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Nature Communications Feb 2024Innate immunity provides the first line of defense through multiple mechanisms, including pyrogen production and cell death. While elevated body temperature during...
Innate immunity provides the first line of defense through multiple mechanisms, including pyrogen production and cell death. While elevated body temperature during infection is beneficial to clear pathogens, heat stress (HS) can lead to inflammation and pathology. Links between pathogen exposure, HS, cytokine release, and inflammation have been observed, but fundamental innate immune mechanisms driving pathology during pathogen exposure and HS remain unclear. Here, we use multiple genetic approaches to elucidate innate immune pathways in infection or LPS and HS models. Our results show that bacteria and LPS robustly increase inflammatory cell death during HS that is dependent on caspase-1, caspase-11, caspase-8, and RIPK3 through the PANoptosis pathway. Caspase-7 also contributes to PANoptosis in this context. Furthermore, NINJ1 is an important executioner of this cell death to release inflammatory molecules, independent of other pore-forming executioner proteins, gasdermin D, gasdermin E, and MLKL. In an in vivo HS model, mortality is reduced by deleting NINJ1 and fully rescued by deleting key PANoptosis molecules. Our findings suggest that therapeutic strategies blocking NINJ1 or its upstream regulators to prevent PANoptosis may reduce the release of inflammatory mediators and benefit patients.
Topics: Humans; Lipopolysaccharides; Gasdermins; Cell Death; Inflammation; Caspases; Heat Stress Disorders; Heat-Shock Response; Pyroptosis; Apoptosis; Nerve Growth Factors; Cell Adhesion Molecules, Neuronal
PubMed: 38409108
DOI: 10.1038/s41467-024-45466-x -
Toxins Aug 2018A pyrogen is a substance that causes fever after intravenous administration or inhalation. Gram negative endotoxins are the most important pyrogens to pharmaceutical... (Comparative Study)
Comparative Study Review
A pyrogen is a substance that causes fever after intravenous administration or inhalation. Gram negative endotoxins are the most important pyrogens to pharmaceutical laboratories. In the International, United States, Japanese and European Pharmacopoeias, there are two official methods to evaluate pyrogenicitythat is, the bacterial endotoxin test, and the pyrogen test. The main objective of this review is to compare the monographs of each test among the different Pharmacopeias, to detect similarities and differences. The former can be considered fully harmonized, and only non-significant differences were detected. The latter, which is the only available assay for some products and formulations to demonstrate apyrogenicity, shows large differences, which should be considered.
Topics: Animals; Biological Assay; Endotoxins; Humans; Pharmacopoeias as Topic; Pyrogens
PubMed: 30115887
DOI: 10.3390/toxins10080331 -
World Journal of Gastrointestinal... May 2024Gastrointestinal (GI) cancer is a malignancy arising in the digestive system and accounts for approximately a third of increasing global cancer-related mortality,...
Gastrointestinal (GI) cancer is a malignancy arising in the digestive system and accounts for approximately a third of increasing global cancer-related mortality, especially in the colorectum, esophagus, stomach, and liver. Interleukin-1β (IL-1β) is a leukocytic pyrogen recognized as a tumor progression-related cytokine. IL-1β secretion and maturation in inflammatory responses could be regulated by nuclear factor-kappaB-dependent expression of NLR family pyrin domain containing 3, inflammasome formation, and activation of IL-1 converting enzyme. Several studies have documented the pro-tumorigenic effects of IL-1β in tumor microenvironments, promoting proliferation and metastatic potential of cancer cells and tumorigenesis . The application of IL-1β inhibitors is also promising for targeted therapy development in some cancer types. However, as a leukocytic pro-inflammatory cytokine, IL-1β may also possess anti-tumorigenic effects and be type-specific in different cancers. This editorial discusses the up-to-date roles of IL-1β in GI cancers, including underlying mechanisms and downstream signaling pathways. Understanding and clarifying the roles of IL-1β would significantly benefit future therapeutic targeting and help improve therapeutic outcomes in patients suffering from GI cancer.
PubMed: 38764841
DOI: 10.4251/wjgo.v16.i5.1676 -
Deutsches Arzteblatt International Mar 2018Persistent fever of unknown cause is only rarely of cardiac origin, but heart disease must be considered in the differential diagnosis. Aside from endocarditis,... (Review)
Review
BACKGROUND
Persistent fever of unknown cause is only rarely of cardiac origin, but heart disease must be considered in the differential diagnosis. Aside from endocarditis, pericarditis and various other conditions may be responsible.
METHODS
This review is based on pertinent articles retrieved by a selective search in PubMed and Google Scholar employing the term "fever" in combination with "myocardial infarction," "pericarditis," "endocarditis," and "postcardiac injury," with additional consideration of current cardiological guidelines.
RESULTS
Endocarditis is associated with fever in 90% of cases, but 25-50% of patients also develop high body temperatures after acute myocardial infarction. In pericarditis, a temperature above 38°C indicates a poorer prognosis; if accompanied by other warning signs, it is an indication for hospitalization and pericardiocentesis. Fever can arise after cardiac surgical procedures as a manifestation of post - cardiotomy syndrome, a special type of perimyocarditis. There may be a latency period of up to 3 months.
CONCLUSION
Fever can have both infectious and non-infectious cardiac causes. Its interpretation depends on the clinical context. The evidence base for treatment is sparse, and controlled trials are needed.
Topics: Anti-Infective Agents; Anti-Inflammatory Agents; Cardiac Surgical Procedures; Cytokines; Endocarditis; Endocarditis, Bacterial; Fever; Humans; Inflammation Mediators; Myocardial Infarction; Pericarditis; Pyrogens; Time Factors
PubMed: 29642989
DOI: 10.3238/arztebl.2018.0193 -
Aging and Disease Oct 2020Recent studies have revealed novel forms of cell death beyond the canonical types of cellular apoptosis and necrosis, and these novel forms of cell death are induced by... (Review)
Review
Recent studies have revealed novel forms of cell death beyond the canonical types of cellular apoptosis and necrosis, and these novel forms of cell death are induced by extreme microenvironmental factors. Pyroptosis, a type of regulated cell death, occurs when pattern recognition receptors (PRRs) induce the activation of cysteine-aspartic protease 1 (caspase-1) or caspase-11, which can trigger the release of the pyrogenic cytokines interleukin-1β (IL-1β) and IL-18. Osteoarthritis (OA), the most common joint disease worldwide, is characterized by low-grade inflammation and increased levels of cytokines, including IL-1β and IL-18. Additionally, some damaged chondrocytes associated with OA exhibit morphological changes consistent with pyroptosis, suggesting that this form of regulated cell death may contribute significantly to the pathology of OA. This review summarizes the molecular mechanisms of pyroptosis and shows the critical role of NLRP3 (NLR family, pyrin domain containing 3; NLR refers to "nucleotide-binding domain, leucine-rich repeat") inflammasomes. We also provide evidence describing potential role of pyroptosis in OA, including the relationship with OA risk factors and the contribution to cartilage degradation, synovitis and OA pain.
PubMed: 33014529
DOI: 10.14336/AD.2019.1127 -
Archives of Toxicology Sep 2017Large-scale production and use of amorphous silica nanoparticles (SiNPs) have increased the risk of human exposure to SiNPs, while their health effects remain unclear.... (Review)
Review
Large-scale production and use of amorphous silica nanoparticles (SiNPs) have increased the risk of human exposure to SiNPs, while their health effects remain unclear. In this review, scientific papers from 2010 to 2016 were systematically selected and sorted based on in vitro and in vivo studies: to provide an update on SiNPs toxicity and to address the knowledge gaps indicated in the review of Napierska (Part Fibre Toxicol 7:39, 2010). Toxicity of SiNPs in vitro is size, dose, and cell type dependent. SiNPs synthesized by wet route exhibited noticeably different biological effects compared to thermal route-based SiNPs. Amorphous SiNPs (particularly colloidal and stöber) induced toxicity via mechanisms similar to crystalline silica. In vivo, route of administration and physico-chemical properties of SiNPs influences the toxicokinetics. Adverse effects were mainly observed in acutely exposed animals, while no significant signs of toxicity were noted in chronically dosed animals. The correlation between in vitro and in vivo toxicity remains less well established mainly due to improper-unrealistic-dosing both in vitro and in vivo. In conclusion, notwithstanding the multiple studies published in recent years, unambiguous linking of physico-chemical properties of SiNPs types to toxicity, bioavailability, or human health effects is not yet possible.
Topics: Animals; Autophagy; Cell Culture Techniques; DNA Damage; Endothelium, Vascular; Humans; Immune System; Inhalation Exposure; Mutagenicity Tests; Nanoparticles; Neurotoxicity Syndromes; Oxidative Stress; Silicon Dioxide; Toxicity Tests
PubMed: 28573455
DOI: 10.1007/s00204-017-1993-y -
International Journal of Molecular... Apr 2024Endotoxin is a general term for toxic substances in Gram-negative bacteria, whose damaging effects are mainly derived from the lipopolysaccharides (LPS) in the cell... (Review)
Review
Endotoxin is a general term for toxic substances in Gram-negative bacteria, whose damaging effects are mainly derived from the lipopolysaccharides (LPS) in the cell walls of Gram-negative bacteria, and is a strong pyrogen. Obesity is a chronic, low-grade inflammatory condition, and LPS are thought to trigger and exacerbate it. The gut flora is the largest source of LPS in the body, and it is increasingly believed that altered intestinal microorganisms can play an essential role in the pathology of different diseases. Today, the complex axis linking gut flora to inflammatory states and adiposity has not been well elucidated. This review summarises the evidence for an interconnection between LPS, obesity, and gut flora, further expanding our understanding of LPS as a mediator of low-grade inflammatory disease and contributing to lessening the effects of obesity and related metabolic disorders. As well as providing targets associated with LPS, obesity, and gut flora, it is hoped that interventions that combine targets with gut flora address the individual differences in gut flora treatment.
Topics: Humans; Lipopolysaccharides; Obesity; Gastrointestinal Microbiome; Animals; Inflammation
PubMed: 38673890
DOI: 10.3390/ijms25084305 -
Molecules (Basel, Switzerland) Jul 2020Understanding the potential contamination of pharmaceutical products with innate immunity modulating impurities (IIMIs) is essential for establishing their safety... (Review)
Review
Understanding the potential contamination of pharmaceutical products with innate immunity modulating impurities (IIMIs) is essential for establishing their safety profiles. IIMIs are a large family of molecules with diverse compositions and structures that contribute to the immune-mediated adverse effects (IMAE) of drug products. Pyrogenicity (the ability to induce fever) and activation of innate immune responses underlying both acute toxicities (e.g., anaphylactoid reactions or pseudoallergy, cytokine storm) and long-term effects (e.g., immunogenicity) are among the IMAE commonly related to IIMI contamination. Endotoxins of gram-negative bacteria are the best-studied IIMIs in that both methodologies for and pitfalls in their detection and quantification are well established. Additionally, regulatory guidance documents and research papers from laboratories worldwide are available on endotoxins. However, less information is currently known about other IIMIs. Herein, we focus on one such IIMI, namely, beta-glucans, and review literature and discuss the experience of the Nanotechnology Characterization Lab (NCL) with the detection of beta-glucans in nanotechnology-based drug products.
Topics: Drug Compounding; Drug Contamination; Nanotechnology; Pharmaceutical Preparations; beta-Glucans
PubMed: 32722261
DOI: 10.3390/molecules25153367 -
BioTechniques May 2021Testing of parenteral pharmaceuticals and medical devices for pyrogens (fever-inducing substances) is critical to patient safety. The original rabbit pyrogen test has...
Testing of parenteral pharmaceuticals and medical devices for pyrogens (fever-inducing substances) is critical to patient safety. The original rabbit pyrogen test has largely been replaced by different bacterial endotoxin tests based on amebocyte lysate (LAL), sourced from the blood equivalent of horseshoe crabs after comparative studies to the rabbit pyrogen test. Since 2004 a bacterial endotoxin test based on recombinant factor C (rFC), the endotoxin sensor protein inside of LAL, has been used as an animal-free alternative to LAL. Likewise, numerous studies compared LAL and rFC. Here we describe the history of pyrogen and bacterial endotoxin testing and summarize the evidence presented by those studies. We demonstrate that rFC and LAL are equivalent and comparable.
Topics: Animal Testing Alternatives; Animals; Endotoxins; Horseshoe Crabs; Pyrogens; Rabbits
PubMed: 33956506
DOI: 10.2144/btn-2020-0165