Long-term antibody response after the third dose of inactivated SARS-CoV-2 vaccine in MASLD patients.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) patients are at an elevated risk of developing severe coronavirus disease 2019 (COVID-19). The objective of this study was to assess antibody responses and safety profiles six months after the third dose of the inactivated acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in MASLD patients. METHODS: This study included MASLD patients and healthy volunteers without a history of SARS-CoV-2 infection. Blood samples were collected six months after receiving the third dose of the inactivated vaccine to measure the levels of neutralizing antibodies (NAbs) and anti-spike IgG antibodies against SARS-CoV-2. RESULTS: A total of 335 participants (214 MASLD patients and 121 healthy volunteers) were enrolled. The seroprevalence of NAb was 61.7% (132 of 214) in MASLD patients and 74.4% (90 of 121) in healthy volunteers, which was a significant difference (p = 0.018). Statistically significant differences in IgG seroprevalence were also observed between MASLD patients and healthy volunteers (p = 0.004). Multivariate analysis demonstrated that the severity of MASLD (OR, 2.97; 95% CI, 1.32-6.68; p = 0.009) and age (OR, 1.03; 95% CI, 1.01-1.06; p = 0.004) were independent risk factors for NAb negativity in MASLD patients. Moderate/severe MASLD patients had a lower NAb seroprevalence than mild MASLD patients (45.0% vs. 65.5%, p = 0.016). CONCLUSION: Lower antibody responses were observed in MASLD patients six months after their third dose of the inactivated vaccine than in healthy volunteers, providing further assistance in monitoring patients who are more vulnerable to hypo-responsiveness to SARS-CoV-2 vaccines.

CT-based radiomics nomogram to predict proliferative hepatocellular carcinoma and explore the tumor microenvironment.

BACKGROUND: Proliferative hepatocellular carcinomas (HCCs) is a class of aggressive tumors with poor prognosis. We aimed to construct a computed tomography (CT)-based radiomics nomogram to predict proliferative HCC, stratify clinical outcomes and explore the tumor microenvironment. METHODS: Patients with pathologically diagnosed HCC following a hepatectomy were retrospectively collected from two medical centers. A CT-based radiomics nomogram incorporating radiomics model and clinicoradiological features to predict proliferative HCC was constructed using the training cohort (n = 184), and validated using an internal test cohort (n = 80) and an external test cohort (n = 89). The predictive performance of the nomogram for clinical outcomes was evaluated for HCC patients who underwent surgery (n = 201) or received transarterial chemoembolization (TACE, n = 104). RNA sequencing data and histological tissue slides from The Cancer Imaging Archive database were used to perform transcriptomics and pathomics analysis. RESULTS: The areas under the receiver operating characteristic curve of the radiomics nomogram to predict proliferative HCC were 0.84, 0.87, and 0.85 in the training, internal test, and external test cohorts, respectively. The radiomics nomogram could stratify early recurrence-free survivals in the surgery outcome cohort (hazard ratio [HR] = 2.25; P < 0.001) and progression-free survivals in the TACE outcome cohort (HR = 2.21; P = 0.03). Transcriptomics and pathomics analysis indicated that the radiomics nomogram was associated with carbon metabolism, immune cells infiltration, TP53 mutation, and heterogeneity of tumor cells. CONCLUSION: The CT-based radiomics nomogram could predict proliferative HCC, stratify clinical outcomes, and measure a pro-tumor microenvironment.

The role of CBL family ubiquitin ligases in cancer progression and therapeutic strategies.

The CBL (Casitas B-lineage lymphoma) family, as a class of ubiquitin ligases, can regulate signal transduction and activate receptor tyrosine kinases through various tyrosine kinase-dependent pathways. There are three members of the family: c-CBL, CBL-b, and CBL-c. Numerous studies have demonstrated the important role of CBL in various cellular pathways, particularly those involved in the occurrence and progression of cancer, hematopoietic development, and regulation of T cell receptors. Therefore, the purpose of this review is to comprehensively summarize the function and regulatory role of CBL family proteins in different human tumors, as well as the progress of drug research targeting CBL family, so as to provide a broader clinical measurement strategy for the treatment of tumors.

Hsp90α promotes chemoresistance in pancreatic cancer by regulating Keap1-Nrf2 axis and inhibiting ferroptosis.

Chemoresistance is the primary reason for poor prognosis in patients with pancreatic cancer (PC). Recent studies have indicated that ferroptosis may improve chemoresistance, but the underlying mechanisms remain unclear. In this study, significant upregulation of heat shock protein 90α (Hsp90α) expression is detected in the peripheral blood and tissue samples of patients with chemoresistant PC. Further studies reveal that Hsp90α promotes the proliferation, migration, and invasion of a chemoresistant pancreatic cell line (Panc-1-gem) by suppressing ferroptosis. Hsp90α competitively binds to Kelch-like ECH-associated protein 1 (Keap1), liberating nuclear factor erythroid 2-related factor 2 (Nrf2) from Keap1 sequestration. Nrf2 subsequently translocates into the nucleus and activates the glutathione peroxidase 4 (GPX4) pathway, thereby suppressing ferroptosis. This process further worsens the chemoresistance of PC cells. This study provides valuable insight into potential molecular targets to overcome chemoresistance in PC. It sheds light on the intricate mechanisms linking Hsp90α and ferroptosis to chemoresistance in PC and provides a theoretical foundation for the development of novel therapeutic strategies.

HSF5 Deficiency Causes Male Infertility Involving Spermatogenic Arrest at Meiotic Prophase I in Humans and Mice.

Meiosis is a specialized cell division process that generates gametes for sexual reproduction. However, the factors and underlying mechanisms involving meiotic progression remain largely unknown, especially in humans. Here, it is first showed that HSF5 is associated with human spermatogenesis. Patients with a pathogenic variant of HSF5 are completely infertile. Testicular histologic findings in the patients reveal rare postmeiotic germ cells resulting from meiotic prophase I arrest. Hsf5 knockout (KO) mice confirms that the loss of HSF5 causes defects in meiotic recombination, crossover formation, sex chromosome synapsis, and sex chromosome inactivation (MSCI), which may contribute to spermatocyte arrest at the late pachytene stage. Importantly, spermatogenic arrest can be rescued by compensatory HSF5 adeno-associated virus injection into KO mouse testes. Mechanistically, integrated analysis of RNA sequencing and chromatin immunoprecipitation sequencing data revealed that HSF5 predominantly binds to promoters of key genes involved in crossover formation (e.g., HFM1, MSH5 and MLH3), synapsis (e.g., SYCP1, SYCP2 and SYCE3), recombination (TEX15), and MSCI (MDC1) and further regulates their transcription during meiotic progression. Taken together, the study demonstrates that HSF5 modulates the transcriptome to ensure meiotic progression in humans and mice. These findings will aid in genetic diagnosis of and potential treatments for male infertility.

Association between severity of nonalcoholic fatty liver disease and major adverse cardiovascular events in patients assessed by coronary computed tomography angiography.

BACKGROUND: The effect of nonalcoholic fatty liver disease (NAFLD) on major adverse cardiovascular events (MACEs) can be influenced by the degree of coronary artery stenosis. However, the association between the severity of NAFLD and MACEs in patients who underwent coronary computed tomography angiography (CCTA) is unclear. METHODS: A total of 341 NAFLD patients who underwent CCTA were enrolled. The severity of NAFLD was divided into mild NAFLD and moderate-severe NAFLD by abdominal CT results. The degree of coronary artery stenosis was evaluated by using Coronary Artery Disease Reporting and Data System (CAD-RADS) category. Cox regression analysis and Kaplan-Meier analysis were used to assess poor prognosis. RESULTS: During the follow-up period, 45 of 341 NAFLD patients (13.20%) who underwent CCTA occurred MACEs. The severity of NAFLD (hazard ratio [HR] = 2.95[1.54-5.66]; p = 0.001) and CAD-RADS categories 3-5 (HR = 16.31[6.34-41.92]; p < 0.001) were independent risk factors for MACEs. The Kaplan-Meier analysis showed that moderate to severe NAFLD patients had a worsen prognosis than mild NAFLD patients (log-rank p < 0.001). Moreover, the combined receiver operating characteristic curve of the severity of NAFLD and CAD-RADS category showed a good predicting performance for the risk of MACEs, with an area under the curve of 0.849 (95% CI = 0.786-0.911). CONCLUSION: The severity of NAFLD was independent risk factor for MACEs in patients with obstructive CAD, having CAD-RADS 3-5 categories on CCTA.

Highly Reactive Peroxide Species Promoted Soot Oxidation over an Ordered Macroporous Ce0.8Zr0.2O2 Integrated Catalyzed Diesel Particulate Filter.

Particulate matter, represented by soot particles, poses a significant global environmental threat, necessitating efficient control technology. Here, we innovatively designed and elaborately fabricated ordered hierarchical macroporous catalysts of Ce0.8Zr0.2O2 (OM CZO) integrated on a catalyzed diesel particulate filter (CDPF) using the self-assembly method. An oxygen-vacancy-enriched ordered macroporous Ce0.8Zr0.2O2 catalyst (VO-OM CZO) integrated CDPF was synthesized by subsequent NaBH4 reduction. The VO-OM CZO integrated CDPF exhibited a markedly enhanced soot oxidation activity compared to OM CZO and powder CZO coated CDPFs (T50: 430 vs 490 and 545 °C, respectively). The well-defined OM structure of the VO-OM CZO catalysts effectively improves the contact efficiency between soot and the catalysts. Meanwhile, oxygen vacancies trigger the formation of a large amount of highly reactive peroxide species (O22-) from molecular oxygen (O2) through electron abstraction from the three adjacent Ce3+ (3Ce3+ + Vö + O2 → 3Ce4+ + O22-), contributing to the efficient soot oxidation. This work demonstrates the fabrication of the ordered macroporous CZO integrated CDPF and reveals the importance of structure and surface engineering in soot oxidation, which sheds light on the design of highly efficient PM capture and removal devices.

Multi-channel prismatic localized surface plasmon resonance biosensor for real-time competitive assay multiple COVID-19 characteristic miRNAs.

A multi-channel prismatic localized surface plasmon resonance (LSPR) biosensor was developed for quantitative and real-time detection of multiple COVID-19 characteristic miRNAs. The well-dispersed and dense gold nanoparticles (AuNPs) arrays for LSPR biosensing were fabricated through a nano-thickness diblock copolymer template (BCPT). Both theoretical and experimental analyses were conducted to investigate the effects of particle size, interparticle spacing, and surface coverage on LSPR sensing spectrum and intensity sensitivity of varied AuNPs sizes. A competitive assay strategy was proposed and used for non-amplification miRNA detection with a low limit detection of 3.41 nM, while a four-channel prismatic LSPR system enables parallel detection of multiple miRNAs. Furthermore, this sensing strategy can effectively and specifically identify target miRNA, distinguish mismatched miRNA and interfering miRNA, and exhibit low non-specific adsorption. This BCPT-based LSPR biosensor demonstrates the practicality and potential of a multi-channel, adaptable, and integrated prismatic sensor in medical testing and diagnostic applications.

Differences of serum glucose and lipid metabolism and immune parameters and blood metabolomics regarding the transition cows in the antepartum and postpartum period.

This study aims to investigate differences in metabolism regarding the transition cows. Eight cows were selected for the test. Serum was collected on antepartum days 14th (ap14) and 7th (ap7) and postpartum days 1st (pp1), 7th (pp7), and 14th (pp14) to detect biochemical parameters. The experiment screened out differential metabolites in the antepartum (ap) and postpartum (pp) periods and combined with metabolic pathway analysis to study the relationship and role between metabolites and metabolic abnormalities. Results: (1) The glucose (Glu) levels in ap7 were significantly higher than the other groups (p < 0.01). The insulin (Ins) levels of ap7 were significantly higher than pp7 (p = 0.028) and pp14 (p < 0.01), and pp1 was also significantly higher than pp14 (p = 0.016). The insulin resistance (HOMA-IR) levels of ap7 were significantly higher than ap14, pp7, and pp14 (p < 0.01). The cholestenone (CHO) levels of ap14 and pp14 were significantly higher than pp1 (p < 0.01). The CHO levels of pp14 were significantly higher than pp7 (p < 0.01). The high density lipoprotein cholesterol (DHDL) levels of pp1 were significantly lower than ap14 (p = 0.04), pp7 (p < 0.01), and pp14 (p < 0.01), and pp14 was also significantly higher than ap14 and ap7 (p < 0.01). (2) The interferon-gamma (IFN-γ) and tumor necrosis factor α (TNF-α) levels of ap7 were significantly higher than pp1 and pp7 (p < 0.01); the immunoglobulin A (IgA) levels of pp1 were significantly higher than ap7 and pp7 (p < 0.01); the interleukin-4 (IL-4) levels of pp7 were significantly higher than ap7 and pp1 (p < 0.01), the interleukin-6 (IL-6) levels of ap7 and pp1 were significantly higher than pp7 (p < 0.01). (3) Metabolomics identified differential metabolites mainly involved in metabolic pathways, such as tryptophan metabolism, alpha-linolenic acid metabolism, tyrosine metabolism, and lysine degradation. The main relevant metabolism was concentrated in lipid and lipid-like molecules, organic heterocyclic compounds, organic acids, and their derivatives. The results displayed the metabolic changes in the transition period, which laid a foundation for further exploring the mechanism of metabolic abnormalities in dairy cows in the transition period.

The value of periportal hyperintensity sign from gadobenate dimeglumine-enhanced hepatobiliary phase MRI for predicting clinical outcomes in patients with decompensated cirrhosis.

OBJECTIVES: To determine the value of periportal hyperintensity sign from gadobenate dimeglumine (Gd-BOPTA)-enhanced hepatobiliary phase (HBP) magnetic resonance imaging (MRI) for predicting clinical outcomes in patients with decompensated cirrhosis. METHODS: A total of 199 cirrhotic patients who underwent Gd-BOPTA-enhanced MRI were divided into control group (n = 56) and decompensated cirrhosis group (n = 143). The presence of periportal hyperintensity sign on HBP MRI was recorded. The Cox regression model was used to investigate the association between periportal hyperintensity sign and clinical outcomes. RESULTS: There was a significant difference in the frequency of periportal hyperintensity sign on HBP between compensated and decompensated cirrhotic patients (p < 0.05). After a median follow-up of 29.0 months (range, 1.0-90.0 months), nine out of 143 patients (6.2%) with decompensated cirrhosis died. Periportal hyperintensity sign on HBP MRI was a significant risk factor for death (hazard ratio (HR) = 23.677; 95% confidence interval (CI) = 4.759-117.788; p = 0.0001), with an area under the curve (AUC) of 0.844 (95% CI = 0.774-0.899). Thirty patients (20.9%) developed further decompensation. Periportal hyperintensity sign on HBP MRI was also a significant risk factor for further decompensation (HR = 2.594; 95% CI = 1.140-5.903; p = 0.023). CONCLUSIONS: Periportal hyperintensity sign from Gd-BOPTA-enhanced HBP MRI is valuable for predicting clinical outcomes in patients with decompensated cirrhosis. CRITICAL RELEVANCE STATEMENT: Periportal hyperintensity sign from gadobenate dimeglumine-enhanced hepatobiliary phase magnetic resonance imaging is a new noninvasive method to predict clinical outcomes in patients with decompensated cirrhosis. KEY POINTS: • There was a significant difference in the frequency of periportal hyperintensity sign on HBP between compensated and decompensated cirrhotic patients. • Periportal hyperintensity sign on the hepatobiliary phase was a significant risk factor for death in patients with decompensated cirrhosis. • Periportal hyperintensity sign on the hepatobiliary phase was a significant risk factor for further decompensation in patients with decompensated cirrhosis.

Global trends and partial forecast of adverse effects of medical treatment from 1990 to 2019: an epidemiological analysis based on the global burden of disease study 2019.

BACKGROUND: The possibility of adverse effects of medical treatment (AEMT) is increasing worldwide, but little is known about AEMT in China. This study analyzed the health burden of AEMT in China in recent years through the Global Burden of Disease Study (GBD) 2019 and compared it with the worldwide average level and those in different sociodemographic index (SDI) regions. METHODS: We calculated the age-standardized rate (ASR) of deaths, disability-adjusted life years (DALYs), years of life lost (YLLs), years lived with disability (YLDs), incidence and prevalence attributed to AEMT in China, worldwide and countries with different sociodemographic indices during 1990-2019 using the latest data and methods from the GBD 2019. RESULTS: From 1990 to 2019, the global age-standardized death rate (ASDR), DALYs, and YLLs for AEMT showed a significant downward trend and were negatively associated with the SDI. By 2040, the ASDR is expected to reach approximately 1.58 (95% UI: 1.33-1.80). From 1990 to 2019, there was no significant change in the global incidence of AEMT. The occurrence of AEMT was related to sex, and the incidence of AEMT was greater among females. In addition, the incidence of AEMT-related injuries and burdens, such as ASR of DALYs, ASR of YLLs and ASR of YLDs, was greater among women than among men. Very old and very young people were more likely to be exposed to AEMT. CONCLUSIONS: From 1990 to 2019, progress was made worldwide in reducing the harm caused by AEMT. However, the incidence and prevalence of AEMT did not change significantly overall during this period. Therefore, the health sector should pay more attention to AEMT and take effective measures to reduce AEMT.

Quantitative information from gadobenate dimeglumine-enhanced MRI can predict proliferative subtype of solitary hepatocellular carcinoma: a multicenter retrospective study.

OBJECTIVES: To investigate the value of quantitative parameters derived from gadobenate dimeglumine-enhanced magnetic resonance imaging (MRI) for predicting molecular subtype of hepatocellular carcinoma (HCC) and overall survival. METHODS: This multicenter retrospective study included 218 solitary HCC patients who underwent gadobenate dimeglumine-enhanced MRI. All HCC lesions were resected and pathologically confirmed. The lesion-to-liver contrast enhancement ratio (LLCER) and lesion-to-liver contrast (LLC) were measured in the hepatobiliary phase. Potential risk factors for proliferative HCC were assessed by logistic regression. The ability of LLCER and LLC to predict proliferative HCC was assessed by the receiver operating characteristic (ROC) curve. Prognostic factors were evaluated using the Cox proportional hazards regression model for survival outcomes. RESULTS: LLCER was an independent predictor of proliferative HCC (odds ratio, 0.015; 95% confidence interval [CI], 0.008-0.022; p < 0.001). The area under the ROC curve was 0.812 (95% CI, 0.748-0.877), higher than that of LLC, alpha-fetoprotein > 100 ng/ml, satellite nodules, and rim arterial phase hyperenhancement (all p ≤ 0.001). HCC patients with LLCER < -4.59% had a significantly higher incidence of proliferative HCC than those with the LLCER ≥ -4.59%. During the follow-up period, LLCER was an independent predictor of overall survival (hazard ratio, 0.070; 95% CI, 0.015-0.324; p = 0.001) in HCC patients. CONCLUSIONS: Gadobenate dimeglumine-enhanced quantitative parameter in the hepatobiliary phase can predict the proliferative subtype of solitary HCC with a moderately high accuracy. CLINICAL RELEVANCE STATEMENT: Quantitative information from gadobenate dimeglumine-enhanced MRI can provide crucial information on hepatocellular carcinoma subtypes. It might be valuable to design novel therapeutic strategies, such as targeted therapies or immunotherapy. KEY POINTS: • The lesion-to-liver contrast enhancement ratio (LLCER) is an independent predictor of proliferative hepatocellular carcinoma (HCC). • The ability of LLCER to predict proliferative HCC outperformed lesion-to-liver contrast, alpha-fetoprotein > 100 ng/ml, satellite nodules, and rim arterial phase hyperenhancement. • HCC patients with LLCER < -4.59% had a significantly higher incidence of proliferative HCC than those with the LLCER ≥ -4.59%.

Microwave ablation versus laparoscopic resection for hepatocellular carcinoma in patients with clinically significant portal hypertension: a propensity score-matched study of postoperative liver decompensation.

OBJECTIVES: The study of postoperative liver decompensation after microwave ablation (MWA) for hepatocellular carcinoma (HCC) in patients with clinically significant portal hypertension (CSPH) is still lacking. The purpose of the present study was to compare the postoperative liver decompensation after MWA and laparoscopic resection (LR) for HCC in patients with CSPH. METHODS: The present retrospective study enrolled 222 HCC patients with CSPH who underwent MWA (n = 67) or LR (n = 155). Postoperative liver decompensation, complications, postoperative hospital stays, and overall survival were analyzed. Factors associated with postoperative liver decompensation were identified. RESULTS: After propensity score matching, the postoperative liver decompensation rate was significantly lower in the MWA group than that in the LR group (15.5% versus 32.8%, p = 0.030). The multivariable regression analysis identified that type of treatment (MWA vs. LR, odds ratio [OR] 0.44; 95% confidence interval [CI], 0.21-0.91; p = 0.026) and Child-Pugh B (OR, 2.86; 95% CI, 1.24-6.61; p = 0.014) were independent predictors for postoperative liver decompensation. The rate of complications for patients in the MWA group was significantly lower than that in the LR group (p < 0.001). And MWA showed shorter postoperative hospital stays than LR (3 days vs. 6 days, p < 0.001). Overall survival rate between the two groups was not significantly different (p = 0.163). CONCLUSION: Compared with laparoscopic resection, microwave ablation has a lower rate of postoperative liver decompensation and might be a better option for HCC patients with CSPH. CLINICAL RELEVANCE STATEMENT: Microwave ablation exhibited a lower incidence of postoperative liver decompensation in comparison to laparoscopic resection, thereby conferring greater advantages to hepatocellular carcinoma patients with clinically significant portal hypertension. KEY POINTS: •Postoperative liver decompensation rate after microwave ablation was lower than that of laparoscopic resection for hepatocellular carcinoma in patients with clinically significant portal hypertension. •Microwave ablation showed shorter postoperative hospital stays than laparoscopic resection. •Microwave ablation had fewer complications than laparoscopic resection.

Advances in targeted therapy for pancreatic cancer.

Pancreatic cancer (PC) represents a group of malignant tumours originating from pancreatic duct epithelial cells and acinar cells, and the 5-year survival rate of PC patients is only approximately 12%. Molecular targeted drugs are specific drugs designed to target and block oncogenes, and they have become promising strategies for the treatment of PC. Compared to traditional chemotherapy drugs, molecular targeted drugs have greater targeting precision, and they have significant therapeutic effects and minimal side effects. This article reviews several molecular targeted drugs that are currently in the experimental stage for the treatment of PC; these include antibody-drug conjugates (ADCs), aptamer-drug conjugates (ApDCs) and peptide-drug conjugates (PDCs). ADCs can specifically recognize cell surface antigens and reduce systemic exposure and toxicity of chemotherapy drugs. By delivering nucleic acid drugs to target cells, the targeting RNA of ApDCs can inhibit the expression or translation of mutated genes, thereby inhibiting tumour development. Moreover, PDCs can effectively penetrate tumour cells, and the peptide groups in PDCs preferentially target tumour cells with minimal side effects. In the targeted therapy of PC, molecular targeted drugs have very broad prospects, which provides new hope for the clinical treatment of PC patients and is worth further research.

Non-Interacting Ni and Fe Dual-Atom Pair Sites in N-Doped Carbon Catalysts for Efficient Concentrating Solar-Driven Photothermal CO2 Reduction.

Solar-to-chemical energy conversion under weak solar irradiation is generally difficult to meet the heat demand of CO2 reduction. Herein, a new concentrated solar-driven photothermal system coupling a dual-metal single-atom catalyst (DSAC) with adjacent Ni-N4 and Fe-N4 pair sites is designed for boosting gas-solid CO2 reduction with H2 O under simulated solar irradiation, even under ambient sunlight. As expected, the (Ni, Fe)-N-C DSAC exhibits a superior photothermal catalytic performance for CO2 reduction to CO (86.16 µmol g-1 h-1 ), CH4 (135.35 µmol g-1 h-1 ) and CH3 OH (59.81 µmol g-1 h-1 ), which are equivalent to 1.70-fold, 1.27-fold and 1.23-fold higher than those of the Fe-N-C catalyst, respectively. Based on theoretical simulations, the Fermi level and d-band center of Fe atom is efficiently regulated in non-interacting Ni and Fe dual-atom pair sites with electronic interaction through electron orbital hybridization on (Ni, Fe)-N-C DSAC. Crucially, the distance between adjacent Ni and Fe atoms of the Ni-N-N-Fe configuration means that the additional Ni atom as a new active site contributes to the main *COOH and *HCO3 dissociation to optimize the corresponding energy barriers in the reaction process, leading to specific dual reaction pathways (COOH and HCO3 pathways) for solar-driven photothermal CO2 reduction to initial CO production.

Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice.

Under normal conditions, insulin promotes hepatic de novo lipogenesis (DNL). However, during insulin resistance (IR), when insulin signalling is blunted and accompanied by hyperinsulinaemia, the promotion of hepatic DNL continues unabated and hepatic steatosis increases. Here, we show that WD40 repeat-containing protein 6 (WDR6) promotes hepatic DNL during IR. Mechanistically, WDR6 interacts with the beta-type catalytic subunit of serine/threonine-protein phosphatase 1 (PPP1CB) to facilitate PPP1CB dephosphorylation at Thr316, which subsequently enhances fatty acid synthases transcription through DNA-dependent protein kinase and upstream stimulatory factor 1. Using molecular dynamics simulation analysis, we find a small natural compound, XLIX, that inhibits the interaction of WDR6 with PPP1CB, thus reducing DNL in IR states. Together, these results reveal WDR6 as a promising target for the treatment of hepatic steatosis.

Four indices on Gd-EOB-DTPA-enhanced MRI can estimate liver functional reserve compared to ICG-R15: A systematic review and meta-analysis.

AIMS: To evaluate the value of four indices of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced (Gd-EOB-DTPA) magnetic resonance as a potential imaging marker of liver functional reserve. METHODS: PubMed/Medline, Embase, Cochrane Library, and Web of Science were searched for studies concerning the relationship between Gd-EOB-DTPA-enhanced MRI and liver functional reserve estimated by ICG-R15, Pooled correlation coefficient (r) and 95% confidence intervals (CIs) were calculated, Meanwhile, Sensitivity and subgroup analyses were performed along with Egger's test for the estimation of publication bias and potential heterogeneity. RESULTS: 14 publications with 1285 patients were included. The pooled r between relative liver enhancement (RLE), reduction rate of T1 relaxation time of the liver (rrT1), liver-to-spleen ratio (LSR), liver-to-muscle ratio (LMR), and ICG-R15 were -0.49 (95% CI, -0.56 to -0.41, p < 0.05), -0.47 (95% CI, -0.57 to -0.36, p < 0.05), -0.45 (95% CI, -0.55 to -0.34, p < 0.05), -0.50 (95% CI, -0.61 to -0.38, p < 0.05). moderate heterogeneity was observed between studies on rrT1, LSR, LMR, and ICG-R15 (p ≤ 0.05), but no significant heterogeneity was observed between RLE and ICG-R15. Further analysis shows that there was a notable heterogeneity between subgroup analysis of LSR and ICG-R15 stratified by years of publication, as well as rrT1 and LMR stratified by total patients and study design, the distribution funnel plots and the results of Egger's test showed no evidence of publication bias. CONCLUSIONS: RLE, LSR, LMR, and rrT1 all correlated significantly with ICG-R15-estimated hepatic functional reserve. The four indices represent a promising imaging biomarker in the prediction of liver functional reserve.

[Molecular mechanism of ligustilide attenuating OGD/R injury in PC12 cells by inhibiting ferroptosis].

The aim of this study is to explore the mechanism of ligustilide, the main active constituent of essential oils of traditional Chinese medicine Angelicae Sinensis Radix, on alleviating oxygen-glucose deprivation/reperfusion(OGD/R) injury in PC12 cells from the perspective of ferroptosis. OGD/R was induced in vitro, and 12 h after ligustilide addition during reperfusion, cell viability was detected by cell counting kit-8(CCK-8) assay. DCFH-DA staining was used to detect the level of intracellular reactive oxygen species(ROS). Western blot was employed to detect the expression of ferroptosis-related proteins, glutathione peroxidase 4(GPX4), transferrin receptor 1(TFR1), and solute carrier family 7 member 11(SLC7A11), and ferritinophagy-related proteins, nuclear receptor coactivator 4(NCOA4), ferritin heavy chain 1(FTH1), and microtubule-associated protein 1 light chain 3(LC3). The fluorescence intensity of LC3 protein was analyzed by immunofluorescence staining. The content of glutathione(GSH), malondialdehyde(MDA), and Fe was detected by chemiluminescent immunoassay. The effect of ligustilide on ferroptosis was observed by overexpression of NCOA4 gene. The results showed that ligustilide increased the viability of PC12 cells damaged by OGD/R, inhibited the release of ROS, reduced the content of Fe and MDA and the expression of TFR1, NCOA4, and LC3, and improved the content of GSH and the expression of GPX4, SLC7A11, and FTH1 compared with OGD/R group. After overexpression of the key protein NCOA4 in ferritinophagy, the inhibitory effect of ligustilide on ferroptosis was partially reversed, indicating that ligustilide may alleviate OGD/R injury of PC12 cells by blocking ferritinophagy and then inhibiting ferroptosis. The mechanism by which ligustilide reduced OGD/R injury in PC12 cells is that it suppressed the ferroptosis involved in ferritinophagy.