Insights into Nucleosome Organization in Mouse Embryonic Stem Cells through Chemical Mapping.

Nucleosome organization influences gene activity by controlling DNA accessibility to transcription machinery. Here, we develop a chemical biology approach to determine mammalian nucleosome positions genome-wide. We uncovered surprising features of nucleosome organization in mouse embryonic stem cells. In contrast to the prevailing model, we observe that for nearly all mouse genes, a class of fragile nucleosomes occupies previously designated nucleosome-depleted regions around transcription start sites and transcription termination sites. We show that nucleosomes occupy DNA targets for a subset of DNA-binding proteins, including CCCTC-binding factor (CTCF) and pluripotency factors. Furthermore, we provide evidence that promoter-proximal nucleosomes, with the +1 nucleosome in particular, contribute to the pausing of RNA polymerase II. Lastly, we find a characteristic preference for nucleosomes at exon-intron junctions. Taken together, we establish an accurate method for defining the nucleosome landscape and provide a valuable resource for studying nucleosome-mediated gene regulation in mammalian cells.

Single-particle rotational microrheology enables pathological staging of macrophage foaming and antiatherosclerotic studies.

The formation of macrophage-derived foam cells has been recognized as the pathological hallmark of atherosclerotic diseases. However, the pathological evolution dynamics and underlying regulatory mechanisms remain largely unknown. Herein, we introduce a single-particle rotational microrheology method for pathological staging of macrophage foaming and antiatherosclerotic explorations by probing the dynamic changes of lysosomal viscous feature over the pathological evolution progression. The principle of this method involves continuous monitoring of out-of-plane rotation-caused scattering brightness fluctuations of the gold nanorod (AuNR) probe-based microrheometer and subsequent determination of rotational relaxation time to analyze the viscous feature in macrophage lysosomes. With this method, we demonstrated the lysosomal viscous feature as a robust pathological reporter and uncovered three distinct pathological stages underlying the evolution dynamics, which are highly correlated with a pathological stage-dependent activation of the NLRP3 inflammasome-involved positive feedback loop. We also validated the potential of this positive feedback loop as a promising therapeutic target and revealed the time window-dependent efficacy of NLRP3 inflammasome-targeted drugs against atherosclerotic diseases. To our knowledge, the pathological staging of macrophage foaming and the pathological stage-dependent activation of the NLRP3 inflammasome-involved positive feedback mechanism have not yet been reported. These findings provide insights into in-depth understanding of evolutionary features and regulatory mechanisms of macrophage foaming, which can benefit the analysis of effective therapeutical drugs as well as the time window of drug treatment against atherosclerotic diseases in preclinical studies.

Cancer-Targeting and Viscosity-Activatable Near-Infrared Fluorescent Probe for Precise Cancer Cell Imaging.

Small-molecule fluorescent probes have emerged as potential tools for cancer cell imaging-based diagnostic and therapeutic applications, but their limited selectivity and poor imaging contrast hinder their broad applications. To address these problems, we present the design and construction of a novel near-infrared (NIR) biotin-conjugated and viscosity-activatable fluorescent probe, named as QL-VB, for selective recognition and imaging of cancer cells. The designed probe exhibited a NIR emission at 680 nm, with a substantial Stokes shift of 100 nm and remarkably sensitive responses toward viscosity changes in solution. Importantly, QL-VB provided an evidently enhanced signal-to-noise ratio (SNR: 6.2) for the discrimination of cancer cells/normal cells, as compared with the control probe without biotin conjugation (SNR: 1.8). Moreover, we validated the capability of QL-VB for dynamic monitoring of stimulated viscosity changes within cancer cells and employed QL-VB for distinguishing breast cancer tissues from normal tissues in live mice with improved accuracy (SNR: 2.5) in comparison with the control probe (SNR: 1.8). All these findings indicated that the cancer-targeting and viscosity-activatable NIR fluorescent probe not only enables the mechanistic investigations of mitochondrial viscosity alterations within cancer cells but also holds the potential as a robust tool for cancer cell imaging-based applications.

Plasmonic Imaging of Multivalent NTD-Nucleic Acid Interactions for Broad-Spectrum Antiviral Drug Analysis.

The discovery and identification of broad-spectrum antiviral drugs are of great significance for blocking the spread of pathogenic viruses and corresponding variants of concern. Herein, we proposed a plasmonic imaging-based strategy for assessing the efficacy of potential broad-spectrum antiviral drugs targeting the N-terminal domain of a nucleocapsid protein (NTD) and nucleic acid (NA) interactions. With NTD and NA conjugated gold nanoparticles as core and satellite nanoprobes, respectively, we found that the multivalent binding interactions could drive the formation of core-satellite nanostructures with enhanced scattering brightness due to the plasmonic coupling effect. The core-satellite assembly can be suppressed in the presence of antiviral drugs targeting the NTD-NA interactions, allowing the drug efficacy analysis by detecting the dose-dependent changes in the scattering brightness by plasmonic imaging. By quantifying the changes in the scattering brightness of plasmonic nanoprobes, we uncovered that the constructed multivalent weak interactions displayed a 500-fold enhancement in affinity as compared with the monovalent NTD-NA interactions. We demonstrated the plasmonic imaging-based strategy for evaluating the efficacy of a potential broad-spectrum drug, PJ34, that can target the NTD-NA interactions, with the IC50 as 24.35 and 14.64 µM for SARS-CoV-2 and SARS-CoV, respectively. Moreover, we discovered that ceftazidime holds the potential as a candidate drug to inhibit the NTD-NA interactions with an IC50 of 22.08 µM from molecular docking and plasmonic imaging-based drug analysis. Finally, we validated that the potential antiviral drug, 5-benzyloxygramine, which can induce the abnormal dimerization of nucleocapsid proteins, is effective for SARS-CoV-2, but not effective against SARS-CoV. All these demonstrations indicated that the plasmonic imaging-based strategy is robust and can be used as a powerful strategy for the discovery and identification of broad-spectrum drugs targeting the evolutionarily conserved viral proteins.

Knockdown of AMIGO2 suppresses proliferation and migration through regulating PPAR-γ in bladder cancer.

PURPOSE: This study aims to reveal the relationship between AMIGO2 and proliferation, migration and tumorigenicity of bladder cancer, and explore the potential molecular mechanisms. METHODS: The expression level of AMIGO2 is measured by qRT-PCR and immunohistochemistry (IHC). Stable AMIGO2 knockdown cell lines T24 and 5637 were established by lentivirus transfection. Cell Counting Kit (CCK-8 assay) was produced to determine cell proliferation, flow cytometry analysis was utilized to detect cell cycle, and wound healing assay was proceeded to test migration ability of bladder cancer cells. Xenograft mouse model was established for investigating the effect of AMIGO2 on tumor formation in vivo. The RNA Sequencing technology was applied to explore the underlying mechanisms. The expression level of PPAR-γ was measured by Western Blot. RESULTS: AMIGO2 was upregulated in bladder cancer cells and tissues. Inhibited expression of AMIGO2 suppresses cell proliferation and migration. Low AMIGO2 expression inhibited tumorigenicity of 5637 in nude mice. According to RNA-Seq and bioinformatics analysis, 917 DEGs were identified. The DEGs were mainly enriched in cell-cell adhesion, peroxisome proliferators-activated receptors (PPARs) signaling pathway and some other pathways. PPAR-γ is highly expressed in bladder cancer cell lines T24 and 5637, but when AMIGO2 is knocked down in T24 and 5637, the expression level of PPAR-γ is also decreased, and overexpression of PPAR-γ could reverse the suppression effect of cell proliferation and migration caused by the inhibition of AMIGO2. CONCLUSION: AMIGO2 is overexpressed in bladder cancer cells and tissues. Knockdown of AMIGO2 suppresses bladder cancer cell proliferation and migration. These processes might be regulated by PPAR-γ signaling pathway.

Ginkgetin exhibits antifibrotic effects by inducing hepatic stellate cell apoptosis via STAT1 activation.

Liver fibrosis affects approximately 800 million patients worldwide, with over 2 million deaths each year. Nevertheless, there are no approved medications for treating liver fibrosis. In this study, we investigated the impacts of ginkgetin on liver fibrosis and the underlying mechanisms. The impacts of ginkgetin on liver fibrosis were assessed in mouse models induced by thioacetamide or bile duct ligation. Experiments on human LX-2 cells and primary mouse hepatic stellate cells (HSCs) were performed to explore the underlying mechanisms, which were also validated in the mouse models. Ginkgetin significantly decreased hepatic extracellular matrix deposition and HSC activation in the fibrotic models induced by thioacetamide (TAA) and bile duct ligation (BDL). Beneficial effects also existed in inhibiting hepatic inflammation and improving liver function. In vitro experiments showed that ginkgetin markedly inhibited HSC viability and induced HSC apoptosis dose-dependently. Mechanistic studies revealed that the antifibrotic effects of ginkgetin depend on STAT1 activation, as the effects were abolished in vitro after STAT1 silencing and in vivo after inhibiting STAT1 activation by fludarabine. Moreover, we observed a meaningful cross-talk between HSCs and hepatocytes, in which IL-6, released by ginkgetin-induced apoptotic HSCs, enhanced hepatocyte proliferation by activating STAT3 signaling. Ginkgetin exhibits antifibrotic effects by inducing HSC apoptosis via STAT1 activation and enhances hepatocyte proliferation secondary to HSC apoptosis via the IL-6/STAT3 pathway.

Dictyophora indusiata polysaccharide attenuated LPS-induced intestinal inflammation of mice via the TLR4/JNK signaling pathway.

BACKGROUND: Dictyophora indusiata polysaccharide is an important bioactive component of D. indusiata, playing an important role in alleviating inflammation. The present study aimed to investigate the anti-inflammatory effect and mechanism of D. indusiata polysaccharide on lipopolysaccharide (LPS)-induced intestinal inflammation in mice. RESULTS: Our results indicated that D. indusiata polysaccharide ameliorated intestinal inflammation of mice by increasing the body weight, the number of goblet cells and decreasing inflammatory cell infiltration. In addition, D. indusiata polysaccharide significantly up-regulated expression of ZO-1, Occuldin mRNA, which were 2.55-fold and 2.28-fold higher than the LPS group, respectively. In particular, D. indusiata polysaccharide effectively inhibited the Toll-like receptor 4 (TLR4)/ c-Jun NH2-terminal kinase (JNK) signalling pathway which was 0.34-fold and 0.49-fold of gene expression and 0.41-fold and 0.39-fold of protein expression in the LPS group, respectively. CONCLUSION: The results of the present study suggested that D. indusiata polysaccharide exerted anti-inflammatory and intestinal protective effects by inhibiting the TLR4/JNK signaling pathway, which will provide a basis for the potential value of D. indusiata polysaccharide as prebiotics in food applications. © 2024 Society of Chemical Industry.

Effects of steam explosion pretreatment on the digestive properties and gut microbiota of Laminaria japonica polysaccharide.

BACKGROUND: Laminaria japonica polysaccharide, which is an important bioactive substance of Laminaria japonica with anti-inflammatory and antioxidant effects. In this study, the molecular weight, functional groups and surface morphology were investigated to evaluate the digestive properties of Laminaria japonica polysaccharide before and after steam explosion. RESULTS: The results indicated that the Laminaria japonica polysaccharide entered the large intestine to be utilized by the gut microbiota after passing through the oral, gastric and small intestinal. Meanwhile, Laminaria japonica polysaccharide of steam explosion promoted the growth of beneficial bacteria Phascolarctobacterium and Intestinimonas, and increased the content of acetic, propionic and butyric acids, which was 2.29-folds, 2.60-folds and 1.63-folds higher than the control group after 48 h of fermentation. CONCLUSION: This study reveals that the effect of steam explosion pretreatment on the digestion in vitro and gut microbiota of Laminaria japonica polysaccharide will provide a basic theoretical basis for the potential application of Laminaria japonica polysaccharide as a prebiotic in the food industry. © 2024 Society of Chemical Industry.

Skeletal Features of Talus in Hepple V Lesion.

The present study was to determine the characteristics of the ankle skeletal structure in patients with talus Hepple V type. We conducted a retrospective study on the skeletal structure of the talus in 110 patients with Hepple V osteochondral lesions of the talus and in control participants. The radiographic measurements taken include the following: in the coronal plane - depth of talus frontal curvature, length of the lateral and medial malleolus; in the sagittal plane - radius and height of talus, angle of tibial lateral surface, tibiotalar sector, and vertical neck angle. The osteochondral lesion of the talus showed a significantly larger mean radius (mean ± SD, 21.4 ± 2.5 mm; p < .001) and height (mean ± SD, 26.0 ± 2.7 mm; p < .005). It also demonstrated a longer mean medial malleolus length (mean ± SD, 15.7 ± 2.4 mm; p < .005), a larger mean vertical neck angle (mean ± SD, 86.2 ± 5.4°; p < .050), and a greater mean tibial lateral surface angle (mean ± SD, 80.0 ± 4.5°; p < .001). And there was a greater mean frontal curvature depth (mean ± SD, 3.9 ± 0.6 mm; p < .005). Overall, this study found that patients with Hepple V osteochondral lesions of the talus had a larger vertical neck angle and tibial lateral surface angle, a longer talus radius and medial malleolus length, a higher talus height, and a deeper frontal curvature depth. STUDY DESIGNS: Retrospective Case-Control Study.

Chemical Approaches to Optimize the Properties of Organic Fluorophores for Imaging and Sensing.

Organic fluorophores are indispensable tools in cells, tissue and in vivo imaging, and have enabled much progress in the wide range of biological and biomedical fields. However, many available dyes suffer from insufficient performances, such as short absorption and emission wavelength, low brightness, poor stability, small Stokes shift, and unsuitable permeability, restricting their application in advanced imaging technology and complex imaging. Over the past two decades, many efforts have been made to improve these performances of fluorophores. Starting with the luminescence principle of fluorophores, this review clarifies the mechanisms of the insufficient performance for traditional fluorophores to a certain extent, systematically summarizes the modified approaches of optimizing properties, highlights the typical applications of the improved fluorophores in imaging and sensing, and indicates existing problems and challenges in this area. This progress not only proves the significance of improving fluorophores properties, but also provide a theoretical guidance for the development of high-performance fluorophores.

Exosome-transmitted miR-29a induces colorectal cancer metastasis by destroying the vascular endothelial barrier.

Metastasis is the leading cause of colorectal cancer treatment failure and mortality. Communication between endothelium and tumor cells in the tumor microenvironment is required for cancer metastasis. Tumor-derived exosomes have been shown to increase vascular permeability by delivering microRNA (miRNA) to vascular endothelial cells, facilitating cancer metastasis. The mechanism by which Epithelial-mesenchymal transition (EMT) tumor cell-derived exosomes influence vascular permeability remains unknown. MicroRNA-29a (miR-29a) expression is up-regulated in colorectal cancer (CRC) tissues, which is clinically significant in metastasis. Exosomal miR-29a secreted by EMT-CRC cells has been found to decrease the expression of Zonula occlusion 1 (ZO-1), Claudin-5, and Occludin via targeting Kruppel-like factor 4 (KLF4). In vitro co-culture investigations further revealed that EMT-cancer cells release exosomal miR-29a, which alters vascular endothelial permeability. Furthermore, exosomal miR-29a promoted liver metastases in CRC mice. Our findings demonstrate that EMT-CRC cells may transport exosomal miR-29a to endothelial cells in the tumor microenvironment (TME). As a result, increased vascular permeability promotes the development and metastasis of CRC. Exosomal miR-29a has the potential to be a predictive marker for tumor metastasis as well as a viable therapeutic target for CRC.

ortho-Methoxycarbonylethynylphenyl Thioglycosides (MCEPTs): Versatile Glycosyl Donors Enabled by Electron-Withdrawing Substituents and Catalyzed by Gold(I) or Cu(II) Complexes.

With easily accessible and operator-friendly reagents, shelf-stable ortho-methoxycarbonylethynylphenyl thioglycosides were efficiently prepared. Based on these MCEPT glycoside donors, a novel glycosylation protocol featuring mild and catalytic promotion conditions with Au(I) or Cu(II) complexes, expanded substrate scope encompassing challenging donors and acceptors and clinically used pharmaceuticals, and versatility in various strategies for highly efficient synthesis of glycosides has been established. The practicality of the MCEPT glycosylation protocol was fully exhibited by highly efficient and scalable synthesis of surface polysaccharide subunits of Acinetobacter baumannii via latent-active, reagent-controlled divergent orthogonal one-pot and orthogonal one-pot strategies. The underlying reaction mechanism was investigated systematically through control reactions, leading to the isolation and characterization of the vital catalyst species in MCEPT glycosylation, the benzothiophen-3-yl-gold(I) complex. Based on the results obtained both from control reactions and from studies leading to the glycosylation protocol establishment, an operative mechanism was proposed and the effect of the vital catalyst species reactivity on the results of metal-catalyzed alkyne-containing donor-involved glycosylation was disclosed. Moreover, the mechanism for C-glycosylation side product formation from ortho-(substituted)ethynylphenyl thioglycoside donors with electron-donating substituents was also illuminated.

Virus-like Plasmonic Nanoprobes for Quick Analysis of Antiviral Efficacy and Mutation-Induced Drug Resistance.

As the pathogenic viruses and the variants of concern greatly threaten human health and global public safety, the development of convenient and robust strategies enabling rapid analysis of antiviral drug efficacy and mutation-induced resistance is quite important to prevent the spread of human epidemics. Herein, we introduce a simple single-particle detection strategy for quick analysis of anti-infective drugs against SARS-CoV-2 and mutation-induced drug resistance, by using the wild-type and mutant spike protein-functionalized AuNPs as virus-like plasmonic nanoprobes. Both the wild-type and mutant virus-like plasmonic nanoprobes can form core-satellite nanoassemblies with the ACE2@AuNPs, providing the opportunity to detect the drug efficacy and mutation-induced resistance by detecting the changes of nanoassemblies upon drug treatment with dark-field microscopy. As a demonstration, we applied the single-particle detection strategy for quantitative determination of antiviral efficacy and mutation-induced resistance of ceftazidime and rhein. The mutations in the receptor-binding domain of Omicron variant could lead to an increase of EC50 values of ceftazidime and rhein, formerly from 49 and 57 µM against wild-type SARS-CoV-2, to 121 and 340 µM, respectively. The mutation-induced remarkable decline in the inhibitory efficacy of drugs was validated with molecule docking analysis and virus-like plasmonic nanoprobe-based cell-incubation assay. Due to the generality and feasibility of the strategy for the preparation of virus-like plasmonic nanoprobes and single-particle detection, we anticipated that this simple and robust method is promising for the discovery and efficacy evaluation of anti-infective drugs against different pathogenic viruses.

LINC00543 promotes colorectal cancer metastasis by driving EMT and inducing the M2 polarization of tumor associated macrophages.

BACKGROUND: The interaction between the tumor-microenvironment (TME) and the cancer cells has emerged as a key player in colorectal cancer (CRC) metastasis. A small proportion of CRC cells which undergo epithelial-mesenchymal transition (EMT) facilitate the reshaping of the TME by regulating various cellular ingredients. METHODS: Immunohistochemical analysis, RNA immunoprecipitation (RIP), RNA Antisense Purification (RAP), dual luciferase assays were conducted to investigate the biological function and regulation of LINC00543 in CRC. A series in vitro and in vivo experiments were used to clarify the role of LINC00543 in CRC metastasis. RESULTS: Here we found that the long non-coding RNA LINC00543, was overexpressed in colorectal cancer tissues, which correlated with advanced TNM stage and poorer prognosis of CRC patients. The overexpression of LINC00543 promoted tumorigenesis and metastasis of CRC cells by enhancing EMT and remodeling the TME. Mechanistically, LINC00543 blocked the transport of pre-miR-506-3p across the nuclear-cytoplasmic transporter XPO5, thereby reducing the production of mature miR-506-3p, resulting in the increase in the expression of FOXQ1 and induction of EMT. In addition, upregulation of FOXQ1 induced the expression of CCL2 that accelerated the recruitment of macrophages and their M2 polarization. CONCLUSIONS: Our study showed that LINC00543 enhanced EMT of CRC cells through the pre-miR-506-3p/FOXQ1 axis. This resulted in the upregulation of CCL2, leading to macrophages recruitment and M2 polarization, and ultimately stimulating the progression of CRC.

Identification and validation of a novel prognosis model based on m5C-related long non-coding RNAs in colorectal cancer.

BACKGROUND: The prognosis of tumor patients can be assessed by measuring the levels of lncRNAs (long non-coding RNAs), which play a role in controlling the methylation of the RNA. Prognosis in individuals with colorectal adenocarcinoma (CRC) is strongly linked to lncRNA expression, making it imperative to find lncRNAs that are associated with RNA methylation with strong prognostic value. METHODS: In this study, by analyzing TCGA dataset, we were able to develop a risk model for lncRNAs that are associated with m5C with prognostic significance by employing LASSO regression and univariate Cox proportional analysis. There were a number of methods employed to ensure the model was accurate, including multivariate and univariate Cox regression analysis, Kaplan analysis, and receiver operating characteristic curve analysis. The principal component analysis, GSEA and GSVA analysis were used for risk model analysis. The CIBERSORT instrument and the TIMER database were used to evaluate the link between the immune cells that infiltrate tumors and the risk model. In vitro experiments were also performed to validate the predicted m5C-related significant lncRNAs. RESULTS: The m5c regulators were differentially expressed in colorectal cancer and normal tissue. Based on the screening criteria and LASSO regression, 11 m5c-related lncRNAs were identified for developing the prognostic risk model. Multivariate and univariate Cox regression analysis showed the risk score is a crucial prognostic factor in CRC patients. The 1-year, 3-year, and 5-year AUC curves showed the risk score was higher than those identified for other clinicopathological characteristics. A nomogram using the risk score as a quantitative tool was developed for predicting patients' outcomes in clinical settings. In addition, the risk profile of m5C-associated lncRNAs can discriminate between tumor immune cells' characteristics in CRC. Mutation patterns and chemotherapy were analyzed between high- and low- risk groups of CRC patients. Moreover, TNFRSF10A-AS1 was chosen for the in vitro verification of the m5C-connected lncRNA to demonstrate impressive effects on the proliferation, migration and invasion of CRC cells. CONCLUSION: A risk model including the prognostic value of 11 m5C-associated lncRNAs proves to be a useful prognostic tool for CRC and improves the care of patients suffering from CRC based on these findings.

TACE versus TACE + entecavir versus TACE + tenofovir in the treatment of HBV associated hepatocellular carcinoma.

BACKGROUND: At present, there are a variety of antiviral drugs for HBV in clinical practice, but there is no standard scheme for transcatheter arterial chemoembolization(TACE) combined with antiviral drugs. The aim of this study was to investigate whether TACE must be combined with antiviral therapy in patients of HBV-related hepatocellular carcinoma(HCC). Meanwhile, the efficacy and safety of TACE combined with entecavir and TACE combined with tenofovir in the treatment of HBV-related HCC were compared. METHOD: This study included 536 patients with HBV-related HCC who underwent TACE in Union Hospital from March 2017 to March 2020, and they met the criteria. They were divided into three groups: control group (N = 212): TACE alone; Entecavir group (N = 220): TACE combined with entecavir; and Tenofovir group (N = 228): TACE combined with tenofovir. We conducted a retrospective study to analyze the efficacy and safety of the three groups of patients. RESULTS: Objective response rate(ORR): 29.2% in control group, 54.1% in entecavir group, and 63.2% in tenofovir group (P < 0.05). Disease control rate(DCR): 63.7% in control group, 80.9% in entecavir group, and 88.1% in tenofovir group (P < 0.05). Median overall survival(mOS): control group, 12.2 months; entecavir group, 17.3 months; tenofovir group, 22.5 months (p < 0.05). Median progression-free survival (mPFS): control group, 9.3 months; entecavir group, 15.5 months; tenofovir group, 16.6 months (p < 0.05). At 6 months, there was an increase in creatinine(Cr) and a decrease in glomeruar filtration rate(GFR) in tenofovir group, which were statistically different from control and entecavir groups (p < 0.05). CONCLUSION: TACE combined with entecavir and TACE combined with tenofovir had higher ORR and DCR, longer OS and PFS than TACE alone. The OS of TACE combined with tenofovir was higher than that of TACE combined with entecavir. TACE combined with tenofovir is a safe strategy, but we cannot completely ignore the impact of tenofovir on renal function.

Predictors of Improvement of Sarcopenia after Transjugular Intrahepatic Portosystemic Shunt Creation in Cirrhotic Patients.

To investigate the risk factors affecting the improvement of sarcopenia after transjugular intrahepatic portosystemic shunt (TIPS) in cirrhotic patients, this study retrospectively analyzed the data of 111 cirrhotic patients with sarcopenia who underwent TIPS creation. Computed tomography-based measurement of skeletal muscle area was used to calculate skeletal muscle index (SMI) in all patients at baseline and 6 months after TIPS creation. Multivariate logistic regression analysis was used to identify independent risk factors, which showed a significant increase in 6-month post-TIPS SMI compared with that at baseline in both men and women (for both, P < .001). Pre-TIPS SMI (odds ratio [OR], 0.93; 95% CI, 0.87-0.99; P = .031) and change in portal pressure gradient (OR, 1.13; 95% CI, 1.03-1.24; P = .009) were found to be independent risk factors for experiencing substantial improvement in post-TIPS SMI.

Reversion of liver cirrhosis after endovascular treatment in Chinese patients with Budd-Chiari syndrome.

AIMS: To investigate the impact of endovascular (EV) treatment on liver cirrhosis in Chinese patients with Budd-Chiari syndrome (BCS). METHODS: From September 2011 to March 2022, 97 patients from four hospitals in China who were diagnosed with primary BCS complicated with liver cirrhosis and received EV treatment were retrospectively enrolled in this study for clinical analysis. In addition, liver tissues for basic research were acquired from 25 patients between June 2022 and March 2023, including six with benign liver tumors, 11 with BCS before EV treatment, and eight with EV-treated BCS. Liver cirrhosis was assessed by clinical outcomes, histological studies, and the expression of related genes at the mRNA and protein levels. RESULTS: The patients with BCS had better liver function after EV treatment, evidenced by an increased albumin level and reduced total bilirubin, ALT, and AST. The imaging findings suggested an amelioration of liver cirrhosis and portal hypertension, including increased portal vein velocity (13.52 ± 8.89 cm/s vs. 17.51 ± 6.67 cm/s, p < 0.001) and decreased liver stiffness (30.37 ± 6.39 kPa vs. 23.70 ± 7.99 kPa, p < 0.001), portal vein diameter (14.97 ± 3.42 mm vs. 13.36 ± 2.89 mm, p < 0.001), and spleen volume (870.00 ± 355.61 cm3 vs. 771.36 ± 277.45 cm3 , p < 0.001). Furthermore, histological studies revealed that EV treatment resulted in a restoration of liver architecture with reduced extracellular matrix deposition. Meanwhile, hepatic angiogenesis and inflammation, which have a close relationship with cirrhosis, were also inhibited. In addition, the state of hepatocytes switches from apoptosis to proliferation after EV treatment. CONCLUSIONS: BCS-induced liver cirrhosis could be reversed by EV treatment from macroscopic to microscopic dimensions. Our study may provide further insights into understanding BCS and treating cirrhosis.

Aerobic exercise and vitamin E improve high-fat diet-induced NAFLD in rats by regulating the AMPK pathway and oxidative stress.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) has emerged as a major chronic liver disease. We explored simple and effective ways to improve NAFLD and investigate the mechanism of action. METHODS: NAFLD was induced in 40 rats fed a high-fat diet (HFD). Magnetic resonance imaging was used to evaluate the progression and improvement of NAFLD. The treatment-related interventions included aerobic exercise (E) and vitamin E (VE) supplementation. Expression levels of proteins related to fat metabolism were also assessed. The activities of antioxidant enzymes in the liver and serum lipid metabolism were analyzed using biochemical methods. RESULTS: Aerobic exercise and vitamin E effectively improved NAFLD in rats, resulting in decreased hepatic fat accumulation, reduced hepatocyte ballooning, and decreased triglyceride levels. Combination therapy achieved the best effect. Both aerobic exercise and vitamin E activate the AMPK pathway to phosphorylate acetyl-CoA carboxylase (ACC) and reduce fatty acid synthesis. The expression of sterol regulatory element-binding protein-1 (SREBP-1) was decreased significantly in the treated groups, particularly in the E + VE + HFD group. The expression of carnitine palmitoyl-transferase 1C (CPT1C) significantly increased in the treated groups, particularly in the E + VE + HFD group. Compared with the control group, reactive oxygen species (ROS) in the E + HFD group were slightly decreased, while that in the VE + HFD group were significantly decreased, with the even greater reduction observed in the E + VE + HFD group. CONCLUSION: Aerobic exercise and vitamin E supplementation can improve HFD-induced NAFLD in rats by regulating the AMPK pathway and reducing oxidative stress.

Pheochromocytoma crisis with refractory Acute Respiratory Distress Syndrome (ARDS), Takotsubo syndrome, emergency adrenalectomy, and need for Extracorporeal Membrane Oxygenation (ECMO) in a previously undiagnosed and asymptomatic patient, due to the use of metoclopramide.

BACKGROUND: Pheochromocytoma (PCC) crisis is a rare life-threatening endocrine emergency. The diagnosis and treatment of PCC crisis, with acute respiratory distress syndrome (ARDS) as the first manifestation, is highly challenging, and traditional PCC management strategies are no longer suitable for these patients. CASE PRESENTATION: A 46-year-old female patient was admitted to the Intensive Care Unit (ICU) following sudden-onset acute respiratory distress and subsequent initiation of mechanical ventilation via endotracheal intubation. She was initially suspected of having a PCC crisis through the bedside critical care ultrasonic examination protocol. The computed tomography examination revealed a left adrenal neoplasm of 6.5cm × 5.9cm. The plasma-free metanephrine level was 100 times higher than the reference value. These findings were compatible with her PCC diagnosis. Alpha-blockers and fluid intake were started immediately. The endotracheal intubation was removed on the 11th day after admission to the ICU. The patient progressed to severe ARDS again, and invasive ventilation and continuous renal replacement therapy were needed. Despite aggressive therapy, her condition deteriorated. Therefore, she underwent veno-arterial extracorporeal membrane oxygenation (VA-ECMO)-assisted emergency adrenalectomy after multidisciplinary discussion. Postoperatively, the patient was supported by VA-ECMO for 7days. She was discharged from the hospital on day 30 after tumor resection. CONCLUSIONS: This case highlighted the challenges in diagnosing and managing ARDS associated with PCC crisis. The traditional preoperative preparation protocol and optimal operation timing for patients with PCC are not suitable for patients with PCC crisis. Patients with life-threatening PCC crisis may benefit from early tumor removal, and VA-ECMO could maintain hemodynamic stability during and after surgery.