Polyguanine alleviated autoimmune hepatitis through regulation of macrophage receptor with collagenous structure and TLR4-TRIF-NF-κB signalling.

Autoimmune hepatitis (AIH) is a progressive and chronic inflammatory disease in the liver. MARCO is a surface receptor of macrophage involving in tissue inflammation and immune disorders. Moreover, polyguanine (PolyG) is considered to bind to macrophage receptor with collagenous structure (MARCO). However, the role of MARCO and PolyG in the development and treatment of AIH still remains unclear. Therefore, this study explores the expression of MARCO and therapeutic activity of PolyG in both S100-induced AIH in mouse and Lipopolysaccharide (LPS)-treated macrophage (RAW264.7 cells). Moreover, there were significant increases in inflammatory factors and MARCO, as well as decrease in I-kappa-B-alpha (Ik-B) in the liver of AIH mice and LPS-induced cells. However, PolyG treatment significantly reversed the elevation of inflammatory cytokins, MARCO and reduction of Ik-B. In addition, PolyG treatment could downregulate the expression of Toll-like receptor 4 (TLR4) and TIR-domain-containing adaptor inducing interferon-ß (TRIF), decrease macrophage M1 polarization and increase macrophage M2 polarization. When hepatocytes were co-cultured with different treatment of macrophages, similar expression profile of inflammatory cytokines was observed in hepatocytes. The research revealed that MARCO expression was elevated in AIH mice. PolyG treatment and inhibition of MARCO significantly reduced inflammatory cytokines expression in the liver as well as hepatocytes and macrophages. Therefore, MARCO could be a target for the treatment of AIH.

Nimbolide attenuated the inflammation in the liver of autoimmune hepatitis's mice through regulation of HDAC3.

A chronic liver disease named autoimmune hepatitis (AIH) will carry elevated levels of inflammatory cytokines, but there is currently no effective treatment to cure it. Histone deacetylase 3 (HDAC3) takes an important position in regulating the expression of inflammatory genes. Nimbolide (NIB) is a limonoid extracted from the neem tree (Azadirachta indica) that has been found to be effective against many diseases, including cancer, scleroderma, and acute respiratory distress syndrome. Here, we investigated the protective effect of nimbolide on AIH liver. Mice and AML12 cells were employed to establish AIH model with liver antigen S100 and cell injury model of LPS, and then treated with different concentrations of nimbolide. After the successful establishment of the animal model and cell model, inflammatory cytokines of IL-1ß, IL-6 and TNF-α as well as cellular signaling related to inflammation such as STAT3, IκB-α and NF-κB were examined. We observed for the first time about nimbolide can effectively inhibit inflammation in AIH mice's liver and AML12 cells by inhibiting HDAC3 expression. HDAC3 knocked down by siRNA in cells can also effectively alleviate the inflammation in AML12 cells, further confirming that HDAC3 plays an important role in the inflammation of liver cells. These results suggest nimbolide could be a potential new treatment for autoimmune hepatitis, and HDAC3 may become a new target for autoimmune hepatitis.

The neutrophil percentage-to-albumin ratio is associated with all-cause mortality in critically ill patients with acute myocardial infarction.

AIM: In this study, we evaluated the utility of neutrophil percentage-to-albumin ratio (NPAR) in predicting in critically ill patients with acute myocardial infarction (AMI). METHODS: The information of patients were collected from Medical Information Mart for Intensive Care III database. Admission NPAR was calculated as neutrophil percentage divided by serum albumin. The endpoints of this study were 30-day, 90-day, 180-day, and 365-day all-cause mortality. Cox proportional hazards models and subgroup analyses were used to determine the relationship between admission NPAR and these endpoints. RESULTS: 798 critically ill patients with AMI were enrolled in. After adjustments for age, race and gender, higher admission NPAR was associated with increased risk of 30-day, 90-day, 180-day, and 365-day all-cause mortality in critically ill patients with AMI. And after adjusting for possible confounding variables, two different trends have emerged. Stratified by tertiles, high admission NPAR was independently associated with 180-day and 365-day all-cause mortality in critically ill patients with AMI (tertile 3 vs. tertile 1: adjusted HR, 95% CI 1.71, 1.10-2.66, p < 0.05; 1.66, 1.10-2.51, p < 0.05). In other hand, stratified by quartiles, highest admission NPAR levels were independently associated with 90-day, 180-day and 365-day all-cause mortality (quartile 4 vs. quartile 1: adjusted HR, 95% CI 2.36, 1.32-4.23, p < 0.05; 2.58, 1.49-4.47, p < 0.05; 2.61, 1.56-4.37, p < 0.05). ROC test showed that admission NPAR had a moderate ability to predict all-cause mortality of critically ill patients with AMI. No obvious interaction was found by subgroup analysis in most subgroups. CONCLUSIONS: Admission NPAR was an independent predictor for 180-day and 365-day all-cause mortality in critically ill patients with AMI.

Effects of high-pressure processing on the physicochemical properties and glycemic index of fruit puree in a hyperglycemia mouse model.

BACKGROUND: In this study, the duration of high-pressure processing (HPP) required to achieve a 5 log reduction of Escherichia coli O157:H7 in fruit purees was evaluated. Banana, cantaloupe, and dragon fruit purees were subjected to HPP at 600 MPa for 300, 270, and 270 s, respectively, and their physicochemical properties and enzyme activities were then analysed. Diabetic mice were fed fresh and HPP-treated purees to observe their effects on the glycemic index (GI) and postprandial blood glucose response. RESULTS: Compared with their fresh counterparts, the HPP-treated banana and dragon fruit purees exhibited significantly higher viscosities, lower glucose concentrations, and higher glucose dialysis retardation indices and showed disrupted sucrose invertase and polygalacturonase activities. The GI and postprandial blood glucose response were not significantly different between the fresh and HPP-treated cantaloupe purees. By contrast, the peak time of glucose response (Tmax ) was delayed from 30 min to 60 min, and the area under the receiver operating characteristic curve was reduced by 40% in the mice fed HPP-treated banana and dragon fruit purees. The GIs of the HPP-treated banana and dragon fruit purees (were 50.3 and 44.8, respectively) were significantly lower than those of their fresh counterparts (85.1 and 75.2, respectively). CONCLUSION: HPP can change the physicochemical properties of fruit purees, resulting in stabilized blood glucose levels and lower GIs after consumption. Therefore, purees processed in this manner would benefit consumers and patients with diabetes/pre-diabetes who need to maintain stable blood glucose levels (Fig. S1). © 2022 Society of Chemical Industry.

An efficient approach for identifying important biomarkers for biomedical diagnosis.

In this paper, we explore the challenges associated with biomarker identification for diagnosis purpose in biomedical experiments, and propose a novel approach to handle the above challenging scenario via the generalization of the Dantzig selector. To improve the efficiency of the regularization method, we introduce a transformation from an inherent nonlinear programming due to its nonlinear link function into a linear programming framework under a reasonable assumption on the logistic probability range. We illustrate the use of our method on an experiment with binary response, showing superior performance on biomarker identification studies when compared to their conventional analysis. Our proposed method does not merely serve as a variable/biomarker selection tool, its ranking of variable importance provides valuable reference information for practitioners to reach informed decisions regarding the prioritization of factors for further investigations.

Ranking the risk of antibiotic resistance genes by metagenomic and multifactorial analysis in hospital wastewater systems.

Antimicrobial resistance poses a serious threat to human health. Hospital wastewater system (HWS) is an important source of antibiotic resistance genes (ARGs). The risk of ARGs in HWS is still an under-researched area. In this study, we collected publicly metagenomic datasets of 71 hospital wastewater samples from 18 hospitals in 13 cities. A total of 9838 contigs were identified to carry 383 unique ARGs across all samples, of which 2946 contigs were plasmid-like sequences. Concurrently, the primary hosts of ARGs within HWS were found to be Escherichia coli and Klebsiella pneumoniae. To further evaluate the risk of each ARG subtype, we proposed a risk assessment framework based on the importance of corresponding antibiotics as defined by the WHO and three other indicators - ARG abundance (A), mobility (M), and host pathogenicity (P). Ninety ARGs were identified as R1 ARGs having high-risk scores, which meant having a high abundance, high mobility, and carried by pathogens in HWS. Furthermore, 25% to 49% of genomes from critically important pathogens accessed from NCBI carried R1 ARGs. A significantly higher number of R1 ARGs was carried by pathogens in the effluents of municipal wastewater treatment plants from NCBI, highlighting the role of R1 ARGS in accelerating health and environmental risks.

Microplastics exacerbate co-occurrence and horizontal transfer of antibiotic resistance genes.

Microplastic pollution is a rising environmental issue worldwide. Microplastics can provide a niche for the microbiome, especially for antibiotic-resistant bacteria, which could increase the transmission of antibiotic resistance genes (ARGs). However, the interactions between microplastics and ARGs are still indistinct in environmental settings. Microplastics were found to be significantly correlated with ARGs (p < 0.001), based on the analysis of samples taken from a chicken farm and its surrounding farmlands. Analysis of chicken feces revealed the highest abundance of microplastics (14.9 items/g) and ARGs (6.24 ×108 copies/g), suggesting that chicken farms could be the hotspot for the co-spread of microplastics and ARGs. Conjugative transfer experiments were performed to investigate the effects of microplastic exposure for different concentrations and sizes on the horizontal gene transfer (HGT) of ARGs between bacteria. Results showed that the microplastics significantly enhanced the bacterial conjugative transfer frequency by 1.4-1.7 folds indicating that microplastics could aggravate ARG dissemination in the environment. Potential mechanisms related to the up-regulation of rpoS, ompA, ompC, ompF, trbBp, traF, trfAp, traJ, and down-regulation of korA, korB, and trbA were induced by microplastics. These findings highlighted the co-occurrence of microplastics and ARGs in the agricultural environment and the exacerbation of ARGs' prevalence via rising the HGT derived from microplastics.

High hydrostatic pressure treatment induced microstructure changes and isothiocyanates biosynthesis in kale.

Effects of high-pressure processing (HPP) on the myrosinase activity, glucosinolate (GLS) content, isothiocyanate (ITC) conversion rate, color, and bacterial count of kale leaves were investigated. Thermal process at 100 °C were used as negative control groups. The sample processed at 600 MPa exhibited the highest myrosinase activity and ITC conversion rate of 70.4%, while the GLS content was significantly lower than those in the raw and the thermally processed samples. However, processing of the samples at elevated temperatures results in gradual loss of myrosinase activity. SEM images showed that HPP induces irregular crushing damage to the veins, edges, and surfaces of the leaves, thereby promoting the conversion process in the myrosinase-GLS-ITC system. Additionally, HPP caused less significant color change of the kale leaves than thermal treatment. HPP achieved the same level of pasteurization as thermal treatment in terms of bacterial count.

Effect of high pressure pretreatment on myrosinase-glucosinolate system, physicochemical and bacterial properties during fermentation of brine-pickled radishes.

The myrosinase-glucosinolate system, physicochemical properties, and bacterial community were profiled during fermentation of high hydrostatic pressure (HHP) pretreated brine-pickled radishes; traditionally brine-pickled radishes were utilised as the control. Scanning electron microscopy (SEM) analysis revealed that 300 MPa pretreatment promoted brine infiltration in radish cells and damaged cellular microstructures, which activated the myrosinase-glucosinolate system. The conversion of glucosinolate (GLs) to isothiocyanates (ITC) increased and significantly enhanced the raphasatin and sulforaphene contents of pickled radish. However, 600 MPa pretreatment suppressed myrosinase activity. HHP pretreatment altered the natural radish bacterial communities by reducing the total bacterial and lactic acid bacteria counts. Lactobacillus spp. became the dominant bacterial genus within 15 d of fermentation. However, the destruction of cellular structures by HHP pretreatment also significantly decreased hardness and caused the dissolution of amino acids and TTA into brine. This caused reduced amino acid and TTA contents compared to the control group, as well as decreases in pH. HHP pretreatment suppressed the growth of spoilage bacteria (e.g. Pseudomonas, Staphylococcus, and Shewanella genera). This study provides new insight into the potential applications of HHP treatment in pickling, as it demonstrates that HHP can increase the ITC conversion rate of pickled radish, modify its physiochemical characteristics, and decrease microbial risk. Therefore, HHP is a promising preprocessing technique to be used for pickle manufacturing industry.

Involvement of hypothalamic PI3K-STAT3 signalling in regulating appetite suppression mediated by amphetamine.

BACKGROUND AND PURPOSE: Appetite suppression induced by amphetamine has been attributed to its inhibition of neuropeptide Y (NPY) neurons and activation of pro-opiomelanocortin (POMC) neurons in the hypothalamus. This study examined whether STAT3 was involved in these actions of amphetamine. EXPERIMENTAL APPROACH: Rats were given amphetamine daily for 4 days. Changes in the expression of NPY, POMC, melanocortin MC3 receptors, PI3K and STAT3 in the hypothalamus were assessed by RT-PCR and Western blotting. Antisense oligonucleotides to STAT3 were also used. KEY RESULTS: Expression of NPY decreased with a maximum effect day 2 of amphetamine treatment. Expression of POMC, MC3 receptors, PI3K and STAT3 increased with a maximum response on day 2. Moreover, phosphorylation of STAT3 and its DNA binding activity increased and was expressed in a similar pattern. Infusion (i.c.v.) of STAT3 antisense at 60 min before amphetamine treatment, partly blocked amphetamine-induced anorexia and modulated expression of NPY, POMC, MC3 receptors and PI3K, indicating the involvement of STAT3 in amphetamine-treated rats. CONCLUSIONS AND IMPLICATIONS: Hypothalamic PI3K-STAT3 signalling participated in the regulation of NPY- and POMC-mediated appetite suppression. These findings may contribute to a better understanding of anorectic drugs.

The grainyhead-like 2 gene (GRHL2) single nucleotide polymorphism is not associated with age-related hearing impairment in Han Chinese.

OBJECTIVES/HYPOTHESIS: The grainyhead-like 2 gene (GRHL2) was found to be associated with age-related hearing impairment (ARHI) in Europeans. We tested whether the same association exists in the Han Chinese population. STUDY DESIGN: Individual cohort study. METHODS: Among a total of 1,175 Han Chinese volunteers, 310 were classified into the case group (the 26% with poorest hearing), and 308 were placed into the control group (the 26% with best hearing) according to the Zhigh scores converted from the original frequency-specific hearing thresholds. The GRHL2 single nucleotide polymorphism locus (rs10955255: A/G) in intron 1 (coordinate: 102605581) shown in the HapMap was genotyped with correlation to the audiologic phenotypes. RESULTS: The genotype distributions of GRHL2 (AA/AG/GG) were not significantly different between the control and the case groups (P = .349). Compared to genotype AA, the odds ratios of the GRHL2 genotypes AG and GG for ARHI were not significantly different after adjustment for other environmental risk factors by logistic regression analyses; 0.78 ± 0.139, 95% confidence interval (CI) = 0.55-1.10, P = .160 for AG; 0.85 ± 0.283, 95% CI = 0.44-1.63, P = .625 for GG. In each audiogram pattern, AA was most common, but the adjusted odds ratios of the genotypes AG and GG for ARHI still were not significantly different. CONCLUSIONS: Our results showed no positive association between GRHL2 polymorphisms and ARHI in Han Chinese individuals. Population differences might be a key factor leading to nonreplication of the association.