Novel Immune-Related Gene-Based Signature Characterizing an Inflamed Microenvironment Predicts Prognosis and Radiotherapy Efficacy in Glioblastoma

Effective treatment of glioblastoma (GBM) remains an open challenge. Given the critical role of the immune microenvironment in the progression of cancers, we aimed to develop an immune-related gene (IRG) signature for predicting prognosis and improving the current treatment paradigm of GBM. Multi-omics data were collected, and various bioinformatics methods, as well as machine learning algorithms, were employed to construct and validate the IRG-based signature and to explore the characteristics of the immune microenvironment of GBM. A five-gene signature (ARPC1B, FCGR2B, NCF2, PLAUR, and S100A11) was identified based on the expression of IRGs, and an effective prognostic risk model was developed. The IRG-based risk model had superior time-dependent prognostic performance compared to well-studied molecular pathology markers. Besides, we found prominent inflamed features in the microenvironment of the high-risk group, including neutrophil infiltration, immune checkpoint expression, and activation of the adaptive immune response, which may be associated with increased hypoxia, epidermal growth factor receptor (EGFR) wild type, and necrosis. Notably, the IRG-based risk model had the potential to predict the effectiveness of radiotherapy. Together, our study offers insights into the immune microenvironment of GBM and provides useful information for clinical management of this desperate disease.

NLRP6 Inflammasome Modulates Disease Progression in a Chronic-Plus-Binge Mouse Model of Alcoholic Liver Disease

A considerable percentage of the population is affected by alcoholic liver disease (ALD). It is characterized by inflammatory signals from the liver and other organs, such as the intestine. The NLR family pyrin domain containing 6 (NLRP6) inflammasome complex is one of the most important inflammatory mediators. The aim of this study was to evaluate a novel mouse model for ALD characterized by 8-week chronic-plus-binge ethanol administration and to investigate the role of NLRP6 inflammasome for intestinal homeostasis and ALD progression using Nlrp6-/- mice. We showed that chronic-plus-binge ethanol administration triggers hepatic steatosis, injury, and neutrophil infiltration. Furthermore, we discovered significant changes of intestinal microbial communities, including increased relative abundances of bacteria within the phyla Bacteroidota and Campilobacterota, as well as reduced Firmicutes. In this ALD model, inhibiting NLRP6 signaling had no effect on liver steatosis or damage, but had a minor impact on intestinal homeostasis via affecting intestinal epithelium function and gut microbiota. Surprisingly, Nlrp6 loss resulted in significantly decreased hepatic immune cell infiltration. As a result, our novel mouse model encompasses several aspects of human ALD, such as intestinal dysbiosis. Interfering with NLRP6 inflammasome activity reduced hepatic immune cell recruitment, indicating a disease-aggravating role of NLRP6 during ALD.

A Novel Approach to Minimising Acute Equine Endometritis That May Help to Prevent the Development of the Chronic State

One of the most commonly encountered challenges in equine breeding is endometritis, which can be difficult to resolve and causes considerable economic losses to the industry. It is a multifactorial condition, developing as an exaggerated form of the normal physiological response to breeding. Seminal plasma proteins, spermatozoa, bacteria and debris initiate an inflammatory response; the resulting fluid and neutrophils are then cleared from the uterus along with the debris. However, in some mares, the response is prolonged or exaggerated, with much fluid formation and neutrophil infiltration leading to acute endometritis. A bacterial cause has been implicated, although in some cases no pathogenic organisms can be isolated on culture. It has been postulated that any one of a variety of bacteria could be involved, or dysbiosis of the uterine microbiome could be responsible. Repeated episodes of acute endometritis may lead to the pathology associated with chronic endometritis, with mucociliary dysfunction, vascular degeneration and plasma cell infiltration. This review examines the information that is currently available about equine endometritis, particularly about the role of the inseminate in the uterus, and its current treatment. There are some promising lines of research into treatment or prevention that may help to resolve the issue.

Clinical, histological and molecular profiling of different stages of alcohol-related liver disease

ObjectiveAlcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the life-threatening decompensated phenotype, known as alcohol-related hepatitis (AH). A multidimensional study of the clinical, histological and molecular features of these subtypes is lacking.DesignTwo large cohorts of patients were recruited in an international, observational multicentre study: a retrospective cohort of patients with ndALD (n=110) and a prospective cohort of patients with AH (n=225). Clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis of both disease phenotypes were performed.ResultsAge and mean alcohol intake were similar in both groups. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma-glutamyl transferase levels than in ndALD patients. Patients with AH demonstrated profound liver failure and increased mortality. One-year mortality was 10% in ndALD and 50% in AH. Histologically, steatosis grade, ballooning and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration and ductular reaction were more frequent among AH patients. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compare to controls. While ndALD was characterised by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in a marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism.ConclusionsDespite comparable alcohol intake, AH patients presented with worse liver function compared with ndALD patients. Bilirubinostasis, severe fibrosis and ductular reaction were prominent features of AH. AH patients exhibited a more profound deregulation of gene expression compared with ndALD patients.

Host tp53 mutation induces gut dysbiosis eliciting inflammation through disturbed sialic acid metabolism

Background Host tp53 mutations are frequently found during the early stages of colitis-associated colorectal cancer (CAC), but whether such mutations induce gut microbiota dysbiosis and chronic intestinal inflammation that contributes to the development of CAC, remains unknown. Results We found that zebrafish tp53 mutant larvae exhibited elevated intestinal inflammation, by monitoring the NFκB activity in the mid-distal intestines of zebrafish larvae using an NFκB:EGFP transgenic reporter line in vivo as well as neutrophil infiltration into the intestine. This inflammation was due to dysbiotic gut microbiota with reduced diversity, revealed using both 16S rRNA amplicon sequencing and a germfree larva model. In this dysbiosis, Aeromonas spp. were aberrantly enriched as major pathobionts and exhibited the capacity for aggressive colonization in tp53 mutants. Importantly, the ex-germfree experiments supported the causality of the host tp53 mutation for inducing the inflammation. Transcriptome and high-performance liquid chromatography analyses of the host gastrointestinal tracts identified dysregulated sialic acid (SA) metabolism concomitant with increased host Neu5Gc levels as the key determinant of aberrant inflammation, which was reversed by the sialidase inhibitors oseltamivir and Philippin A. Conclusions These results demonstrate a crucial role for host tp53 in maintaining symbiosis and immune homeostasis via SA metabolism. Disturbed SA metabolism via a tp53 mutation may be exploited by specific elements of the gut microbiome, eliciting both dysbiosis and inflammation. Manipulating sialometabolism may therefore provide an efficacious therapeutic strategy for tp53 mutation-induced dysbiosis, inflammation, and ultimately, related cancers.

Neutrophil Infiltration Induces Myocardial Injury in COVID-19 Post-Mortem Cases

Background: The pathological features of severe cardiac injury induced by COVID-19 and relevant clinical features is unknown. This post-mortem study intended to determine the pathological findings of hearts from critically ill COVID-19 cases and explore the association of pathological changes and clinical characteristics.Methods: This autopsy cohort study, including hearts from 26 deceased COVID-19 patients admitted in intensive care unit, was conducted at four sites in Wuhan, China. Pathological changes were evaluated using hematoxylin and eosin, and immunohistochemical staining. Cases were divided into neutrophil-infiltration group and no-neutrophil group according to histopathological identification of neutrophilic infiltrates or not. Results: Among 26 cases, four cases had active myocarditis with histopathological examination. All cases with myocarditis accompanied with extensive neutrophil infiltration, while cases without myocarditis did not. Detection rates of interleukin-6 and tumor necrosis factor-α in neutrophil-infiltration group were significantly higher compared to no-neutrophil group. At admission, patients with neutrophil infiltration in myocardium had significantly higher baseline values of aspartate aminotransferase, D dimer and high-sensitivity C reactive protein compared to other 22 patients (P<0.05 for all). During hospitalization, patients with neutrophil infiltration had a significantly higher maximum of creatine kinase (CK)-MB than patients without neutrophil infiltration. Conclusions: In hearts from deceased patients with severe COVID-19, active myocarditis was commonly infiltrated with neutrophils. Cases with neutrophil-infiltrated myocarditis had severe abnormal laboratory tests involving multiple organs at admission, and a high peak value of CK-MB during hospitalization. Role of neutrophil on severe heart injury and even systemic condition in COVID-19 should be emphasized.

Hemochromatosis drives acute lethal intestinal responses to hyperyersiniabactin-producing Yersinia pseudotuberculosis

Hemachromatosis (iron-overload) increases host susceptibility to siderophilic bacterial infections that cause serious complications, but the underlying mechanisms remain elusive. The present study demonstrates that oral infection with hyperyersiniabactin (Ybt) producing Yersinia pseudotuberculosis Δfur mutant (termed Δfur) results in severe systemic infection and acute mortality to hemochromatotic mice due to rapid disruption of the intestinal barrier. Transcriptome analysis of Δfur-infected intestine revealed up-regulation in cytokine–cytokine receptor interactions, the complement and coagulation cascade, the NF-κB signaling pathway, and chemokine signaling pathways, and down-regulation in cell-adhesion molecules and Toll-like receptor signaling pathways. Further studies indicate that dysregulated interleukin (IL)-1β signaling triggered in hemachromatotic mice infected with Δfur damages the intestinal barrier by activation of myosin light-chain kinases (MLCK) and excessive neutrophilia. Inhibiting MLCK activity or depleting neutrophil infiltration reduces barrier disruption, largely ameliorates immunopathology, and substantially rescues hemochromatotic mice from lethal Δfur infection. Moreover, early intervention of IL-1β overproduction can completely rescue hemochromatotic mice from the lethal infection.

Pharmacological Inhibition of CCR2 Signaling Exacerbates Exercise-Induced Inflammation Independently of Neutrophil Infiltration and Oxidative Stress

Although exercise-induced humoral factors known as exerkines benefit systemic health, the role of most exerkines has not been investigated. Monocyte chemoattractant protein-1 (MCP-1) is a representative chemokine whose circulating concentrations increase after exercise, and it is one of the exerkines. MCP-1 is a ligand for CC chemokine receptor 2 (CCR2), which is expressed on monocytes, macrophages, and muscle cells. However, there is no information on the role of CCR2 signaling in exercise. Therefore, to investigate the research question, we administrated CCR2 antagonist or PBS to mice to inhibit CCR2 signaling before and after exercise. Our results showed that CCR2 signaling inhibition promoted exercise-induced macrophage infiltration and inflammation 24 h after exercise in muscle. CCR2 signaling inhibition also exacerbated exercise-induced inflammation immediately after exercise in muscle. However, neutrophil infiltration and oxidative stress had no contribution to exercise-induced inflammation by CCR2 signaling inhibition. CCR2 signaling inhibition also exacerbated exercise-induced inflammation immediately after exercise in kidney, liver, and adipose tissues. To summarize, pharmacological inhibition of CCR2 signaling exacerbated exercise-induced inflammation independently of neutrophil infiltration and oxidative stress.

Dual mode of action of Talaromyces purpureogenus CFRM02 pigment to ameliorate alcohol induced liver toxicity in rats

Talaromyces purpureogenus CFRM02 pigment exhibited antioxidant activity by scavenging free radicals. The alcohol feeding lead to free radical generation causing pathophysiological processes of alcoholic liver disease (ALD) and alcoholic hepatitis. The T. purpureogenus CFRM02 pigment administered to rats ameliorated the ALD by scavenging ROS. The haematological analysis revealed the increased neutrophil circulation. The neutrophil infiltration was observed in the hepatocytes of the rats fed with pigment (600 mg/kg body weight). The increase in number of neutrophils help in the liver regeneration caused by alcoholic hepatitis. The dual mechanism of action of pigment, antioxidant and liver regeneration through neutrophil production is attributed to alleviate the ALD. These results suggested T. purpureogenus CFRM02 pigment represents a novel protective and therapeutic strategy against ALD.

A Rapid Screening Method of Candidate Probiotics for Inflammatory Bowel Diseases and the Anti-inflammatory Effect of the Selected Strain Bacillus smithii XY1

Inflammatory bowel disease (IBD) is a chronic intestinal disease associated with the inflammatory gastrointestinal tract and microbiome dysbiosis. Probiotics are a promising intervention, and several probiotics have been reported to positively affect IBD remission and prevention, particularly on ulcerative colitis (UC). However, there is still a limitation in the knowledge of effectiveness and safety of probiotics therapies for IBD. Exploring more potential probiotics helps to find extensive evidence for probiotic intervention. This study established a rapid method for probiotics candidate screening and finally screened out one strain with the best protective effect. Forty strains isolated from four different sources were used for this screening. Hemolysis tests and acute toxic test evaluated strain safety. Zebrafish were first treated with dextran sodium sulfate (DSS) for colitis induction, and every bacteria were individually added to the fish water subsequently. Results showed eight strains could lower the larvae mortality within 3 days under a 0.6% DSS concentration, including Lacticaseibacillus rhamnosus GG, L. rhamnosus NBRC3425, Bacillus smithii DSM4216, B. smithii XY1, Bacillus coagulans NBRC12583, Bacillus coagulans XY2, Lactobacillus parafarraginis XYRR2, and Bacillus licheniformis XYT3. Among eight, B. smithii XY1 was the only strain having the equal ability to alleviate neutrophil infiltration in the larvae intestine with that ability of prednisolone under a 0.5% DSS concentration. Bacillus smithii XY1 restored intestinal epithelial cell integrity after DSS damage, as well as regulated the gene expression inflammation-related factors, indicating its bio-function of inflammatory response alleviation.