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Frontiers in Bioscience (Scholar... Jan 2013Increasing clinical observations reveal that persistent low-grade inflammation is associated with the pathogenesis of severe chronic diseases such as atherosclerosis,... (Review)
Review
Increasing clinical observations reveal that persistent low-grade inflammation is associated with the pathogenesis of severe chronic diseases such as atherosclerosis, diabetes, and aging-related neurological diseases. Intriguingly, low levels of circulating Gram-negative bacterial endotoxin lipopolysaccharide (LPS) appear to be one of the key culprits in provoking a non-resolving low-grade inflammation. Adverse life styles, chronic infection, and aging can all contribute to the rise of circulating endotoxin levels and lead to low-grade endotoxemia. As a consequence, low-grade endotoxemia may skew host immune environment into a mild non-resolving pro-inflammatory state, which eventually leads to the pathogenesis and progression of inflammatory diseases. This review aims to highlight the recent progress in the causes and consequences of low-grade endotoxemia, as well as the emerging molecular mechanisms responsible.
Topics: Animals; Endotoxemia; Endotoxins; Humans; Inflammation; Lipopolysaccharides
PubMed: 23277084
DOI: 10.2741/s405 -
American Journal of Physiology. Lung... Jun 2003Gram-negative bacterial sepsis remains a common, life-threatening event. The prognosis for patients who develop sepsis-related complications, including the development... (Review)
Review
Gram-negative bacterial sepsis remains a common, life-threatening event. The prognosis for patients who develop sepsis-related complications, including the development of acute respiratory distress syndrome (ARDS), remains poor. A common finding among patients and experimental animals with sepsis and ARDS is endothelial injury and/or dysfunction. A component of the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS) or endotoxin, has been implicated in the pathogenesis of much of the endothelial cell injury and/or dysfunction associated with these disease states. LPS is a highly proinflammatory molecule that elicits a wide array of endothelial responses, including the upregulation of cytokines, adhesion molecules, and tissue factor. In addition to activation, LPS induces endothelial cell death that is apoptotic in nature. This review summarizes the evidence for LPS-induced vascular endothelial injury and examines the molecular signaling pathways that activate and inhibit LPS-induced endothelial apoptosis. Furthermore, the role of apoptotic signaling molecules in mediating LPS-induced activation of endothelial cells will be considered.
Topics: Animals; Apoptosis; Endothelium, Vascular; Endotoxemia; Humans; Lipopolysaccharides; Sepsis; Vasculitis
PubMed: 12736186
DOI: 10.1152/ajplung.00338.2002 -
Hepatology International Feb 2018The term gut-liver axis is used to highlight the close anatomical and functional relationship between the intestine and the liver. The intestine has a highly specialized...
The term gut-liver axis is used to highlight the close anatomical and functional relationship between the intestine and the liver. The intestine has a highly specialized epithelial membrane which regulates transport across the mucosa. Due to dysbiosis, impairment of the intestinal barrier and altered immunity status, bacterial products can reach the liver through the portal vein, where they are recognized by specific receptors, activate the immune system and lead to a proinflammatory response. Gut microbiota and bacterial translocation play an important role in the pathogenesis of chronic liver diseases, including alcoholic and non-alcoholic fatty liver disease, cirrhosis, and its complications, such as portal hypertension, spontaneous bacterial peritonitis and hepatic encephalopaty. The gut microbiota also plays a critical role as a modulator of bile acid metabolism which can also influence intestinal permeability and portal hypertension through the farnesoid-X receptor. On the other hand, cirrhosis and portal hypertension affect the microbiota and increase translocation, leading to a "chicken and egg" situation, where translocation increases portal pressure, and vice versa. A myriad of therapies targeting gut microbiota have been evaluated specifically in patients with chronic liver disease. Further studies targeting intestinal microbiota and its possible hemodynamic and metabolic effects are needed. This review summarizes the current knowledge about the role of gut microbiota in the pathogenesis of chronic liver diseases and portal hypertension.
Topics: Adrenergic beta-Antagonists; Bacterial Infections; Bacterial Translocation; Bile Acids and Salts; Endotoxemia; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Hepatic Encephalopathy; Humans; Hypertension, Portal; Intestinal Mucosa; Intestines; Lipopolysaccharide Receptors; Liver; Liver Cirrhosis; Liver Diseases; Non-alcoholic Fatty Liver Disease; Peritonitis; Probiotics; Receptors, Cytoplasmic and Nuclear
PubMed: 28550391
DOI: 10.1007/s12072-017-9798-x -
Journal of Dairy Science Nov 2014Acute puerperal metritis (APM) is an acute systemic illness with fever ≥ 39.5 °C and signs of toxemia due to an infection of the uterus occurring within 21 d after... (Review)
Review
Acute puerperal metritis (APM) is an acute systemic illness with fever ≥ 39.5 °C and signs of toxemia due to an infection of the uterus occurring within 21 d after parturition. Because of the infectious nature of APM, antibiotics are considered beneficial for its treatment. Each use of an antimicrobial drug, however, is associated with selective pressure for the emergence of resistant bacteria. Hence, there is a significant need to encourage prudent use of antibiotics and alternative therapies to antibiotics. Therefore, the objective of this study was to systematically review the current literature on treatment of APM. A comprehensive and systematic literature search was conducted utilizing the PubMed and CAB Abstracts databases to identify literature focusing on the antibiotic therapy of puerperal metritis in the cow. After application of specific exclusion criteria, 21 publications comprising 23 trials remained for final evaluation. Data extraction revealed that the majority of the studies (n = 19) were attributable to the highest evidence level. Of 21 studies controlled, 11 had an untreated group and 3 a positive control group. The majority of the studies (n = 17) applied ceftiofur for the treatment of APM. Concerning the efficacy of ceftiofur, 7 studies observed clinical improvement, whereas none found improved reproductive performance. Fewer than half of the studies (n = 10) performed a bacteriological examination and only 4 implemented an antibiotic susceptibility test. Also, 3 studies (13.0%) described a self-cure rate per se. Little attention was given to the issue of bacterial resistance (n = 3), the need for reducing the application of antibiotics (n = 2), or guidelines for prudent use of antibiotics (n = 1). Our findings demonstrate that implementation of bacteriological examinations, sensitivity testing, and determination of minimum inhibitory concentrations, as well as reporting and discussion of critical issues (e.g., self-cure rates, resistance, prudent drug use), were suboptimal. On the other hand, the quality of studies on the treatment of APM was good, as indicated by evidence level 1. Nevertheless, more high-quality research considering self-cure rates is necessary to address critical issues related to APM and crucial to the dairy industry, such as resistance, prudent use of antibiotics, animal welfare, and cost-benefit ratios.
Topics: Animals; Anti-Bacterial Agents; Cattle; Cattle Diseases; Cephalosporins; Drug Resistance, Bacterial; Endometritis; Female; Fever; Microbial Sensitivity Tests; Postpartum Period; Puerperal Disorders; Reproduction
PubMed: 25218751
DOI: 10.3168/jds.2014-8462 -
Journal of Bacteriology Nov 2021Anthrax disease is caused by infection with the bacteria Bacillus anthracis which, if left untreated, can result in fatal bacteremia and toxemia. Current treatment for...
Anthrax disease is caused by infection with the bacteria Bacillus anthracis which, if left untreated, can result in fatal bacteremia and toxemia. Current treatment for infection requires prolonged administration of antibiotics. Despite this, inhalational and gastrointestinal anthrax still result in lethal disease. By identifying key metabolic steps that B. anthracis uses to grow in host-like environments, new targets for antibacterial strategies can be identified. Here, we report that the gene, which encodes dihydroxyacid dehydratase in the putative pathway for synthesizing branched chain amino acids, is necessary for B. anthracis to synthesize isoleucine in an otherwise limiting microenvironment. We observed that Δ B. anthracis cannot grow in media lacking isoleucine, but growth is restored when exogenous isoleucine is added. In addition, bacilli are unable to utilize human hemoglobin or serum albumin to overcome isoleucine auxotrophy, but can when provided with the murine forms. This species-specific effect is due to the lack of isoleucine in human hemoglobin. Furthermore, even when supplemented with physiological levels of human serum albumin, apotransferrin, fibrinogen, and IgG, the knockout strain grew poorly relative to nonsupplemented wild type. In addition, comparisons upon infecting humanized mice suggest that murine hemoglobin is a key source of isoleucine for both WT and Δ bacilli. Further growth comparisons in murine and human blood show that the auxotrophy is detrimental for growth in human blood, not murine. This report identifies as necessary for isoleucine production in B. anthracis, and that it plays a key role in allowing the bacilli to effectively grow in isoleucine poor hosts. Anthrax disease, caused by B. anthracis, can cause lethal bacteremia and toxemia, even following treatment with antibiotics. This report identifies the gene, which encodes a dihydroxyacid dehydratase, as necessary for B. anthracis to synthesize the amino acid isoleucine in a nutrient-limiting environment, such as its mammalian host. The use of this strain further demonstrated a unique species-dependent utilization of hemoglobin as an exogenous source of extracellular isoleucine. By identifying mechanisms that B. anthracis uses to grow in host-like environments, new targets for therapeutic intervention are revealed.
Topics: Animals; Bacillus anthracis; Blood Proteins; Culture Media; Gene Deletion; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Enzymologic; Hemoglobins; Humans; Hydro-Lyases; Mice; Mutation
PubMed: 34570623
DOI: 10.1128/JB.00415-21 -
Toxins May 2016Clostridium difficile infection (CDI) has significant clinical impact especially on the elderly and/or immunocompromised patients. The pathogenicity of Clostridium... (Review)
Review
Clostridium difficile infection (CDI) has significant clinical impact especially on the elderly and/or immunocompromised patients. The pathogenicity of Clostridium difficile is mainly mediated by two exotoxins: toxin A (TcdA) and toxin B (TcdB). These toxins primarily disrupt the cytoskeletal structure and the tight junctions of target cells causing cell rounding and ultimately cell death. Detectable C. difficile toxemia is strongly associated with fulminant disease. However, besides the well-known intestinal damage, recent animal and in vitro studies have suggested a more far-reaching role for these toxins activity including cardiac, renal, and neurologic impairment. The creation of C. difficile strains with mutations in the genes encoding toxin A and B indicate that toxin B plays a major role in overall CDI pathogenesis. Novel insights, such as the role of a regulator protein (TcdE) on toxin production and binding interactions between albumin and C. difficile toxins, have recently been discovered and will be described. Our review focuses on the toxin-mediated pathogenic processes of CDI with an emphasis on recent studies.
Topics: Animals; Bacterial Proteins; Bacterial Toxins; Clostridium Infections; Enterotoxins; Humans; Toxemia
PubMed: 27153087
DOI: 10.3390/toxins8050134 -
Marine Drugs Jun 2013This paper concerns the potential use of compounds, including lipid A, chitosan, and carrageenan, from marine sources as agents for treating endotoxemic complications... (Review)
Review
This paper concerns the potential use of compounds, including lipid A, chitosan, and carrageenan, from marine sources as agents for treating endotoxemic complications from Gram-negative infections, such as sepsis and endotoxic shock. Lipid A, which can be isolated from various species of marine bacteria, is a potential antagonist of bacterial endotoxins (lipopolysaccharide (LPSs)). Chitosan is a widespread marine polysaccharide that is derived from chitin, the major component of crustacean shells. The potential of chitosan as an LPS-binding and endotoxin-neutralizing agent is also examined in this paper, including a discussion on the generation of hydrophobic chitosan derivatives to increase the binding affinity of chitosan to LPS. In addition, the ability of carrageenan, which is the polysaccharide of red alga, to decrease the toxicity of LPS is discussed. We also review data obtained using animal models that demonstrate the potency of carrageenan and chitosan as antiendotoxin agents.
Topics: Animals; Anti-Bacterial Agents; Aquatic Organisms; Carrageenan; Chitosan; Endotoxemia; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Lipid A; Sepsis
PubMed: 23783404
DOI: 10.3390/md11062216 -
Analytical and Bioanalytical Chemistry May 2019Inhalation of Bacillus anthracis spores can cause a rapidly progressing fatal infection. B. anthracis secretes three protein toxins: lethal factor (LF), edema factor...
Inhalation of Bacillus anthracis spores can cause a rapidly progressing fatal infection. B. anthracis secretes three protein toxins: lethal factor (LF), edema factor (EF), and protective antigen (PA). EF and LF may circulate as free or PA-bound forms. Both free EF (EF) and PA-bound-EF (ETx) have adenylyl cyclase activity converting ATP to cAMP. We developed an adenylyl cyclase activity-based method for detecting and quantifying total EF (EF+ETx) in plasma. The three-step method includes magnetic immunocapture with monoclonal antibodies, reaction with ATP generating cAMP, and quantification of cAMP by isotope-dilution HPLC-MS/MS. Total EF was quantified from 5PL regression of cAMP vs ETx concentration. The detection limit was 20 fg/mL (225 zeptomoles/mL for the 89 kDa protein). Relative standard deviations for controls with 0.3, 6.0, and 90 pg/mL were 11.7-16.6% with 91.2-99.5% accuracy. The method demonstrated 100% specificity in 238 human serum/plasma samples collected from unexposed healthy individuals, and 100% sensitivity in samples from 3 human and 5 rhesus macaques with inhalation anthrax. Analysis of EF in the rhesus macaques showed that it was detected earlier post-exposure than B. anthracis by culture and PCR. Similar to LF, the kinetics of EF over the course of infection were triphasic, with an initial rise (phase-1), decline (phase-2), and final rapid rise (phase-3). EF levels were ~ 2-4 orders of magnitude lower than LF during phase-1 and phase-2 and only ~ 6-fold lower at death/euthanasia. Analysis of EF improves early diagnosis and adds to our understanding of anthrax toxemia throughout infection. The LF/EF ratio may also indicate the stage of infection and need for advanced treatments.
Topics: Adenosine Triphosphate; Animals; Anthrax; Antigens, Bacterial; Bacillus anthracis; Bacterial Toxins; Case-Control Studies; Chromatography, High Pressure Liquid; Cyclic AMP; Disease Progression; Enzyme-Linked Immunosorbent Assay; Humans; Limit of Detection; Macaca mulatta; Polymerase Chain Reaction; Respiratory Tract Infections; Tandem Mass Spectrometry; Toxemia
PubMed: 30911800
DOI: 10.1007/s00216-019-01730-4 -
FEBS Letters Nov 2002Anthrax is a severe bacterial infection that occurs when Bacillus anthracis spores gain access into the body and germinate in macrophages, causing septicemia and... (Review)
Review
Anthrax is a severe bacterial infection that occurs when Bacillus anthracis spores gain access into the body and germinate in macrophages, causing septicemia and toxemia. Anthrax toxin is a binary A-B toxin composed of protective antigen (PA), lethal factor (LF), and edema factor (EF). PA mediates the entry of either LF or EF into the cytosol of host cells. LF is a zinc metalloprotease that inactivates mitogen-activated protein kinase kinase inducing cell death, and EF is an adenylyl cyclase impairing host defences. Inhibitors targeting different steps of toxin activity have recently been developed. Anthrax toxin has also been exploited as a therapeutic agent against cancer.
Topics: Animals; Anthrax Vaccines; Antigens, Bacterial; Bacillus anthracis; Bacterial Toxins; Humans
PubMed: 12435580
DOI: 10.1016/s0014-5793(02)03609-8 -
Critical Care (London, England) Aug 2012The interdependence between endotoxemia, gram negative (GN) bacteremia and mortality has been extensively studied. Underlying patient risk and GN bacteremia types are... (Review)
Review
INTRODUCTION
The interdependence between endotoxemia, gram negative (GN) bacteremia and mortality has been extensively studied. Underlying patient risk and GN bacteremia types are possible confounders of the relationship.
METHODS
Published studies with ≥ 10 patients in either ICU or non-ICU settings, endotoxemia detection by limulus assay, reporting mortality proportions and ≥ 1 GN bacteremia were included. Summary odds ratios (OR) for mortality were derived across all studies by meta-analysis for the following contrasts: sub-groups with either endotoxemia (group three), GN bacteremia (group two) or both (group one) each versus the group with neither detected (group four; reference group). The mortality proportion for group four is the proxy measure of study level risk within L'Abbé plots.
RESULTS
Thirty-five studies were found. Among nine studies in an ICU setting, the OR for mortality was borderline (OR <2) or non-significantly increased for groups two (GN bacteremia alone) and three (endotoxemia alone) and patient group one (GN bacteremia and endotoxemia co-detected) each versus patient group four (neither endotoxemia nor GN bacteremia detected). The ORs were markedly higher for group one versus group four (OR 6.9; 95% confidence interval (CI), 4.4 -to 11.0 when derived from non-ICU studies. The distributions of Pseudomonas aeruginosa and Escherichia coli bacteremias among groups one versus two are significantly unequal.
CONCLUSIONS
The co-detection of GN bacteremia and endotoxemia is predictive of increased mortality risk versus the detection of neither but only in studies undertaken in a non-ICU setting. Variation in GN bacteremia species types and underlying risk are likely unrecognized confounders in the individual studies.
Topics: Bacteremia; Confounding Factors, Epidemiologic; Endotoxemia; Gram-Negative Bacterial Infections; Hospital Mortality; Humans; Intensive Care Units; Limulus Test; Odds Ratio; Prognosis; Risk Factors
PubMed: 22871090
DOI: 10.1186/cc11462