Mitochondrial GRIM19 Loss Induces Liver Fibrosis through NLRP3/IL33 Activation via Reactive Oxygen Species/NF-кB Signaling.

Background and Aims: Hepatic fibrosis (HF) is a critical step in the progression of hepatocellular carcinoma (HCC). Gene associated with retinoid-IFN-induced mortality 19 (GRIM19), an essential component of mitochondrial respiratory chain complex I, is frequently attenuated in various human cancers, including HCC. Here, we aimed to investigate the potential relationship and underlying mechanism between GRIM19 loss and HF pathogenesis. Methods: GRIM19 expression was evaluated in normal liver tissues, hepatitis, hepatic cirrhosis, and HCC using human liver disease spectrum tissue microarrays. We studied hepatocyte-specific GRIM19 knockout mice and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 (Cas9) lentivirus-mediated GRIM19 gene-editing in murine hepatocyte AML12 cells in vitro and in vivo. We performed flow cytometry, immunofluorescence, immunohistochemistry, western blotting, and pharmacological intervention to uncover the potential mechanisms underlying GRIM19 loss-induced HF. Results: Mitochondrial GRIM19 was progressively downregulated in chronic liver disease tissues, including hepatitis, cirrhosis, and HCC tissues. Hepatocyte-specific GRIM19 heterozygous deletion induced spontaneous hepatitis and subsequent liver fibrogenesis in mice. In addition, GRIM19 loss caused chronic liver injury through reactive oxygen species (ROS)-mediated oxidative stress, resulting in aberrant NF-кB activation via an IKK/IкB partner in hepatocytes. Furthermore, GRIM19 loss activated NLRP3-mediated IL33 signaling via the ROS/NF-кB pathway in hepatocytes. Intraperitoneal administration of the NLRP3 inhibitor MCC950 dramatically alleviated GRIM19 loss-driven HF in vivo. Conclusions: The mitochondrial GRIM19 loss facilitates liver fibrosis through NLRP3/IL33 activation via ROS/NF-кB signaling, providing potential therapeutic approaches for earlier HF prevention.

Diphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects.

Diphthamide is a modified histidine residue unique for eukaryotic translation elongation factor 2 (eEF2), a key ribosomal protein. Loss of this evolutionarily conserved modification causes developmental defects through unknown mechanisms. In a patient with compound heterozygous mutations in Diphthamide Biosynthesis 1 (DPH1) and impaired eEF2 diphthamide modification, we observe multiple defects in neural crest (NC)-derived tissues. Knockin mice harboring the patient's mutations and Xenopus embryos with Dph1 depleted also display NC defects, which can be attributed to reduced proliferation in the neuroepithelium. DPH1 depletion facilitates dissociation of eEF2 from ribosomes and association with p53 to promote transcription of the cell cycle inhibitor p21, resulting in inhibited proliferation. Knockout of one p21 allele rescues the NC phenotypes in the knockin mice carrying the patient's mutations. These findings uncover an unexpected role for eEF2 as a transcriptional coactivator for p53 to induce p21 expression and NC defects, which is regulated by diphthamide modification.

The estimated effect of increasing fruit interventions on controlling body weight in children and adolescents: A meta-analysis.

BACKGROUND: The impact of increased fruit consumption on weight change remains a matter of debate. OBJECTIVE: This study aimed to evaluate the effects of interventions targeted at promoting fruit consumption and managing body weight in children and adolescents. METHODS: Four electronic databases, including PubMed, Web of science, Embase, and the Cochrane Library, were searched from January 1, 2000, to October 10th, 2023, to identify Randomized controlled trials (RCTs) that assessed changes in fruit consumption and obesity indicators. RESULTS: A total of 22 trials including 12,678 participants who met our inclusion criteria were selected for this review. The meta-analysis demonstrated that the interventions increased fruit intake (MD = 78.58 g/day (95% CI 53.09 to 104.07), P < 0.001) in children and adolescents. The mean reduction of body mass index was 0.27 kg/m2 (95% CI -0.59 to 0.05 kg/m2, P = 0.101). And no significant decreases were observed in body mass index-z scores, but there was a significant decrease in waist circumference (MD = -0.65 cm (95% CI -1.15 to -0.05 cm), P < 0.05). Increased fruit intake was shown to be associated with a lower prevalence of obesity when compared to the control group (odds ratio [OR]: 0.74, 95% CI 0.60 to 0.90), P < 0.05). CONCLUSIONS: This meta-analysis provided evidence that interventions aimed at increasing fruit consumption were effective at reducing obesity prevalence.

Meta-Analysis of the Efficacy of Levosimendan in the Treatment of Severe Sepsis Complicated with Septic Cardiomyopathy.

INTRODUCTION: Sepsis is a medical condition characterized by acute organ dysfunction and uncontrolled inflammation. Organ dysfunction in sepsis is the primary cause of mortality in patients with myocardial dysfunction. Levosimendan is a vasodilating and inotropic agent used in patients with acute heart failure and has resulted in decreased morbidity and mortality in these patients. Our main objective is to examine levosimendan's efficacy in treating severe sepsis complicated with septic cardiomyopathy. METHODS: We systematically searched five databases, PubMed, Web of Science, Embase, Cochrane Library and BioMed Central, for articles and publications from their inception to 2023. Our study adopted the PICOS approach in identifying suitable publications during the systematic search. Inclusion criteria included randomized, controlled trials utilizing levosimendan in adult patients diagnosed with septic shock or severe sepsis. We excluded non-English publications and non-randomized controlled trials. The Newcastle-Ottawa scale (NOS) scale was used to assess the methodological quality, while the risk of bias was assessed through the Cochrane Risk of bias tool. All statistical analyses were performed using RevMan version 5.4. RESULTS: Eight studies met the eligibility criteria and were included in the analysis. There was a statistically significant positive effect on cardiac input in patients treated with levosimendan compared to those treated with dobutamine (p < 0.001). Similarly, there were positive effects on left ventricular ejection fraction (LVEF) (p < 0.001) and left ventricular stroke work index (LVSWI) (p < 0.001). We observed a significant reduction in mortality (p < 0.01) and serum levels of lactic acid (p < 0.01). DISCUSSION: Levosimendan is a calcium sensitizer associated with an influx of calcium ions and activation of ATP-dependent potassium channels that increases myocardial contractility contractions, enhances vasodilation and improves oxygen supply to the cells and tissues. CONCLUSION: Levosimendan is highly efficacious and safe in the management of sepsis and sepsis-induced cardiomyopathy.

The associations between hematological parameters and the incidence of prehypertension and hypertension in children and adolescents: a prospective cohort study.

Uncontrolled pediatric hypertension may increase the risk of hypertension in adulthood. Several studies have reported an association between hematological parameters and blood pressure (BP) levels. However, epidemiologic evidence of this association in children and adolescents remains scarce. This study aims to explore the associations between hematological parameters and the incidence of prehypertension and hypertension in children and adolescents. This longitudinal study was conducted with 1368 participants aged 6-8 years from baseline visit to follow-up visit. Compared with participants from the normal blood pressure (BP) group, participants from the elevated BP group had significantly higher baseline red blood cell (RBC) counts, hemoglobin (Hb) counts and hematocrit (Hct) levels (all P < 0.001). A multilevel linear mixed model was conducted to analyze the relationship between hematological parameters and BP levels. The results suggested that SBP, DBP and MAP increased significantly with a quartile increase of levels of hematological parameters (all P < 0.05). Furthermore, a multilevel mixed logistic regression model was used to analyze the risk of per interquartile range increase in hematological parameters on the incidence of prehypertension and hypertension. The risk of prehypertension and hypertension incidence increased by (1.34 (95%CIs: 1.20, 1.50)), (1.38 (95%CIs: 1.24,1.54)), (1.33 (95%CIs: 1.19,1.50)), (1.14 (95%CIs: 1.03,1.26)) fold with a one-quartile increase in levels of RBC, Hb, Hct and Fe, respectively (all P < 0.05). This longitudinal study showed that hematological parameters were positively associated with BP levels in healthy children and adolescents, which excluded the effect of antihypertensive drugs on BP levels that often appeared in adults.

Bivalirudin versus heparin anticoagulation in patients receiving extracorporeal membrane oxygenation.

OBJECTIVE: Bivalirudin has been suggested as an alternative to heparin for anticoagulation in patients receiving extracorporeal membrane oxygenation (ECMO). Nevertheless, there is limited evidence about the benefit of bivalirudin in ECMO patients compared with heparin. Hence, we conducted a meta-analysis to assess the effect of bivalirudin versus heparin on clinical outcomes in patients receiving ECMO. METHODS: PubMed, Embase, and the Cochrane Library were systematically searched from inception up to 1 April 2022 for cohort studies and randomized controlled trials comparing bivalirudin versus heparin in patients who received ECMO. The primary outcome was short-term death. Secondary outcomes included thrombotic events and bleeding events. RESULTS: We selected 12 retrospective cohort studies with 1232 ECMO patients focusing on bivalirudin anticoagulation (n = 497) versus heparin anticoagulation (n = 735). Two hundred and one of 497 patients (40.4%) in the bivalirudin group versus 350 of 735 patients (47.6%) in the heparin group did not survive to hospital discharge. Compared with the heparin group, bivalirudin anticoagulation did not significantly decrease in-hospital mortality in patients receiving ECMO (RR, 0.95; 95% CI, 0.79-1.13; p = 0.546). Fifty-seven of 374 patients (15.2%) in the bivalirudin versus 99 of 381 patients (26.0%) in the heparin group suffered from thrombotic events. Compared with the heparin group, bivalirudin anticoagulation did not significantly decrease the rate of thrombotic events for patients receiving ECMO (RR, 0.78; 95% CI, 0.45-1.35; p = 0.378). However, bivalirudin anticoagulation significantly decreased the incidence of bleeding events compared to the heparin group (RR, 0.48; 95% CI, 0.25-0.95; p = 0.035). CONCLUSIONS: Compared with heparin anticoagulation, bivalirudin did not decrease the rates of short-term mortality and thrombotic events, but reduced the incidence of bleeding events in patients receiving ECMO.

Venous-arterial extracorporeal membrane oxygenation support for patients poisoned by Macleaya cordata.

Macleaya cordata is a Chinese herbal medicine containing a variety of highly cardiotoxic alkaloids, and might result in cardiac failure. Venous-arterial Extracorporeal membrane oxygenation (VA-ECMO) could be used as a therapeutic option in patients poisoned by Macleaya cordata complicating refractory cardiogenic shock or cardiac arrest. A 60-year-old man suffered from severe arrhythmia, cardiogenic shock and cardiac arrest after consuming Macleaya cordata. The patient received VA-ECMO support in the emergency department at 5 hours after hospitalization, and was weaned from VA-ECMO on day 4, and was discharged with complete clinical improvement on Day 12. VA-ECMO is an effective method in treating cardiogenic shock or cardiac arrest induced by severe poisoning from Chinese herbal medicine. Timely and appropriate interventions with venoarterial extracorporeal membrane oxygenation devices could improve clinical outcomes in these patients.

Venoarterial extracorporeal membrane oxygenation with intra-aortic balloon pump for postcardiotomy cardiogenic shock: A systematic review and meta-analysis.

OBJECTIVE: Intra-aortic balloon pump (IABP) is currently recommended as a strategy to address the increased afterload in patients who received venoarterial extracorporeal membrane oxygenation (VA-ECMO). The benefit of VA-ECMO with IABP in postcardiotomy cardiogenic shock is inconclusive. A systematic review and meta-analysis was conducted to assess the influence of VA-ECMO with IABP for postcardiotomy cardiogenic shock (PCS). METHODS: The Cochrane Library, PubMed, and Embase were searched for all articles published from 1 January, 1964 to July 11, 2020. Retrospective cohort studies targeting the comparison of VA-ECMO with IABP and isolated VA-ECMO were included in this study. RESULTS: We included 2251 patients in the present study (917 patients in the VA-ECMO with IABP group and 1334 patients in the isolated VA-ECMO group). Deaths occurred in 589 of 917 patients (64.2%) in the VA-ECMO with IABP group and occurred in 885 of 1334 patients (66.3%) in isolated VA-ECMO group. Pooling the results of all studies showed that VA-ECMO with IABP was not related to a reduced in-hospital mortality in patients who received VA-ECMO for PCS (RR, 0.95; 95% CI, 0.86-1.04; p = 0.231). In addition, VA-ECMO with IABP was not related to an increased rate of VA-ECMO weaning in patients who received VA-ECMO for PCS (RR, 1.28; 95% CI, 0.99-1.66; p = 0.058). CONCLUSIONS: This study indicates that VA-ECMO with IABP did not improve either in-hospital survival or weaning for VA-ECMO in postcardiotomy cardiogenic shock patients.

Association of decreases in PM2.5 levels due to the implementation of environmental protection policies with the incidence of obesity in adolescents: A prospective cohort study.

AIMS: To explore the association between decreased levels of particulate matter (≤2.5 µm; PM2.5) due to the implementation of environmental protection policies and the incidence of obesity in adolescents in Chongqing, China through a prospective cohort study. METHODS: A total of 2105 children (52.02% male; aged 7.33 ± 0.60 years at baseline) were enrolled from the Chongqing Children's Health Cohort. A mixed linear regression model was used to analyse the relationships of PM2.5 levels with obesity indicators after adjusting for covariates. Additionally, a Poisson regression model was used to determine the relationship between PM2.5 exposure and the incidence of overweight/obesity. RESULTS: The average PM2.5 exposure levels from participant conception to 2014, from 2015 to 2017, and from 2018 to 2019 were 66.64 ± 5.33 µg/m3, 55.49 ± 3.78 µg/m3, and 42.50 ± 1.87 µg/m3, respectively; these levels significantly decreased over time (P < 0.001). Throughout the entire follow-up period, the incidence of overweight/obesity after a ≥ 25 µg/m3 decrease in the PM2.5 level was 4.57% among females; this incidence was the lowest among females who experienced remarkable decreases in PM2.5 exposure. A 1-µg/m3 decrease in the PM2.5 level significantly decreased the body mass index (BMI), BMI z score (BMIz), and weight of adolescents (all P < 0.001). Compared with a < 20-µg/m3 decrease in the PM2.5 level, a ≥ 25-µg/m3 decrease protected against increased BMI (net difference= -0.93; 95% confidence interval [CI]: (-1.23,-0.63) kg/m2), BMIz (-0.28 (-0.39, -0.17)), weight (-1.59 (-2.44, -0.74) kg), and incidence of overweight/obesity (0.48 (0.37, 0.62), P < 0.001). Moreover, compared with a < 20-µg/m3 decrease in the PM2.5 level, a ≥ 25-µg/m3 decrease resulted in significant absolute differences in BMI (-1.26 (-1.56, -0.96) kg/m2), BMIz (-0.53 (-0.65, -0.40)) and weight (-3.01 (-3.8, -2.19) kg) (all P < 0.001). CONCLUSIONS: This study showed the etiological relevance of declining PM2.5 concentrations for the incidence of obesity in children and adolescents, suggesting that controlling ambient air pollutants may prevent the development of obesity in this age group. Continuous implementation of environmental protection policies in China has led to substantial health benefits.

An Auxiliary Scoring Model for Patients with Acute Pulmonary Embolism Complicated with Atrial Fibrillation Was Established Based on Random Forests.

The purpose of this study was to explore the establishment of an auxiliary scoring model for patients with acute pulmonary embolism (APE) complicated with atrial fibrillation (AF) based on random forest (RF) and its application effect. A retrospective analysis was performed on the general data, underlying diseases, laboratory indicators, and cardiac indicators of 100 patients with APE admitted to our hospital from 2018 to 2021. The occurrence of atrial fibrillation in patients with pulmonary embolism was taken as a categorical variable, and the general data, underlying diseases, laboratory indicators, and cardiac indicators were taken as input variables. Then, the risk auxiliary scoring model for patients with APE complicated with AF was established based on RF and logistic regression. Finally, the accuracy, sensitivity, specificity, recall rate, accuracy, F1 value, and the receiver operator characteristic (ROC) curve were used to evaluate the predictive value of the models. After statistical analysis, the optimal node value was 3 and the optimal number of decision trees was 500 in the RF model. The importance of predictors in descending order were Hcy, diabetes mellitus, FT3 level, UA level, left atrial diameter, hypertension, and smoking history. The prediction accuracy of the RF model was 0.934, sensitivity 0.966, specificity 0.876, recall rate 0.9660, accuracy 0.934, and F1 value 0.950. The logistic regression model prediction accuracy was 0.816, sensitivity 0.915, specificity 0.125, recall rate 0.902, accuracy 0.811, and F1 value 0.896. The RF model and logistic regression prediction model AUC values were 0.984 and 0.883, respectively. From this, we conclude that the RF model was better than the logistic regression model in predicting AF in APE patients. So, the RF model had the clinical application value.

The relationship of remnant cholesterol and abdominal obesity in children: A cross-sectional study.

Background: Previous studies found that remnant cholesterol (RC) is a risk factor for cardiovascular diseases and childhood obesity is associated with cardiometabolic diseases. This study aimed to explore the relationship between RC and abdominal obesity in children. Methods: A total of 5,959 children, aged 6-12 years old, were selected from a cross-sectional study in urban-rural areas of Chongqing, China. RC was calculated by total cholesterol (TC)-high-density lipoprotein (HDL-C) cholesterol-low-density lipoprotein (LDL-C) cholesterol and was divided into four groups by quartiles (Q1-Q4). Results: Compared to children with the lowest RC (Q1), children with higher RC had significantly higher odds of abdominal obesity (Q2: OR = 1.450, 95% CI: 1.131-1.859, p < 0.05; Q3: OR = 2.127, 95% CI: 1.632-2.772, p < 0.001; Q4: OR = 2.386, 95% CI: 1.819-3.130, p < 0.001). In the stratified analyses by urban-rural areas, the odds ratios were greater in rural areas (Q2: OR = 2.228, 95% CI: 1.572-3.160, p < 0.001; Q3: OR = 3.668, 95% CI: 2.191-6.140, p < 0.001; Q4: OR = 6.490, 95% CI: 2.271-18.551, p < 0.001) than in urban areas (Q2: OR = 1.644, 95% CI: 1.192-2.266, p < 0.05; Q3: OR = 2.266, 95% CI: 1.667-3.082, p < 0.001; Q4: OR = 2.711, 95% CI: 2.005-3.665, p < 0.001). Conclusions: Our study found that RC was positively correlated with abdominal obesity in children, and this association was higher for children living in rural areas.

The Impact of PM2.5 on the Growth Curves of Children's Obesity Indexes: A Prospective Cohort Study.

Aims: To explore the effect of long-term exposure to particulate matter with an aerodynamic diameter of 2.5 µm or less (PM2.5) on childhood obesity based on a cohort study in Chongqing. Methods: A total of 4,284 children aged 6-8 years at baseline were enrolled from the Chongqing Children Health Cohort in 2014-2015 and were followed up in 2019. A stratified cluster sampling was applied to select the participants. A Mixed-effects linear regression model was used to examine the effect of long-term exposure to PM2.5 on the growth curve of obesity indicators [including body mass index (BMI), BMI Z-score (BMIz), and waist-to-height ratio (WHtR)]. A mixed-effects logistic regression model was used to study the dose relationship between PM2.5 exposure and the risk of obesity indicators. Results: A higher level of accumulating exposure to PM2.5 was associated with an increased childhood obesity index, and the effect was the most significant for WHtR than BMI and BMIz. This effect was more pronounced in boys than in girls except for WHtR, and it was the most significant under the PM2.5 exposure period from pregnancy to 6 years old. Compared the annual average PM2.5 exposure level of <60 µg/m3, the WHtR and BMI were increased by 0.019 [(95% CIs): 0.014, 0.024] and 0.326 [(95% CIs): 0.037, 0.616] Kg/m2 for participants living with the PM2.5 exposure level of 70-75 µg/m3, respectively. For every 5 µg/m3 increase in PM2.5 levels (from pregnancy to 6 years old), the risk of central obesity was increased by 1.26 {odds ratio [OR] (95% CIs): 1.26 (1.16, 1.37), p < 0.001} times. Conclusions: This study confirmed a dose-response relationship between PM2.5 exposure and childhood obesity, especially central obesity, suggesting that controlling ambient air pollution can prevent the occurrence of obesity in children and adolescents.

Chronic Alcohol Exposure Alters Gene Expression and Neurodegeneration Pathways in the Brain of Adult Mice.

BACKGROUND: Chronic alcohol consumption can alter the structure of the central nervous system and disrupt cognitive function. Alcoholics are more likely to develop neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, the role of alcohol in promoting neurotoxicity and neurodegeneration remains unclear. OBJECTIVE: In this study, we aimed at estimating the effects of chronic binge alcohol exposure on brain transcriptome and behavior changes in a chronic "Drinking in the Dark" (DID) mouse model. METHODS: The adult C57BL/6J male mice were exposed to alcohol for 4 weeks. RNA-seq was applied to assess the effects of chronic alcohol exposure on transcriptome in brain. The open field test and novel object recognition test were used to assess the changes of anxiety level, locomotive function, and short-term memory induced by alcohol. RNA-seq analysis revealed that chronic alcohol exposure caused significant change in the brain transcriptome, especially in prefrontal cortex. RESULTS: The gene dysregulation caused by chronic alcohol exposure includes pathways related to mitochondrial energy metabolism (such as oxidative phosphorylation) and multiple neurodegenerative diseases (such as AD and PD). Furthermore, the pathway and network analyses suggest that the genes involved in mitochondrial energy metabolism, ubiquitin-proteasome system, Wnt signaling pathway, and microtubules may attribute to the neurotoxicity and neurodegeneration caused by chronic alcohol consumption. Additionally, locomotive function was also significantly impaired. CONCLUSION: This work provides gene transcriptional profile data for future research on alcohol-induced neurodegenerative diseases, especially AD and PD.

Analysis of vaccine-like lumpy skin disease virus from flies near the western border of China.

Lumpy skin disease (LSD) is a devastating viral disease that occurs in cattle. In China, it was first detected in the Xin-Jiang autonomous region, near the border with Kazakhstan, in August 2019. As there were no new occurrences of LSD in either country following the first detection, the initial introduction of the virus remains unknown. Arthropod vectors were considered as potential vectors. Consequently, to identify the arthropod vectors involved in transmitting LSD virus (LSDV), an insect surveillance campaign was launched at four different sites scattered along the border, and samples from 22 flying insect species were collected and subjected to PCR assays. Following the Agianniotaki LSDV vaccine and Sprygin's general LSDV assays, two kinds of non-biting flies, namely, Musca domestica L and Muscina stabulans, were positive for LSDV. However, all the other insects tested negative. Viral DNA was only detected in wash fluid, implying body surface contamination of the virus. The negative test results suggest that non-biting flies are the dominant insects involved in the observed local epidemic. Three genomic regions encoding RPO30, GPCR, and LW126 were successfully sequenced and subjected to phylogenetic analysis. The sequences shared high homology with LSDV/Russia/Saratov/2017, a recombinant vaccine-like strain formerly identified in Russia, and clustered with LSDV vaccine strains in phylogenetic trees of RPO30 and LW126. However, the GPCR gene was seen to be solely clustered with LSDV field strains, implying differences in host affinity between these closely related vaccine-like strains. Despite this, there is no direct evidence to support cross-border transmission of the vaccine-like LSDV. To our knowledge, this is the first report of vaccine-like LSDV DNA detection in non-biting flies in China.

[Pathogenic role of NDUFA13 inactivation in spontaneous hepatitis in mice and the mechanism].

OBJECTIVE: To investigate the role of NDUFA13 inactivation in the pathogenesis of spontaneous hepatitis in mice and explore the possible mechanisms. METHODS: Hepatocyte-specific NDUFA13 knockout (NDUFA13fl/-) mice were generated by intercrossing NDUFA13fl/fl and Alb-Cre mice based on Cre/loxP transgenic technology, and tail and liver DNA of the mice was genotyped by PCR analysis. Ten NDUFA13fl/- mice and 10 littermate control NDUFA13fl/fl mice were housed, and in each group, 5 mice were euthanized at the age of 4 weeks and the other 5 at two years for pathological examination of the liver tissues with HE staining. Immunohistochemistry was used to verify the expression levels of NDUFA13, NF-κB/p65, NF-κB/p-p65 and inflammasome NLRP3. The total intracellular ROS and mitochondrial ROS levels were measured with a ROS staining kit. The expressions of the inflammatory cell markers (CD45, MPO, and F4/80) and inflammatory cytokines (IL1ß and IL33) in the liver were detected with immunohistochemistry and immunofluorescence assay. RESULTS: Liver-specific NDUFA13 heterozygous knockout mice were successfully constructed as verified by PCR results. HE staining revealed severe liver damage in both 4- week-old and 2-year-old NDUFA13fl/- mice as compared with their littermate controls. Immunohistochemistry showed a significant decrease of NDUFA13 expression in both 4-week-old and 2-year-old NDUFA13fl/- mice (P < 0.05). The expression levels of NF-κB signals p65, p-p65 and NLRP3 inflammasomes were all significantly increased in NDUFA13fl/- mice (P < 0.05). The total intracellular ROS and mitochondrial ROS levels in NDUFA13fl/- mice were also significantly increased. NDUFA13 knockout obviously promoted the expression of the inflammatory cell markers (CD45, MPO and F4/80) and the secretion of IL-1ß and IL-33 in the liver tissue of the mice (P < 0.05). CONCLUSIONS: Hepatocytes-specific NDUFA13 ablation can trigger spontaneous hepatitis in mice possibly mediated by the activation of ROS/NF-κB/NLRP3 signaling.

A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling.

Presenilin-1 (PSEN1) is the catalytic subunit of the γ-secretase complex, and pathogenic mutations in the PSEN1 gene account for the majority cases of familial AD (FAD). FAD-associated mutant PSEN1 proteins have been shown to affect APP processing and Aß generation and inhibit Notch1 cleavage and Notch signaling. In this report, we found that a PSEN1 mutation (S169del) altered APP processing and Aß generation, and promoted neuritic plaque formation as well as learning and memory deficits in AD model mice. However, this mutation did not affect Notch1 cleavage and Notch signaling in vitro and in vivo. Taken together, we demonstrated that PSEN1S169del has distinct effects on APP processing and Notch1 cleavage, suggesting that Notch signaling may not be critical for AD pathogenesis and serine169 could be a critical site as a potential target for the development of novel γ-secretase modulators without affecting Notch1 cleavage to treat AD.

MicroRNA-7 as a potential therapeutic target for aberrant NF-κB-driven distant metastasis of gastric cancer.

BACKGROUND: Dysregulated miR-7 and aberrant NF-κB activation were reported in various human cancers. However, the expression profile, clinical relevance and dysregulated mechanism of miR-7 and NF-κB RelA/p65 in human gastric cancers (GC) metastasis remain largely unknown. This study is to investigate the expression profile, clinical relevance and dysregulated mechanism of miR-7 and NF-κB RelA/p65 in GC and to explore the potential therapeutic effect of miR-7 to GC distant metastasis. METHODS: TCGA STAD and NCBI GEO database were used to investigate the expression profile of miR-7 and NF-κB RelA/p65 and clinical relevance. Lentivirus-mediated gene delivery was applied to explore the therapeutic effect of miR-7 in GC. Real-time PCR, FACS, IHC, IF, reporter gene assay, IP, pre-miRNA-7 processing and binding assays were performed. RESULTS: Low miR-7 correlated with high RelA/p65 in GC with a clinical relevance that low miR-7 and high RelA/p65 as prognostic indicators of poor survival outcome of GC patients. Moreover, an impaired pre-miR-7 processing caused by dysregulated Dicer1 expression is associated with downregulated miR-7 in GC cells. Functionally, delivery of miR-7 displays therapeutic effects to GC lung and liver metastasis by alleviating hemangiogenesis, lymphangiogenesis as well as inflammation cells infiltration. Mechanistically, miR-7 suppresses NF-κB transcriptional activity and its downstream metastasis-related molecules Vimentin, ICAM-1, VCAM-1, MMP-2, MMP-9 and VEGF by reducing p65 and p-p65-ser536 expression. Pharmacologic prevention of NF-κB activator LPS obviously restored miR-7-suppressed NF-κB transcriptional activation and significantly reverted miR-7-inhibited cell migration and invasion. CONCLUSIONS: Our data suggest loss of miR-7 in GC promotes p65-mediated aberrant NF-κB activation, facilitating GC metastasis and ultimately resulting in the worse clinical outcome. Thus, miR-7 may act as novel prognostic biomarker and potential therapeutic target for aberrant NF-κB-driven GC distant metastasis.

Transcriptional activation of USP16 gene expression by NFκB signaling.

Ubiquitin Specific Peptidase 16 (USP16) has been reported to contribute to somatic stem-cell defects in Down syndrome. However, how this gene being regulated is largely unknown. To study the mechanism underlying USP16 gene expression, USP16 gene promoter was cloned and analyzed by luciferase assay. We identified that the 5' flanking region (- 1856 bp ~ + 468 bp) of the human USP16 gene contained the functional promotor to control its transcription. Three bona fide NFκB binding sites were found in USP16 promoter. We showed that p65 overexpression enhanced endogenous USP16 mRNA level. Furthermore, LPS and TNFα, strong activators of the NFκB pathway, upregulated the USP16 transcription. Our data demonstrate that USP16 gene expression is tightly regulated at transcription level. NFκB signaling regulates the human USP16 gene expression through three cis-acting elements. The results provide novel insights into a potential role of dysregulation of USP16 expression in Alzheimer's dementia in Down Syndrome.

Ethanol Alters APP Processing and Aggravates Alzheimer-Associated Phenotypes.

The majority of Alzheimer's disease (AD) cases are sporadic with unknown causes. Many dietary factors including excessive alcohol intake have been reported to increase the risk to develop AD. The effect of alcohol on cognitive functions and AD pathogenesis remains elusive. In this study, we investigated the relationship between ethanol exposure and Alzheimer's disease. Cell cultures were treated with ethanol at different dosages for different durations up to 48 h and an AD model mouse was fed with ethanol for 4 weeks. We found that ethanol treatment altered amyloid ß precursor protein (APP) processing in cells and transgenic AD model mice. High ethanol exposure increased the levels of APP and beta-site APP cleaving enzyme 1 (BACE1) and significantly promoted amyloid ß protein (Aß) production both in vitro and in vivo. The upregulated APP and BACE1 expressions upon ethanol treatment were at least partially due to the activation of APP and BACE1 transcriptions. Furthermore, ethanol treatment increased the deposition of Aß and neuritic plaque formation in the brains and exuberated learning and memory impairments in transgenic AD model mice. Taken together, our results demonstrate that excessive ethanol intake facilitates AD pathogenesis.

Traumatic Brain Injury Alters the Metabolism and Facilitates Alzheimer's Disease in a Murine Model.

A majority of Alzheimer's disease (AD) cases are sporadic without known cause. People who suffered from traumatic brain injury (TBI) are more likely to develop neurodegeneration and cognitive impairments. However, the role of TBI in pathophysiology of AD remains elusive. The present study intended to explore the effect of TBI on metabolism and its role in AD pathogenesis. We subjected double transgenic AD model mice APP23/PS45 to TBI. We found that TBI promoted ß-secretase cleavage of amyloid ß precursor protein and amyloid ß protein deposition, and exuberated the cognitive impairments in AD mouse models. 1H nuclear magnetic resonance (1H-NMR)-based metabolomics with multivariate analysis was performed to investigate the characteristic metabolites and the related metabolic pathways in the serum and urine samples of the mice. TBI affected the metabolic patterns, methylamine metabolism, and amino acid metabolism in serum samples. Urinary metabolites showed that glycolysis and the tricarboxylic acid (TCA) cycle were perturbed. The results indicate that TBI might facilitate Alzheimer's pathogenesis by altering metabolism and inducing mitochondrial dysfunction. The study suggests that metabolite changes could also serve as biomarkers for TBI-induced neurodegeneration.