ABSTRACT
Ischemia reperfusion injury represents a common pathological condition that is triggered by the release of endogenous ligands. While neutrophils are known to play a critical role in its pathogenesis, the tissue-specific spatiotemporal regulation of ischemia-reperfusion injury is not understood. Here, using oxidative lipidomics and intravital imaging of transplanted mouse lungs that are subjected to severe ischemia reperfusion injury, we discovered that necroptosis, a nonapoptotic form of cell death, triggers the recruitment of neutrophils. During the initial stages of inflammation, neutrophils traffic predominantly to subpleural vessels, where their aggregation is directed by chemoattractants produced by nonclassical monocytes that are spatially restricted in this vascular compartment. Subsequent neutrophilic disruption of capillaries resulting in vascular leakage is associated with impaired graft function. We found that TLR4 signaling in vascular endothelial cells and downstream NADPH oxidase 4 expression mediate the arrest of neutrophils, a step upstream of their extravasation. Neutrophil extracellular traps formed in injured lungs and their disruption with DNase prevented vascular leakage and ameliorated primary graft dysfunction. Thus, we have uncovered mechanisms that regulate the initial recruitment of neutrophils to injured lungs, which result in selective damage to subpleural pulmonary vessels and primary graft dysfunction. Our findings could lead to the development of new therapeutics that protect lungs from ischemia reperfusion injury.
Subject(s)
Endothelium, Vascular/metabolism , Lung/metabolism , Necroptosis , Neutrophil Infiltration , Neutrophils/metabolism , Reperfusion Injury/metabolism , Animals , Endothelium, Vascular/injuries , Humans , Lung/blood supply , Mice , Mice, Knockout , Reperfusion Injury/genetics , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolismABSTRACT
Atherosclerosis is viewed as not just as a problem of lipid build-up in blood vessels, but also as a chronic inflammatory disease involving both innate and acquired immunity. In atherosclerosis, the inflammation of the arterial walls is the key characteristic that significantly contributes to both the instability of plaque and the occlusion of arteries by blood clots. These events ultimately lead to stroke and acute coronary syndrome. Probiotics are living microorganisms that, when consumed in the right quantities, offer advantages for one's health. The primary objective of this study was to investigate the influence of Lactiplantibacillus plantarum ATCC 14917 (ATCC 14917) on the development of atherosclerotic plaques and its underlying mechanism in Apo lipoprotein E-knockout (Apoe-/- mice). In this study, Apoe-/- mice at approximately 8 weeks of age were randomly assigned to three groups: a Normal group that received a normal chow diet, a high fat diet group that received a gavage of PBS, and a Lactiplantibacillus plantarum ATCC 14917 group that received a high fat diet and a gavage of 0.2 ml ATCC 14917 (2 × 109 CFU/mL) per day for a duration of 12 weeks. Our strain effectively reduced the size of plaques in Apoe-/- mice by regulating the expression of inflammatory markers, immune cell markers, chemokines/chemokine receptors, and tight junction proteins (TJPs). Specifically, it decreased the levels of inflammatory markers (ICAM-1, CD-60 MCP-1, F4/80, ICAM-1, and VCAM-1) in the thoracic aorta, (Ccr7, cd11c, cd4, cd80, IL-1ß, TNF-α) in the colon, and increased the activity of ROS-scavenging enzymes (SOD-1 and SOD-2). It also influenced the expression of TJPs (occludin, ZO-1, claudin-3, and MUC-3). In addition, the treatment of ATCC 14917 significantly reduced the level of lipopolysaccharide in the mesenteric adipose tissue. The findings of our study demonstrated that our strain effectively decreased the size of atherosclerotic plaques by modulating inflammation, oxidative stress, intestinal integrity, and intestinal immunity.
Subject(s)
Apolipoproteins E , Atherosclerosis , Plaque, Atherosclerotic , Probiotics , Animals , Probiotics/administration & dosage , Probiotics/pharmacology , Mice , Atherosclerosis/microbiology , Apolipoproteins E/genetics , Male , Disease Models, Animal , Mice, Knockout , Diet, High-Fat , Lactobacillus plantarum , Cytokines/metabolism , Mice, Inbred C57BL , InflammationABSTRACT
Atherosclerosis is a chronic inflammatory disease mediated by monocyte infiltration and cholesterol deposition into the subendothelial area, resulting in foam cell development. Probiotics are live bacteria that are beneficial for health when administered orally in adequate amounts. In this study, 8-week-old atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice were fed with or without Lactobacillus plantarum ATCC 14917 per day for 12 weeks. Serum was collected to analyse the lipid profile, oxidative status and proinflammatory cytokines. The heart was isolated to quantify the atherosclerotic lesion size in the aortic arch. Quantitative real-time polymerase chain reaction was performed to determine the expression levels of tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-1ß in the aorta. The proteins extracted from the aorta were used for Western blot analysis to assess the expression levels of nuclear factor kappa B (NF-κB) and inhibitor of NF-κB (IκBα). The composition of gut microbiota was also examined through high-throughput sequencing. Results showed that the daily consumption of L. plantarum ATCC 14917 had no effect on body weight and lipid profile. L. plantarum ATCC 14917 treatment significantly inhibited atherosclerotic lesion formation. In addition, the oxLDL, MDA, TNF-α and IL-1ß levels were significantly reduced, whereas the SOD level was induced in the bacteria + high-fat diet group. Furthermore, the administration of L. plantarum ATCC 14917 significantly attenuated IκBα protein degradation and inhibited the translocation of P65 subunits of NF-κB. L. plantarum ATCC 14917 treatment also modulated the composition of gut microbiota in ApoE-/- mice. Our findings showed that L. plantarum ATCC 14917 supplementation decreases the progression of atherosclerotic lesion formation by alleviating the inflammatory process and lowering oxidative stress.
Subject(s)
Apolipoproteins E/deficiency , Atherosclerosis/prevention & control , Cytokines/metabolism , Lactobacillus plantarum/physiology , Oxidative Stress/drug effects , Probiotics/pharmacology , Animals , Aorta/drug effects , Aorta/metabolism , Aorta/pathology , Atherosclerosis/pathology , Gastrointestinal Microbiome/drug effects , Inflammation , Mice , Mice, Knockout , NF-KappaB Inhibitor alpha/metabolism , Probiotics/administration & dosage , Transcription Factor RelA/metabolismABSTRACT
BACKGROUND: In orthotopic heart transplant recipients, surveillance with endomyocardial biopsy is crucial to detect acute cellular rejection (ACR) early. ACR is a common and serious complication of transplantation with substantial morbidity and mortality. Speckle tracking echocardiography with global longitudinal strain (GLS) assessment of the left ventricle has emerged as a possible noninvasive screening modality. We have conducted a systematic literature review and meta-analysis to evaluate the role of GLS in diagnosing ACR. METHODS: The following databases were queried: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and Embase. We compiled all articles evaluating changes in GLS in comparison to endomyocardial biopsy in ACR dated prior to September 2019. Weighted mean differences (WMD) and 95% confidence intervals (CIs) were pooled by using a random effects model. In order to determine the risk of bias, we used the revised version of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. RESULTS: Twelve studies met inclusion criteria of which ten were chosen. These studies encompassed 511 patients and 1267 endomyocardial biopsies. There was a significant difference in GLS between patients who did and did not have ACR proven by biopsy (WMD = 2.18; 95% CI: 1.57-2.78, P = <.001; I2 = 76%). The overall sensitivity for GLS in detecting ACR was 78% (CI: 63%-90%, P = .123; I2 = 52.2%) while the overall specificity was 68% (CI: 50%-83%, P = <.001; I2 = 88.3%). CONCLUSION: Global longitudinal strain assessment of the left ventricle by speckle tracking echocardiography is useful in detecting ACR and could potentially reduce the burden of frequent endomyocardial biopsies in heart transplant recipients.
Subject(s)
Heart Transplantation , Heart Ventricles , Echocardiography , Graft Rejection/diagnostic imaging , Heart/diagnostic imaging , Heart Ventricles/diagnostic imaging , HumansABSTRACT
Hypercholesterolemia plays a critical role in the development of atherosclerosis and cardiovascular diseases. Many works have been reported that gut microbiota could affect hypercholesterolemia through cholesterol metabolism. However, the role of gut microbiota on cholesterol transportation remains unclear. In this study, 8-week-old C57BL/6J mice were fed with high-cholesterol diet to build the hypercholesterolemic mice. Then, the hypercholesterolemic mice got the oral administration of Enterococcus faecalis ATCC19433 at a dose of 109 CFU/mL/day or PBS with high-cholesterol diet for 4 weeks. Serum was collected to detect the concentration of total cholesterol (TC). Meanwhile, pathology, histology, real-time polymerase chain reaction, Western blot, and immunofluorescence were used to evaluate the expression of ABCG5 and ABCG8 in the liver and small intestine. We also analyzed the composition of gut microbiota through high-throughput sequencing method. Oral administration of E. faecalis ATCC19433 significantly decreased the concentration of serum cholesterol in hypercholesterolemic mice. Furthermore, E. faecalis ATCC19433 reduced the concentration of liver cholesterol and improved cholesterol by increasing the expression of ABCG5 and ABCG8. Moreover, oral administration of E. faecalis ATCC19433 modulated the composition of gut microbiota and increased the counts of Lactobacillus, Bifidobacterium, and Akkermansia. Our results showed that E. faecalis ATCC19433 could exert hypocholesterolemic effect on hypercholesterolemic mice by improving transporter ABCG5 and ABCG8. E. faecalis ATCC19433 maybe contribute to the transportation of cholesterol potentially and modulate the composition of gut microbiota.
Subject(s)
Cholesterol/metabolism , Enterococcus faecalis/metabolism , Gastrointestinal Microbiome , Microbial Interactions , ATP Binding Cassette Transporter, Subfamily G, Member 5/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 8/genetics , Administration, Oral , Animals , Bifidobacterium/isolation & purification , Biological Transport , Cholesterol/blood , Hypercholesterolemia/therapy , Lactobacillus/isolation & purification , Lipid Metabolism , Lipoproteins/genetics , Liver/metabolism , Male , Mice , Mice, Inbred C57BLABSTRACT
Atherosclerosis is a major cause of mortalities and morbidities worldwide. It is associated with hyperlipidemia and inflammation, and become chronic by triggering metabolites in different metabolic pathways. Disturbance in the human gut microbiota is now considered a critical factor in the atherosclerosis. Trimethylamine-N-oxide (TMAO) attracts attention and is regarded as a vital contributor in the development of atherosclerosis. TMAO is generated from its dietary precursors choline, carnitine, and phosphatidylcholine by gut microbiota into an intermediate compound known as trimethylamine (TMA), which is then oxidized into TMAO by hepatic flavin monooxygenases. The present review focus on advances in TMAO preventing strategies through probiotics, including, modulation of gut microbiome, metabolomics profile, miRNA, or probiotic antagonistic abilities. Furthermore, possible recommendations based on relevant literature have been presented, which could be applied in probiotics and atherosclerosis-preventing strategies.
Subject(s)
Atherosclerosis/prevention & control , Methylamines/antagonists & inhibitors , Microbiota , Probiotics/therapeutic use , Animals , Atherosclerosis/physiopathology , Humans , Metabolomics , Methylamines/metabolism , Mice , MicroRNAsABSTRACT
Atherosclerosis is the major cause of cardiovascular diseases, which are considered the fatal ailment globally. Hypercholesterolaemia plays a critical role in the development of atherosclerosis and cardiovascular diseases. Many studies have been stated that probiotics could affect hypercholesterolemia via cholesterol metabolism. Probiotics are live bacteria which are good for our health when administered orally in high amounts. Recently, many studies have revealed the beneficial effects of the nutritional ingestion of probiotics which can decrease serum cholesterol levels. The aim of this review is, firstly, to explore the hypercholesterolemia effect of how it progresses into atherosclerosis and, secondly, to summarize the hypocholesterolaemia effect of probiotics on atherosclerosis and the up-to-date information on their basic mechanisms. The most important mechanisms responsible for the hypocholesterolemic effect of probiotics are the suppression of the reabsorption of bile acids and inhibition of the intestinal cholesterol absorption. Current studies indicate that numerous mechanisms within the cholesterol metabolism, e.g., ones involving the Niemann-Pick C1-Like 1 protein, 3-hydroxy-3-methylglutaryl-CoA reductase, and 7α- and 27α-hydroxylases, have been recommended where regulation may take place after oral intake of probiotics. However, these mechanisms are still poorly understood. Thus, further studies are required to examine the possible mechanisms, whereby probiotics can be utilized safely and considered for the treatment of hypercholesterolemia.
Subject(s)
Atherosclerosis/prevention & control , Atherosclerosis/physiopathology , Hypercholesterolemia/complications , Hypercholesterolemia/therapy , Probiotics/administration & dosage , Probiotics/pharmacology , Animals , Cholesterol/metabolism , HumansABSTRACT
BACKGROUND: Dobutamine stress echocardiography (DSE) is a well-established imaging modality used to screen patients with mild-to-moderate risk for coronary artery disease. In heart transplantation recipients, cardiac allograft vasculopathy (CAV) is a common and lethal complication. The use of DSE to detect CAV showed promising results initially, but later studies showed limitation in its use to detect CAV. It is unclear if this cohort of patients derives benefit from DSE. METHODS: We searched PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and Scopus from inception through March 2018 for studies examining the accuracy of DSE in correlation to coronary angiography (CA) or intravascular ultrasound (IVUS) to detect CAV. Original studies comparing the ability of DSE to detect CAV in comparison with CA or IVUS were included. Relevant data were extracted and hierarchical summary receiver operating characteristic analysis was conducted to test the overall diagnostic accuracy of DSE for patients with CAV. RESULTS: Eleven studies (749 participants) met the inclusion criteria. The sensitivity of DSE varied from 1.7% to 93.8%, and specificity, from 54.8% to 98.8%. Pooled sensitivity was 60.2% (95% confidence interval (CI), 33.0%-82.3%) and specificity 85.7% (95% CI, 73.8%-92.7%). DSE had an overall diagnostic odds ratio (OR) of 9.1 (95% CI, 4.6-17.8), positive likelihood ratio (LR+) of 4.1 (95% CI, 2.8-6.1), negative likelihood ratio (LR-) of 0.47 (95% CI: 0.23-0.73), and area under curve (AUC) of 0.73 (95% CI, 0.72-0.75). Heterogeneity among studies was not statistically significant (τ2 = 0.32, Cochran's Q = 9.5, P = 0.483). CONCLUSION: Dobutamine stress echocardiography has a limited sensitivity to detect early CAV but its specificity is much higher. There remains a need for an alternative noninvasive modality which will have both high sensitivity and high specificity for detecting CAV.
Subject(s)
Coronary Artery Disease/diagnostic imaging , Echocardiography, Stress/methods , Heart Transplantation , Postoperative Complications/diagnostic imaging , Allografts , Dobutamine , Humans , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
Depression is considered a multifaceted and intricate mental disorder of growing concern due to its significant impact on global health issues. The human gut microbiota, also known as the "second brain," has an important role in the CNS by regulating it through chemical, immunological, hormonal, and neurological processes. Various studies have found a significant bidirectional link between the brain and the gut, emphasizing the onset of depression therapies. The biological and molecular processes underlying depression and microbiota are required, as the bidirectional association may represent a novel study. However, profound insights into the stratification and diversity of the gut microbiota are still uncommon. This article investigates the emerging evidence of a bacterial relationship between the gut and the brain's neurological system and its potential pathogenicity and relevance. The interplay of microbiota, immune system, nervous system neurotransmitter synthesis, and neuroplasticity transitions is also widely studied. The consequences of stress, dietary fibers, probiotics, prebiotics, and antibiotics on the GB axis are being studied. Multiple studies revealed the processes underlying this axis and led to the development of effective microbiota-based drugs for both prevention and treatment. Therefore, the results support the hypothesis that gut microbiota influences depression and provide a promising area of research for an improved knowledge of the etiology of the disease and future therapies.
ABSTRACT
The gut microbiome is a heterogeneous population of microbes comprising viruses, bacteria, fungi, and protozoa. Such a microbiome is essential for sustaining host equilibrium, and its impact on human health can be altered by a variety of factors such as external variables, social behavior, age, nutrition, and genetics. Gut microbes' imbalances are related to a variety of chronic diseases including cancer, obesity, and digestive disorders. Globally, recent findings show that intestinal microbes have a significant role in the formation of cardiovascular disease (CVD), which is still the primary cause of fatalities. Atherosclerosis, hypertension, diabetes, inflammation, and some inherited variables are all cardiovascular risk variables. However, studies found correlations between metabolism, intestinal flora, and dietary intake. Variations in the diversity of gut microbes and changes in their activity are thought to influence CVD etiology. Furthermore, the gut microbiota acts as an endocrine organ, producing bioactive metabolites such as TMA (trimethylamine)/TMAO (trimethylamine N-oxide), SCFA (short-chain fatty acids), and bile acids, which have a substantial impact on host wellness and disease by multiple mechanisms. The purpose of this overview is to compile current evidence highlighting the intricate links between gut microbiota, metabolites, and the development of CVD. It focuses on how intestinal dysbiosis promotes CVD risk factors such as heart failure, hypertension, and atherosclerosis. This review explores the normal physiology of intestinal microbes and potential techniques for targeting gut bacteria for CVD treatment using various microbial metabolites. It also examines the significance of gut bacteria in disease treatment, including supplements, prebiotics, probiotics, antibiotic therapies, and fecal transplantation, which is an innovative approach to the management of CVD. As a result, gut bacteria and metabolic pathways become increasingly attractive as potential targets for CVD intervention.
Subject(s)
Atherosclerosis , Cardiovascular Diseases , Gastrointestinal Microbiome , Hypertension , Methylamines , Microbiota , Humans , Cardiovascular Diseases/therapy , Cardiovascular Diseases/etiology , Gastrointestinal Microbiome/physiology , Hypertension/complications , Atherosclerosis/complicationsABSTRACT
The gut microbiota plays an important role in the disease progression of inflammatory bowel disease. Although probiotics are effective against IBD, not many studies have investigated their effects on gut microbiota composition and immunomodulation in mouse colitis models. Our study aimed at the therapeutic effects of Lacticaseibacillus paracasei BNCC345679 for the first time and explored its impact on gut microbiome dysbiosis, inflammatory cytokines, related miRNAs, VCAM-1, oxidative stress, intestinal integrity, and mucus barrier. We found that oral intervention of L. paracasei BNCC345679 affects recovering beneficial microbial taxa, including lactobacillus spp. and akkermansia spp., followed by improved body weight, DAI score, and inflammatory cytokines. L. paracasei BNCC345679 mitigated oxidative stress and increased the expression of intestinal integrity proteins MUC2 and ZO-1. These results suggested that L. paracasei BNCC345679 has the capacity to reduce DSS-induced colitis and has the potential as a supplement for the mitigation of IBD.
ABSTRACT
The Fontan procedure is the final palliative surgery in a series of staged surgeries to reroute the systemic venous blood flow directly to the lungs, with the ventricle(s) pumping oxygenated blood to the body. Advances in medical and surgical techniques have improved patients' overall survival after the Fontan procedure. However, Fontan-associated chronic comorbidities are common. In addition to chronic cardiac dysfunction and arrhythmias, complications involving other organs such as the liver, lungs, intestine, lymphatic system, brain, and blood frequently occur. This narrative review focuses on the immediate and late consequences in children, pregnant women, and other adults with Fontan circulation. In addition, we describe the technical advancements that might change the way single-ventricle patients are managed in future.
Subject(s)
Fontan Procedure , Heart Defects, Congenital , Child , Adult , Humans , Female , Pregnancy , Fontan Procedure/adverse effects , Fontan Procedure/methods , Heart Defects, Congenital/surgery , Heart Ventricles , Arrhythmias, Cardiac , Palliative Care/methods , Treatment OutcomeABSTRACT
A 53-year-old man presented acutely to the Accident and Emergency department with a 2-day history of progressive odynophagia and shortness of breath. The patient had stridor at rest and acute epiglottitis was suspected. The patient was transferred urgently to theatre for intubation but due to a severely oedematous airway, this was unsuccessful and emergency tracheotomy was performed by the ENT team. Throughout admission the only positive microbiological sample was a nasopharyngeal swab for SARS-CoV-2 infection. In the absence of other positive microbiology, it is highly likely that COVID-19 was the aetiological cause of acute epiglottitis in this instance. LEARNING POINTS: COVID-19 infection is a novel disease with multiple presentations; it should be considered as a possible causative organism in patients presenting with acute epiglottitis.Due to the time delay in taking samples for microbiology and results being available, treatment should be commenced with antibiotics, nebulised adrenaline and steroids to cover bacterial infection.Presentation can occur following a delayed inflammatory response and treatment should target the organ system involved.
ABSTRACT
In December 2019, a pneumonia outbreak of unknown etiology was reported which caused panic in Wuhan city of central China, which was later identified as Coronavirus disease (COVID-19) caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by the Chinese Centre for Disease Control and Prevention (CDC) and WHO. To date, the SARS-CoV-2 spread has already become a global pandemic with a considerable death toll. The associated symptoms of the COVID-19 infection varied with increased inflammation as an everyday pathological basis. Among various other symptoms such as fever, cough, lethargy, gastrointestinal (GI) symptoms included diarrhea and IBD with colitis, have been reported. Currently, there is no sole cure for COVID-19, and researchers are actively engaged to search out appropriate treatment and develop a vaccine for its prevention. Antiviral for controlling viral load and corticosteroid therapy for reducing inflammation seems to be inadequate to control the fatality rate. Based on the available related literature, which documented GI symptoms with diarrhea, inflammatory bowel diseases (IBD) with colitis, and increased deaths in the intensive care unit (ICU), conclude that dysbiosis occurs during SARS-COV-2 infection as the gut-lung axis cannot be ignored. As probiotics play a therapeutic role for GI, IBD, colitis, and even in viral infection. So, we assume that the inclusion of studies to investigate gut microbiome and subsequent therapies such as probiotics might help decrease the inflammatory response of viral pathogenesis and respiratory symptoms by strengthening the host immune system, amelioration of gut microbiome, and improvement of gut barrier function.
Subject(s)
COVID-19/microbiology , Dysbiosis , Gastrointestinal Microbiome , Probiotics , Humans , SARS-CoV-2ABSTRACT
Probiotics are known to be beneficial in preventing different diseases in model animals, including inflammatory bowel disease. However, there are few studies on probiotics related to miRNA regulation and disease status. In this article, the beneficial role and mechanisms of the probiotic strain Bifidobacterium bifidum ATCC 29521 have been studied in ulcerative colitis using dextran sodium sulphate (DSS) model. Male C57JBL/6 mice were randomly divided into three groups (n=7): Normal group, dextran sulphate sodium (DSS) group, and Bifido group gavage with Bifidobacterium bifidum ATCC 29521 (2×108 CFU/day). Our strain restored the DSS-caused damage by regulating the expression of immune markers and tight junction proteins (TJP) in the colon; briefly by up-regulating ROS-scavenging enzymes (SOD1, SOD2, CAT, and GPX2), anti-inflammatory cytokines (IL-10, PPARγ, IL-6), TJP's (ZO-1, MUC-2, Claudin-3, and E Cadherin-1) and downregulating inflammatory genes (TNF-α, IL-1ß) in Bifido group mice. Inflammatory markers appeared to be regulated by NF-κB nuclear P65 subunit, and its translocation was inhibited in Bifido group mice colon. In addition, the expression of inflammatory genes and colonic TJP were also associated with the restoration of miRNAs (miR-150, miR-155, miR-223) in B. bifidum ATCC 29521 treated Bifido group. The dysbiosis executed by DSS was restored in the Bifido group, demonstrating that B. bifidum ATCC 29521 possessed a probiotic role in our DSS colitis mouse model. B. bifidum ATCC 29521 exhibited its probiotic role through its anti-inflammatory role by modulating miRNA-associated TJP and NF-κB regulation and by partially restoring dysbiosis.
Subject(s)
Bifidobacterium bifidum , Colitis, Ulcerative/drug therapy , Probiotics/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/metabolism , Colon/metabolism , Cytokines/metabolism , Dextran Sulfate/adverse effects , Disease Models, Animal , Dysbiosis/chemically induced , Dysbiosis/drug therapy , Gastrointestinal Microbiome/drug effects , Interleukin-1beta/metabolism , Male , Mice , Mice, Inbred C57BL , MicroRNAs/metabolism , NF-kappa B/metabolism , Probiotics/administration & dosage , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Non-apoptotic forms of cell death can trigger sterile inflammation through the release of danger-associated molecular patterns, which are recognized by innate immune receptors. However, despite years of investigation the mechanisms which initiate inflammatory responses after heart transplantation remain elusive. Here, we demonstrate that ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, decreases the level of pro-ferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamine, reduces cardiomyocyte cell death and blocks neutrophil recruitment following heart transplantation. Inhibition of necroptosis had no effect on neutrophil trafficking in cardiac grafts. We extend these observations to a model of coronary artery ligation-induced myocardial ischemia reperfusion injury where inhibition of ferroptosis resulted in reduced infarct size, improved left ventricular systolic function, and reduced left ventricular remodeling. Using intravital imaging of cardiac transplants, we uncover that ferroptosis orchestrates neutrophil recruitment to injured myocardium by promoting adhesion of neutrophils to coronary vascular endothelial cells through a TLR4/TRIF/type I IFN signaling pathway. Thus, we have discovered that inflammatory responses after cardiac transplantation are initiated through ferroptotic cell death and TLR4/Trif-dependent signaling in graft endothelial cells. These findings provide a platform for the development of therapeutic strategies for heart transplant recipients and patients, who are vulnerable to ischemia reperfusion injury following restoration of coronary blood flow.
Subject(s)
Adaptor Proteins, Vesicular Transport/immunology , Ferroptosis/immunology , Heart Transplantation , Myocardial Reperfusion Injury/immunology , Myocardium/immunology , Neutrophil Infiltration , Neutrophils/immunology , Signal Transduction/immunology , Toll-Like Receptor 4/immunology , Adaptor Proteins, Vesicular Transport/genetics , Animals , Cyclohexylamines/pharmacology , Ferroptosis/drug effects , Ferroptosis/genetics , Inflammation/drug therapy , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology , Mice , Mice, Knockout , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/pathology , Myocardium/pathology , Neutrophils/pathology , Phenylenediamines/pharmacology , Signal Transduction/drug effects , Signal Transduction/genetics , Toll-Like Receptor 4/genetics , Ventricular Function, Left/drug effects , Ventricular Function, Left/genetics , Ventricular Function, Left/immunologyABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is often linked with impaired hepatic autophagy. Here, we studied the alterations in hepatocellular autophagy by high cholesterol and high-fat diet (HC-HF) diet in C57BL/6J mice, and by palmitic acid (PA), in AML-12 and HepG2 cells. Further, we analysed role of Trigonelline (TG), a plant alkaloid, in preventing NAFLD, by modulating autophagy. For this, C57BL/6J mice were fed with Standard Chow (SC) or HC-HF diet, with and without TG for 16 weeks. In-vitro; AML-12â¯cells and HepG2 cells, were exposed to PA with and without TG, for 24â¯h. Cellular events related to autophagy, lipogenesis, and lipo-toxicity were studied. The HC-HF diet fed mice showed hepatic autophagy blockade, increased triglycerides and steatosis. PA exposure to AML-12â¯cells and HepG2 cells induced impaired autophagy, ER stress, resulting in lipotoxicity. TG treatment in HC-HF fed mice, restored hepatic autophagy, and prevented steatosis. TG treated AML-12, and HepG2 cells exposed to PA showed autophagy restoration, and reduced lipotoxicity, however, these effects were diminished in Atg7-/- HepG2 cells, and in the presence of chloroquine. This study shows that HC-HF diet-induced impaired autophagy, and steatosis is prevented by TG, which attributes to its novel mechanism in treating NAFLD.
Subject(s)
Alkaloids/pharmacology , Autophagy/drug effects , Cholesterol/administration & dosage , Diet, High-Fat/adverse effects , Fatty Liver/chemically induced , Animal Feed/analysis , Animals , Autophagy-Related Protein 7/genetics , Autophagy-Related Protein 7/metabolism , Cell Line , Cell Survival/drug effects , Fatty Liver/prevention & control , Gene Silencing , Humans , Insulin Resistance , Lipid Metabolism/drug effects , Mice , Mice, Inbred C57BL , Up-Regulation , Weight GainABSTRACT
We report a 35-year-old female receiving natalizumab as monotherapy for multiple sclerosis who subsequently developed severe cytomegalovirus gastritis. As cytomegalovirus gastritis has not been previously described during natalizumab treatment, we discuss the biological plausibility of this potential association and avenues for further study.
ABSTRACT
Polymorphisms in miRNA binding sites have been shown to affect miRNA binding to target genes, resulting in differential mRNA and protein expression and susceptibility to common diseases. Our purpose was to predict SNPs (single nucleotide polymorphisms) within miRNA binding sites of inflammatory genes in relation to gastric cancer. A complete list of SNPs in the 3'UTR regions of all inflammatory genes associated with gastric cancer was obtained from Pubmed. miRNA target prediction databases (MirSNP, Targetscan Human 6.2, PolymiRTS 3.0, miRNASNP 2.0, and Patrocles) were used to predict miRNA target sites. There were 99 SNPs with MAF>0.05 within the miRNA binding sites of 41 genes among 72 inflammation-related genes associated with gastric cancer. NF-κB and JAK-STAT are the two most important signaling pathways. 47 SNPs of 25 genes with 95 miRNAs were predicted. CCL2 and IL1F5 were found to be the shared target genes of hsa-miRNA-624-3p. Bioinformatic methods could identify a set of SNPs within miRNA binding sites of inflammatory genes, and provide data and direction for subsequent functional verification research.