Loss of NAT10 alleviates maternal high-fat diet-induced hepatic steatosis in male offspring of mice.

OBJECTIVE: Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming an escalating health problem in pediatric populations. This study aimed to investigate the role of N-acetyltransferase 10 (NAT10) in maternal high-fat diet (HFD)-induced MASLD in offspring at early life. METHODS: We generated male hepatocyte-specific NAT10 knockout (Nat10HKO) mice and mated them with female Nat10fl/fl mice under chow or HFD feeding. Body weight, liver histopathology, and expression of lipid metabolism-associated genes (Srebp1c, Fasn, Pparα, Cd36, Fatp2, Mttp, and Apob) were assessed in male offspring at weaning. Lipid uptake assays were performed both in vivo and in vitro. The mRNA stability assessment and RNA immunoprecipitation were performed to determine NAT10-regulated target genes. RESULTS: NAT10 deletion in hepatocytes of male offspring alleviated perinatal lipid accumulation induced by maternal HFD, decreasing expression levels of Srebp1c, Fasn, Cd36, Fatp2, Mttp, and Apob while enhancing Pparα expression. Furthermore, Nat10HKO male mice exhibited reduced lipid uptake. In vitro, NAT10 promoted lipid uptake by enhancing the mRNA stability of CD36 and FATP2. RNA immunoprecipitation assays exhibited direct interactions between NAT10 and CD36/FATP2 mRNA. CONCLUSIONS: NAT10 deletion in offspring hepatocytes ameliorates maternal HFD-induced hepatic steatosis through decreasing mRNA stability of CD36 and FATP2, highlighting NAT10 as a potential therapeutic target for pediatric MASLD.

Day-to-Night Street View Image Generation for 24-Hour Urban Scene Auditing Using Generative AI.

A smarter city should be a safer city. Nighttime safety in metropolitan areas has long been a global concern, particularly for large cities with diverse demographics and intricate urban forms, whose citizens are often threatened by higher street-level crime rates. However, due to the lack of night-time urban appearance data, prior studies based on street view imagery (SVI) rarely addressed the perceived night-time safety issue, which can generate important implications for crime prevention. This study hypothesizes that night-time SVI can be effectively generated from widely existing daytime SVIs using generative AI (GenAI). To test the hypothesis, this study first collects pairwise day-and-night SVIs across four cities diverged in urban landscapes to construct a comprehensive day-and-night SVI dataset. It then trains and validates a day-to-night (D2N) model with fine-tuned brightness adjustment, effectively transforming daytime SVIs to nighttime ones for distinct urban forms tailored for urban scene perception studies. Our findings indicate that: (1) the performance of D2N transformation varies significantly by urban-scape variations related to urban density; (2) the proportion of building and sky views are important determinants of transformation accuracy; (3) within prevailed models, CycleGAN maintains the consistency of D2N scene conversion, but requires abundant data. Pix2Pix achieves considerable accuracy when pairwise day-and-night-night SVIs are available and are sensitive to data quality. StableDiffusion yields high-quality images with expensive training costs. Therefore, CycleGAN is most effective in balancing the accuracy, data requirement, and cost. This study contributes to urban scene studies by constructing a first-of-its-kind D2N dataset consisting of pairwise day-and-night SVIs across various urban forms. The D2N generator will provide a cornerstone for future urban studies that heavily utilize SVIs to audit urban environments.

Revealing the mechanism of Dahuang Huanglian Xiexin Decoction attenuates dysbiosis via IL-17 signaling pathway based on network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Dahuang Huanglian Xiexin Decoction (XXD), derived from Zhang Zhongjing's Treatise on Typhoid Fever, has a long history of medicinal use and is widely used for digestive system diseases. It is mainly composed of three natural medicines, including Dahuang (Rheum palmatum L.), Huanglian (Coptis chinensis Franch.), and Huangqin (Scutellaria baicalensis Georgi). Modern pharmacological research shows that the active ingredients of XXD can have a positive effect on intestinal flora regulatory effect, but its mechanism of action is unclear. AIMS OF THIS STUDY: Clarify the effect of XXD on regulating dysbiosis, and elucidate the mechanism of XXD in alleviating dysbiosis based on network pharmacology, molecular docking and experimental verification. METHODS: Histopathological observation and intestinal high-throughput sequencing were used to observe the effect. Preliminary prediction of the mechanism of action of XXD in treating dysbiosis through network pharmacology and molecular docking. Finally, the effect of XXD on the IL-17 signaling pathway was verified through in vivo experiments. RESULTS: Histopathology and high-throughput sequencing of intestinal flora indicated that XXD has a good regulatory effect on bacterial dysbiosis. At the same time, network pharmacology identified a total of 40 active compounds, 14 of which may be key compounds for XXD to treat dysbiosis. In addition, the study also revealed 14 potential key targets as well as the top 5 therapeutic targets: IL-6, TNF-α, IL-1ß, TP53 and PTGS2. GO and KEGG predicted the key pathway for IL-17 signaling pathway to play a role in XXD. In the verification of the prediction results, it was found that the above targets and the IL-17 target showed strong activity in molecular docking. Furthermore, it was found that XXD can reduce the levels of IL-17, IL-6, TNF-α, IL-1ß, p53 and COX-2 in serum, while inhibiting the expression of IL-17, IL-17RA, Act-1 and NF-κB protein and the mRNA expression of IL-17, IL-17RA and Act-1 in colon tissue. CONCLUSIONS: This study found that XXD has a good regulatory effect on dysbiosis and its induced symptoms. Network pharmacology was used to predict the key compounds and therapeutic targets of XXD, and preliminary experiments confirmed that XXD may regulate bacterial dysbiosis by inhibiting the IL-17 signaling pathway.

High-rate Gamma Spectrometry Using a LaBr3(Ce) Scintillator with a Fast Pulse Shaping.

ABSTRACT: The performance of a LaBr3(Ce) gamma spectrometer at high count rates was investigated up to an input count rate of 1.3 Mcps. In order to make its pulse processing faster, a preamplifier provided by the detector manufacturer was eliminated, and the signal from the photomultiplier tube was fed directly to a digital pulse processing system. To accomplish both fast pulse processing and good energy resolution, the pulse-shaping parameters were optimized at a low count rate of 1.5 kcps, and then measurements were carried out at various count rates. Input count rates ranging from 1.5 kcps to 21 kcps were produced using a set of 137Cs resin sources, while higher rates between 45 kcps and 1.3 Mcps were produced using a 1.2-GBq 137Cs source. The spectrometer showed an excellent performance for the input rate up to 150 kcps, while the dead time increased rapidly for the input rates above 150 kcps. The system dead time has been improved greatly by eliminating the preamplifier.

Torsion constants and virtual mechanical tests are valid image-based surrogate measures of ovine fracture healing.

In large animal studies, the mechanical reintegration of the bone fragments is measured using postmortem physical testing, but these assessments can only be performed once, after sacrifice. Image-based virtual mechanical testing is an attractive alternative because it could be used to monitor healing longitudinally. However, the procedures and software required to perform finite element analysis (FEA) on subject-specific models for virtual mechanical testing can be time consuming and costly. Accordingly, the goal of this study was to determine whether a simpler image-based geometric measure-the torsion constant, sometimes known as polar moment of inertia-can be reliably used as a surrogate measure of bone healing in large animals. To achieve this, postmortem biomechanical testing and microCT scans were analyzed for a total of 33 operated and 20 intact ovine tibiae. An image-processing procedure to compute the attenuation-weighted torsion constant from the microCT scans was developed in MATLAB and this code has been made freely available. Linear regression analysis was performed between the postmortem biomechanical data, the results of virtual mechanical testing using FEA, and the torsion constants measured from the scans. The results showed that virtual mechanical testing is the most reliable surrogate measure of postmortem torsional rigidity, having strong correlations and high absolute agreement. However, when FEA is not practical, the torsion constant is a viable alternative surrogate measure that is moderately correlated with postmortem torsional rigidity and can be readily calculated.

Novel and efficient techniques in the discovery of antioxidant peptides.

As a research hotspot in food science and nutrition, antioxidant peptides can function by scavenging free radicals, inhibiting peroxides, and chelating metal ions. Therefore, how to efficiently discover and screen antioxidant peptides has become a key issue in research and production. Traditional discovery methods are time-consuming and costly, but also challenging to resolve the quantitative structure-activity relationship of antioxidant peptides. Several novel techniques, including artificial intelligence, molecular docking, bioinformatics, quantum chemistry, phage display, switchSENSE, surface plasmon resonance, and fluorescence polarization, are emerging rapidly as solutions. These techniques possess efficient capability for the discovery of antioxidant peptides, even with the potential for high-throughput screening. In addition, the quantitative structure-activity relationship can be resolved. Notably, combining these novel techniques can overcome the drawbacks of a single one, thus improving efficiency and expanding the discovery horizon. This review has summarized eight novel and efficient techniques for discovering antioxidant peptides and the combination of techniques. This review aims to provide scientific evidence and perspectives for antioxidant peptide research.

Prolyl endopeptidase remodels macrophage function as a novel transcriptional coregulator and inhibits fibrosis.

Macrophages are immune cells crucial for host defense and homeostasis maintenance, and their dysregulation is involved in multiple pathological conditions, such as liver fibrosis. The transcriptional regulation in macrophage is indispensable for fine-tuning of macrophage functions, but the details have not been fully elucidated. Prolyl endopeptidase (PREP) is a dipeptidyl peptidase with both proteolytic and non-proteolytic functions. In this study, we found that Prep knockout significantly contributed to transcriptomic alterations in quiescent and M1/M2-polarized bone marrow-derived macrophages (BMDMs), as well as aggravated fibrosis in an experimental nonalcoholic steatohepatitis (NASH) model. Mechanistically, PREP predominantly localized to the macrophage nuclei and functioned as a transcriptional coregulator. Using CUT&Tag and co-immunoprecipitation, we found that PREP was mainly distributed in active cis-regulatory genomic regions and physically interacted with the transcription factor PU.1. Among PREP-regulated downstream genes, genes encoding profibrotic cathepsin B and D were overexpressed in BMDMs and fibrotic liver tissue. Our results indicate that PREP in macrophages functions as a transcriptional coregulator that finely tunes macrophage functions, and plays a protective role against liver fibrosis pathogenesis.

New murine model of alcoholic hepatitis in obesity-induced metabolic-associated fatty liver disease.

Metabolic-associated fatty liver disease (MAFLD) and alcoholic hepatitis (AH) are among the most prevalent liver diseases worldwide, and their coexistence is common in clinical practice. However, currently established models of MAFLD-AH coexistence do not fully replicate their pathological characteristics and require sophisticated experimental techniques. Therefore, we aimed to develop an easily replicable model that mimics obesity-induced MAFLD-AH in patients. Our goal was to establish a murine model that replicates MAFLD and AH coexistence, resulting in significant liver injury and inflammation. To this end, we administered a single ethanol gavage dose to ob/ob mice on a chow diet. The administration of a single dose of ethanol led to elevated serum transaminase levels, increased liver steatosis, and apoptosis in ob/ob mice. Furthermore, ethanol binge caused a significant increase in oxidative stress in ob/ob mice, as measured via 4-hydroxynonenal. Importantly, the single dose of ethanol also markedly exacerbated liver neutrophil infiltration and upregulated the hepatic mRNA expression of several chemokines and neutrophil-related proteins, including Cxcl1, Cxcl2, and Lcn2. Whole-liver transcriptomic analysis revealed that ethanol-induced changes in gene expression profile shared similar features with AH and MAFLD. In ob/ob mice, a single dose of ethanol binge caused significant liver injury and neutrophil infiltration. This easy-to-replicate murine model successfully mimics the pathological and clinical features of patients with coexisting MAFLD and AH and closely resembles the transcriptional regulation seen in human disease.

Premorbid Steatohepatitis Increases the Seriousness of Dextran Sulfate Sodium-induced Ulcerative Colitis in Mice.

Background and Aims: The concurrence of nonalcoholic steatohepatitis (NASH) and ulcerative colitis (UC) is increasingly seen in clinical practice, but the underlying mechanisms remain unclear. This study aimed to develop a mouse model of the phenomenon by combining high-fat high-cholesterol diet (HFHCD)-induced NASH and dextran sulfate sodium (DSS)-induced UC, that would support mechanistic studies. Methods: Male C57BL/6 mice were randomly assigned to two groups receiving either a chow diet or HFHCD for 12 weeks of NASH modeling. The mice were the divided into four subgroups for UC modeling: (1) A control group given a chow diet with normal drinking water; (2) A colitis group given chow diet with 2% DSS in drinking water; (3) A steatohepatitis group given HFHCD with normal drinking water; and (4) A steatohepatitis + colitis group given HFHCD with 2% DSS in drinking water. Results: NASH plus UC had high mortality (58.3%). Neither NASH nor UC alone were fatal. Although DSS-induced colitis did not exacerbate histological liver injury in HFHCD-fed mice, premorbid NASH significantly increased UC-related gut injury compared with UC alone. It was characterized by a significantly shorter colon, more colonic congestion, and a higher histopathological score (p<0.05). Inflammatory (tumor necrosis factor-alpha, interleukin 1 beta, C-C motif chemokine ligand 2, and nuclear factor kappa B) and apoptotic (Bcl2, Bad, Bim, and Bax) signaling pathways were significantly altered in distal colon tissues collected from mice with steatohepatitis + colitis compared with the other experimental groups. Conclusions: Premorbid steatohepatitis significantly aggravated DSS-induced colitis and brought about a lethal phenotype. Potential links between NASH and UC pathogeneses can be investigated using this model.

Ammonia Scavenger Restores Liver and Muscle Injury in a Mouse Model of Non-alcoholic Steatohepatitis With Sarcopenic Obesity.

Recent studies have revealed that sarcopenia is closely associated with obesity and non-alcoholic steatohepatitis (NASH). However, few attempted to explore the cause-and-effect relationship between sarcopenic obesity and NASH. In this study, we investigated muscular alterations in a rodent NASH model to elucidate their intrinsic relations and explore the potential therapeutic target. Forty-six 8-week-old and twenty 42-week-old male C57BL/6 mice (defined as young and middle-aged mice, respectively) were fed with a high-fat diet (HFD) for 12 or 20 weeks. A subset of young mice was subjected to ammonia lowering treatment by L-ornithine L-aspartate (LOLA). We examined body composition and muscle strength by nuclear magnetic resonance and grip strength meter, respectively. At the end of the 12th week, all HFD-fed mice developed typical steatohepatitis. Meanwhile, sarcopenia occurred in HFD-fed middle-aged mice, whereas young mice only demonstrated decreased grip strength. Until the end of week 20, young mice in the HFD group exhibited significant sarcopenia and obesity phenotypes, including decreased lean body mass and grip strength, and increased body fat mass and percentage body fat. Additionally, plasma ammonia level was markedly increased in HFD-fed mice of both ages at week 20. Plasma ammonia level was negatively associated with muscle strength and myofiber diameter in young mice. LOLA can significantly reduce plasma levels of ammonia, alanine aminotransaminase, aspartate aminotransaminase, and cholesterol in mice fed an HFD. Hepatic infiltration of inflammatory cells and collagen deposition area were significantly decreased in HFD group by LOLA treatment. Meanwhile, LOLA significantly increased lean body mass, grip strength, and average muscle fiber diameter of HFD-fed mice. These findings suggest that the occurrence of NASH precedes sarcopenia in HFD mice, and the steatohepatitis-related hyperammonemia might contribute to the pathogenesis of sarcopenia. LOLA might be an effective drug for both steatohepatitis and sarcopenic obesity.

Image-based radiodensity profilometry measures early remodeling at the bone-callus interface in sheep.

Bone healing has been traditionally described as a four-phase process: inflammatory response, soft callus formation, hard callus development, and remodeling. The remodeling phase has been largely neglected in most numerical mechanoregulation models of fracture repair in favor of capturing early healing using a pre-defined callus domain. However, in vivo evidence suggests that remodeling occurs concurrently with repair and causes changes in cortical bone adjacent to callus that are typically neglected in numerical models of bone healing. The objective of this study was to use image processing techniques to quantify this early-stage remodeling in ovine osteotomies. To accomplish this, we developed a numerical method for radiodensity profilometry with optimization-based curve fitting to mathematically model the bone density gradients in the radial direction across the cortical wall and callus. After assessing data from 26 sheep, we defined a dimensionless density fitting function that revealed significant remodeling occurring in the cortical wall adjacent to callus during early healing, a 23% average reduction in density compared to intact. This fitting function is robust for modeling radial density gradients in both intact bone and fracture repair scenarios and can capture a wide variety of the healing responses. The fitting function can also be scaled easily for comparison to numerical model predictions and may be useful for validating future mechanoregulatory models of coupled fracture repair and remodeling.

The burden and sexual dimorphism with nonalcoholic fatty liver disease in Asian children: A systematic review and meta-analysis.

BACKGROUND: Despite substantial attention paid to the epidemic of nonalcoholic fatty liver disease (NAFLD) in adults, data on the burden and sexual dimorphism of NAFLD in Asian children have not yet been synthesized. METHODS: We conducted a literature search of 735 references up to April 2021. Pooled analyses, stratified analyses and meta-regression were all performed. RESULTS: Thirty-three study populations were finally included. Nine of them comprising 20 595 children showed an overall NAFLD prevalence of 5.53% (95% CI 3.46%-8.72%), in which, 36.64% (95% CI, 27.99%-46.26%) NAFLD subjects had elevated levels of ALT. The prevalence rate of NAFLD increased about 1.6-fold from 2004 to 2010 to the last decade. Male predominant trends were observed in paediatric NAFLD (boys: 8.18%, 95% CI 4.93%-13.26%; girls: 3.60%, 95% CI 1.60%-7.87%). Moreover, meta-analysis showed that after 10 years of age, boys were more prone to have NAFLD than girls (OR = 1.75; P = .0012). In addition, the pooled prevalence of NAFLD increased sequentially in normal-weight (1.49%, 95% CI 0.88%-2.51%, n = 2610), overweight (16.72%, 95% CI 7.07%-34.65%, n = 1265) and obese children (50.13%, 95% CI 41.99%-58.27%, n = 6434 individuals). After full covariate adjustment, the multivariate meta-regression also showed that boy percentage (P = .0396) and body mass index (P < .0001) were positively correlated with prevalent NAFLD. CONCLUSIONS: In Asia, paediatric NAFLD is becoming prevalent over the recent decades, particularly among obese children and boys after 10 years old. The hormonal and chromosomal origins of paediatric NAFLD dimorphism need further investigation.

Efficacy of Intragastric Balloons in the Markers of Metabolic Dysfunction-associated Fatty Liver Disease: Results from Meta-analyses.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease, now renamed metabolic dysfunction-associated fatty liver disease (MAFLD), is common in obese patients. Intragastric balloon (IGB), an obesity management tool with low complication risk, might be used in MAFLD treatment but there is still unexplained heterogeneity in results across studies. METHODS: We conducted a systematic search of 152 citations published up to September 2020. Meta-analyses, stratified analyses, and meta-regression were performed to evaluate the efficacy of IGB on homeostasis model assessment of insulin resistance (HOMA-IR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT), and to identify patients most appropriate for IGB therapy. RESULTS: Thirteen observational studies and one randomized controlled trial met the inclusion criteria (624 participants in total). In the overall estimate, IGB therapy significantly improved the serum markers change from baseline to follow-up [HOMA-IR: 1.56, 95% confidence interval (CI)=1.16-1.95; ALT: 11.53 U/L, 95% CI=7.10-15.96; AST: 6.79 U/L, 95% CI=1.69-11.90; GGT: 10.54 U/L, 95% CI=6.32-14.75]. In the stratified analysis, there were trends among participants with advanced age having less change in HOMA-IR (1.07 vs. 1.82). The improvement of insulin resistance and liver biochemistries with swallowable IGB therapy was no worse than that with endoscopic IGB. Multivariate meta-regression analyses showed that greater HOMA-IR loss was predicted by younger age (p=0.0107). Furthermore, effectiveness on ALT and GGT was predicted by basal ALT (p=0.0004) and GGT (p=0.0026), respectively. CONCLUSIONS: IGB is effective among the serum markers of MAFLD. Younger patients had a greater decrease of HOMA-IR after IGB therapy.

Sodium Butyrate Supplementation Inhibits Hepatic Steatosis by Stimulating Liver Kinase B1 and Insulin-Induced Gene.

BACKGROUND AND AIMS: Butyric acid is an intestinal microbiota-produced short-chain fatty acid, which exerts salutary effects on alleviating nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism of butyrate on regulating hepatic lipid metabolism is largely unexplored. METHODS: A mouse model of NAFLD was induced with high-fat diet feeding, and sodium butyrate (NaB) intervention was initiated at the eighth week and lasted for 8 weeks. Hepatic steatosis was evaluated and metabolic pathways concerning lipid homeostasis were analyzed. RESULTS: Here, we report that administration of NaB by gavage once daily for 8 weeks causes an augmentation of insulin-induced gene (Insig) activity and inhibition of lipogenic gene in mice fed with high-fat diet. Mechanistically, NaB is sufficient to enhance the interaction between Insig and its upstream kinase AMP-activated protein kinase (AMPK). The stimulatory effects of NaB on Insig-1 activity are abolished in AMPKα1/α2 double knockout (AMPK-/-) mouse primary hepatocytes. Moreover, AMPK activation by NaB is mediated by LKB1, as evidenced by the observations showing NaB-mediated induction of phosphorylation of AMPK, and its downstream target acetyl-CoA carboxylase is diminished in LKB1-/- mouse embryonic fibroblasts. CONCLUSIONS: These studies indicate that NaB serves as a negative regulator of hepatic lipogenesis in NAFLD and that NaB attenuates hepatic steatosis and improves lipid profile and liver function largely through the activation of LKB1-AMPK-Insig signaling pathway. Therefore, NaB has therapeutic potential for treating NAFLD and related metabolic diseases.

Domain-independent simulation of physiologically relevant callus shape in mechanoregulated models of fracture healing.

Mechanoregulatory models have been used to predict the progression of bone fracture healing for more than two decades. However, many published studies share the same fundamental limitation: callus development proceeds within a pre-defined domain that both restricts and directs healing and leads to some non-physiologic healing patterns. To address this limitation, we added two spatial proximity functions to an existing mechanoregulatory model of fracture healing to control the localization of callus within the healing domain. We tested the performance of the new model in an idealized ovine tibial osteotomy with medial plate fixation using three sizes of healing domains and multiple variations of the spatial proximity functions. All model variations produced outward callus growth and bridging weighted toward the far cortex, which is consistent with in vivo healing. With and without the proximity functions, there were marked differences in the predicted callus volume and shape. With no proximity functions, the callus produced was strongly domain dependent, with a 15% difference in volume between the smallest and largest initialization domains. With proximity function control, callus growth was restricted to near the fracture line and there was only 2% difference in volume between domain sizes. Superimposing both proximity functions - one to control outward growth and one representing a decay in periosteal activity away from the fracture - produced a predicted callus size that was within the physiologic range for sheep and had a realistic morphology when compared with fluorescent dye co-localization with calcium deposition over time and histology.

Interleukin-20 exacerbates acute hepatitis and bacterial infection by downregulating IκBζ target genes in hepatocytes.

BACKGROUND & AIMS: Interleukin (IL)-20 and IL-22 belong to the IL-10 family. IL-10 is a well-documented anti-inflammatory cytokine while IL-22 is well known for epithelial protection and its antibacterial function, showing great therapeutic potential for organ damage; however, the function of IL-20 remains largely unknown. METHODS: Il20 knockout (Il20-/-) mice and wild-type littermates were generated and injected with Concanavalin A (ConA) and Klebsiella pneumoniae (K.P.) to induce acute hepatitis and bacterial infection, respectively. RESULTS: Il20-/- mice were resistant to acute hepatitis and exhibited selectively elevated levels of the hepatoprotective cytokine IL-6. Such selective inhibition of IL-6 by IL-20 was due to IL-20 targeting hepatocytes that produce high levels of IL-6 but a limited number of other cytokines. Mechanistically, IL-20 upregulated NAD(P)H: quinone oxidoreductase 1 (NQO1) expression and subsequently promoted the protein degradation of transcription factor IκBζ, resulting in selective downregulation of the IκBζ-dependent gene Il6 as well several other IκBζ-dependent genes including lipocalin-2 (Lcn2). Given the important role of IL-6 and LCN2 in limiting bacterial infection, we examined the effect of IL-20 on bacterial infection and found Il20-/- mice were resistant to K.P. infection and exhibited elevated levels of hepatic IκBζ-dependent antibacterial genes. Moreover, IL-20 upregulated hepatic NQO1 by binding to IL-22R1/IL-20R2 and activating ERK/p38MAPK/NRF2 signaling pathways. Finally, the levels of hepatic IL1B, IL20, and IκBζ target genes were elevated, and correlated with each other, in patients with severe alcoholic hepatitis. CONCLUSIONS: IL-20 selectively inhibits hepatic IL-6 production rather than exerting IL-10-like broad anti-inflammatory properties. Unlike IL-22, IL-20 aggravates acute hepatitis and bacterial infection. Thus, anti-IL-20 therapy could be a promising option to control acute hepatitis and bacterial infection. LAY SUMMARY: Several interleukin (IL)-20 family cytokines have been shown to play important roles in controllimg inflammatory responses, infection and tissue damage, but the role of IL-20 remains unclear. Herein, we elucidated the role of IL-20 in liver disease and bacterial infection. We show that IL-20 can aggravate hepatitis and bacterial infection; thus, targeting IL-20 holds promise for the treatment of patients with liver disease.

A new 7-gene survival score assay for pancreatic cancer patient prognosis prediction.

Gene expression features that are valuable for pancreatic ductal adenocarcinoma (PDAC) prognosis are still largely unknown. We aimed to explore pivotal molecular signatures for PDAC progression and establish an efficient survival score to predict PDAC prognosis. Overall, 163 overlapping genes were identified from three statistical methods, including differentially expressed genes (DEGs), coexpression network analysis (WGCNA), and target genes for miRNAs that were significantly related to PDAC patients' overall survival (OS). Then, according to the optimal value of the cross-validation curve (lambda = 0.031), 7 non-zero coefficients (ARNTL2, DSG3, PTPRR, ANLN, S100A14, ANKRD22, and TSPAN7) were selected to establish a prognostic prediction model of PDAC patients. We further confirmed the expression level of 7 genes using RT-PCR, western blot, and immunohistochemistry staining in PDAC patients' tissues. Our results showed that the ROC curve of the 7-mRNA model indicated good predictive ability for 1- and 2-year OS in three datasets (TCGA: 0.71, 0.69; ICGC: 0.8, 0.74; GEO batch: 0.61, 0.7, respectively). The hazard ratio (HR) of the low-risk group had a similar significant result (TCGA: HR = 0.3723; ICGC: HR = 0.2813; GEO batch: HR = 0.4999; all P < 0.001). Furthermore, Log-rank test results in three cohorts showed that the 7-mRNA assay excellently predicted the prognosis and metastasis, especially in TNM stage I&II subgroups of PDAC. In conclusion, the strong validation of our 7-mRNA signature indicates the promising effectiveness of its clinical application, especially in patients with TNM stages I&II.

S100A16 induces epithelial-mesenchymal transition in human PDAC cells and is a new therapeutic target for pancreatic cancer treatment that synergizes with gemcitabine.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a poor 5-year survival rate of approximately 6%, mostly due to poor treatment response and early progression. The S100 gene family participates in various pathophysiological processes in various malignancies. S100A16 is a member of the S100 family, which is abnormally expressed in PDAC; however, its biological functions and mechanisms of action remain unclear. We analysed the Gene Expression Omnibus (GEO) public database and the gene ChIP data collected in our previous study of human PDAC cell line PANC-1 cocultured with M2 macrophages to identify differentially expressed genes (DEGs). Twenty-three overexpressed genes were identified by screening. Then, the selected genes were analysed using The Cancer Genome Atlas (TCGA) database to assess whether they have significant impact on the overall survival (OS) of PDAC patients. Of the 14 DEGs identified, S100A16 was associated with poor prognosis and was selected for further investigation; the results indicate that S100A16 is positively correlated with epithelial-mesenchymal transition (EMT)-related genes in the TCGA dataset. Subsequent in vitro and in vivo experiments demonstrated that S100A16 induces the EMT to promote the metastasis of human PDAC cells and that the effect is mediated by the enhanced expression of TWIST1 and activation of the STAT3 signalling pathway. The antitumour effect of gemcitabine (GEM) was enhanced in combination with S100A16 downregulation. In conclusion, our findings suggest that S100A16 is a novel potential therapeutic target for human PDAC treatment.