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Critical Care (London, England) Oct 2023Septic shock can be caused by a variety of mechanisms including direct effects of bacterial toxins such as endotoxin. Annually, approximately 5-7 million patients... (Review)
Review
Septic shock can be caused by a variety of mechanisms including direct effects of bacterial toxins such as endotoxin. Annually, approximately 5-7 million patients worldwide develop sepsis with very high endotoxin activity in the blood and more than half die. The term endotoxic septic shock has been used for these patients but it is important to emphasize that endotoxin may be a factor in all forms of septic shock including non-bacterial etiologies like COVID-19 since translocation of bacterial products is a common feature of septic shock. A pattern of organ failure including hepatic dysfunction, acute kidney injury and various forms of endothelial dysfunction ranging from disseminated intravascular coagulation to thrombotic microangiopathy characterize endotoxic septic shock. However, while characteristic, the clinical phenotype is not unique to patients with high endotoxin, and the diagnosis relies on the measurement of endotoxin activity in addition to clinical assessment. Therapies for endotoxic septic shock are limited with immune modulating therapies under investigation and extracorporeal blood purification still controversial in many parts of the world.
Topics: Humans; Shock, Septic; Endotoxins; COVID-19; Sepsis
PubMed: 37858258
DOI: 10.1186/s13054-023-04690-5 -
Medicine Jul 2023Studies in the 1920s found that botulinum neurotoxin type A (BoNT/A) inhibited the activity of motor and parasympathetic nerve endings, confirmed several decades later...
Studies in the 1920s found that botulinum neurotoxin type A (BoNT/A) inhibited the activity of motor and parasympathetic nerve endings, confirmed several decades later to be due to decreased acetylcholine release. The 1970s were marked by studies of cellular mechanisms aided by use of neutralizing antibodies as pharmacologic tools: BoNT/A disappeared from accessibility to neutralizing antibodies within minutes, although it took several hours for onset of muscle weakness. The multi-step mechanism was experimentally confirmed and is now recognized to consist broadly of binding to nerve terminals, internalization, and lysis or cleavage of a protein (SNAP-25: synaptosomal associated protein-25 kDa) that is part of the SNARE (Soluble NSF Attachment protein REceptor) complex needed for synaptic vesicle docking and fusion. Clinical use of the BoNT/A product onabotulinumtoxinA was based on its ability to reduce muscle contractions via inhibition of acetylcholine from motor terminals. Sensory mechanisms of onabotulinumtoxinA have now been identified, supporting its successful treatment of chronic migraine and urgency in overactive bladder. Exploration into migraine mechanisms led to anatomical studies documenting pain fibers that send axons through sutures of the skull to outside the head-a potential route by which extracranial injections could affect intracranial processes. Several clinical studies have also identified benefits of onabotulinumtoxinA in major depression, which have been attributed to central responses induced by feedback from facial muscle and skin movement. Overall, the history of BoNT/A is distinguished by basic science studies that stimulated clinical use and, conversely, clinical observations that spurred basic research into novel mechanisms of action.
Topics: Humans; Botulinum Toxins, Type A; Acetylcholine; Urinary Bladder, Overactive; Migraine Disorders; Muscle Contraction
PubMed: 37499078
DOI: 10.1097/MD.0000000000032372 -
Nature Communications Oct 2023Metabolic reprogramming is a hallmark of the immune cells in response to inflammatory stimuli. This metabolic process involves a switch from oxidative phosphorylation...
Metabolic reprogramming is a hallmark of the immune cells in response to inflammatory stimuli. This metabolic process involves a switch from oxidative phosphorylation (OXPHOS) to glycolysis or alterations in other metabolic pathways. However, most of the experimental findings have been acquired in murine immune cells, and little is known about the metabolic reprogramming of human microglia. In this study, we investigate the transcriptomic, proteomic, and metabolic profiles of mouse and iPSC-derived human microglia challenged with the TLR4 agonist LPS. We demonstrate that both species display a metabolic shift and an overall increased glycolytic gene signature in response to LPS treatment. The metabolic reprogramming is characterized by the upregulation of hexokinases in mouse microglia and phosphofructokinases in human microglia. This study provides a direct comparison of metabolism between mouse and human microglia, highlighting the species-specific pathways involved in immunometabolism and the importance of considering these differences in translational research.
Topics: Animals; Mice; Humans; Microglia; Lipopolysaccharides; Proteomics; Oxidative Phosphorylation; Glycolysis
PubMed: 37833292
DOI: 10.1038/s41467-023-42096-7 -
International Journal of Molecular... Feb 2024Infection is a major contributor to the development of cancer, with more than 15% of new cancer diagnoses estimated to be caused by infection [...].
Infection is a major contributor to the development of cancer, with more than 15% of new cancer diagnoses estimated to be caused by infection [...].
Topics: Humans; Bacterial Toxins; Neoplasms
PubMed: 38396805
DOI: 10.3390/ijms25042128 -
Proceedings of the National Academy of... Aug 2023Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and...
Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and Irf3, which induces inflammatory cytokines and interferons that trigger an intense inflammatory response, which is critical for host defense but can also cause serious inflammatory pathology, including sepsis. Although TLR4 inhibition is an attractive therapeutic approach for suppressing overexuberant inflammatory signaling, previously identified TLR4 antagonists have not shown any clinical benefit. Here, we identify disulfiram (DSF), an FDA-approved drug for alcoholism, as a specific inhibitor of TLR4-mediated inflammatory signaling. TLR4 cell surface expression, LPS sensing, dimerization and signaling depend on TLR4 binding to MD-2. DSF and other cysteine-reactive drugs, previously shown to block LPS-triggered inflammatory cell death (pyroptosis), inhibit TLR4 signaling by covalently modifying Cys133 of MD-2, a key conserved residue that mediates TLR4 sensing and signaling. DSF blocks LPS-triggered inflammatory cytokine, chemokine, and interferon production by macrophages in vitro. In the aggressive N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease (PD) in which TLR4 plays an important role, DSF markedly suppresses neuroinflammation and dopaminergic neuron loss, and restores motor function. Our findings identify a role for DSF in curbing TLR4-mediated inflammation and suggest that DSF and other drugs that target MD-2 might be useful for treating PD and other diseases in which inflammation contributes importantly to pathogenesis.
Topics: Animals; Mice; Disulfiram; Toll-Like Receptor 4; Lipopolysaccharides; Signal Transduction; Alcoholism; Cytokines
PubMed: 37487070
DOI: 10.1073/pnas.2306399120 -
Naunyn-Schmiedeberg's Archives of... May 2024Trauma and toxic substances are connected in several aspects. On the one hand, toxic substances can be the reason for traumatic injuries in the context of accidental or... (Review)
Review
Trauma and toxic substances are connected in several aspects. On the one hand, toxic substances can be the reason for traumatic injuries in the context of accidental or violent and criminal circumstances. Examples for the first scenario is the release of toxic gases, chemicals, and particles during house fires, and for the second scenario, the use of chemical or biological weapons in the context of terroristic activities. Toxic substances can cause or enhance severe, life-threatening trauma, as described in this review for various chemical warfare, by inducing a tissue trauma accompanied by break down of important barriers in the body, such as the blood-air or the blood-gut barriers. This in turn initiates a "vicious circle" as the contribution of inflammatory responses to the traumatic damage enhances the macro- and micro-barrier breakdown and often results in fatal outcome. The development of sophisticated methods for detection and identification of toxic substances as well as the special treatment of the intoxicated trauma patient is summarized in this review. Moreover, some highly toxic substances, such as the protein toxins from the pathogenic bacterium Clostridioides (C.) difficile, cause severe post-traumatic complications which significantly worsens the outcome of hospitalized patients, in particular in multiply injured trauma patients. Therefore, novel pharmacological options for the treatment of such patients are necessarily needed and one promising strategy might be the neutralization of the toxins that cause the disease. This review summarizes recent findings on the molecular and cellular mechanisms of toxic chemicals and bacterial toxins that contribute to barrier breakdown in the human body as wells pharmacological options for treatment, in particular in the context of intoxicated trauma patients. "trauma-toxicology" comprises concepts regrading basic research, development of novel pharmacological/therapeutic options and clinical aspects in the complex interplay and "vicious circle" of severe tissue trauma, barrier breakdown, pathogen and toxin exposure, tissue damage, and subsequent clinical complications.
Topics: Humans; Animals; Wounds and Injuries
PubMed: 37999755
DOI: 10.1007/s00210-023-02845-3 -
Movement Disorders : Official Journal... Jul 2023The endotoxin hypothesis of Parkinson's disease (PD) is the idea that lipopolysaccharide (LPS) endotoxins contribute to the pathogenesis of this disorder. LPS endotoxins... (Review)
Review
The endotoxin hypothesis of Parkinson's disease (PD) is the idea that lipopolysaccharide (LPS) endotoxins contribute to the pathogenesis of this disorder. LPS endotoxins are found in, and released from, the outer membrane of Gram-negative bacteria, for example in the gut. It is proposed that gut dysfunction in early PD leads to elevated LPS levels in the gut wall and blood, which promotes both α-synuclein aggregation in the enteric neurons and a peripheral inflammatory response. Communication to the brain via circulating LPS and cytokines in the blood and/or the gut-brain axis leads to neuroinflammation and spreading of α-synuclein pathology, exacerbating neurodegeneration in brainstem nuclei and loss of dopaminergic neurons in the substantia nigra, and manifesting in the clinical symptoms of PD. The evidence supporting this hypothesis includes: (1) gut dysfunction, permeability, and bacterial changes occur early in PD, (2) serum levels of LPS are increased in a proportion of PD patients, (3) LPS induces α-synuclein expression, aggregation, and neurotoxicity, (4) LPS causes activation of peripheral monocytes leading to inflammatory cytokine production, and (5) blood LPS causes brain inflammation and specific loss of midbrain dopaminergic neurons, mediated by microglia. If the hypothesis is correct, then treatment options might include: (1) changing the gut microbiome, (2) reducing gut permeability, (3) reducing circulating LPS levels, or (4) blocking the response of immune cells and microglia to LPS. However, the hypothesis has a number of limitations and requires further testing, in particular whether reducing LPS levels can reduce PD incidence, progression, or severity. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Endotoxins; Lipopolysaccharides; Dopaminergic Neurons
PubMed: 37157885
DOI: 10.1002/mds.29432 -
Aesthetic Surgery Journal Oct 2023Treatment of wrinkles and dynamic lines with botulinum toxin has been a routine practice for years in aesthetic clinical settings. The effective treatment of wrinkles... (Review)
Review
Treatment of wrinkles and dynamic lines with botulinum toxin has been a routine practice for years in aesthetic clinical settings. The effective treatment of wrinkles requires a comprehensive understanding of facial expression muscles and their interactions, the mechanism of action of botulinum toxin, and individual patient preferences. The dose adjustment practice and injection technique of physicians are affected by cultural differences; most Asian patients prefer natural-looking results. This article aims to present an expert consensus on the injection sites, doses, and levels of botulinum toxin for various indications in Asians, with the hope of providing guidance to some clinicians. This consensus paper reviews LetibotulinumtoxinA for patient evaluation, dosage, and delivery techniques in Asians from the time LetibotulinumtoxinA was approved up to December 2022. Panelists proposed individualized treatment plans for botulinum toxin type A (BTxA) treatments in 3 areas-wrinkle removal, contour adjustment, and face lifting-for Asians based on their extensive experience and knowledge of facial anatomy. When using a different BTxA, clinicians should start with a conservative dose and carefully individualize the treatment for each patient, and adjust it according to feedback to obtain a higher satisfaction level.
Topics: Humans; Botulinum Toxins, Type A; Neuromuscular Agents; Consensus; Asian People; Esthetics; Skin Aging
PubMed: 37220644
DOI: 10.1093/asj/sjad151 -
Current Opinion in Immunology Dec 2023Enterotoxin adjuvants have been researched for their ability to promote immunity to co-delivered antigens. Outside of cholera vaccines, however, these proteins have yet... (Review)
Review
Enterotoxin adjuvants have been researched for their ability to promote immunity to co-delivered antigens. Outside of cholera vaccines, however, these proteins have yet to be included in any currently licensed vaccines. They include molecules derived from the bacterial toxins of Vibrio cholerae, cholera toxin, or Escherichia coli, heat-labile toxin, such as detoxified mutants or subunits. This class of adjuvants is distinguished by their delivery possibilities, which include parenteral injection, skin applications, or direct mucosal administration by oral, sublingual, or nasal routes. In addition, inclusion of an enterotoxin adjuvant is associated with development of multifaceted cellular and humoral immune responses to vaccination. Here, we review exciting progress in the past few years in clinical trials for safety and efficacy, preclinical vaccines studies, and new mechanistic insights for enterotoxin adjuvants. This includes recent reports of their use in vaccines targeting microbial infections (bacterial, viral, parasitic) or substance abuse drugs.
Topics: Humans; Enterotoxins; Adjuvants, Vaccine; Cholera Toxin; Bacterial Toxins; Vaccines; Adjuvants, Immunologic; Escherichia coli
PubMed: 37976963
DOI: 10.1016/j.coi.2023.102398 -
MBio Jan 2024Microbes use protein toxins as important tools to attack neighboring cells, microbial or eukaryotic, and for self-killing when attacked by viruses. These toxins work...
Microbes use protein toxins as important tools to attack neighboring cells, microbial or eukaryotic, and for self-killing when attacked by viruses. These toxins work through different mechanisms to inhibit cell growth or kill cells. Microbes also use antitoxin proteins to neutralize the toxin activities. Here, we developed a comprehensive database called Toxinome of nearly two million toxins and antitoxins that are encoded in 59,475 bacterial genomes. We described the distribution of bacterial toxins and identified that they are depleted by bacteria that live in hot and cold temperatures. We found 5,161 cases in which toxins and antitoxins are densely clustered in bacterial genomes and termed these areas "Toxin Islands." The Toxinome database is a useful resource for anyone interested in toxin biology and evolution, and it can guide the discovery of new toxins.
Topics: Bacterial Proteins; Bacterial Toxins; Bacteria; Antitoxins; Genome, Bacterial
PubMed: 38117054
DOI: 10.1128/mbio.01911-23