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International Journal of Molecular... Nov 2023In patients with portal hypertension, there are many complications including cardiovascular abnormalities, hepatorenal syndrome, ascites, variceal bleeding, and hepatic... (Review)
Review
In patients with portal hypertension, there are many complications including cardiovascular abnormalities, hepatorenal syndrome, ascites, variceal bleeding, and hepatic encephalopathy. The underlying mechanisms are not yet completely clarified. It is well known that portal hypertension causes mesenteric congestion which produces reactive oxygen species (ROS). ROS has been associated with intestinal mucosal injury, increased intestinal permeability, enhanced gut bacterial overgrowth, and translocation; all these changes result in increased endotoxin and inflammation. Portal hypertension also results in the development of collateral circulation and reduces liver mass resulting in an overall increase in endotoxin/bacteria bypassing detoxication and immune clearance in the liver. Endotoxemia can in turn aggravate oxidative stress and inflammation, leading to a cycle of gut barrier dysfunction → endotoxemia → organ injury. The phenotype of cardiovascular abnormalities includes hyperdynamic circulation and cirrhotic cardiomyopathy. Oxidative stress is often accompanied by inflammation; thus, blocking oxidative stress can minimize the systemic inflammatory response and alleviate the severity of cardiovascular diseases. The present review aims to elucidate the role of oxidative stress in cirrhosis-associated cardiovascular abnormalities and discusses possible therapeutic effects of antioxidants on cardiovascular complications of cirrhosis including hyperdynamic circulation, cirrhotic cardiomyopathy, and hepatorenal syndrome.
Topics: Humans; Esophageal and Gastric Varices; Hepatorenal Syndrome; Reactive Oxygen Species; Endotoxemia; Gastrointestinal Hemorrhage; Liver Cirrhosis; Hypertension, Portal; Oxidative Stress; Inflammation; Cardiomyopathies; Cardiovascular Abnormalities; Endotoxins
PubMed: 38069125
DOI: 10.3390/ijms242316805 -
Frontiers in Medicine 2016Preeclampsia (PE) is a complex, multisystem disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany... (Review)
Review
Preeclampsia (PE) is a complex, multisystem disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused. We here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is, in fact, microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication-dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, and urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of "preeclampsia" that we assessed has, in fact, also been shown to be raised in response to infection. An infectious component to PE fulfills the Bradford Hill criteria for ascribing a disease to an environmental cause and suggests a number of treatments, some of which have, in fact, been shown to be successful. PE was classically referred to as endotoxemia or toxemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the etiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one.
PubMed: 27965958
DOI: 10.3389/fmed.2016.00060 -
International Journal of Molecular... Nov 2021Circulating endotoxin, also called lipopolysaccharide (LPS) and (1→3)-β-d-Glucan (β-d-glucan), major constituents of bacterial and fungal cell walls, respectively,...
Circulating endotoxin, also called lipopolysaccharide (LPS) and (1→3)-β-d-Glucan (β-d-glucan), major constituents of bacterial and fungal cell walls, respectively, are determined as biomarkers for Gram-negative sepsis and invasive fungal diseases [...].
Topics: Cell Wall; Endotoxemia; Fungi; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Invasive Fungal Infections; Proteoglycans; Sepsis
PubMed: 34884705
DOI: 10.3390/ijms222312900 -
FASEB Journal : Official Publication of... Nov 2021Inosine monophosphate (IMP) is the intracellular precursor for both adenosine monophosphate and guanosine monophosphate and thus plays a central role in intracellular...
Inosine monophosphate (IMP) is the intracellular precursor for both adenosine monophosphate and guanosine monophosphate and thus plays a central role in intracellular purine metabolism. IMP can also serve as an extracellular signaling molecule, and can regulate diverse processes such as taste sensation, neutrophil function, and ischemia-reperfusion injury. How IMP regulates inflammation induced by bacterial products or bacteria is unknown. In this study, we demonstrate that IMP suppressed tumor necrosis factor (TNF)-α production and augmented IL-10 production in endotoxemic mice. IMP exerted its effects through metabolism to inosine, as IMP only suppressed TNF-α following its CD73-mediated degradation to inosine in lipopolysaccharide-activated macrophages. Studies with gene targeted mice and pharmacological antagonism indicated that A , A and A adenosine receptors are not required for the inosine suppression of TNF-α production. The inosine suppression of TNF-α production did not require its metabolism to hypoxanthine through purine nucleoside phosphorylase or its uptake into cells through concentrative nucleoside transporters indicating a role for alternative metabolic/uptake pathways. Inosine augmented IL-β production by macrophages in which inflammasome was activated by lipopolysaccharide and ATP. In contrast to its effects in endotoxemia, IMP failed to affect the inflammatory response to abdominal sepsis and pneumonia. We conclude that extracellular IMP and inosine differentially regulate the inflammatory response.
Topics: Adenosine A2 Receptor Antagonists; Adenosine A3 Receptor Antagonists; Animals; Disease Models, Animal; Endotoxemia; Inosine; Inosine Monophosphate; Interleukin-10; Male; Mice; Mice, Inbred C57BL; Pneumonia, Pneumococcal; Quinazolines; Receptor, Adenosine A2A; Receptor, Adenosine A2B; Receptor, Adenosine A3; Signal Transduction; Streptococcus pneumoniae; Triazoles; Tumor Necrosis Factor-alpha
PubMed: 34591327
DOI: 10.1096/fj.202100862R -
Advances in Nutrition (Bethesda, Md.) May 2018The Mediterranean diet pattern is increasingly associated with improved metabolic health. Two mechanisms by which consuming a Mediterranean diet pattern may contribute... (Review)
Review
The Mediterranean diet pattern is increasingly associated with improved metabolic health. Two mechanisms by which consuming a Mediterranean diet pattern may contribute to improved metabolic health are modulation of the gastrointestinal (GI) microbiota and reduction of metabolic endotoxemia. Metabolic endotoxemia, defined as a 2- to 3-fold increase in circulating levels of bacterial endotoxin, has been proposed as a cause of inflammation during metabolic dysfunction. As the largest source of endotoxins in the human body, the GI microbiota represents a crucial area for research on strategies for reducing endotoxemia. Diets high in saturated fat and low in fiber contribute to metabolic endotoxemia through several mechanisms, including changes in the GI microbiome and bacterial fermentation end products, intestinal physiology and barrier function, and enterohepatic circulation of bile acids. Thus, the Mediterranean diet pattern, rich in unsaturated fats and fiber, may be one dietary strategy to reduce metabolic endotoxemia. Preclinical studies have demonstrated the differential effects of dietary saturated and unsaturated fats on the microbiota and metabolic health, but human studies are lacking. The role of dietary fiber and the GI microbiome in metabolic endotoxemia is underinvestigated. Clinical research on the effects of different types of dietary fat and fiber on the GI microbiota and GI and systemic inflammation is necessary to determine efficacious dietary strategies for reducing metabolic endotoxemia, inflammation, and subsequent metabolic disease.
Topics: Diet, High-Fat; Diet, Mediterranean; Dietary Fats; Dietary Fiber; Dysbiosis; Endotoxemia; Endotoxins; Fatty Acids, Unsaturated; Feeding Behavior; Gastrointestinal Microbiome; Humans; Inflammation; Intestinal Mucosa
PubMed: 29767701
DOI: 10.1093/advances/nmy013 -
Journal of Investigative Medicine : the... Jan 2020Renal failure is a challenging problem in patients with cirrhosis since mortality increases with worsening renal function, hence the inclusion of serum creatinine in... (Review)
Review
Renal failure is a challenging problem in patients with cirrhosis since mortality increases with worsening renal function, hence the inclusion of serum creatinine in calculating the Model for End-Stage Liver Disease score for liver transplant evaluation. Among the various causes, infection is the leading etiology of mortality associated with cirrhosis. Bacterial infection frequently precipitates renal failure in patients with cirrhosis with the reported prevalence around 34%. Patients with cirrhosis are at increased risk of infections due to impaired immunity and increased gut permeability leading to bacterial translocation in the setting of portal hypertension. One of the most feared complications of severely decompensated liver and renal failure is hepatorenal syndrome, of which liver transplant may be the only available treatment. Furthermore, in those with spontaneous bacterial peritonitis and urinary tract infection, progressive renal failure occurs despite resolution of infection. Thus, the effects of endotoxemia on renal function in cirrhosis have become a major focus of research. The mechanisms of the damaging effects of endotoxin on renal function are complex but, in essence, involve dysregulated inflammation, circulatory dysfunction, poor clearance of endotoxin burden, as well as vasomotor nephropathy. In this article, we will review the mechanisms of endotoxemia-induced renal dysfunction in the setting of cirrhosis through the effects on renal blood flow, renal vascular endothelium, glomerular filtration rate, and tubular function.
Topics: Endotoxemia; Glomerular Filtration Rate; Humans; Kidney; Liver Cirrhosis; Renal Insufficiency
PubMed: 31324695
DOI: 10.1136/jim-2019-001056 -
Nutricion Hospitalaria Dec 2018diet plays a decisive role in the prevention and treatment of diseases such as obesity, diabetes, allergies and inflammatory diseases. In addition to this, there are... (Review)
Review
INTRODUCTION
diet plays a decisive role in the prevention and treatment of diseases such as obesity, diabetes, allergies and inflammatory diseases. In addition to this, there are numerous investigations about the role of the microbiota in the genesis of metabolic diseases, especially obesity and its comorbidities.
OBJECTIVE
the aim of this review is to discuss the influence of high-fat diets on dysbiosis and metabolic endotoxemia.
RESULTS AND CONCLUSION
the intestinal microbial ecosystem has been shown to be essential in the performance of functions in the host organism, however, several factors can lead to an imbalance in the homeostasis of the microbiota, known as dysbiosis. High-fat diets are associated with a reduction in intestinal bacterial diversity, changes in membrane integrity, inducing increased permeability and increased lipopolysaccharide (LPS) translocation, changes in the immune system, and generation of low-intensity systemic inflammation. The installed endotoxemia can be considered as a causal factor of subclinical inflammation related to several chronic diseases, and as a result of this, it is essential to know the real impact of hyperlipidic diets on the intestinal microbiota. Thus, it becomes essential to identify dietary strategies that can minimize the inflammatory effects generated from changes in the intestinal microbiota.
Topics: Animals; Diet, High-Fat; Dysbiosis; Endotoxemia; Female; Gastrointestinal Microbiome; Humans; Intestines; MEDLINE; Male; Mice
PubMed: 30525859
DOI: 10.20960/nh.1792 -
Frontiers in Immunology 2023The recent discovery of TAK981(Subasumstat), the first-in-class selective inhibitor of SUMOylation, enables new immune treatments. TAK981 is already in clinical trials...
INTRODUCTION
The recent discovery of TAK981(Subasumstat), the first-in-class selective inhibitor of SUMOylation, enables new immune treatments. TAK981 is already in clinical trials to potentiate immunotherapy in metastatic tumors and hematologic malignancies. Cancer patients have more than ten times higher risk of infections, but the effects of TAK981 in sepsis are unknown and previous studies on SUMO in infections are conflicting.
METHODS
We used TAK981 in two sepsis models; polymicrobial peritonitis (CLP) and LPS endotoxemia. Splenectomy was done in both models to study the role of spleen. Western blotting of SUMO-conjugated proteins in spleen lysates was done. Global SUMO1 and SUMO3 knockout mice were used to study the specific SUMO regulation of inflammation in LPS endotoxemia. Splenocytes adoptive transfer was done from SUMO knockouts to wild type mice to study the role of spleen SUMOylation in experimental sepsis.
RESULTS AND DISCUSSION
Here, we report that inhibition of SUMOylation with TAK981 improved survival in mild polymicrobial peritonitis by enhancing innate immune responses and peritoneal bacterial clearance. Thus, we focused on the effects of TAK981 on the immune responses to bacterial endotoxin, showing that TAK981 enhanced early TNFα production but did not affect the resolution of inflammation. Splenectomy decreased serum TNFα levels by nearly 60% and TAK981-induced TNFα responses. In the spleen, endotoxemia induced a distinct temporal and substrate specificity for SUMO1 and SUMO2/3, and both were inhibited by TAK981. Global genetic depletion of SUMO1, but not SUMO3, enhanced TNFα production and metabolic acidosis. The transfer of SUMO1-null, but not wild-type, splenocytes into splenectomized wild-type mice exacerbated TNFα production and metabolic acidosis in endotoxemia.
CONCLUSION
These results suggest that specific regulation of splenic SUMO1 can modulate immune and metabolic responses to bacterial infection.
Topics: Animals; Mice; Endotoxemia; Lipopolysaccharides; Mice, Knockout; Peritonitis; Small Ubiquitin-Related Modifier Proteins; Spleen; Tumor Necrosis Factor-alpha; SUMO-1 Protein
PubMed: 37520526
DOI: 10.3389/fimmu.2023.1200939 -
Nutrients Sep 2020Betaine has been demonstrated to increase tolerance to hypertonic and thermal stressors. At the cellular level, intracellular betaine functions similar to molecular... (Review)
Review
Betaine has been demonstrated to increase tolerance to hypertonic and thermal stressors. At the cellular level, intracellular betaine functions similar to molecular chaperones, thereby reducing the need for inducible heat shock protein expression. In addition to stabilizing protein conformations, betaine has been demonstrated to reduce oxidative damage. For the enterocyte, during periods of reduced perfusion as well as greater oxidative, thermal, and hypertonic stress (i.e., prolonged exercise in hot-humid conditions), betaine results in greater villi length and evidence for greater membrane integrity. Collectively, this reduces exercise-induced gut permeability, protecting against bacterial translocation and endotoxemia. At the systemic level, chronic betaine intake has been shown to reduce core temperature, all-cause mortality, markers of inflammation, and change blood chemistry in several animal models when exposed to heat stress. Despite convincing research in cell culture and animal models, only one published study exists exploring betaine's thermoregulatory function in humans. If the same premise holds true for humans, chronic betaine consumption may increase heat tolerance and provide another avenue of supplementation for those who find that heat stress is a major factor in their work, or training for exercise and sport. Yet, this remains speculative until data demonstrate such effects in humans.
Topics: Animals; Betaine; Body Temperature Regulation; Carbohydrates; Caseins; Dietary Supplements; Endotoxemia; Heat-Shock Proteins; Heat-Shock Response; Hot Temperature; Humans; Lipids; Lipopolysaccharides; Molecular Chaperones; Osmotic Pressure; Plant Proteins, Dietary; Thermotolerance
PubMed: 32992781
DOI: 10.3390/nu12102939 -
Blood Purification 2022Uncontrolled systemic inflammation may occur in severe coronavirus disease 19 (COVID-19). We have previously shown that endotoxemia, presumably from the gut, may... (Observational Study)
Observational Study
INTRODUCTION
Uncontrolled systemic inflammation may occur in severe coronavirus disease 19 (COVID-19). We have previously shown that endotoxemia, presumably from the gut, may complicate COVID-19. However, the role of endotoxin adsorbent (EA) therapy to mitigate organ dysfunction in COVID-19 has not been explored.
METHODS
We conducted a retrospective observational study in COVID-19 patients who received EA therapy at the King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between March 13 and April 17, 2020. Relevant clinical and laboratory data were collected by inpatient chart review.
RESULTS
Among 147 hospitalized COVID-19 patients, 6 patients received EA therapy. All of the 6 patients had severe COVID-19 infection with acute respiratory distress syndrome (ARDS). Among these, 5 of them were mechanically ventilated and 4 had complications of secondary bacterial infection. The endotoxin activity assay (EAA) results of pre-EA therapy ranged from 0.47 to 2.79. The choices of EA therapy were at the discretion of attending physicians. One patient was treated with oXiris® along with continuous renal replacement therapy, and the others received polymyxin B hemoperfusion sessions. All patients have survived and were finally free from the mechanical ventilation as well as had improvement in PaO2/FiO2 ratio and decreased EAA level after EA therapy.
CONCLUSIONS
We demonstrated the clinical improvement of severe COVID-19 patients with elevated EAA level upon receiving EA therapy. However, the benefit of EA therapy in COVID-19 ARDS is still unclear and needs to be elucidated with randomized controlled study.
Topics: Acute Kidney Injury; Adsorption; COVID-19; Critical Care; Endotoxemia; Female; Hemoperfusion; Heparin; Humans; Male; Membranes, Artificial; Middle Aged; Polymyxin B; Renal Replacement Therapy; Respiratory Distress Syndrome; Retrospective Studies; SARS-CoV-2; Treatment Outcome
PubMed: 33857940
DOI: 10.1159/000515628