by treatment with aminoethoxyvinylglycine (an inhibitor of ethylene biosynthesis), which restored ethylene level and transcription levels of OsIAA3 and cell elongation-related genes. Supraoptimal CK content increases ethylene level by promoting ethylene biosynthesis, which in turn inhibits rice seminal root growth by reducing root meristem size and cell length.

Localization and Stabilization of Photogenerated Electrons at TiO2 Nanoparticle Surface by Oxygen at Ambient Temperature.

Understanding the mechanism by which oxygen adsorption influences the separation behavior of charge carriers is important in photocatalytic removal of air pollutants. In this study, we performed steady-state surface photovoltage and surface photocurrent spectroscopy combined with an atmosphere control system to determine the effect of oxygen on the charge separation behavior at the surface of anatase TiO2 nanoparticles at ambient temperature. Results showed that photogenerated electrons were movable in N2 atmosphere but were localized in O2 atmosphere. O2 obviously enhanced the stabilization of the localized photogenerated electrons when the surface defects of TiO2 were fully occupied by adsorbed O2. Moreover, O2 adsorption increased the energy demand for exciting electrons from the valence band to localized surface defect states and reduced the density of band tail states. These findings suggest us that the effect of gaseous species on the mobility and stability of charge carriers should be considered to understand the photocatalytic degradation of air pollutants.

Consumption of preserved egg, a high-lead-containing food, is strongly associated with depressive symptoms in Chinese adults.

Previous studies have demonstrated adverse mental health effects of Pb exposure. The purpose of this study is to investigate the relationship between consumption of preserved egg (PE), a high-Pb-containing food and depressive symptoms among adults in China. A sample of 25 213 adults (mean age 41·4 (sd 11·8) years; males, 53·9 %) in Tianjin, China, was studied in a cross-sectional analysis. Dietary intake including PE was assessed using a valid self-administered FFQ. Depressive symptoms were assessed using the Self-Rating Depression Scale (SDS). The association was estimated by OR using logistic regression models adjusted for multiple confounders. The prevalence of elevated depressive symptoms was 6·6 % (SDS≥50). Compared with the least frequent PE consumption (

Comparing the diagnostic ability of inflammatory markers in metabolic syndrome.

BACKGROUND: Chronic low-grade inflammation contributes to the pathogenesis of the metabolic syndrome (MetS). Although some studies have demonstrated that several standard inflammatory markers provide diagnostic value for MetS, few studies have compared the diagnostic ability of various inflammatory markers. We demonstrated the diagnostic ability of several inflammatory markers in detecting MetS. METHODS: Complement component 3 (C3), C4, high-sensitivity C-reactive protein (hs-CRP), leukocyte count, neutrophil, lymphocyte and neutrophil-to-lymphocyte ratio (NLR) concentrations were measured in 6312 participants living in Tianjin, China. MetS was defined according to American Heart Association criteria. Adjusted logistic models were used to assess associations between inflammatory markers and MetS. Receiver operating characteristic (ROC) curves were performed to determine the diagnostic values of inflammatory markers for MetS. RESULTS: The adjusted odds ratio (95% CI) of MetS for the highest inflammatory markers (C3, leukocyte, neutrophil, lymphocyte) quintile, when compared to the lowest quintile were 2.68 (2.12-3.38), 2.53 (2.05-3.11), 1.31 (1.06-1.62) and 1.94 (1.60-2.37), respectively. ROC analysis showed that the optimal cut-off values were 101.0mg/dl for C3 (Area under the ROC curve (AUC)=0.68), 5.41×1000cells/mm3 for leukocyte (AUC=0.63), 3.20×1000cells/mm3 for neutrophil (AUC=0.60) and 1.82×1000cells/mm3 for lymphocyte (AUC=0.62). No significant association was observed between the other inflammatory markers and MetS. CONCLUSIONS: Among the inflammatory markers assessed in this population, C3 has the strongest diagnostic value in detecting MetS. Further studies are encouraged to determine the efficacy of applying C3 to diagnosis and treatment in the clinical setting.

MicroRNA-519a promotes proliferation and inhibits apoptosis of hepatocellular carcinoma cells by targeting FOXF2.

Recent studies report that microRNA-519a (miR-519a) is a novel oncomir, which facilitates the onset and progression of human cancers. However, the clinical significance of miR-519a and its functional role and underlying mechanisms in hepatocellular carcinoma (HCC) are poorly investigated. In the present study, elevated expression of miR-519a was observed in HCC tissues compared with adjacent non-tumor tissues. The increased level of miR-519a expression was significantly correlated with adverse clinical features of HCC including hepatitis B virus (HBV) infection, large tumor size, cirrhosis and advanced tumor-node-metastasis tumor stage. Furthermore, high expression of miR-519a was prominently associated with a poorer 5-year overall survival and recurrence-free survival of HCC patients. Gain- and loss-of function experiments showed that miR-519a overexpression enhanced proliferation and reduced apoptosis of Huh7 cells. By contrast, miR-519a knockdown inhibited SMMC-7721 cell proliferation and induced apoptosis. Importantly, up-regulation of miR-519a reduced the expression of FOXF2 mRNA and protein in Huh7 cells, while down-regulation of miR-519a resulted in increased expression of FOXF2 in SMMC-7721 cells. An inverse correlation between mRNA levels of miR-519a and FOXF2 was observed in HCC tissues. Thus, Forkhead box F2 (FOXF2) was identified as a downstream target of miR-519a in HCC. Mechanistically, the effects of miR-519a knockdown on SMMC-7721 cells were abrogated by FOXF2 repression. In conclusion, miR-519a is a novel prognostic predictor for HCC patients and it may potentiate proliferation and inhibits apoptosis of HCC cells by targeting FOXF2.