TRIB3-TRIM8 complex drives NAFLD progression by regulating HNF4α stability.

BACKGROUND & AIMS: Endoplasmic reticulum (ER) stress of hepatocytes plays a causative role in non-alcoholic fatty liver disease (NAFLD). Reduced expression of hepatic nuclear factor 4α (HNF4α) is a critical event in the pathogenesis of NAFLD and other liver diseases. Whether ER stress regulates HNF4α expression remains unknown. The aim of this study was to delineate the machinery of HNF4α protein degradation and explore a therapeutic strategy based on protecting HNF4α stability during NAFLD progression. METHODS: Correlation of HNF4α and tribbles homologue 3 (TRIB3), an ER stress sensor, was evaluated in human and mouse NAFLD tissues. RNA-sequencing, mass spectrometry analysis, co-immunoprecipitation, in vivo and in vitro ubiquitination assays were used to elucidate the mechanisms of TRIB3-mediated HNF4α degradation. Molecular docking and co-immunoprecipitation analyses were performed to identify a cell-penetrating peptide that ablates the TRIB3-HNF4α interaction. RESULTS: TRIB3 directly interacts with HNF4α and mediates ER stress-induced HNF4α degradation. TRIB3 recruits tripartite motif containing 8 (TRIM8) to form an E3 ligase complex that catalyzes K48-linked polyubiquitination of HNF4α on lysine 470. Abrogating the degradation of HNF4α attenuated the effect of TRIB3 on a diet-induced NAFLD model. Moreover, the TRIB3 gain-of-function variant p.Q84R is associated with NAFLD progression in patients, and induces lower HNF4α levels and more severe hepatic steatosis in mice. Importantly, disrupting the TRIB3-HNF4α interaction using a cell-penetrating peptide restores HNF4α levels and ameliorates NAFLD progression in mice. CONCLUSIONS: Our findings unravel the machinery of HNF4α protein degradation and indicate that targeting TRIB3-TRIM8 E3 complex-mediated HNF4α polyubiquitination may be an ideal strategy for NAFLD therapy. IMPACT AND IMPLICATIONS: Reduced expression of hepatic nuclear factor 4α (HNF4α) is a critical event in the pathogenesis of NAFLD and other liver diseases. However, the mechanism of HNF4α protein degradation remains unknown. Herein, we reveal that TRIB3-TRIM8 E3 ligase complex is responsible for HNF4α degradation during NAFLD. Inhibiting the TRIB3-HNF4α interaction effectively stabilized HNF4α protein levels and transcription factor activity in the liver and ameliorated TRIB3-mediated NAFLD progression. Our findings demonstrate that disturbing the TRIM8-TRIB3-HNF4α interaction may provide a novel approach to treat NAFLD and even other liver diseases by stabilizing the HNF4α protein.

ZO-1 and IL-1RAP Phosphorylation: Potential Role in Mediated Brain-Gut Axis Dysregulation in Irritable Bowel Syndrome-like Stressed Mice.

Background and Objectives: Irritable Bowel Syndrome (IBS) is a common gastrointestinal disorder often exacerbated by stress, influencing the brain-gut axis (BGA). BGA dysregulation, disrupted intestinal barrier function, altered visceral sensitivity and immune imbalance defects underlying IBS pathogenesis have been emphasized in recent investigations. Phosphoproteomics reveals unique phosphorylation details resulting from environmental stress. Here, we employ phosphoproteomics to explore the molecular mechanisms underlying IBS-like symptoms, mainly focusing on the role of ZO-1 and IL-1RAP phosphorylation. Materials and Methods: Morris water maze (MWM) was used to evaluate memory function for single prolonged stress (SPS). To assess visceral hypersensitivity of IBS-like symptoms, use the Abdominal withdrawal reflex (AWR). Colonic bead expulsion and defecation were used to determine fecal characteristics of the IBS-like symptoms. Then, we applied a phosphoproteomic approach to BGA research to discover the molecular mechanisms underlying the process of visceral hypersensitivity in IBS-like mice following SPS. ZO-1, p-S179-ZO1, IL-1RAP, p-S566-IL-1RAP and GFAP levels in BGA were measured by western blotting, immunofluorescence staining, and enzyme-linked immunosorbent assay to validate phosphorylation quantification. Fluorescein isothiocyanate-dextran 4000 and electron-microscopy were performed to observe the structure and function of the intestinal epithelial barrier. Results: The SPS group showed changes in learning and memory ability. SPS exposure affects visceral hypersensitivity, increased fecal water content, and significant diarrheal symptoms. Phosphoproteomic analysis displayed that p-S179-ZO1 and p-S566-IL-1RAP were significantly differentially expressed following SPS. In addition, p-S179-ZO1 was reduced in mice's DRG, colon, small intestine, spinal and hippocampus and intestinal epithelial permeability was increased. GFAP, IL-1ß and p-S566-IL-1RAP were also increased at the same levels in the BGA. And IL-1ß showed no significant difference was observed in serum. Our findings reveal substantial alterations in ZO-1 and IL-1RAP phosphorylation, correlating with increased epithelial permeability and immune imbalance. Conclusions: Overall, decreased p-S179-ZO1 and increased p-S566-IL-1RAP on the BGA result in changes to tight junction structure, compromising the structure and function of the intestinal epithelial barrier and exacerbating immune imbalance in IBS-like stressed mice.

PD-L1 upregulation promotes drug-induced pulmonary fibrosis by inhibiting vimentin degradation.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality and limited therapeutic options. The immune checkpoint PD1/PD-L1 axis is related to the pathogenesis of pulmonary fibrosis, and upregulated expression levels of PD-L1 have been demonstrated in IPF patients. However, the mechanism of PD-L1 in pulmonary fibrosis is not fully understood. Here, we demonstrated upregulated expression of PD-L1 in fibrotic lung tissues and sera of IPF patients. Bleomycin (BLM) treatment induced PD-L1 upregulation, EMT (Epithelial-Mesenchymal Transition) and fibrosis-like morphology changes in human pulmonary alveolar epithelial cells (HPAEpiCs). Silencing PD-L1 attenuated BLM-induced EMT and fibrosis-like morphology changes in HPAEpiCs. In addition, we identified that PD-L1 directly binds to vimentin and inhibits vimentin ubiquitination, thereby increasing vimentin levels in HPAEpiCs. Silencing of vimentin inhibited BLM- and PD-L1-induced fibrosis in HPAEpiCs. The correlation between PD-L1 and EMT or vimentin expression was further confirmed in clinical samples and animal models. Finally, we used BLM- and paraquat-induced pulmonary fibrosis animal models to confirm the anti-pulmonary fibrosis effects of PD-L1 silencing. Taken together, our findings suggest that upregulated PD-L1 stimulates EMT of alveolar epithelial cells by increasing vimentin levels by inhibiting vimentin ubiquitination, thereby contributing to pulmonary fibrosis.

Monitoring the remediation of groundwater polluted by MSW landfill leachates by activated carbon and zeolite with spectral induced polarization technique.

The municipal solid waste (MSW) landfill in Hangzhou, China utilized zeolite and activated carbon (AC) as permeable reactive barrier (PRB) fill materials to remediate groundwater contaminated with MSW leachates containing ammonium, chemical oxygen demand (COD), and heavy metals. The spectral induced polarization (SIP) technique was chosen for monitoring the PRB because of its sensitivity to pore fluid chemistry and mineral-fluid interface composition. During the experiment, authentic groundwater collected from the landfill site was used to permeate two columns filled with zeolite and AC, and the SIP responses were measured at the inlet and outlet over a frequency range of 0.01-1000 Hz. The results showed that zeolite had a higher adsorption capacity for COD (7.08 mg/g) and ammonium (9.15 mg/g) compared to AC (COD: 2.75 mg/g, ammonium: 1.68 mg/g). Cation exchange was found to be the mechanism of ammonium adsorption for both zeolite and AC, while FTIR results indicated that π-complexation, π-π interaction, and electrostatic attraction were the main mechanisms of COD adsorption. The Cole-Cole model was used to fit the SIP responses and determine the relaxation time (τ) and normalized chargeability (mn). The calculated characteristic diameters of zeolite and AC based on the Schwarz equation and relaxation time (τ) matched the pore sizes observed from SEM and MIP, providing valuable information on contaminant distribution. The mn of zeolite was positively linear with adsorbed ammonium (R2 = 0.9074) and COD (R2 = 0.8877), while the mn of AC was negatively linear with adsorbed ammonium (R2 = 0.8192) and COD (R2 = 0.7916), suggesting that mn could serve as a surrogate for contaminant saturation. The laboratory-based real-time non-invasive SIP results showed good performance in monitoring saturation and provide a strong foundation for future field PRB monitoring.

The antibacterial activity of a novel NK-lysin homolog and its molecular characterization and expression in the striped catfish, Pangasianodon hypophthalmus.

Aeromonas hydrophila was a common bacterial pathogen in aquaculture resulting in considerable losses to the striped catfish aquaculture industry. As an emergent antimicrobial peptide (AMP), NK-lysin (NKL) had activity against various microorganisms. However, the antibacterial activity of NKL from striped catfish (Pangasianodon hypophthalmus) both in vitro and vivo remains unclear. In this study, the cDNA sequence of P. hypophthalmus NK-lysin gene (PhNK-lysin) was cloned and characterized. The amino acid sequence of PhNK-lysin contains a signal peptide sequence of 17 amino acid (aa) residues and a mature peptide composed of 130 aa. The saposin B domain of mature peptide comprised six conserved cysteines forming three putative disulfide bonds. Phylogenetic analysis revealed that the PhNK-lysin was most closely related to that of the channel catfish (Ictalurus punctatus) NK-lysin. The transcriptional levels of the PhNK-lysin were significantly upregulated in response to A. hydrophila infection in various tissues including heart, liver, spleen, head kidney, trunk kidney and gill. The synthetic PhNK-lysin-derived peptide consisting of 38aa showed antibacterial activity against Vibrio harveii, Aeromonas hydrophila and Escherichia coli. The MIC for V. harveii, A. hydrophila and E. coli were 15.625 µM, 250 µM and 31.25 µM respectively. Besides, the synthetic PhNK-lysin decreased the bacterial load of liver and trunk kidney in vivo as well as increased the survival rate of A. hydrophila infected striped catfish. Hence, these data suggest that PhNK-lysin had antimicrobial effect and protects the host from pathogenic infection.

Knockdown of lncRNA PVT1 attenuated macrophage M1 polarization and relieved sepsis induced myocardial injury via miR-29a/HMGB1 axis.

BACKGROUND: LncRNA PVT1 was reported to be elevated in septic myocardial tissue. The underlying mechanism by which PVT1 aggravated sepsis induced myocardial injury needs further investigation. METHODS: Mice was subjected to LPS injection to mimic in vivo sepsis model. HE staining was applied to observe tissue injury. Cardiac function of mice was determined by echocardiography. Bone marrow derived macrophage (BMDM) was used to confirm the regulatory effect of PVT1 in macrophage polarization. Western blotting or qRT-PCR were performed to evaluate protein or mRNA levels, respectively. ELISA was conducted to determine cytokine levels. Interaction between PVT1 and miR-29a, miR-29a and HMGB1 were accessed by dual luciferase assay. RESULTS: Expression of PVT1 was elevated in myocardial tissue and heart infiltrating macrophages of sepsis mice. PVT1 knockdown alleviated LPS induced myocardial injury and attenuated M1 macrophage polarization. The mechanic study suggested that PVT1 targeted miR-29a, thus elevated expression of HMGB1, which was repressed by miR-29a targeting. The effect of PVT1 on M1 macrophage polarization was dependent on targeting miR-29a. CONCLUSION: PVT1 promoted M1 polarization and aggravated LPS induced myocardial injury via miR-29a/HMGB1 axis.

Detachable string magnetically controlled capsule endoscopy for complete viewing of the esophagus and stomach.

BACKGROUND: Esophageal capsule endoscopy is reported to be insufficiently accurate to replace esophagogastroduodenoscopy (EGD) because the passage of the capsule through the esophagus is passive and precludes a thorough investigation. We developed a modified capsule endoscopy technique, called detachable string magnetically controlled capsule endoscopy (DS-MCE), and performed a pilot study to assess the feasibility and safety of this novel technique. METHODS: 4 healthy volunteers and 21 patients with suspected esophageal disease first underwent DS-MCE followed by EGD within 1 week. Outcomes included technical success of DS-MCE, adverse events, discomfort, and diagnostic accuracy. RESULTS: DS-MCE was successfully carried out in all 25 participants. No adverse events were observed. Mean overall discomfort score during DS-MCE was 0.96 (range 0 - 3). DS-MCE diagnoses were in accordance with EGD in all 25 participants. The per-patient sensitivity of DS-MCE for esophageal disease detection was 100 %. The accuracy of DS-MCE for grading esophageal varices and reflux esophagitis were 66.7 % and 100 %, respectively. CONCLUSIONS: DS-MCE was a feasible, safe, and well-tolerated method for viewing the esophagus and proceeding with gastric examination after string detachment.

Magnetic Steering of Capsule Endoscopy Improves Small Bowel Capsule Endoscopy Completion Rate.

BACKGROUND: Capsule endoscopy is currently available as a noninvasive and effective diagnostic modality to identify small bowel abnormalities, with a completion rate to the cecum between 75.1 and 95.6%. A novel magnetically controlled capsule endoscopy (MCE) system could facilitate passage of the capsule through the pylorus, thereby reducing the gastric transit time (GTT). OBJECTIVE: We performed this study to determine whether magnetic steering could improve the capsule endoscopy completion rate (CECR) compared to standard protocol. METHODS: Patients referred for MCE in our center from June 2017 to November 2017 were prospectively enrolled. Magnetic steering of the capsule through the pylorus was performed after standard gastric examination. CECR, GTT, pyloric transit time (PTT), and rapid gastric transit (GTT ≤ 30 min) rate were compared with a historical control group enrolled from January 2017 to May 2017. RESULTS: CECR was significantly higher in the intervention group (n = 107) than control group (n = 120) (100% vs. 94.2%, P = 0.02), with a significantly shorter GTT (22.2 vs. 84.5 min, P < 0.001) and PTT (4.4 vs. 56.7 min, P < 0.001). Rapid gastric transit rate in the intervention group was significantly higher than the control group (58.9% vs. 15.0%, P < 0.001). There were no statistical differences in the diagnostic yields between the two groups. CONCLUSIONS: Magnetic steering of capsule endoscopy improves small bowel CECR by reducing GTT, adding further support to MCE as a practical tool for noninvasive examination of both the stomach and small bowel. Trial registration ClinicalTrials.gov, ID: NCT03482661.

Impact of magnetic steering on gastric transit time of a capsule endoscopy (with video).

BACKGROUNDS AND AIMS: Delayed gastric transit of the capsule may lead to incomplete small bowel examination, reducing the diagnostic yield. Thus, this study was designed to determine if magnetic steering could enhance capsule gastric emptying and mucosal visualization within the duodenum. METHODS: The intervention group comprised 100 patients undergoing magnetic-controlled capsule endoscopy between May to September 2017 in whom magnetic control was used to assist transpyloric passage of the capsule and duodenal inspection. A cohort of 100 patients who had undergone the procedure before May 2017 was randomly selected from the database as an historic control group in whom transpyloric movement of the capsule occurred spontaneously (without magnetic assistance). The difference in the pyloric transit time (PTT) and duodenal papilla detection rate (DPDR) between the 2 groups were compared, and related factors were also investigated. RESULTS: Transpyloric passage of the capsule under magnetic control was successfully performed in 59 patients (59%). Median PTT was greatly reduced in the intervention group from 58.38 minutes (range, 13.45-87.47) to 4.69 minutes (range, 1.56-55.00; P < .001), and DPDR was also greatly improved with magnetic steering (30.5% vs 9%, P < .001). Magnetic steering, male gender, and higher body mass index were independently associated with reduced gastric transit time and magnetic steering with an enhanced DPDR. CONCLUSIONS: Magnetic steering of the capsule can enhance gastric emptying of the capsule and may prove useful in nonobese and female patients who appeared to have longer gastric transit time and achieved a better DPDR than that under the action of peristalsis alone. (Clinical trial registration number: NCT03441945.).

Enantiospecific Semisynthesis of Puupehedione-Type Marine Natural Products.

An enantiospecific semisynthesis of puupehedione was achieved from sclareolide in only 7 steps with an overall yield of 25%. The key drimanal trimethoxystyrene skeleton was constructed by the palladium-catalyzed cross-coupling reaction of an aryl iodine and a drimanal hydrazone. An in situ CAN-oxidation/intramolecular oxa-Stork-Danheiser transposition tandem reaction was used as a powerful tool to install concurrently the C and D rings of puupehedione in a one-pot fashion. Its applicability was also showcased by the semisynthesis of puupehenone and puupehenol.

Electrochemical Synthesis of Amorphous VO2 Colloids and Their Rapid Thermal Transforming to VO2 (M) Nanoparticles with Good Thermochromic Performance.

Amorphous VO2 (a-VO2 ) colloids were synthesized by electrochemical anodic oxidation of metallic vanadium. It was found that the a-VO2 colloids have a cotton-like morphology composed of very small clusters, and that the crystallization temperature of the a-VO2 colloids can be adjusted either by the electrolyte of the anodic oxidation or/and the dispersion agent of the colloids. VO2 (M) nanoparticles (NPs) (and a NP film) with an average size of about 50 nm can be obtained by a rapid thermal annealing of the a-VO2 colloids at 310 °C under air, which is beneficial for practical applications. The VO2 (M) NP film shows an obvious metal-semiconductor transition with a resistance less than 10â€…Ω in the metallic state. An integral visible transmittance of 40.7 %, a solar transmittance modulation of 9.4 %, and a resistance modulation in the order of 5×104 were realized in the VO2 (M) NP film.

Assessing myocardial indices and inflammatory factors to determine anxiety and depression severity in patients with chronic heart failure.

BACKGROUND: Patients with chronic heart failure (CHF) have a progressive disease that is associated with poor quality of life and high mortality. Many patients experience anxiety and depression (A&D) symptoms, which can further accelerate disease progression. We hypothesized that indicators of myocardial function and inflammatory stress may reflect the severity of A&D symptoms in patients with CHF. Changes in these biomarkers could potentially predict whether A&D symptoms will deteriorate further in these individuals. AIM: To measure changes in cardiac and inflammatory markers in patients with CHF to determine A&D severity and predict outcomes. METHODS: We retrospectively analyzed 233 patients with CHF treated at the Jingzhou Hospital, Yangtze University between 2018-2022 and grouped them according to Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) scores. We compared clinical data in the no-A&D, mild-A&D, moderate-A&D, and severe-A&D groups, the SAS and SDS scores with the New York Heart Association (NYHA) functional classification, and cardiac markers and inflammatory factors between the no/mild-A&D and moderate/severe-A&D groups. Regression analysis was performed on the markers with P < 0.05 to determine their ability to predict A&D severity in patients and the area under the receiver operating characteristic curve (AUROC) was used to evaluate their accuracy. RESULTS: In the inter-group comparison, the following variables had an effect on A&D severity in patients with CHF: NYHA class, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter, N-terminal pro-brain natriuretic peptide (NT-proBNP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (P < 0.05). Other variables did not differ significantly between the A&D groups (P > 0.05). In addition, we found that higher NYHA classes were associated with higher the SAS and SDS scores (P < 0.05). Regression analysis showed that LVEF, NT-proBNP, and IL-6 were independent risk factors for A&D severity (P < 0.05). Among them, NT-proBNP had the best predictive ability as a single indicator (AUROC = 0.781). Furthermore, the combination of these three indicators exhibited a good predictive effect toward discriminating the extent of A&D severity among patients (AUROC = 0.875). CONCLUSION: Cardiac and inflammatory biomarkers, such as LVEF, NT-proBNP, and IL-6, are correlated with A&D severity in patients with CHF and have predictive value.

Quantification and forecast of GHG emissions from municipal solid wastes by multi-expression programming method.

The municipal solid waste (MSW) management is significantly contributing to global greenhouse gas (GHG) emissions. Analyzing the emission pattern of GHGs from MSW is essential for formulating appropriate carbon mitigation policies. Based on IPCC Models, GHG emissions from MSW were calculated in Chinese provinces from 2004 to 2021 by landfilling and incineration operations, separately. Landfilling and incineration generated approximately 1271 MtCO2-eq and 198 MtCO2-eq from 2004 to 2021, respectively. GHG emissions from landfilling increased from 2004 to 2020 and declined in 2021, while GHG emissions from incineration demonstrated an increasing trend with three distinct growth stages. A panel regression model was then employed to identify the key factors influencing GHG emissions. GDP and population are positively related to GHG emissions from landfills, while PCCE is negatively related to GHG emissions from landfills. GDP and PCCE have a positive impact on GHG emissions from incineration, while population showed no significant impact. Multi-expression programming was used to develop an explicit model, forecasting GHG emissions from MSW by 2030. From 2022 to 2024, GHG emissions from landfills will quickly decrease, while GHG emissions from incineration will rapidly increase. Subsequently, the GHG emission rate of incineration will slow down, and GHGs from landfilling will slowly decrease due to no MSW for landfill disposal. The methods and results provide insightful information for policy-makers and waste management sector.

Adipocyte-specific FAK deletion promotes pancreatic ß-cell apoptosis via adipose inflammatory response to exacerbate diabetes mellitus.

BACKGROUND: White adipose tissue (WAT) has a key role in maintaining energy balance throughout the body, and their dysfunction take part in the regulation of diabetes mellitus. However, the internal regulatory mechanisms underlying are still unknown. METHODS AND RESULTS: We generated adipocyte-specific FAK KO (FAK-AKO) mice and investigated their phenotype. The cascade of adipocyte, macrophage in adipocyte tissues, and pancreatic ß-cells were proposed in FAK-AKO mice and validated by cell line studies using 3T3-L1, Raw264.7 and Min6. The FAK-AKO mice exhibited glucose intolerance, reduced adipose tissue mass and increased apoptosis, lipolysis and inflammatory response in adipose tissue. We further demonstrate that adipocyte FAK deletion increases ß cell apoptosis and inflammatory infiltrates into islets, which is potentiated if mice were treated with STZ. In the STZ-induced diabetes model, FAK AKO mice exhibit less serum insulin content and pancreatic ß cell area. Moreover, serum pro-inflammatory factors increased and insulin levels decreased after glucose stimulation in FAK AKO mice. In a parallel vitro experiment, knockdown or inhibition of FAK during differentiation also increased apoptosis, lipolysis and inflammatory in 3T3-L1 adipocytes, whereas the opposite was observed upon overexpression of FAK. Moreover, coculturing LPS-treated RAW264.7 macrophages with knockdown FAK of 3T3-L1 adipocytes increased macrophage pro-inflammatory response. Furthermore, conditioned medium from above stimulated Min6 cells apoptosis (with or without STZ), whereas the opposite was observed upon overexpression of FAK. Mechanistically, FAK protein interact with TRAF6 in adipocytes and knockdown or inhibition of FAK activated TRAF6/TAK1/NF-κB signaling, which exacerbates inflammation of adipocytes themselves. CONCLUSION: Adipocyte FAK deletion promotes both adipocyte apoptosis and adipose tissue inflammation. Pro-inflammatory factors released by the FAK-null adipose tissue further trigger apoptosis in pancreatic islets induced by the administration of STZ, thereby exacerbating the diabetes mellitus. This study reveals a link between FAK-mediated adipose inflammation and diabetes mellitus, a mechanism that has not been previously recognized.

Adipocyte-secreted PRELP promotes adipocyte differentiation and adipose tissue fibrosis by binding with p75NTR to activate FAK/MAPK signaling.

Adipocyte-secreted factors intricately regulate adipose tissue function, and the underlying molecular mechanisms are only partially understood. However, the function of PRELP, which is a key component of the extracellular matrix (ECM) in adipocytes, remains largely unknown. In this study, we demonstrate that PRELP was upregulated in both obese humans and mice, which exhibited a positive correlation with metabolic disorders. PRELP knockout could resist HFD-induced obesity and inhibit adipocyte differentiation. PRELP knockout improved glucose tolerance, insulin sensitivity and alleviated adipose tissue fibrosis. Mechanistically, PRELP was secreted into the ECM and bound to the extracellular domain of its receptor p75NTR in adipocytes, which further activated the FAK/MAPK (JNK, p38 MAPK, ERK1/2) signaling pathway, promoting adipocyte differentiation and exacerbating adipocyte fibrosis. Adipocyte PRELP plays a pivotal role in regulating obesity and adipose tissue fibrosis through an autocrine manner, and PRELP may be a therapeutic target for obesity and its related metabolic disorders.

ZBED3 exacerbates hyperglycemia by promoting hepatic gluconeogenesis through CREB signaling.

BACKGROUND: Elevated hepatic glucose production (HGP) is a prominent manifestation of impaired hepatic glucose metabolism in individuals with diabetes. Increased hepatic gluconeogenesis plays a pivotal role in the dysregulation of hepatic glucose metabolism and contributes significantly to fasting hyperglycemia in diabetes. Previous studies have identified zinc-finger BED domain-containing 3 (ZBED3) as a risk gene for type 2 diabetes (T2DM), and its single nucleotide polymorphism (SNPs) is closely associated with the fasting blood glucose level, suggesting a potential correlation between ZBED3 and the onset of diabetes. This study primarily explores the effect of ZBED3 on hepatic gluconeogenesis and analyzes the relevant signaling pathways that regulate hepatic gluconeogenesis. METHODS: The expression level of ZBED3 was assessed in the liver of insulin-resistant (IR)-related disease. RNA-seq and bioinformatics analyses were employed to examine the ZBED3-related pathway that modulated HGP. To investigate the role of ZBED3 in hepatic gluconeogenesis, the expression of ZBED3 was manipulated by upregulation or silencing using adeno-associated virus (AAV) in mouse primary hepatocytes (MPHs) and HHL-5 cells. In vivo, hepatocyte-specific ZBED3 knockout mice were generated. Moreover, AAV8 was employed to achieve hepatocyte-specific overexpression and knockdown of ZBED3 in C57BL/6 and db/db mice. Immunoprecipitation and mass spectrometry (IP-MS) analyses were employed to identify proteins that interacted with ZBED3. Co-immunoprecipitation (co-IP), glutathione S-transferase (GST) - pulldown, and dual-luciferase reporter assays were conducted to further elucidate the underlying mechanism of ZBED3 in regulating hepatic gluconeogenesis. RESULTS: The expression of ZBED3 in the liver of IR-related disease models was found to be increased. Under the stimulation of glucagon, ZBED3 promoted the expression of hepatic gluconeogenesis-related genes PGC1A, PCK1, G6PC, thereby increasing HGP. Consistently, the rate of hepatic gluconeogenesis was found to be elevated in mice with hepatocyte-specific overexpression of ZBED3 and decreased in those with ZBED3 knockout. Additionally, the knockdown of ZBED3 in the liver of db/db mice resulted in a reduction in hepatic gluconeogenesis. Moreover, the study revealed that ZBED3 facilitated the nuclear translocation of protein arginine methyltransferases 5 (PRMT5) to influence the regulation of PRMT5-mediated symmetrical dimethylation of arginine (s-DMA) of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), which in turn affects the phosphorylation of CREB and ultimately promotes HGP. CONCLUSIONS: This study indicates that ZBED3 promotes hepatic gluconeogenesis and serves as a critical regulator of the progression of diabetes.

Skeletal muscle alterations indicate poor prognosis in cirrhotic patients: a multicenter cohort study in China.

INTRODUCTION: We aimed to determine the diagnostic criteria of myosteatosis in a Chinese population and investigate the effect of skeletal muscle abnormalities on the outcomes of cirrhotic patients. METHODS: Totally 911 volunteers were recruited to determine the diagnostic criteria and impact factors of myosteatosis, and 480 cirrhotic patients were enrolled to verify the value of muscle alterations for prognosis prediction and establish new noninvasive prognostic strategies. RESULTS: Multivariate analysis showed age, sex, weight, waist circumference, and biceps circumference had a remarkable influence on the L3 skeletal muscle density (L3-SMD). Based on the cut-off of a mean - 1.28 × SD among adults aged < 60 years, the diagnostic criteria for myosteatosis was L3-SMD < 38.93 Hu in males and L3-SMD < 32.82 Hu in females. Myosteatosis rather than sarcopenia has a close correlation with portal hypertension. The concurrence of sarcopenia and myosteatosis not only is associated with poor liver function but also evidently reduced the overall and liver transplantation-free survival of cirrhotic patients (p < 0.001). According to the stepwise Cox regression hazard model analysis, we established nomograms including TBil, albumin, history of HE, ascites grade, sarcopenia, and myosteatosis for easily determining survival probabilities in cirrhotic patients. The AUC is 0.874 (95% CI 0.800-0.949) for 6-month survival, 0.831 (95% CI 0.764-0.898) for 1-year survival, and 0.813 (95% CI 0.756-0.871) for 2-year survival prediction, respectively. CONCLUSIONS: This study provides evidence of the significant correlation between skeletal muscle alterations and poor outcomes of cirrhosis, and establishes valid and convenient nomograms incorporating musculoskeletal disorders for the prognostic prediction of liver cirrhosis. Further large-scale prospective studies are necessary to verify the value of the nomograms.

IRX3 promotes adipose tissue browning and inhibits fibrosis in obesity-resistant mice.

Obesity is one of the threats to human health and survival. High fat diet (HFD)-induced obesity leads to adipose tissue fibrosis and a series of metabolic diseases. There are some people still thin under HFD, a phenomenon known as the "obesity resistance (OR) phenotype". It was found that Iroquois homeobox 3 (IRX3) is considered as a regulator in obesity, but the regulatory mechanism between OR and IRX3 is still unclear. In this study, we investigated OR on a HFD and the role of the IRX3 gene. Using mice, we observed that OR mice had lower body weights, reduced liver lipid synthesis, and increased white adipose tissue (WAT) lipolysis compared to obesity-prone (OP) mice. Additionally, OR mice exhibited spontaneous WAT browning and less fibrosis, correlating with higher Irx3 expression. Utilizing 3T3-L1 differentiated adipocytes, our study demonstrated that overexpression of Irx3 promoted thermogenesis-related gene expression and reduced adipocyte fibrosis. Therefore, Irx3 promotes WAT browning and inhibits fibrosis in OR mice. These results provide insight into the differences between obesity and OR, new perspectives on obesity treatment, and guidance for lessening adipose tissue fibrosis.

Effects of written plus oral information vs. oral information alone on precolonoscopy anxiety.

AIMS AND OBJECTIVES: To determine the effect of written plus oral information vs. oral information alone on precolonoscopy anxiety. BACKGROUND: Information provision has been considered to reduce precolonoscopy anxiety. However, the best means to provide information before colonoscopy has not yet been determined as there is inconsistency in the outcomes of the clinical trials. DESIGN: A two-group, pretest, post-test, prospective, quasi-experimental design with non-random assignment. METHODS: Participants were assigned to group 1 or 2 in the study. In the enrolment all the participants completed the questionnaires to collect personal characteristics data and assessed subjects' anxiety level by the Chinese version of the State Scale of State-Trait Anxiety Inventory as baseline data. After that, subjects in group 1 received written plus oral information before colonoscopy, while those in group 2 received oral information before colonoscopy. On the day for colonoscopy all subjects completed the Chinese version of the State Scale of State-Trait Anxiety Inventory again. RESULTS: There was no difference in state anxiety and personal characteristic between the two groups at enrolment. After the intervention, although the state anxiety scores were dropped, there were no statistical significant differences between two groups or within groups 1 and 2. CONCLUSIONS: Information provision before colonoscopy did not reduce the anxiety level in patients directly before colonoscopy. RELEVANCE TO CLINICAL PRACTICE: There was a trend that information had a positive effect on patients' state anxiety. Future information provision studies may need to add more interactive methods appropriately and take patients' gender, educational level and coping style into consideration.

Clinical study on cognitive impairment in Duchenne muscular dystrophy.

Our study aimed to explore the intellectual function of patients with Duchenne muscular dystrophy (DMD) in China and examine the correlation of full-scale intelligence quotient (FSIQ) with age, mutation locations, mutation class, and dystrophin isoforms. We assessed 64 boys with DMD using The Wechsler Intelligence Scales for Children-Fourth Edition and compared intellectual function at enrollment and follow-up in the 15 patients who completed the follow-up. Our findings confirm that boys with DMD may exhibit cognitive impairment, with the Working Memory Index being the most impaired. There was no significant correlation between FSIQ and age; however, a positive correlation was noted between age and the Verbal Comprehension Index. FSIQ was not associated with mutation class, the number of affected mutated exons, or mutation locations. However, there was a significant difference in FSIQ between the groups with intact and deficient Dp140. Fifteen participants adhered to glucocorticoid therapy throughout the two-year follow-up period, and eleven of them showed an improvement in FSIQ compared to their initial scores, with improvement ranging from 2 to 20. In conclusion, patients with the cumulative loss of isoforms in the brain are at a higher risk of cognitive deficits and may require early cognitive interventions.