A CDAHFD-induced mouse model mimicking human NASH in the metabolism of hepatic phosphatidylcholines and acyl carnitines.

Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of a cluster of conditions associated with lipid metabolism disorders. Ideal animal models mimicking the human NASH need to be explored to better understand the pathogenesis. A choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) has recently been used to induce the NASH model, but the advantages are not established. NASH models were induced using the well-known traditional methionine- and choline-deficient (MCD) diet for 5 weeks and the recently used CDAHFD for 3 weeks. Liver phenotypes were analyzed to evaluate the differences in markers related to NASH. Lipidomics and metabolism analyses were used to investigate the effects of dietary regimens on the lipidome of the liver. The CDAHFD induced stronger NASH responses than the MCD, including lipid deposition, liver injury, inflammation, bile acid overload and hepatocyte proliferation. A significant difference in the hepatic lipidome was revealed between the CDAHFD and MCD-induced NASH models. In particular, the CDAHFD reduced the hepatic levels of phosphatidylcholines (PCs) and acylcarnitines (ACs), which was supported by the metabolism analysis and in line with the tendency of human NASH. Pathologically, the CDAHFD could effectively induce a more human-like NASH model over the traditional MCD. The hepatic PCs, ACs and their metabolism in CDAHFD-treated mice were down-regulated, similar to those in human NASH.

Clinical effect of high-flow nasal cannula oxygen therapy combined with naloxone on severe respiratory failure in older adult patients: a randomized controlled trial.

OBJECTIVE: To analyze the clinical effect of high-flow nasal cannula (HFNC) oxygen therapy combined with naloxone on severe respiratory failure (SRF) in older adult patients. METHODS: We enrolled 96 older adult patients with SRF who were admitted to Hai'an People's Hospital between February 2019 and March 2022. The patients were divided into two groups: the control group (treated with non-invasive positive pressure ventilation combined with naloxone) and the observation group (treated with HFNC oxygen therapy combined with naloxone). The blood gas measurement, respiratory rate (RR), St. George's Respiratory Questionnaire (SGRQ) score, Clara cell secreted protein (CC16) level, tumor necrosis factor-alpha (TNF-α) level, interleukin-1 (IL-1) level, length of intensive care unit (ICU) stay, tracheal intubation rate, and 28-day mortality rate were compared between the groups. RESULTS: Blood gas measurement or RR did not differ significantly between the groups (P>0.05). The observation group showed improved outcome, including reduced partial pressure of CO2, RR, and pH, and increased partial pressure of O2 (PaO2), PaO2/fraction of inspired O2 ratio, and O2 saturation after treatment (P<0.05). Additionally, the observation group exhibited lower TNF-α level, IL-1 level, and SGRQ score, and higher CC16 level (P<0.05). The length of ICU stay, tracheal intubation rate, and 28-day mortality rate were lower in the observation group (P<0.05). CONCLUSIONS: HFNC oxygen therapy combined with naloxone in older adult patients with SRF could improve blood gas results, disease duration, tracheal intubation rate, and 28-day mortality rate. This may occur through regulation of TNF-α, IL-1, and CC16 expression.

Impacts of short-term low-level exposure to air pollutants on hospital admissions for pulmonary sepsis in elderly patients.

BACKGROUND: Acute exposures to high levels of air pollutants are thought to be associated with hospitalization of patients with lung infection, while relatively little is known about the association between air pollutants and HOSPITAL ADMISSIONS FOR pulmonary sepsis. OBJECTIVES: To assess the correlation between low-level exposure to air pollutants and the hospitalizations for pulmonary sepsis in elderly patients. METHODS: A total of 249 elderly patients with pulmonary sepsis from January 2018 to December 2020 in Shenzhen people's hospital were included. The data regarding hospitalizations for pulmonary sepsis, meteorological factors, and daily average levels of air pollutants on single-day lags (Lag0 to Lag7) in Shenzhen were collected. Low-level exposure was defined as the annual means of air pollutants below the levels of the Ambient Air Quality Standard (AAQS) in China (NO. GB3095-2012) and/or Global Air Quality Guidelines (AQG). A time-stratified case-crossover study design approach was used to evaluate the associations between exposure to air pollutants and incidence of the disease, univariate and multivariate logistic regression analysis to analyze the association between levels of air pollutants and hospitalizations for pulmonary sepsis in elderly patients. RESULTS: Exposure to PM1(P = 0.007, Lag 2 day; P = 0.038, Lag6 day), PM2.5(P = 0.046, Lag2 day), PM10(P = 0.048, Lag4 day), and O3(P = 0.044, Lag6 day) was positively correlated with elevated risk of hospitalizations for pulmonary sepsis. In addition, logistic regression analysis revealed that exposure to PM1 (OR = 1.833, 95%CI:1.032 ~ 3.256, Lag6 day) and O3 (OR = 2.091, 95%CI:1.019 ~ 4.289, Lag6 day) were the independent risk factors of pulmonary sepsis in elderly patients. CONCLUSION: Our results demonstrate that short-term low-level exposure to PM1 and O3 could elevate the risk of hospitalizations for pulmonary sepsis in elderly patients in Shenzhen, providing evidence for developing early warning and screening systems for pulmonary sepsis.

Celastrol as an intestinal FXR inhibitor triggers tripolide-induced intestinal bleeding: Underlying mechanism of gastrointestinal injury induced by Tripterygium wilfordii.

BACKGROUND: Tripterygium wilfordii has been widely used for the treatment of rheumatoid arthritis, which is frequently accompanied by severe gastrointestinal damage. The molecular mechanism underlying the gastrointestinal injury of Tripterygium wilfordii are yet to be elucidated. METHODS: Transmission electron microscopy, and pathological and biochemical analyses were applied to assess intestinal bleeding. Metabolic changes in the serum and intestine were determined by metabolomics. In vivo (time-dependent effect and dose-response) and in vitro (double luciferase reporter gene system, DRATs, molecular docking, HepG2 cells and small intestinal organoids) studies were used to identify the inhibitory role of celastrol on intestinal farnesoid X receptor (FXR) signaling. Fxr-knockout mice and FXR inhibitors and agonists were used to evaluate the role of FXR in the intestinal bleeding induced by Tripterygium wilfordii. RESULTS: Co-treatment with triptolide + celastrol (from Tripterygium wilfordii) induced intestinal bleeding in mice. Metabolomic analysis indicated that celastrol suppressed intestinal FXR signaling, and further molecular studies revealed that celastrol was a novel intestinal FXR antagonist. In Fxr-knockout mice or the wild-type mice pre-treated with pharmacological inhibitors of FXR, triptolide alone could activate the duodenal JNK pathway and induce intestinal bleeding, which recapitulated the pathogenic features obtained by co-treatment with triptolide and celastrol. Lastly, intestinal bleeding induced by co-treatment with triptolide and celastrol could be effectively attenuated by the FXR or gut-restricted FXR agonist through downregulation of the duodenal JNK pathway. CONCLUSIONS: The synergistic effect between triptolide and celastrol contributed to the gastrointestinal injury induced by Tripterygium wilfordii via dysregulation of the FXR-JNK axis, suggesting that celastrol should be included in the quality standards system for evaluation of Tripterygium wilfordii preparations. Determining the mechanism of the FXR-JNK axis in intestinal bleeding could aid in the identification of additional therapeutic targets for the treatment of gastrointestinal hemorrhage diseases. This study also provides a new standard for the quality assessment of Tripterygium wilfordii used in the treatment of gastrointestinal disorders.

[Analysis of clinical characteristics and risk factors of early heat stroke-related acute liver injury].

OBJECTIVE: To analyze the clinical characteristics and risk factors of early acute liver injury in patients with heat stroke (HS), and to provide basis for early identification of HS-related liver injury and its pathogenesis in clinical practice. METHODS: The clinical data of patients with HS admitted to the department of critical care medicine of Haian People's Hospital from June 2015 to August 2022 were retrospectively analyzed. The patients with HS were divided into early liver injury group and early non-liver injury group according to the occurrence of acute liver injury within 24 hours of admission. The differences of basic data, clinical data, laboratory indexes and clinical outcomes of the two groups were analyzed. Logistic regression was used to analyze the risk factors for early HS-related acute liver injury, and receiver operator characteristic (ROC) curves were drawn to evaluate their value in predicting the occurrence of early HS-related acute liver injury. RESULTS: A total of 76 patients with HS were enrolled, and 46 patients with acute liver injury, accounting for 60.53%. In the early liver injury group, 14 patients (30.43%) had elevated aminotransferase alone, 9 patients (19.57%) had elevated total bilirubin (TBil) alone, and 23 patients (50.00%) had elevated both aminotransferase and TBil. Among the patients with elevated aminotransferases, 24 patients (64.87%) had mild elevation, 5 patients (13.51%) had moderate elevation, 8 patients (21.62%) had severe elevation. Compared with the early non-liver injury group, acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), arterial blood lactate (Lac), interleukin-6 (IL-6), procalcitonin (PCT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), TBil, γ-gamma glutamyl transferase (γ-GGT), lactate dehydrogenase (LDH), creatine kinase (CK), MB isoenzyme of creatine kinase (CK-MB), cardiac troponin I (cTnI), myoglobin (MYO), N-terminal B-type pro-brain natriuretic peptide (NT-proBNP), prothrombin time (PT), activated partial thromboplastin time (APTT), D-dimer in the early liver injury group were significantly increased, while platelet count (PLT) were significantly decreased within 24 hours after admission, the 28-day mortality was significantly increased [28.26% (13/46) vs. 6.67% (2/30)], and the differences were statistically significant (all P < 0.05). Univariate Logistic regression analysis showed that APACHE II score, SOFA score, PLT, Lac, IL-6, PCT, γ-GGT, LDH, CK, CK-MB, cTnI, MYO, PT, APTT, D-dimer were risk factors of early HS-related acute liver injury (all P < 0.05). Multivariate Logistic regression analysis showed that PLT, IL-6, and LDH were independent risk factors of early HS-related acute liver injury [odds ratio (OR) and 95% confidence interval (95%CI) were 0.986 (0.974-0.998), 1.027 (1.012-1.041), and 1.002 (1.000-1.004), all P < 0.05]. The ROC curve analysis showed that the area under the ROC curve (AUC) of PLT, IL-6 and LDH for predicting the occurrence of early HS-related acute liver injury was 0.672 (95%CI was 0.548-0.797), 0.897 (95%CI was 0.824-0.971) and 0.833 (95%CI was 0.739-0.927), respectively. IL-6 had the highest predictive value for early HS-related liver injury. When the optimal diagnostic threshold of IL-6 was 48.25 ng/L, the sensitivity was 95.7%, the specificity was 73.3%, and the predictive value of PLT was the lowest. CONCLUSIONS: The early HS-related liver injury is mainly manifested as the simultaneous elevation of aminotransferase and TBil, and most of cases are mild liver injury. PLT, IL-6 and LDH are independent risk factors of early HS-related acute liver injury.

Effects of high-flow nasal cannula oxygen therapy for patients with acute exacerbation of chronic obstructive pulmonary disease in combination with type II respiratory failure.

OBJECTIVE: To evaluate the therapeutic effects of high-flow nasal cannula (HFNC) oxygen therapy in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and type II respiratory failure. METHODS: Seventy-two patients with AECOPD and type II respiratory failure were randomly allocated to an HFNC oxygen therapy trial group or a non-invasive positive-pressure ventilator therapy (NIPPV) control group. Their arterial blood gas parameters and comfort, evaluated using a questionnaire, were compared before and after the therapeutic interventions. RESULTS: The PaCO2 and blood HCO3- concentration of both groups were significantly reduced by the treatments, whereas the pH, PaO2 and PaO2/FiO2 were increased. The PaCO2 of the experimental group was significantly lower than that of the control group following treatment. The PaO2 of the experimental group was significantly higher than that of the control group. The tracheal intubation rates of the two groups did not significantly differ. After treatment, all the indices of comfort were rated higher in the HFNC group than in the NIPPV group. CONCLUSIONS: HFNC has a good therapeutic effect in patients with AECOPD and type II respiratory failure. It improves patient comfort and has clinical value.

PPARα is involved in high-fat diet-induced risk avoidance impairment via the regulation of hippocampal BDNF.

Risk avoidance behaviors are essential for survival. "Uncontrollable" risk-taking behaviors in animals or humans may have severe adverse consequences. In humans, a large proportion of psychiatric disorders are accompanied by impairments in risk avoidance. Obesity is associated with psychiatric disorders. Peroxisome proliferator-activated receptor α (PPARα) takes part in regulating lipid metabolism and neuronal function. Here, we investigated the effect of high-fat diet (HFD)-induced obesity on risk avoidance and the role of PPARα in this behavior. Male PPARα-null (KO) mice and wild-type (WT) mice were assigned to four different groups: WT-CON and KO-CON (normal diet); WT-HFD and KO-HFD (high fat diet). The HFD began at week 6 and was continued until sampling. A series of behavioral tests were performed at week 11. We found that WT but not KO mice fed with a HFD exhibited weight gain and risk avoidance impairment, compared with the mice fed with a normal diet. The staining of c-Fos revealed that the hippocampus was the main brain region involved in risk avoidance behavior. Moreover, biochemical analysis suggested that the decreased levels of the brain-derived neurotrophic factor (BDNF) in the hippocampus might contribute to risk avoidance impairment induced by a HFD. These results indicated that PPARα is involved in HFD-induced risk avoidance impairment via the regulation of hippocampal BDNF.

Therapeutic effect of fenofibrate for non-alcoholic steatohepatitis in mouse models is dependent on regime design.

Background: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver diseases. In most cases, NAFLD progresses from benign steatosis to steatohepatitis (NASH), and then to cirrhosis. No treatment is currently approved for NAFLD/NASH in the clinic. Fenofibrate (FENO) has been clinically used to treat dyslipidemia for more than a half century, but its effects on NASH are not established. FENO's half-life is quite different between rodent and human. The aim of this study was to investigate the potential of pharmacokinetic-based FENO regime for NASH treatment and the underlying mechanisms. Methods: Two typical mouse NASH models, methionine-choline deficient (MCD) diet-fed mice and choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-fed mice, were used. MCD model was designed as therapeutic evaluation in experiment 1 and CDAHFD model was designed as preventive in experiment 2. Three doses of FENO (5, 25, 125 mg/kg), two times a day (BID), were administered to the above models. Serum markers of liver injury, cholestasis, and the histology of liver tissues were investigated. Normal mice were used as a model in experiment 3 for toxicity evaluation, Quantitative-PCR and Western Blot assays were used to investigate the inflammatory responses, bile acid synthesis as well as lipid catabolism. Results: Mice on the MCD and CDAHFD diets developed steatohepatitis as expected. Treatment with FENO (25 mg/kg·BID) significantly decreased hepatic steatosis, inflammation and fibrosis in both therapeutic and preventive models. In the MCD model, the therapeutic action of FENO (25 mg/kg·BID) and 125 mg/kg·BID on histopathology and the expression of inflammatory cytokines were comparable. In reducing macrophage infiltration and bile acid load, FENO (25 mg/kg·BID) was superior to 125 mg/kg·BID. In all the aspects mentioned above, FENO (25 mg/kg·BID) was the best among the 3 doses in the CDAHFD model. In a third experiment, the effects of FENO (25 mg/kg·BID) and 125 mg/kg·BID on lipid catabolism were comparable, but 125 mg/kg·BID increased the expression of inflammatory factors and bile acid load. In both models, FENO (5 mg/kg·BID) showed little effect in hepatic steatosis and inflammation, neither the adverse effects. FENO (125 mg/kg·BID) aggravated liver inflammation, increased bile acid synthesis, and promoted the potential of liver proliferation. In toxicity risk assay, FENO (25 mg/kg·BID) treatment showed low potential to trigger bile acid synthesis, inflammation and hepatocyte proliferation. Conclusion: A new regime, FENO (25 mg/kg·BID) is potentially a therapeutic strategy for the NASH treatment. Translational medicine is warranted to prove its effectiveness in the clinic.

An investigation of the psychological stress of medical staff in Shanghai shelter hospital during COVID-19.

Objective: The purpose of this study was to assess the psychological status of medical workers from other locations who helped support the fight against COVID-19 in Shanghai and to provide a basis for psychological crisis intervention plans under designated emergencies. Methods: While supporting the Shanghai Lingang Shelter Hospital, we investigated 1,097 medical staff from other cities working in the hospital. A questionnaire comprising the general information questionnaire, health questionnaire depression scale, generalized anxiety scale, insomnia severity index scale, and mental health self-assessment questionnaire was used. Results: There were no statistically significant differences in the incidence rates of anxiety, depression, and sleep disorders among subjects of different genders, ages, and educational levels. There were statistically significant differences in the incidences of anxiety, depression, stress response, and sleep disturbance among subjects with different levels of worry about COVID-19. Conclusion: During the COVID-19 pandemic, the Lingang Shelter Hospital team experienced more psychological pressure, suggesting that medical institutions should pay attention to the mental health of frontline medical workers during COVID-19 and prepare psychological intervention measures for team members.

Down-regulation of hepatic CLOCK by PPARα is involved in inhibition of NAFLD.

This work aimed to investigate the role of nuclear factor peroxisome proliferator-activated receptor α (PPARα) in modification of circadian clock and their relevance to development of nonalcoholic fatty liver disease (NAFLD). Both male wild-type (WT) and Pparα-null (KO) mice treated with high-fat diet (HFD) were used to explore the effect of PPARα and lipid diet on the circadian rhythm. WT, KO, and PPARα-humanized (hPPARα) mice were treated with PPARα agonist fenofibrate to reveal the hPPARα dependence of circadian locomotor output cycles kaput (CLOCK) down-regulation. The mouse model and hepatocyte experiments were designed to verify the action of PPARα in down-regulating CLOCK and lipid accumulation in vivo and in vitro. Strongest NAFLD developed in mice fed 45%HFD, and it was inhibited in WT mice. The activity rhythm of WT mice was found to be different from that of the KO mice on normal diet and HFD. The core circadian factor CLOCK was down-regulated by HFD in both WT and KO mice in the liver, not in the hypothalamus. More interestingly, hepatic CLOCK was down-regulated by basal PPARα and activated PPARα in dose dependence of fenofibrate. Accordingly, CLOCK down-regulation dependent of PPARα activity was involved in inhibition of lipid metabolism in hepatocytes. Down-regulation of hepatic CLOCK by basal PPARα contributes to tolerance against development of NAFLD. Inhibition of CLOCK by activated PPARα is involved in inhibition of NAFLD by PPARα agonists. KEY MESSAGES: • PPARα inhibited NAFLD development induced by HFD. • PPARα mediated modifications of circadian rhythm and the hepatic circadian factor CLOCK in NAFLD models. • Down-regulation of hepatic CLOCK by basal PPARα contributed to tolerance against development of NAFLD. • Inhibition of CLOCK by activated PPARα was involved in therapeutic actions against fatty liver diseases by PPARα agonists.

Hepatocytic AP-1 and STAT3 contribute to chemotaxis in alphanaphthylisothiocyanate-induced cholestatic liver injury.

The development of cholestatic liver injury (CLI) involves inflammation, but the dominant pathway mediating the chemotaxis is not yet established. This work explored key signaling pathway mediating chemotaxis in CLI and the role of Kupffer cells in the inflammatory liver injury. Probe inhibitors T-5224 (100 mg/kg) for AP-1 and C188-9 (100 mg/kg) for STAT3 were used to validate key inflammatory pathways in alpha-naphthylisothiocyanate (ANIT, 100 mg/kg)-induced CLI. Two doses of GdCl3 (10 mg/kg and 40 mg/kg) were used to delete Kupffer cells and explore their role in CLI. Serum and liver samples were collected for biochemical and mechanism analysis. The liver injury in ANIT-treated mice were significantly increased supported by biochemical and histopathological changes, and neutrophils gathering around the necrotic loci. Inhibitor treatments down-regulated liver injury biomarkers except the level of total bile acid. The chemokine Ccl2 increased by 170-fold and to a less degree Cxcl2 by 45-fold after the ANIT treatment. p-c-Jun and p-STAT3 were activated in the group A but inhibited by the inhibitors in western blot analysis. The immunofluorescence results showed AP-1 not STAT3 responded to inhibitors in ANIT-induced CLI. With or without GdCl3, there was no significant difference in liver injury among the CLI groups. In necrotic loci in CLI, CXCL2 colocalized with hepatocyte biomarker Albumin, not with the F4/80 in Kupffer cells. Conclusively, AP-1 played a more critical role in the inflammation cascade than STAT3 in ANIT-induced CLI. Hepatocytes, not the Kupffer cells released chemotactic factors mediating the chemotaxis in CLI.

Relationship between Dynamic Changes of Microcirculation Flow, Tissue Perfusion Parameters, and Lactate Level and Mortality of Septic Shock in ICU.

Background: Septic shock is a common clinical critical disease with high mortality, hemodynamic instability, and easy to be complicated with multiple organ failure. The rapid progress of the patient's condition poses a serious threat to patient's safety. Aim: To investigate the relationship between the dynamic monitoring of microcirculation perfusion parameters and blood lactic acid level and the prognosis of patients with infection shock in ICU. Methods: A total of 104 patients with septic shock admitted to ICU of Affiliated Hai'an Hospital of Nantong University from February 2018 to June 2021 were selected for clinical research. According to the survival situation of patients after 28 days of treatment, they were divided into the death group (n = 48) and the survival group (n = 56). The central venous-arterial carbon dioxide partial pressure difference (Pcv-aCO2), the ratio of central venous-arterial carbon dioxide partial pressure difference to arterial central venous oxygen content difference (Pcv-aCO2/Ca-cvO2), and blood lactic acid level were retrospectively analyzed and compared between the two groups on the first, third, and seventh days after admission to ICU. The odds ratio (OR) of three indexes affecting the prognosis of patients with septic shock was analyzed by univariate and multivariate mathematical models, and the value of three indexes in predicting the prognosis of patients was analyzed by receiver operating curve (ROC). Results: Pcv-aCO2 and lactic acid in the death group were higher than those in the survival group on the 1st, 3rd, and 7th day of ICU stay (P < 0.05). The Pcv-aCO2/Ca-cvO2 of the death group was higher than that of the survival group on the 3rd and 7th day of ICU stay (P < 0.05). Logistic model results showed that age, SOFA score, APACHE II score, the number of multiple organ failure (MODS), intracranial infection, the increase of Pcv-aCO2, Pcv-aCO2/Ca-cvO2, and the increase of lactic acid were independent risk factors for death in patients with septic shock (OR values were 1.519, 1.808, 1.781, 1.912, 2.069, 1.848, 1.781, and 1.642, respectively, P < 0.05). The results showed that the AUC value of Pcv-aCO2 in predicting death was 0.943, and the sensitivity and specificity were 93.72% and 83.09%, respectively. The AUC value of Pcv-aCO2/Ca-cvO2 for predicting death was 0.887, and the sensitivity and specificity were 81.63% and 77.56%, respectively. The AUC value of lactic acid in predicting death of patients was 0.825, and the sensitivity and specificity were 71.66% and 82.09%, respectively. Conclusion: Changes of microcirculation flow tissue perfusion parameters and blood lactic acid level changes are closely related to the prognosis of patients with septic shock, which is of great value in the evaluation of the prognosis of patients with septic shock.

Role of Apolipoprotein A1 in PPAR Signaling Pathway for Nonalcoholic Fatty Liver Disease.

Peroxisome proliferator-activated receptors (PPARs) have been suggested to play crucial roles in the pathology of NAFLD with a vague understanding of the underlying mechanism. Here, we integrated large-scale literature data and clinical data to explore the potential role of the PPAR-APOA1 signaling pathway in the pathology of NAFLD. First, the signaling pathway connecting PPARs, APOA1, and NAFLD was constructed. Then, we employed clinical data to explore the association between APOA1 levels and NAFLD. In addition, we built the APOA1-driven pathway analysis to explore the potential mechanism of the APOA1-NAFLD association. Pathway analysis showed that APOA1 serves as a hubprotein connecting PPARs and NAFLD through a beneficial modulation of 16 out of 21 NAFLD upstream regulators. Each relationship within the composed pathway was supported by results from multiple previous studies. Clinical data analysis showed that an increase of APOA1 level was associated with a significantly decreased NAFLD prevalence (χ 2 = 292.109; P < 0.001). When other confounding factors were adjusted, serum APOA1 level was shown as an independent risk factor for the prevalence of NAFLD (P value<.0001; OR = 0.562). Our results suggested that the three PPARs (PPARA, PPARD, and PPARG) might promote the expression and molecular transportation of APOA1 to form a PPAR-APOA1 signaling pathway that demonstrated a beneficial role in the pathogenesis of NAFLD.

Critical role of peroxisome proliferator-activated receptor α in promoting platelet hyperreactivity and thrombosis under hyperlipidemia.

Platelet hyperreactivity and increased atherothrombotic risk are specifically associated with dyslipidemia. Peroxisome proliferator-activated receptor alpha (PPARα) is an important regulator of lipid metabolism. It has been suggested to affect both thrombosis and hemostasis, yet the underlying mechanisms are not well understood. In this study, the role and mechanism of PPARα in platelet activation and thrombosis related to dyslipidemia were examined. Employing mice with deletion of PPARα (Pparα-/-), we demonstrated that PPARa is required for platelet activation and thrombus formation. The effect of PPARα is critically dependent on platelet dense granule secretion, and is contributed by p38MAPK/Akt, fatty acid b-oxidation, and NAD(P)H oxidase pathways. Importantly, PPARα and the associated pathways mediated a prothrombotic state induced by a high-fat diet and platelet hyperactivity provoked by oxidized low density lipoproteins. Platelet reactivity was positively correlated with the levels of expression of PPARα, as revealed by data from wild-type, chimeric (Pparα+/-), and Pparα-/- mice. This positive correlation was recapitulated in platelets from hyperlipidemic patients. In a lipid-treated megakaryocytic cell line, the lipid-induced reactive oxygen species-NF-kB pathway was revealed to upregulate platelet PPARα in hyperlipidemia. These data suggest that platelet PPARα critically mediates platelet activation and contributes to the prothrombotic status under hyperlipidemia.

Promoter CAG is more efficient than hepatocyte­targeting TBG for transgene expression via rAAV8 in liver tissues.

The recombinant adeno­associated virus 8 (rAAV8) vector is a widely used tool in basic research and clinical trials. The cytomegalovirus immediate­early enhancer/chicken ß­actin (CAG) promoter is a synthetic promoter used in adenoviral constructs with a wide spectrum and notable efficiency. The thyroxine binding globulin (TBG) promoter is a liver­specific promoter, which directs transgene expression in hepatocytes. However, the transduction efficiency of the rAAV vector is dependent on both the administration routes and the promoter elements. In the present study, the transduction efficiency in the liver following intraperitoneal (IP) and intravenous (IV) injections of rAAV8 with the CAG, TBG669 and TBG410 promoters was compared. Enhanced green fluorescent protein (EGFP) expression was used as the biomarker to indicate efficiency. Among the three different promoters, CAG exhibited the highest efficiency from both IV and IP injections. Following IV administration, EGFP expression, induced by the CAG promoter, was 67­fold higher compared with that in the TBG410 promoter group and 26­fold higher compared with that in the TBG669 promoter group. EGFP protein expression was higher with IV injection compared with that for IP injection for both the CAG and TBG669 promoters (P<0.05). With the CAG promoter, EGFP protein expression was 1.5­fold higher with the use of IV injection than with IP injection. With the TBG410 promoter, no differences were observed between the two administrations. In conclusion, these findings demonstrated that the CAG promoter was much more efficient at driving gene expression in the liver compared with that for the TBG promoters in rAAV8. In addition, IP administration produced comparable efficiency for gene delivery via the rAAV8 vector, particularly with the promoter TBG410.

Effects of Air Pollutant Exposure on Exacerbation Severity in Asthma Patients with or without Reversible Airflow Obstruction.

BACKGROUND: Reversible airflow obstruction (RO) and fixed airflow obstruction (FO) are two important clinical phenotypes of asthma. However, the relationship between air pollutant exposure and exacerbation of the two phenotypes is unknown. OBJECTIVE: To study the effects of air pollutant exposure on exacerbation severity in asthma patients with or without FO. METHODS: A total of 197 severe asthma patients were enrolled, and divided into two groups: the FO group (n=81) and the RO group (n=116). We collected the demographic data, laboratory parameters, pulmonary function test parameters, and the daily average concentrations of different air particles in Shenzhen on the different lag days of each subject. The receiver operating characteristic (ROC) curve was used to identify the effects of major air pollutants on the severity of asthma patients with RO. RESULTS: Compared with the RO group, the FO group had fewer women, lower body mass index (BMI), longer disease duration, higher smoking history rate, allergic family history rate, FeNO level, and lower levels of large airway parameters. The median exposure levels of PM10 and PM2.5 in the severe RO subgroup were both higher than those in the mild-to-moderate RO subgroup on Lag0, 1 and 3, and the median exposure level of PM1 on Lag0 in the severe RO subgroup was significantly higher than that in the mild-to-moderate RO subgroup. Logistic regression modeling indicated exposure to PM2.5 and PM1.0 on Lag0, and PM10 on Lag0-2 were the independent risk factors for hospital admissions for asthma patients with RO. By performing an ROC curve analysis, PM2.5 on Lag0 (AUC = 0.645, p = 0.027) provided a best performance to predict severe asthma exacerbations with RO, with a sensitivity of 36.0% and a specificity of 91.2%. CONCLUSION: Short-term exposure to PM10, PM2.5 and PM1 may play a role in exacerbation severity among asthma patients with RO.

Index-based dietary patterns and stomach cancer in a Chinese population.

OBJECTIVES: Dietary factors are of importance in the development of stomach cancer. This study aims to examine index-based dietary patterns associated with stomach cancer in a Chinese population. METHODS: Using data from a population-based case-control study conducted in Jiangsu Province, China, we included a total of 8432 participants (1900 stomach cancer cases and 6532 controls). Dietary data collected by food frequency questionnaire was evaluated by modified Chinese Healthy Eating Index-2016 (mCHEI-2016) and the US Healthy Eating Index-2015 (HEI-2015). Multiple logistic regression analyses were applied to examine the association of mCHEI-2016 and HEI-2015 with stomach cancer while adjusting for potential confounders. The possible interactions between mCHEI-2016 or HEI-2015 and established risk factors were explored. RESULTS: Among nonproxy interviews, after adjusting for potential confounding factors, a higher score of sodium, reflecting lower intake per day, was inversely associated with stomach cancer [odds ratio (OR), 0.95; 95% CI, 0.91-0.99 for mCHEI-2016; OR, 0.97; 95% CI, 0.94-0.99 for HEI-2015]. No clear associations with stomach cancer were identified for total scores of HEI-2015 (OR, 0.98; 95% CI, 0.87-1.10 with a 10-point increase, P trend = 0.98) and mCHEI-2016 (OR, 1.05; 95% CI, 0.94-1.17 with a 10-point increase, P trend = 0.22). However, the relation between stomach cancer and the mCHEI-2016 was modified by BMI, with a possible inverse association in normal-weight subjects. CONCLUSIONS: Our findings highlight that reduced intake of dietary sodium would prevent the development of stomach cancer. The data indicate a heterogeneity between normal weight and overweight's dietary factors in relation to stomach cancer.

Fenofibrate reverses liver fibrosis in cholestatic mice induced by alpha-naphthylisothiocyanate.

Cholestatic liver fibrosis occurs in liver injuries accompanied by inflammation, which develops into cirrhosis if not effectively treated in early stage. The aim of the study is to explore the effect of fenofibrate on liver fibrosis in chronic cholestatic mice. In this study, wild-type (WT) and Pparα-null (KO) mice were dosed alpha-naphthylisothiocyanate (ANIT) diet to induce chronic cholestasis. Induced liver fibrosis was determined by pathological biomarkers. Then fenofibrate 25 mg/kg was orally administrated to mice twice/day for 14 days. Serum and liver samples were collected for analysis of biochemistry and fibrosis. In WT mice, cholestatic biomarkers were increased by 5-8-fold and the expression of tissue inhibitors of metalloproteinases 1 (TIMP-1), Monocyte chemoattractant protein 1 (MCP-1), Collagen protein I (Collagen I) was increased by more than 10-fold. Fenofibrate significantly downgraded the biochemical and fibrotic biomarkers. In Western blot analysis, levels of collagenI and alpha-smooth muscle actin (α-SMA) were strongly inhibited by fenofibrate. In KO mice, liver fibrosis was induced successfully, but no improvement after fenofibrate treatment was observed. These data showed low-dose fenofibrate reverses cholestatic liver fibrosis in WT mice but not in KO mice, suggesting the dependence of therapeutic action on peroxisome proliferator-activated receptor alpha (PPARα). The study offers an additional therapeutic strategy for cholestatic liver fibrosis in practice.

Low-dose PPI to prevent bleeding after ESD: A multicenter randomized controlled study.

BACKGROUND: Although proton pump inhibitors (PPIs) are widely used in the prevention of gastric bleeding caused by endoscopic submucosal dissection (ESD), there is no consensus on the optimal regimen for these patients. Therefore, we aim to investigate whether intermittent use of low-dose PPI is sufficient to prevent post-ESD bleeding. METHODS: This multicenter, non-inferiority, randomized controlled trial was conducted at 9 hospitals in China. Consecutive eligible patients with a diagnosis of gastric mucosal lesions after ESD treatment were randomly assigned (1:1) to receive either intermittent low-dose or continuous high-dose PPIs treatment. After three days, all patients administered orally esomeprazole 40 mg once a day for 8 weeks. The primary endpoint was post-ESD bleeding within 7 days. Analysis was done according to the intention-to-treat principle with the non-inferiority margin (Δ) of 5%. RESULTS: 526 consecutive patients were assessed for eligibility from 30 September 2017 to 30 July 2019, of whom 414 were randomly assigned to low-dose (n = 209) or high-dose (n = 205) esomeprazole treatment group without dropouts within7 days. The total post-ESD bleeding is occurred in 13 (6.2 %, 95 % CI 3.3-9.6) of 209 within 7 days in the intermittent low-dose group, and 12 (5.9 %, 95 % CI 2.9-9.3) of 205 in the continuous high-dose group. The absolute risk reduction (ARR) was 0.4 % (-4.2, 4.9). One month after ESD, There are 44 patients (21.1 %, 95 % CI 15.8, 26.8) and 39 patients (19.0 % 95 % CI 13.7, 24.4) in scar stage respectively in low-dose group and high-dose group (P = 0.875).The hospital costs in the low-dose PPI group was lower than high -dose group (P = 0.005). CONCLUSION: The intermittent use of low-dose PPIs is sufficient to prevent post-ESD bleeding. It might be applied in clinical practice to prevent post-ESD bleeding and reduce the costs related to PPIs.

[Effect of early intervention bundle on clinical prognosis of patients with latent/overt septic shock in emergency department].

OBJECTIVE: To observe the effect of early intervention bundle on clinical prognosis of patients with latent/overt septic shock in emergency department and analyze the risk factors for mortality. METHODS: Patients with latent and overt septic shock admitted to the North Hospital of Huashan Hospital Affiliated to Fudan University from January 2018 to December 2019 were retrospectively analyzed and divided into latent shock group and overt shock group. The gender, age, main infection site, the time of shock diagnosis, the indicators of early (3-hour) intervention bundle, 6-hour compliance rate of intervention bundle, the remission time and 28-day prognosis were observed. Logistic regression analysis was used to identify risk factors for 28-day mortality. Receiver operating characteristic (ROC) curve was used to analyze its prognostic value. RESULTS: Totally 181 patients were included in the analysis. There were 102 cases in the latent shock group, and 28-day mortality was 15.69% (16 cases); 79 cases in the overt shock group, and 28-day mortality was 31.65% (25 cases). Compared with the latent shock group, patients in overt shock group had higher compliance rate of early intervention bundle (93.67% vs. 58.82%), higher blood lactate acid at admission [Lac (mmol/L): 7.09±2.08 vs. 5.69±1.27], higher compliance rate of blood culture before antibiotics (93.67% vs. 63.73%), higher proportion of antibiotics use at the first and second hours (45.57% vs. 31.37%, 54.43% vs. 33.33%), higher proportion of rapid fluid resuscitation at the first hour (crystal liquid: 59.49% vs. 11.76%, crystal fluid combined with human serum albumin: 40.51% vs. 0%), and higher proportion of vasoactive use at the first hour (100% vs. 9.80%). The stable time was significantly prolonged (days: 4.40±1.35 vs. 1.49±0.55), while the onset time (days: 1.47±0.97 vs. 2.95±1.61), the time of diagnosis (minutes: 31.30±12.54 vs. 79.15±13.81), 6-hour lactate clearance [(50.27±21.53)% vs. (61.82±13.12)%], the proportion of antibiotics use at the third hour (0% vs. 35.29%), the proportion of rapid fluid resuscitation at the second and third hour (second hour crystal liquid: 0% vs. 60.78%, second hour crystal fluid combined with human serum albumin: 0% vs. 14.71%, third hour crystal liquid: 0% vs. 12.75%), 6-hour compliance rate of the standard of central venous blood saturation (ScvO2, 60.76% vs. 78.43%) and the success rate of treatment (28-day mortality: 31.65% vs. 15.69%) were lower than those of the latent shock group (all P < 0.05). Ten patients with latent shock developed into overt shock within 24 hours after admission. All patients with overt shock needed vasoactive drugs to maintain mean arterial pressure (MAP) ≥ 65 mmHg (1 mmHg = 0.133 kPa). Compared with the survival patients, the Lac (mmol/L: 7.59±2.27 vs. 5.92±1.24) and the proportion of vasoactive drugs use (65.85% vs. 44.29%) were significantly increased in the death patients, while the 6-hour lactate clearance [(46.58±15.83)% vs. (59.60±17.92)%], the proportion of antibiotics use in the third hour (4.88% vs. 24.29%), and 6-hour compliance rate of urine volume and ScvO2 (56.10% vs. 82.86%, 43.90% vs. 78.57%) were significantly decreased (all P < 0.05). Binary Logistic regression analysis showed that Lac at admission, 6-hour lactate clearance, the use of antibiotics at the third hour, rapid fluid resuscitation at the first hour, and 6-hour compliance rate of ScvO2 were independent risk factors for 28-day mortality [odds ratio (OR) was 1.618, 0.021, 0.100, 0.307 and 3.018, all P < 0.05]. ROC curve analysis showed that the Lac at admission had the highest predictive value for 28-day mortality, the area under the ROC curve (AUC) was 0.706; followed by 6-hour compliance rate of ScvO2 (AUC was 0.673). CONCLUSIONS: Patients with latent/overt septic shock need early diagnosis and intervention bundle to improve the 6-hour blood lactate clearance and 6-hour compliance rate of ScvO2 and reduce the mortality.