Country-specific determinants for COVID-19 case fatality rate and response strategies from a global perspective: an interpretable machine learning framework.

BACKGROUND: There are significant geographic inequities in COVID-19 case fatality rates (CFRs), and comprehensive understanding its country-level determinants in a global perspective is necessary. This study aims to quantify the country-specific risk of COVID-19 CFR and propose tailored response strategies, including vaccination strategies, in 156 countries. METHODS: Cross-temporal and cross-country variations in COVID-19 CFR was identified using extreme gradient boosting (XGBoost) including 35 factors from seven dimensions in 156 countries from 28 January, 2020 to 31 January, 2022. SHapley Additive exPlanations (SHAP) was used to further clarify the clustering of countries by the key factors driving CFR and the effect of concurrent risk factors for each country. Increases in vaccination rates was simulated to illustrate the reduction of CFR in different classes of countries. FINDINGS: Overall COVID-19 CFRs varied across countries from 28 Jan 2020 to 31 Jan 31 2022, ranging from 68 to 6373 per 100,000 population. During the COVID-19 pandemic, the determinants of CFRs first changed from health conditions to universal health coverage, and then to a multifactorial mixed effect dominated by vaccination. In the Omicron period, countries were divided into five classes according to risk determinants. Low vaccination-driven class (70 countries) mainly distributed in sub-Saharan Africa and Latin America, and include the majority of low-income countries (95.7%) with many concurrent risk factors. Aging-driven class (26 countries) mainly distributed in high-income European countries. High disease burden-driven class (32 countries) mainly distributed in Asia and North America. Low GDP-driven class (14 countries) are scattered across continents. Simulating a 5% increase in vaccination rate resulted in CFR reductions of 31.2% and 15.0% for the low vaccination-driven class and the high disease burden-driven class, respectively, with greater CFR reductions for countries with high overall risk (SHAP value > 0.1), but only 3.1% for the ageing-driven class. CONCLUSIONS: Evidence from this study suggests that geographic inequities in COVID-19 CFR is jointly determined by key and concurrent risks, and achieving a decreasing COVID-19 CFR requires more than increasing vaccination coverage, but rather targeted intervention strategies based on country-specific risks.

NB-TCM-CHM: Image dataset of the Chinese herbal medicine fruits and its application in classification through deep learning.

Chinese herbal medicine (CHM) is integral to a traditional Chinese medicine (TCM) system. Accurately identifying Chinese herbal medicine is crucial for quality control and prescription compounding verification. However, with many Chinese herbal medicines and some with similar appearances but different therapeutic effects, achieving precise identification is a challenging task. Traditional manual identification methods have certain limitations, including labor-intensive, inefficient. Deep learning techniques for Chinese herbal medicine identification can enhance accuracy, improve efficiency and lower coats. However, few high-quality Chinese herbal medicine datasets are currently available for deep learning applications. To alleviate this problem, this study constructed a dataset (Dataset 1) containing 3,384 images of 20 common Chinese herbal medicine fruits through web crawling. All images are annotated by TCM experts, making them suitable for training and testing Chinese herbal medicine identification methods. Furthermore, this study establishes another dataset (Dataset 2) of 400 images by taking pictures using smartphones to provide materials for the practical efficacy evaluation of Chinese herbal medicine identification methods. The two datasets form a Ningbo Traditional Chinese Medicine Chinese Herb Medicine (NB-TCM-CHM) Dataset. In Dataset 1 and Dataset 2, each type of Chinese medicine herb is stored in a separate folder, with the folder named after its name. The dataset can be used to develop Chinese herbal medicine identification algorithms based on deep learning and evaluate the performance of Chinese herbal medicine identification methods.

Electroacupuncture intervention alleviates depressive-like behaviors and regulates gut microbiome in a mouse model of depression.

Electroacupuncture (EA) is a neuroregulatory therapy for depression. Nonetheless, the effects of EA on the gut microbiome in mice models of depression are not well established. Here, using a chronic unpredictable mild stress (CUMS) model in mice, we evaluated the antidepressant effects of EA and changes in gut microbiota with behavioral tests and 16S rRNA gene sequencing. The results found that EA increased the time spent in the center area of the open-field test and the percentage of sucrose preference and reduced the immobility time in the tail suspension test in CUMS-treated mice. Furthermore, the genus Lachnoclostridium, Ruminococcaceae_UCG-002 and Rikenellaceae_RC9_gut_group were enriched in the CUMS group, which was positively correlated with depressive-like behaviors. Whereas phylum Actinobacteria and genus Allobaculum, Bifidobacterium, Dubosiella, Rikenella and Ileibacterium were enriched in the EA and CUMS + EA groups, all of which were negatively correlated with depressive-like behaviors. This study characterizes gut microbiota under EA treatment and provides new insights into the association of anti-depressive-like effects of EA and gut microbiota.

Roseburia intestinalis Supplementation Could Reverse the Learning and Memory Impairment and m6A Methylation Modification Decrease Caused by 27-Hydroxycholesterol in Mice.

The abnormality in N6-methyladenosine (m6A) methylation is involved in the course of Alzheimer's disease (AD), while the intervention of 27-Hydroxycholesterol (27-OHC) can affect the m6A methylation modification in the brain cortex. Disordered gut microbiota is a key link in 27-OHC leading to cognitive impairment, and further studies have found that the abundance of Roseburia intestinalis in the gut is significantly reduced under the intervention of 27-OHC. This study aims to investigate the association of 27-OHC, Roseburia intestinalis in the gut, and brain m6A modification in the learning and memory ability injury. In this study, 9-month-old male C57BL/6J mice were treated with antibiotic cocktails for 6 weeks to sweep the intestinal flora, followed by 27-OHC or normal saline subcutaneous injection, and then Roseburia intestinalis or normal saline gavage were applied to the mouse. The 27-OHC level in the brain, the gut barrier function, the m6A modification in the brain, and the memory ability were measured. From the results, we observed that 27-OHC impairs the gut barrier function, causing a disturbance in the expression of m6A methylation-related enzymes and reducing the m6A methylation modification level in the brain cortex, and finally leads to learning and memory impairment. However, Roseburia intestinalis supplementation could reverse the negative effects mentioned above. This study suggests that 27-OHC-induced learning and memory impairment might be linked to brain m6A methylation modification disturbance, while Roseburia intestinalis, as a probiotic with great potential, could reverse the damage caused by 27-OHC. This research could help reveal the mechanism of 27-OHC-induced neural damage and provide important scientific evidence for the future use of Roseburia intestinalis in neuroprotection.

Mass Spectrometry-Based Proteomics Analysis Unveils PTPRS Inhibits Proliferation and Inflammatory Response of Keratinocytes in Psoriasis.

In this study, we used data-independent acquisition-mass spectrometry (DIA-MS) to analyze the serum proteome in psoriasis vulgaris (PsO). The serum proteomes of seven healthy controls and eight patients with PsO were analyzed using DIA-MS. Weighted gene co-expression network analysis was used to identify differentially expressed proteins (DEPs) that were closely related to PsO. Hub proteins of PsO were also identified. The Proteomics Drug Atlas 2023 was used to predict candidate hub protein drugs. To confirm the expression of the candidate factor, protein tyrosine phosphatase receptor S (PTPRS), in psoriatic lesions and the psoriatic keratinocyte model, immunohistochemical staining, quantitative real-time polymerase chain reaction, and western blotting were performed. A total of 129 DEPs were found to be closely related to PsO. The hub proteins for PsO were PVRL1, FGFR1, PTPRS, CDH2, CDH1, MCAM, and THY1. Five candidate hub protein drugs were identified: encorafenib, leupeptin, fedratinib, UNC 0631, and SCH 530348. PTPRS was identified as a common pharmacological target for these five drugs. PTPRS knockdown in keratinocytes promoted the proliferation and expression of IL-1α, IL-1ß, IL-23A, TNF-α, MMP9, CXCL8, and S100A9. PTPRS expression was decreased in PsO, and PTPRS negatively regulated PsO. PTPRS may be involved in PsO pathogenesis through the inhibition of keratinocyte proliferation and inflammatory responses and is a potential treatment target for PsO.

Mitochondrial RelA empowers mtDNA G-quadruplex formation for hypoxia adaptation in cancer cells.

Mitochondrial DNA (mtDNA) G-quadruplexes (G4s) have important regulatory roles in energy metabolism, yet their specific functions and underlying regulatory mechanisms have not been delineated. Using a chemical-genetic screening strategy, we demonstrated that the JAK/STAT3 pathway is the primary regulatory mechanism governing mtDNA G4 dynamics in hypoxic cancer cells. Further proteomic analysis showed that activation of the JAK/STAT3 pathway facilitates the translocation of RelA, a member of the NF-κB family, to the mitochondria, where RelA binds to mtDNA G4s and promotes their folding, resulting in increased mtDNA instability, inhibited mtDNA transcription, and subsequent mitochondrial dysfunction. This binding event disrupts the equilibrium of energy metabolism, catalyzing a metabolic shift favoring glycolysis. Collectively, the results provide insights into a strategy employed by cancer cells to adapt to hypoxia through metabolic reprogramming.

Hydronidone induces apoptosis in activated hepatic stellate cells through endoplasmic reticulum stress-associated mitochondrial apoptotic pathway.

BACKGROUND AND AIM: Hydronidone (HDD) is a novel pirfenidone derivative developed initially to reduce hepatotoxicity. Our previous studies in animals and humans have demonstrated that HDD treatment effectively attenuates liver fibrosis, yet the underlying mechanism remains unclear. This study aimed to investigate whether HDD exerts its anti-fibrotic effect by inducing apoptosis in activated hepatic stellate cells (aHSCs) through the endoplasmic reticulum stress (ERS)-associated mitochondrial apoptotic pathway. METHODS: The carbon tetrachloride (CCl4)- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver fibrosis models were used for in vivo studies. In vitro studies were conducted using the human hepatic stellate cell line LX-2. The apoptotic effect of HDD on aHSCs was examined using TUNEL and flow cytometry assays. The small interfering RNA (siRNA) technique was employed to downregulate the expression of interest genes. RESULTS: HDD treatment significantly promoted apoptosis in aHSCs in both the CCl4- and DDC-induced liver fibrosis in mice and LX-2 cells. Mechanistic studies revealed that HDD triggered ERS and subsequently activated the IRE1α-ASK1-JNK pathway. Furthermore, the influx of cytochrome c from the mitochondria into the cytoplasm was increased, leading to mitochondrial dysfunction and ultimately triggering apoptosis in aHSCs. Notably, inhibition of IRE1α or ASK1 by siRNA partially abrogated the pro-apoptotic effect of HDD in aHSCs. CONCLUSIONS: The findings of both in vivo and in vitro studies suggest that HDD induces apoptosis in aHSCs via the ERS-associated mitochondrial apoptotic pathway, potentially contributing to the amelioration of liver fibrosis.

High performance supercapacitors deploying cube-templated tracheid cavities of wood-derived carbon.

Wood-derived carbon, with its strong tracheid array structure, is an ideal material for use as a self-supporting electrode in supercapacitors. By leveraging the inherent through pore structure and surface affinity found in wood tracheids, we successfully engineered a highly spatially efficient cube-templated porous carbon framework inside carbonized wood tracheid cavities through precise control over precursor crystallization temperatures. This innovative cubic channel architecture effectively maximizes up to (79 ± 1)% of the cavity volume in wood-derived carbon while demonstrating exceptional hydrophilicity and high conductivity properties, facilitating the development of supercapacitors with enhanced areal/volumetric capacitances (2.65F cm-2/53.0F cm-3 at 5.0 mA cm-2) as well as superior areal/volumetric energy densities (0.37 mWh cm-2/7.36 mWh cm-3 at 2.5 mW cm-2). The fabrication of these cube-templated channels with high cube filling content is not only simple and precisely controllable, but also environmentally friendly. The proposed method eliminates the conventional acid-base treatment process for pore formation, facilitating the rapid development and practical implementation of thick electrodes with superior performance in supercapacitors. Moreover, it offers a universal research approach for the commercialization of wood-derived thick electrodes.

Analysis of airway structural parameters in Han Chinese adults: a prospective cross-sectional study.

INTRODUCTION: Establishing reference ranges for central airway parameters and exploring their influencing factors in Han Chinese non-smoking adults. METHODS: This prospective cross-sectional study was conducted on Han Chinese non-smoking adults who underwent chest CT scans at the Tongzhou Campus of Dongzhimen Hospital Affiliated with the Beijing University of Chinese Medicine between September 2022 and November 2022. The SYNAPSE 3D image analysis software was utilized, enabling the extraction of critical parameters such as central airway length, airway wall thickness (AWT), airway lumen area (ALA), and subcarinal angle (SCA). Pearson's correlation coefficient analysis and multiple linear regression analysis methods were employed to evaluate the relationship between central airway parameters and age, sex, weight, and height. RESULTS: The study encompassed 888 Han Chinese non-smoking adults, comprising 456 females and 432 males. Significant sex differences were noted in central airway length, AWT, and ALA, with measurements in males exceeding those in females (p < 0.01) with no significant difference in SCA. Correlation analyses unveiled relationships between central airway parameters and age, sex, weight, and height. During multiple linear regression analyses, no conclusive evidence emerged to demonstrate the independent or combined explanatory or predictive capacity of the aforementioned variables for central airway length and SCA. Although sex has a significant impact on AWT and ALA, its capability in explanation or prediction remains limited. The conclusions drawn from the primary analysis receive reinforcement from the outcomes of sensitivity analyses. CONCLUSION: Establishing the distribution range of central airway parameters in non-smoking Han Chinese adults. It observed significant sex differences in these parameters, except for the SCA. However, the study found that the predictive or explanatory power of age, sex, weight, and height for central airway parameters was either limited or non-significant.

Design, synthesis and biological evaluation of the positional isomers of the galactose conjugates able to target hepatocellular carcinoma cells via ASGPR-mediated cellular uptake and cytotoxicity.

Galactose as a recognizing motif for asialoglycoprotein receptor (ASGPR) is a widely accepted vector to deliver cytotoxic agents in the therapy of hepatocellular carcinoma (HCC), however, the individual hydroxyl group of galactose (Gal) contributed to recognizing ASGPR is obscure and remains largely unanswered in the design of glycoconjugates. Herein, we designed and synthesized five positional isomers of Gal-anthocyanin Cy5.0 conjugates and three Gal-doxorubicin (Dox) isomers, respectively. The fluorescence intensity of Gal-Cy5.0 conjugates accumulated in cancer cells hinted the optimal modification sites of positions C2 and C6. Comparing to the cytotoxicity of other conjugates, C2-Gal-Dox (11) was the most potent. Moreover, Gal-Dox conjugates significantly the toxicity of Dox. A progressively lower internalization capacity and siRNA technology implied the cellular uptake and cytotoxicity directly related to the ASGPR expression level. Accordingly, position C2 of galactose may be the best substitution site via ASGPR mediation in the design of anti-HCC glycoconjugates.

Association between erythrocyte membrane fatty acids and gut bacteria in obesity-related cognitive dysfunction.

Obesity increases the risk of cognitive impairment and dementia, and the gut microbiota can affect brain cognitive function and obesity through a variety of pathways such as the gut-brain axis. This study aimed to discover how fatty acid affect cognitive function by regulating intestinal flora in obesity. Obese subjects were recruited for cognitive function assessment, and participants were divided into obese group with cognitive impairment (MCI, n = 49) and obese cognitively normal group (Non_MCI, n = 55). In the erythrocyte membrane, the proportion of polyunsaturated fatty acids (PUFA), linoleic acid (C18:2 n-6) and arachidonic acid (C20:4 n-6) and n-6/n-3 ratio was higher in the MCI group than in the Non_MCI group. However, the α-linolenic acid (C18:3 n-3) percentage of the erythrocyte membrane was lower in the MCI group. We found that Coriobacteriales_Incertae_Sedis was positively correlated with erythrocyte membrane C20:4 n-6 and n-6 PUFA and negatively correlated with cognitive scores in obese patients. In addition, several of the functional pathways we predicted were significantly different in the MCI and Non_MCI groups. Higher levels of n-6/n-3 polyunsaturated fatty acids ratio in the erythrocyte membranes may influence the inflammatory response in the organism causing obesity induced cognitive damage. Moreover, high levels of n-6/n-3 polyunsaturated fatty acids ratio may also affect the intestinal flora of obese patients, which in turn may affect the cognitive function of obese patients.

Allergenicity evaluation of quinoa proteins - A study in Brown Norway rats.

The popularity of quinoa seeds has increased in the last decade due to their high nutritional value and natural gluten-free composition. Consumption of new proteins may pose a risk of introducing new allergies. In the present study the immunogenicity and sensitising capacity of quinoa proteins were assessed in a dose-response experiment in Brown Norway rats in comparison to proteins from spinach and peanut. Cross-reactivity between quinoa proteins and known allergens was evaluated by in silico analyses followed by analyses with 11 selected protein extracts and their anti-sera by means of ELISAs and immunoblotting. Further, an in vitro simulated gastro-duodenal digestion was performed. Quinoa proteins were found to have an inherent medium to high immunogenicity and sensitising capacity, being able to induce specific IgG1 and IgE levels higher than spinach but lower than peanut and elicit reactions of clinical relevance similar to peanut. Quinoa proteins were generally shown to resist digestion and retain capacity to bind quinoa-specific antibodies. Quinoa proteins were shown to be cross-reactive with peanut and tree nut allergens as high sequence homology and antibody cross-binding were demonstrated. Present study suggests that quinoa pose a medium to high level of allergenicity that should be further investigated in human studies.

Glabridin Functions as a Quorum Sensing Inhibitor to Inhibit Biofilm Formation and Swarming Motility of Multidrug-Resistant Acinetobacter baumannii.

Objective: Acinetobacter baumannii is a hazardous bacterium that causes hospital-acquired nosocomial infections, and the advent of multidrug-resistant A. baumannii (MDR-AB) strains is concerning. Novel antibacterial therapeutic strategies must be developed. The biological effects of glabridin on MDR-AB were investigated in this study. Methods: The minimum inhibitory concentrations (MICs) of glabridin against eight clinical MDR-AB strains were determined using the broth microdilution technique. Crystal violet staining was used to assess biofilm development, which has significant contribution to bacterial resistance. Swarming motility was measured according to surface growth zone of MDR-AB on LB agar medium. qRT-PCR was used to evaluate the expression of quorum sensing genes abaI and abaR. Glabridin and routinely used therapeutic antimicrobial agents were tested for synergistic action using the checkerboard method. Results: According to our findings, glabridin suppressed MDR-AB growth at high doses (512-1024 µg/mL). The 1/4 MIC of glabridin significantly decreased MDR-AB biofilm formation by 19.98% (P < 0.05), inhibited MDR-AB motility by 44.27% (P < 0.05), whereas the 1/2 MIC of glabridin dramatically reduced MDR-AB biofilm development by 27.43% (P < 0.01), suppressed MDR-AB motility by 50.64% (P < 0.05). Mechanistically, glabridin substantially downregulated the expression of quorum sensing-related genes abaI and abaR by up to 39.12% (P < 0.001) and 25.19% (P < 0.01), respectively. However, no synergistic effect between glabridin and antibacterial drugs was found. Conclusion: Glabridin might be a quorum sensing inhibitor that inhibits MDR-AB biofilm development and swarming motility.

Octominin: An antimicrobial peptide with antibacterial and anti-inflammatory activity against carbapenem-resistant Escherichia coli both in vitro and in vivo.

OBJECTIVES: The emergence of carbapenem-resistant Escherichia coli (CREC) is a global concern as its prevalence restricts treatment options and poses a considerable threat to public health. In this study, in vitro and in vivo activity of the antimicrobial peptide Octominin against CREC was investigated to reveal possible mechanisms of action. Furthermore, its safety and factors influencing its antibacterial effect were assessed. Additionally, the anti-inflammatory effects of Octominin were examined. METHODS: The antimicrobial activity of Octominin against 11 strains of CREC was determined using the broth microdilution method, growth curve, and time-kill assay. Its possible mechanism of action was unraveled using the propidium iodide and N-phenyl-1-naphthylamine fluorochrome and lipopolysaccharide-binding assays. To understand the safety and stability of Octominin, its cytotoxicity, hemolysis, and antibacterial activity under various conditions (i.e, temperature, ions) were estimated. Additionally, a Galleria mellonella infection model was utilized to evaluate the efficacy of Octominin in vivo, and qRT-PCR was performed to assess its effect on the expression of proinflammatory cytokines. RESULTS: Octominin displayed a significant antibacterial effect, with MICs of 4-8 µg/mL and MBCs of 8-16 µg/mL. Octominin exerted its antibacterial effect by disrupting bacterial membranes. Cytotoxicity and hemolysis tests demonstrated the potential application of Octominin in vivo. The G. mellonella infection model asserted the in vivo efficacy of Octominin. Furthermore, Octominin inhibited the expression of proinflammatory cytokines. Although the temperature had little effect on its the activity, serum and ions reduced activity. CONCLUSION: Octominin is a promising alternative agent with remarkable antibacterial and anti-inflammatory effects for treating infections caused by CREC.

The Properties of Linezolid, Rifampicin, and Vancomycin, as Well as the Mechanism of Action of Pentamidine, Determine Their Synergy against Gram-Negative Bacteria.

Combining pentamidine with Gram-positive-targeting antibiotics has been proven to be a promising strategy for treating infections from Gram-negative bacteria (GNB). However, which antibiotics pentamidine can and cannot synergize with and the reasons for the differences are unclear. This study aimed to identify the possible mechanisms for the differences in the synergy of pentamidine with rifampicin, linezolid, tetracycline, erythromycin, and vancomycin against GNB. Checkerboard assays were used to detect the synergy of pentamidine and the different antibiotics. To determine the mechanism of pentamidine, fluorescent labeling assays were used to measure membrane permeability, membrane potential, efflux pump activity, and reactive oxygen species (ROS); the LPS neutralization assay was used to evaluate the target site; and quantitative PCR was used to measure changes in efflux pump gene expression. Our results revealed that pentamidine strongly synergized with rifampicin, linezolid, and tetracycline and moderately synergized with erythromycin, but did not synergize with vancomycin against E. coli, K. pneumoniae, E. cloacae, and A. baumannii. Pentamidine increased the outer membrane permeability but did not demolish the outer and inner membranes, which exclusively permits the passage of hydrophobic, small-molecule antibiotics while hindering the entry of hydrophilic, large-molecule vancomycin. It dissipated the membrane proton motive force and inactivated the efflux pump, allowing the intracellular accumulation of antimicrobials that function as substrates of the efflux pump, such as linezolid. These processes resulted in metabolic perturbation and ROS production which ultimately was able to destroy the bacteria. These mechanisms of action of pentamidine on GNB indicate that it is prone to potentiating hydrophobic, small-molecule antibiotics, such as rifampicin, linezolid, and tetracycline, but not hydrophilic, large-molecule antibiotics like vancomycin against GNB. Collectively, our results highlight the importance of the physicochemical properties of antibiotics and the specific mechanisms of action of pentamidine for the synergy of pentamidine-antibiotic combinations. Pentamidine engages in various pathways in its interactions with GNB, but these mechanisms determine its specific synergistic effects with certain antibiotics against GNB. Pentamidine is a promising adjuvant, and we can optimize drug compatibility by considering its functional mechanisms.

Predictive factors of atopic-like dermatitis induced by IL-17A inhibitors in patients with psoriasis: A 2-year follow-up study.

BACKGROUND: Atopic-like dermatitis (ALD) is a common side effect of interleukin-17A (IL-17A) inhibitors. OBJECTIVE: To determine the prevalence, risk factors, outcomes and treatment of ALD in a cohort of psoriasis patients treated with IL-17A inhibitors. METHODS: This retrospective study included 226 psoriasis patients treated with an IL-17A inhibitor in our dermatology department between July 2020 and July 2022. The patients were reviewed over 2 years. A logistic regression model in rare events data (relogit) was used to predict the risk factors for ALD. RESULTS: Of the 226 patients, 14 had ALD. Data including age, body mass index, IL-17A inhibitor use, personal and family history of atopic disease, pet ownership history, and immunoglobulin E (IgE) levels were analysed using the relogit regression model. It indicated a personal history of atopic disease (odd ratio [OR] 27.830, 95% confidence interval [CI] 3.801-203.770; p = 0.001) and elevated IgE levels (OR 5.867, 95% CI 1.131-30.434; p = 0.035) as independent predictors of incident ALD. In one patient, anti-IL-17A therapy was discontinued, and treatment was switched to tofacitinib. Thirteen patients who continued with IL-17A inhibitor were treated with topical therapy and/or antihistamines, and their ALD was partially or completely resolved. CONCLUSION: In this study, the incidence rate of ALD was 6.19%. Elevated IgE levels and a personal history of atopic disease were found to be the risk factors for ALD. Our study findings suggest that treatment should be provided based on the severity of psoriasis and incident ALD. Prior to treatment, psoriasis patients who have the risk factors for ALD should be informed of the possible development of ALD, and alternative psoriatic therapeutic options should be considered if severe ALD develops.

Escherichia coli Promotes Endothelial to Mesenchymal Transformation of Liver Sinusoidal Endothelial Cells and Exacerbates Nonalcoholic Fatty Liver Disease Via Its Flagellin.

BACKGROUND＆AIMS: Gut bacteria translocate into the liver through a disrupted gut vascular barrier, which is an early and common event in the development of nonalcoholic fatty liver disease (NAFLD). Liver sinusoidal endothelial cells (LSECs) are directly exposed to translocated gut microbiota in portal vein blood. Escherichia coli, a commensal gut bacterium with flagella, is markedly enriched in the gut microbiota of patients with NAFLD. However, the impact of E coli on NAFLD progression and its underlying mechanisms remains unclear. METHODS: The abundance of E coli was analyzed by using 16S ribosomal RNA sequencing in a cohort of patients with NAFLD and healthy controls. The role of E coli was assessed in NAFLD mice after 16 weeks of administration, and the features of NAFLD were evaluated. Endothelial to mesenchymal transition (EndMT) in LSECs induced by E coli was analyzed through Western blotting and immunofluorescence. RESULTS: The abundance of gut Enterobacteriaceae increased in NAFLD patients with severe fat deposition and fibrosis. Importantly, translocated E coli in the liver aggravated hepatic steatosis, inflammation, and fibrosis in NAFLD mice. Mechanistically, E coli induced EndMT in LSECs through the TLR5/MYD88/TWIST1 pathway during NAFLD development. The toll-like receptor 5 inhibitor attenuated E coli-induced EndMT in LSECs and liver injury in NAFLD mice. Interestingly, flagellin-deficient E coli promoted less EndMT in LSECs and liver injury in NAFLD mice. CONCLUSIONS: E coli promoted the development of NAFLD and promoted EndMT in LSECs through toll-like receptor 5/nuclear factor kappa B-dependent activation of TWIST1 mediated by flagellin. Therapeutic interventions targeting E coli and/or flagellin may represent a promising candidate for NAFLD treatment.

Hydronidone ameliorates liver fibrosis by inhibiting activation of hepatic stellate cells via Smad7-mediated degradation of TGFßRI.

BACKGROUND AND PURPOSE: Liver fibrosis is a wound-healing reaction that eventually leads to cirrhosis. Hydronidone is a new pyridine derivative with the potential to treat liver fibrosis. In this study, we explored the antifibrotic effects of hydronidone and its potential mode of action. METHODS: The anti-hepatic fibrosis effects of hydronidone were studied in carbon tetrachloride (CCl4 )- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- induced animal liver fibrosis. The antifibrotic mechanisms of hydronidone were investigated in hepatic stellate cells (HSCs). The antifibrotic effect of hydronidone was further tested after Smad7 knockdown in HSCs in mouse models of fibrosis. RESULTS: In animal models, hydronidone attenuated liver damage and collagen accumulation, and reduced the expression of fibrosis-related genes. Hydronidone decreased the expression of fibrotic genes in HSCs. Impressively, hydronidone significantly upregulated Smad7 expression and promoted the degradation of transforming growth factor ß receptor I (TGFßRI) in HSCs and thus inhibited the TGFß-Smad signalling pathway. Specific knockdown of Smad7 in HSCs in vivo blocked the antifibrotic effect of hydronidone. CONCLUSION: Hydronidone ameliorates liver fibrosis by inhibiting HSCs activation via Smad7-mediated TGFßRI degradation. Hydronidone is a potential drug candidate for the treatment of liver fibrosis.

FABP4 in LSECs promotes CXCL10-mediated macrophage recruitment and M1 polarization during NAFLD progression.

BACKGROUND AND AIMS: Non-alcoholic liver disease (NAFLD) is emerging as the leading cause of end-stage liver disease with a serious threat to global health burden. Fatty acid-binding protein 4 (FABP4) is closely associated with metabolic syndromes. We aimed to explore the potential mechanisms of FABP4 in NAFLD progression. MATERIALS AND METHODS: For NAFLD mice, animals were fed with high fat diet (HFD) for 20 weeks. The assays of hematoxylin and eosin, Sirius Red, oil red O staining and immunohistology were performed to evaluate hepatic pathology. Flow cytometric analysis was used to distinguish macrophage subtypes. RESULTS: Serum FABP4 level was positively correlate with the severity of hepatic steatosis in NAFLD patients. FABP4 expression was mainly distributed in liver sinusoidal endothelial cells (LSECs), which was significantly increased in HFD mice. The level of CXCL10 was positively correlated with FABP4 at mRNA and serum level. FABP4 inhibition resulted in decreased expression of CXCL10. The percentage of M1 macrophage and CXCR3+ cells in infiltrated macrophage was increased in liver of HFD mice. Inhibition of FABP4 ameliorated HFD-induced M1 macrophage polarization as well as CXCR3+ macrophages recruitment. Recombinant CXCL10 and co-culturing with TMNK-1 stimulated macrophage toward M1 polarization, which could be reversed by CXCR3 inhibitor. Palmitic acid treatment resulted in increased nuclear P65 expression, which could be reversed by inhibiting FABP4. Cxcl10 expression was dramatically suppressed by NF-κB inhibitor. CONCLUSIONS: FABP4 in LSECs may play a pathogenic role in NAFLD course by promoting CXCL10-mediated macrophage M1 polarization and CXCR3+ macrophage infiltration via activating NF-κB/p65 signaling.