STING modulates iron metabolism to promote liver injury and inflammation in acute immune hepatitis.

The pathogenesis of Autoimmune Hepatitis (AIH) is closely associated with perturbations in iron ion metabolism, during which Stimulator of Interferon Genes (STING) plays an important role. However, the precise regulatory mechanism remains elusive. In this study, we investigated the relationship between iron dysregulation and STING activation in Concanavalin A (ConA)-induced AIH liver injury. STING knockout (STING-/-) mice and AAV (Adeno-Associated virus)-Sting1-RNAi-treated mice were involved and subjected in AIH. We observed that increased iron dysregulation was linked with STING activation, but this effect was effectively reversed by the administration of iron chelating agent Desferoxamine (DFO) and the antioxidant Ferrostatin-1 (Fer-1). Notably, the iron transport protein Transferrin (TF) and Transferrin Receptor (TfR) exhibited significant accumulation in AIH along with upregulated expression of ferritin protein. Additionally, the deficiency of STING reduced hepatic iron accumulation, mitigated oxidative stress, and attenuated macrophage activation during ConA treatment. Furthermore, liver-specific knockdown of STING using AAV-Sting1-RNAi significantly ameliorated liver iron dysregulation and oxidative stress response induced by Kupffer cells (KCs). KC-derived STING exacerbates liver damage severity in AIH through promoting disturbances in hepatic iron ion metabolism as well as oxidative stress response. These findings provide valuable insights into the pathogenesis of AIH and may pave the way for potential therapeutic strategies targeting STING and iron metabolism in the future.

Erchen decoction alleviates the progression of NAFLD by inhibiting lipid accumulation and iron overload through Caveolin-1 signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: A combination of 6 different Chinese herbs known as Erchen decoction (ECD) has been traditionally used to treat digestive tract diseases and found to have a protective effect against nonalcoholic fatty liver disease (NAFLD). Despite its efficacy in treating NAFLD, the precise molecular mechanism by which Erchen Decoction regulated iron ion metabolism to prevent disease progression remained poorly understood. AIM OF STUDY: Our study attempted to confirm the specific mechanism of ECD in reducing lipid and iron in NAFLD from the perspective of regulating the expression of Caveolin-1 (Cav-1). STUDY DESIGN: In our study, the protective effect of ECD was investigated in Palmitic Acid + Oleic Acid-induced hepatocyte NAFLD model and high-fat diet-induced mice NAFLD model. To investigate the impact of Erchen Decoction (ECD) on lipid metabolism and iron metabolism via mediating Cav-1 in vitro, Cav-1 knockdown cell lines were established using lentivirus-mediated transfection techniques. MATERIALS AND METHODS: We constructed NAFLD model by feeding with high-fat diet for 12 weeks in vivo and Palmitic Acid + Oleic Acid treatment for 24 h in vitro. The regulation of Lipid and iron metabolism results by ECD were detected by serological diagnosis, immunofluorescent and immunohistochemical staining, and western blotting. The binding ability of 6 small molecules of ECD to Cav-1 was analyzed by molecular docking. RESULTS: We demonstrated that ECD alleviated the progression of NAFLD by inhibiting lipid accumulation, nitrogen oxygen stress, and iron accumulation in vivo and in vitro experiments. Furthermore, ECD inhibited lipid and iron accumulation in liver by up-regulating the expression of Cav-1, which indicated that Cav-1 was an important target for ECD to exert its curative effect. CONCLUSIONS: In summary, our study demonstrated that ECD alleviated the accumulation of lipid and iron in NAFLD through promoting the expression of Cav-1, and ECD might serve as a novel Cav-1 agonist to treat NAFLD.

Exploring the potential mechanism of Taohong Siwu decoction in the treatment of avascular necrosis of the femoral head based on network pharmacology and molecular docking.

Based on network pharmacology and molecular docking, this study seeks to investigate the mechanism of Taohong Siwu decoction (THSWD) in the treatment of avascular necrosis of the femoral head (AVNFH). The Traditional Chinese Medicine Systems Pharmacology database was used in this investigation to obtain the active ingredients and related targets for each pharmaceutical constituent in THSWD. To find disease-related targets, the terms "avascular necrosis of the femoral head," "necrosis of the femoral head," "steroid-induced necrosis of the femoral head," "osteonecrosis," and "avascular necrosis of the bone" were searched in the databases DisGeNET, GeneCards, Comparative Toxicogenomics Database, and MalaCards. Following the identification of the overlap targets of THSWD and AVNFH, enrichment analysis using gene ontology, Kyoto Encyclopedia of Genes and Genomes, Reactome, and WikiPathways was conducted. The "THSWD-drug-active compound-intersection gene-hub gene-AVNFH" network and protein-protein interaction network were built using Cytoscape 3.9.1 and string, and CytoHubba was used to screen hub genes. The binding activities of hub gene targets and key components were confirmed by molecular docking. 152 prospective therapeutic gene targets were found in the bioinformatics study of ONFH treated with THSWD, including 38 major gene targets and 10 hub gene targets. The enrichment analysis of 38 key therapeutic targets showed that the biological process of gene ontology analysis mainly involved cytokine-mediated signaling pathway, angiogenesis, cellular response to reactive oxygen species, death-inducing signaling complex. The Kyoto Encyclopedia of Genes and Genomes signaling pathway mainly involves TNF signaling pathway, IL-17 signaling pathway, and the Recactome pathway mainly involves Signaling by Interleukins, Apoptosis, and Intrinsic Pathway for Apoptosis. WikiPathways signaling pathway mainly involves TNF-related weak inducer of apoptosis signaling pathway, IL-18 signaling pathway. According to the findings of enrichment analysis, THSWD cured AVNFH by regulating angiogenesis, cellular hypoxia, inflammation, senescence, apoptosis, cytokines, and cellular proliferation through the aforementioned targets and signaling pathways. The primary component of THSWD exhibits a strong binding force with the key protein of AVNFH. This study sheds new light on the biological mechanism of THSWD in treating AVNFH by revealing the multi-component, multi-target, and multi-pathway features and molecular docking mechanism of THSWD.

Caveolin-1 is critical for hepatic iron storage capacity in the development of nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is associated with disordered lipid and iron metabolism. Our previous study has substantiated the pivotal role of Caveolin-1 (Cav-1) in protecting hepatocytes and mediating iron metabolism in the liver. This study aimed to explore the specific mechanisms underlying the regulation of iron metabolism by Cav-1 in NAFLD. METHODS: Hepatocyte-specific Cav-1 overexpression mice and knockout mice were used in this study. Cav-1-knockdown of RAW264.7 cells and mouse primary hepatocytes were performed to verify the changes in vitro. Moreover, a high-fat diet and palmitic acid plus oleic acid treatment were utilized to construct a NAFLD model in vivo and in vitro, respectively, while a high-iron diet was used to construct an in vivo iron overload model. Besides, iron concentration, the expression of Cav-1 and iron metabolism-related proteins in liver tissue or serum were detected using iron assay kit, Prussian blue staining, Western blotting, immunofluorescence staining, immunohistochemical staining and ELISA. The related indicators of lipid metabolism and oxidative stress were evaluated by the corresponding reagent kit and staining. RESULTS: Significant disorder of lipid and iron metabolism occurred in NAFLD. The expression of Cav-1 was decreased in NAFLD hepatocytes (P < 0.05), accompanied by iron metabolism disorder. Cav-1 enhanced the iron storage capacity of hepatocytes by activating the ferritin light chain/ferritin heavy chain pathway in NAFLD, subsequently alleviating the oxidative stress induced by excess ferrous ions in the liver. Further, CD68+CD163+ macrophages expressing Cav-1 were found to accelerate iron accumulation in the liver, which was contrary to the effect of Cav-1 in hepatocytes. Positive correlations were also observed between the serum Cav-1 concentration and the serum iron-related protein levels in NAFLD patients and healthy volunteers (P < 0.05). CONCLUSIONS: These findings confirm that Cav-1 is an essential target protein that regulates iron and lipid metabolic homeostasis. It is a pivotal molecule for predicting and protecting against the development of NAFLD.

Network pharmacological analysis on the mechanism of Coix seed decoction for osteoarthritis of the knee.

Based on network pharmacology methods, we explored the mechanism of the classic Chinese medicine formula Coix seed decoction (CSD) in treating knee osteoarthritis (KOA). We searched each single drug in the CSD in the traditional Chinese medicine systematic pharmacology database in turn to obtain information on the active ingredients and target proteins of the CSD, and obtain the name of the genes corresponding to the target proteins through the UniProt database. We collected KOA-related genes from DisGeNET, GeneCards, comparative toxicogenomics database, and MalaCards database. The Venny online tool identified potential therapeutic targets by intersecting CSD and KOA target genes, while gene ontology and Kyoto encyclopedia of genes and genomes analysis was performed using the Oebiotech Cloud Platform. A protein-protein interaction network was established using the String database; a "CSD-active ingredient-target gene-KOA" network plot was constructed using Cytoscape 3.9.1 software and screened for key targets and hub targets. Finally, molecular docking was performed for hub genes with high Degree values. A total of 227 effective target genes for CSD and 8816 KOA-related target genes were obtained, as well as 191 cross-target genes for CSD and KOA. We screened 37 key gene targets and identified the top 10 hub target genes in descending order of Degree value using protein-protein interaction and Cytoscape 3.9.1 software (TNF, IL-6, MMP-9, IL-1ß, AKT-1, VEGFα, STAT-3, PTGS-2, IL-4, TP53). Gene ontology analysis showed that the biological process of CSD treatment of KOA mainly involves cytokine-mediated signaling pathway, negative regulation of apoptotic process, cellular response to hypoxia, cellular response to cadmium ion, response to estradiol, and extrinsic apoptotic signaling pathway in absence of ligand. Kyoto encyclopedia of genes and genomes analysis revealed major signaling pathways including Cellular senescence, TNF signaling pathway, and PI3K-Akt signaling pathway. The molecular docking results show that the core components bind well to the core targets. In conclusion, CSD may exert therapeutic effects on KOA by inhibiting pathological processes such as inflammatory response, apoptosis, cellular senescence, and oxidative stress.

Avoidance-motivational intensity modulated the effect of negative emotion on working memory.

Although many studies have explored the association between negative emotion and working memory, the findings remain controversial. The present study investigated the role of avoidance-motivational intensity in modulating the effect of negative emotion on different processes (maintenance versus manipulation) of verbal and spatial working memory. Two experiments employed the modified delayed match-to-sample paradigms to separate the two processes of verbal and spatial working memory under different emotional states, respectively. In Experiment 1, participants were asked to perform the delayed match-to-sample task with or without reordering the characters (manipulation process of verbal working memory). In Experiment 2, mental rotation was used as the manipulation process of spatial working memory. The results showed that negative emotion only affected the manipulation process, but not the maintenance process. Relative to neutral and low avoidance-motivated negative conditions, the manipulation processes of both types of working memory were impaired under the high avoidance-motivated negative condition. No significant difference was observed between low avoidance-motivated negative condition and neutral condition. Our results are discussed in relation to efficiency processing theory and motivational dimensional model of affect. We conclude that negative emotional states with high avoidance-motivational intensity impair the manipulation process of verbal and spatial working memory.

Exocarpium Citri Grandis alleviates the aggravation of NAFLD by mitigating lipid accumulation and iron metabolism disorders.

ETHNOPHARMACOLOGICAL RELEVANCE: Exocarpium Citri grandis (ECG, Huajuhong in Chinese), the epicarp of C. grandis 'Tomentosa', has been used for hundreds of years as an anti-inflammatory, expectorant, hypoglycemic, and lipid-lowering medication in China. Nevertheless, there have been few papers that have explored the mechanism behind ECG's hypolipidemic characteristics from the perspective of treating nonalcoholic fatty liver disease (NAFLD). AIM OF STUDY: The purpose of our study was to confirm the therapeutic and preventative effects of ECG in NAFLD by regulating lipid accumulation and iron metabolism, and to explore the specific mechanism of ECG in enhancing hepatic iron transport and excretion capabilities. STUDY DESIGN: We constructed a NAFLD model by feeding male C57BL/6 J mice with a high-fat diet for 12 weeks. Mice were gavaged with ECG beginning in the seventh week of modeling, and three dosage gradients were established: low dose group (2.5 g/kg/d), medium dose group (5 g/kg/d) y, and high dose group (10 g/kg/d) until the end of model construction in week 12. MATERIALS AND METHODS: We used network pharmacology to analyze the relationship between ECG and NAFLD. In addition, we constructed a nonalcoholic fatty liver disease model by feeding male C57BL/6 J mice a high-fat diet for 12 weeks. Finally, lipid accumulation, iron accumulation, inflammation and oxidative stress were evaluated by serological index detection, histological detection, immunofluorescent and immunohistochemical staining, and western blotting. RESULTS: Network pharmacology confirmed the treatment effect of ECG in NAFLD. Three active components of ECG, including Naringenin, Naringin and Neohesperidin, were detected by UHPLC-HRMS analysis. The results of serum TC, TG, LDL concentration, HE staining, Oil red staining and Nile red staining demonstrated that ECG could improve lipid metabolism disorders. The results of serum iron concentration, liver tissue iron concentration, iron metabolism-related proteins Ferritin light chain, Ferroportin1, Transferrin receptor, and Transferrin demonstrated that ECG improved the iron transport and storage capacities of hepatic cells. CONCLUSIONS: Our results demonstrated that ECG relieved liver injury by inhibiting lipid accumulation and iron accumulation in NAFLD.

RAGE promotes dysregulation of iron and lipid metabolism in alcoholic liver disease.

Alcoholic liver disease (ALD) is associated with hepatic inflammatory activation and iron overload. The receptor for advanced glycation end products (RAGE) is an important metabolic mediator during the development of ALD. The aim of this study was to determine the effect of RAGE on iron homeostasis in ALD. We found increased circulating transferrin, hepcidin and ferritin in ALD patients and positively correlated with RAGE level. RAGE knockout (RAGE-/-) and wild-type mice were subjected to chronic alcoholic feeding for 6 weeks to induce ALD, and RAGE inhibitor, iron chelator or lipid peroxidation inhibitor were administered. We showed that chronic alcohol administration triggered hepatic steatosis, inflammation, and oxidative stress, which were eliminated by deficiency or inhibition of RAGE. Surprisingly, pathways of hepatic iron metabolism were significantly altered, including increased iron uptake (Tf/TfR) and storage (Ferritin), as well as decreased iron export (FPN1/Hepcidin). In vitro experiments confirmed that RAGE had different effects on the mechanism of iron metabolism of hepatocytes and macrophages respectively. In conclusion, our data revealed preclinical evidence for RAGE inhibition as an effective intervention for alleviating alcohol-induced liver injury.

Protective effects of Dendrobium huoshanense polysaccharide on D-gal induced PC12 cells and aging mice, in vitro and in vivo studies.

Dendrobium huoshanense C. Z. Tang et S. J. Cheng polysaccharide (DHP) is the essential active ingredient of D.huoshanense and has high medicinal value. A high dose of D-galactose (D-gal) is commonly utilized in the aging model establishment. In this study, we explored whether DHP shields PC12 cells and aging mice from D-gal caused damage and the possible mechanism. In vitro experiments, D-gal induced PC12 cells were used to investigate, and then DHP was used for treatment. In vivo experiments, 72 SPF ICR male mice were randomly divided into six groups (control: normal saline; model: D-gal (400 mg/kg); VE group: VE (50 µg/ml); DHP groups: D-gal + DHP (15.6 mg/ml; 31.2 mg/ml; 62.4 mg/ml)). The results showed that DHP could enhance the viability of D-gal injured PC12 cells and prevent cell apoptosis. DHP effectively promoted the transition from phase G0/G1 to phase S and inhibited cell cycle arrest. DHP has a potential neuroprotective effect on D-gal caused cognitive and memory disorders in mice. On the one hand, DHP protects the antioxidant enzymes SOD, GSH-PX, and CAT from excessive ROS buildup. On the other hand, DHP was demonstrated to block the expression of the P53/P21 signaling pathway-related proteins P53, P21, and P16. These results imply that DHP could be a potential neuroprotective agent against aging. PRACTICAL APPLICATIONS: Cognitive and memory decline caused by aging problems has become a problem in recent years. There are many theories about aging, among which oxidative stress is considered to be one of the important pathophysiological parts of various diseases in the aging process. In this study, DHP could not only improve the damage of D-Gal to PC12 cells, but also improve the cognitive and memory impairment caused by D-Gal in mice. In conclusion, this study verified the anti-aging effect of DHP from in vitro and in vivo experiments, and its mechanism may involve the P53/P21 pathway. Therefore, this study indicated that polysaccharides from Dendrobium huoshanense, a traditional Chinese medicine of homologous medicine and food, had potential and industrial value as potential anti-aging drugs.

Psychophysical Risk Perceptions and Sleep Quality of Medical Assistance Team Members in Square Cabin Hospitals: A Repeated Cross-Sectional Study.

Objective: This study aimed to evaluate the association between the perceptions of psychophysical risks and sleep quality of Medical Assistance Team Members (MATMs) in Square Cabin Hospitals. Methods: Repeated cross-sectional data collection was conducted in Square Cabin Hospitals during two large-scale lockdowns. The first wave was sampled from MATMs dispatched to Wuhan and the second was from MATMs dispatched to Shanghai. Participants completed online questionnaires comprised of the Risk Perception Questionnaire (RPQ), Positive and negative emotions scale (PANAS), and Sleep Quality Scale (SQS), measuring the psychophysical risk perceptions about the MATMs' current work, emotional states, and sleep quality. Changes across two waves of data collection were statistically parsed using the exploratory factor analysis and regression models. Results: Data of 220 participants from first-wave samples [S1] and 300 from second-wave samples [S2] were analyzed. Participants reported more worries about physical risks, such as inadequate protection methods and being infected, and S1 rated higher on all risks compared with S2 (as the biggest p-value was 0.021). Across the different situations, the dominant emotional states of MATMs were positive; a higher level of psychophysical risk perceptions, negative emotional states, and poor sleep quality were consistently interrelated. The psychophysical risk perceptions predicted sleep quality. Negative emotions as a state variable intensified the relationship between physical risk perceptions and sleep quality (bindirect effect = 1.084, bootstrapped CI = [0.705, 1.487]). Conclusions: The results provide important evidence that MATMs' higher level of psychophysical risk perceptions associated with negative emotions could indicate worse sleep quality.

Poria cocos polysaccharides rescue pyroptosis-driven gut vascular barrier disruption in order to alleviates non-alcoholic steatohepatitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Poria cocos polysaccharides (PCP) are abundant in Poria cocos (Schw.) Wolf (Poria). This is a common traditional Chinese medicine used to treat gastrointestinal and liver diseases. Poria cocos dispel dampness and enhance gastrointestinal functions, strongly affecting the treatment of non-alcoholic fatty liver disease. Still, the mechanism is not yet clear. AIM OF THE STUDY: The latest research found that protecting the integrity of the intestinal barrier can slow down the progression of non-alcoholic fatty liver disease (NAFLD). Hence, our research ought to explore the protective mechanism of PCP on the intestinal barrier under a high-fat diet and to clarify the relationship between intestinal barrier damage and steatohepatitis. MATERIALS AND METHODS: H&E staining was done to evaluate pathological damage, whereas Nile red and oil red O staining was conducted to evaluate hepatic fat infiltration. Immunofluorescence staining and immunohistochemical staining were used to detect protein expression and locations. Bone marrow-derived macrophages were isolated for in vitro experiments. ONOO- and ROS fluorescent probes and MDA, SOD, and GSH kits assessed the levels of nitrogen and oxidative stress. LPS levels were detected with a Limulus Amebocyte Lysate assay. The Western blot analysis and reverse transcription-quantitative PCR detected the expression of related proteins and genes. The Elisa kit detected the level of the inflammatory factors in the cell supernatant. For the vivo NAFLD experiments, in briefly, mice were randomly chosen to receive either a High-fat diet or control diet for 12 weeks. Drug treatments started after 4 weeks of feeding. Zebrafish larvae were raised separately in fish water or 7 mM thioacetamide as the control or model group for approximately 72 h. In the therapy groups, different concentrations of PCP were added to the culture environment at the same time. RESULTS: In zebrafish, we determined the safe concentration of PCP and found that PCP could effectively reduce the pathological damage in the liver and intestines induced by the NAFLD model. In mice, PCP could slow down weight gain, hyperlipidemia, and liver steatosis caused by a high-fat diet. More importantly, PCP could reduce the destruction of the gut-vascular barrier and the translocation of endotoxins caused by a high-fat diet. Further, we found that PCP could inhibit intestinal pyroptosis by regulating PARP-1. Pyroptosis inhibitors, such as MCC950, could effectively protect the intestinal and liver damage induced by a high-fat diet. We also found that pyroptosis mainly occurred in intestinal macrophages. PCP could effectively improve the survival rate of bone marrow-derived macrophages in a high-fat environment and inhibit pyroptosis. CONCLUSIONS: These results indicated that PCP inhibited the pyroptosis of small intestinal macrophages to protect the intestinal barrier integrity under a high-fat diet. This resulted in decreased endotoxin translocation and progression of steatohepatitis.

[Effect of Gegen Qinlian Decoction on cardiac diastolic function of diabetic mice with damp-heat syndrome].

This study was designed to explore the effect and mechanism of Gegen Qinlian Decoction(GQD) on cardiac function of diabetic mice with damp-heat syndrome. The db/db diabetic mice were exposed to the damp-heat environment test chamber for inducing the damp-heat syndrome. Forty-eight six-week-old db/db mice were randomly divided into six groups, namely the db/db diabetic model group, db/db diabetic mouse with damp-heat syndrome(db/db-dh) group, db/db diabetic mouse with damp-heat syndrome treated with low-dose GQD(db/db-dh+GQD-L) group, db/db-dh+GQD-M(medium-dose) group, db/db-dh+GQD-H(high-dose) group, and db/db-dh+lipro(liprostatin-1, the inhibitor of ferroptosis) group, with eight six-week-old db/m mice classified into the control group. The results showed that mice presented with the damp-heat syndrome after exposure to the "high-fat diet" and "damp-heat environment", manifested as the elevated fasting blood glucose, reduced food intake, low urine output, diarrhea, listlessness, loose and coarse hair, and dark yellow and lusterless fur. However, the intragastric administration of the high-dose GQD for 10 weeks ameliorated the above-mentioned symptoms, inhibited myocardial hypertrophy and fibrosis, and improved the cardiac diastolic function of db/db-dh mice. qPCR suggested that GQD regulated the expression of ferroptosis-related genes, weakened the lipid peroxidation in the myocardium, and up-regulated glutathione peroxidase 4(GPX4) expression in comparison with those in the db/db-dh group. At the same time, the ferroptosis inhibitor liprostatin-1 significantly improved the cardiac function and reversed the cardiac remodeling of db/db-dh mice. It can be concluded that the damp-heat syndrome may aggravate myocardial ferroptosis and accelerate cardiac remodeling of db/db mice, thus leading to diastolic dysfunction. GQD is able to improve cardiac remodeling and diastolic function in diabetic mice with damp-heat syndrome, which may be related to its inhibition of myocardial ferroptosis.

Corrigendum: Risk Perception and PTSD Symptoms of Medical Staff Combating Against COVID-19: A PLS Structural Equation Model.

[This corrects the article DOI: 10.3389/fpsyt.2021.607612.].

Education and subjective well-being in Chinese rural population: A multi-group structural equation model.

PURPOSES: This study aimed to explore the effect of education on subjective well-being (SWB) of Chinese rural dwellers who just shook off poverty in 2019 and to investigate the mediating role of social support and moderating role of age on the association. METHODS: Social support rating scale (SSRS) and General Well-Being Schedule (GWBS) were administrated among 1094 Chinese rural dwellers from Anqing, Anhui Province, China. Structural equation modeling (SEM) and multi-group SEM were performed to examine the mediating role of social support and moderating role of age in the link between education and SWB, respectively. RESULTS: The findings indicated that social support fully mediated the relationship between education and SWB in rural residents. Age moderated the indirect relationship between education and SWB (first stage moderation model) such that the effect of education on social support would be strengthened with aging process. CONCLUSIONS: The results add to our understanding of the protective role of education in SWB among Chinese rural dwellers, and shed new light on the potential mechanisms underlying the association between education and SWB with respect to the mediating role of social support and moderating role of age.

Hepatic TGFßr1 Deficiency Attenuates Lipopolysaccharide/D-Galactosamine-Induced Acute Liver Failure Through Inhibiting GSK3ß-Nrf2-Mediated Hepatocyte Apoptosis and Ferroptosis.

BACKGROUND & AIMS: Acute liver failure (ALF) is a condition with high mortality and morbidity, characterized by glutathione depletion, oxidative stress, and mitochondrial dysfunction. Ferroptosis may be involved in ALF. Indeed, emerging studies have shown that ferroptosis plays a significant role in ALF. However, the mechanism of ferroptosis in hepatocytes during ALF remains unknown. METHODS: Hepatic-specific transforming growth factor ß receptor 1 knockout (TGFßr1Δhep-CKO) mice and nuclear factor erythroid 2-related factor 2 knockout (Nrf2-/-) mice were generated and subjected to ALF. Electron microscopy was used to detect mitochondrial and other cell substructure changes during ALF. RESULTS: In this study, we noticed that lipopolysaccharide (LPS)/D-galactosamine (D-GalN) induced caspases-mediated apoptosis as current research reported, we also found lipid peroxidation, reactive oxygen species accumulation, and glutathione, co-enzyme Q10 system inhibition mediated ferroptosis during LPS/D-GalN-induced ALF. Rescue studies have shown that ferrostatin-1 (Fer-1) and deferoxamine mesylate (DFOM), the inhibitor of ferroptosis, could alleviate LPS/D-GalN-induced ALF. In addition, we noticed that TGFß1 was increased during ALF, while ALF was relieved in TGFßr1Δhep-CKO mice. We also noticed that liver TGFßr1 deficiency alleviated LPS/D-GalN-induced apoptosis and ferroptosis by affecting the phosphorylation of glycogen synthase kinase 3ß and Nrf2, a key antioxidant factor, by up-regulating the levels of glutathione peroxidase 4 (GPX4), glutamine antiporter xCT (XCT), dihydroorotate dehydrogenase (DHODH), and ferroptosis suppressor protein 1 (FSP1), and down-regulating transferrin receptor (TFR), prostaglandin-endoperoxide synthase (Ptgs2), chaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1), and cytochrome P450 reductase (POR) expression. The further supplemental experiment showed that ferroptosis was aggravated significantly in Nrf2-/- mice compared with its wild-type controls and reversed by ferrostatin-1. CONCLUSIONS: This study shows that TGFßr1 plays a critical role in mediating LPS/D-GalN-induced ALF by promoting apoptosis and ferroptosis.

Inhibition of Connexin 36 attenuates HMGB1-mediated depressive-like behaviors induced by chronic unpredictable mild stress.

BACKGROUND: High mobility group box 1 (HMGB1) released by neurons and microglia was demonstrated to be an important mediator in depressive-like behaviors induced by chronic unpredictable mild stress (CUMS), which could lead to the imbalance of two different metabolic approaches in kynurenine pathway (KP), thus enhancing glutamate transmission and exacerbating depressive-like behaviors. Evidence showed that HMGB1 signaling might be regulated by Connexin (Cx) 36 in inflammatory diseases of central nervous system (CNS). Our study aimed to further explore the role of Cx36 in depressive-like behaviors and its relationship with HMGB1. METHODS: After 4-week chronic stress, behavioral tests were conducted to evaluate depressive-like behaviors, including sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and open field test (OFT). Western blot analysis and immunofluorescence staining were used to observe the expression and location of Cx36. Enzyme-linked immunosorbent assay (ELISA) was adopted to detect the concentrations of inflammatory cytokines. And the excitability and inward currents of hippocampal neurons were recorded by whole-cell patch clamping. RESULTS: The expression of Cx36 was significantly increased in hippocampal neurons of mice exposed to CUMS, while treatment with glycyrrhizinic acid (GZA) or quinine could both down-regulate Cx36 and alleviate depressive-like behaviors. The proinflammatory cytokines like HMGB1, tumor necrosis factor alpha (TNF-α), and interleukin-1ß (IL-1ß) were all elevated by CUMS, and application of GZA and quinine could decrease them. In addition, the enhanced excitability and inward currents of hippocampal neurons induced by lipopolysaccharide (LPS) could be reduced by either GZA or quinine. CONCLUSIONS: Inhibition of Cx36 in hippocampal neurons might attenuates HMGB1-mediated depressive-like behaviors induced by CUMS through down-regulation of the proinflammatory cytokines and reduction of the excitability and intracellular ion overload.

Posttraumatic stress symptoms among health care workers during the COVID-19 epidemic: The roles of negative coping and fatigue.

Healthcare workers (HCWs) exposed to Coronavirus disease 2019 (COVID-19) are not immune to stressors. This study aimed to explore the prevalence of posttraumatic stress symptoms (PTSS) among HCWs during the COVID-19 epidemic and investigate the associations among negative coping, fatigue and PTSS. A total of 507 HCWs from Anhui province enrolled in the study and completed the cross-sectional survey including demographic data, Simplified Coping Style Questionnaire (SCSQ), 14-item Fatigue Scale (FS-14), and PTSD Checklist-civilian Version (PCL-C). Univariate linear regression, Pearson correlation and Mackinnon's four-step procedure were performed in the statistical analysis. Results indicated that the prevalence of PTSS among HCWs during the pandemic was 24%. Univariate linear regression showed HCWs aged 31-40 years exhibited significantly higher scores of PTSS than those aged 51-60 (ß = 0.20, 95% CI: 0.59 to 9.41). Having at least one child was associated with a higher risk of developing PTSS (ß = 0.01, 95% CI: 0.36 to 5.45). Negative coping and fatigue were positively correlated with all three PTSS (all P < 0.001), including re-experiencing, avoidance and hyper-arousal. Fatigue has mediated the association between negative coping and PTSS among HCWs during the pandemic (ab = 0.09, SE = 0.03, bootstrap 95% CI: 0.04 to 0.14). A considerable proportion of HCWs was traumatized during the COVID-19 outbreak. Hence, the institutions should screen out and pay close attention to HCWs who tend to use negative coping (e.g., withdrawal thinking, distraction and blaming others) and arrange work scientifically to avoid overfatigue and PTSS amid the public health crisis.

Indoleamine 2, 3-dioxygenase 1 aggravates acetaminophen-induced acute liver failure by triggering excess nitroxidative stress and iron accumulation.

Acetaminophen (APAP) is the leading cause of acute liver failure (ALF), which is characterized by GSH depletion, oxidative stress and mitochondrial dysfunction. However, the specific mechanism of APAP-induced ALF remains to be clarified. In this study, we demonstrated that indoleamine 2,3-dioxygenase 1 (IDO1) aggravated APAP-induced ALF associated with excess lipid peroxidation, which was reversed by lipid peroxidation inhibitor (ferrostatin-1). Meanwhile, IDO1 deficiency effectively decreased the accumulation of reactive nitrogen species. Additionally, IDO1 deficiency prevented against APAP-induced liver injury through suppressing the activation of macrophages, thereby reduced their iron uptake and export, eventually reduced iron accumulation in hepatocytes through transferrin and transferrin receptor axis. In summary, our study confirmed that APAP-induced IDO1 aggravated ALF by triggering excess oxidative and nitrative stress and iron accumulation in liver. These results offer new insights for the clinical treatment of ALF or iron-dysregulated liver diseases in the future.

Efficacy of the Chinese version interpretation bias modification training in an unselected sample: A randomized trial.

Training individuals to interpret ambiguous information in positive ways might be an effective method of reducing social anxiety. However, little research had been carried out in Chinese samples, and the effect of interpretation training on other processes such as attentional bias also remained unclear. This study examined the effect of interpretation bias modification program (IMP) on interpretation bias, social anxiety and attentional bias, and the possible mediation effects. 51 healthy adults were randomly assigned to either a 5-session IMP training that guided them to endorse benign interpretation in ambiguous scenarios or an interpretation control condition (ICC). Self-reported measures of social anxiety symptoms, attentional bias and interpretation bias were evaluated before and after training. Results showed that compared to control group, IMP group generated more positive interpretations and less negative interpretations after training (F(1,49) = 7.65, p<0.01, ηp2 = 0.14; F(1,49) = 14.60, p<0.01, ηp2 = 0.23respectively). IMP yielded greater interpretation bias reduction (F(1,49) = 12.84, p<0.01, ηp2 = 0.21) and social anxiety reduction (F(1,49) = 21.39, p<0.01, ηp2 = 0.30) than ICC, but change in attentional bias was not significant between IMP and the control group. Change in interpretation bias did not show a significant mediation effect in the relationship between training condition and social anxiety reduction. This study provided preliminary evidence for the efficacy of the Chinese version of IMP training. Possible methodological issues and interpretations underlying the findings were discussed. This study was registered in Chinese Clinical Trial Registry (www.chitr.org.cn), a WHO approved registry. The title of registration trial was "A Study on the efficiency of cognitive bias and attentional bias training on fear and phobia" and the registration number was ChiCTR2100045670.