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Developmental and Comparative Immunology Jan 2017Fever is an evolutionary conserved defense mechanism which is present in both endothermic and ectothermic vertebrates. Ectotherms in response to infection can increase...
Fever is an evolutionary conserved defense mechanism which is present in both endothermic and ectothermic vertebrates. Ectotherms in response to infection can increase their body temperature by moving to warmer places. This process is known as behavioral fever. In this review, we summarize the current knowledge on the mechanisms of induction of fever in mammals. We further discuss the evolutionary conserved mechanisms existing between fever of mammals and behavioral fever of ectothermic vertebrates. Finally, the experimental evidences supporting an adaptive value of behavioral fever expressed by ectothermic vertebrates are summarized.
Topics: Animals; Biological Evolution; Body Temperature; Body Temperature Regulation; Central Nervous System; Fever; Immunity, Innate; Motor Activity; Prostaglandins; Vertebrates
PubMed: 27381718
DOI: 10.1016/j.dci.2016.06.027 -
Biomolecules Dec 2021Nonwoven textiles are used extensively in the field of medicine, including wound healing, but these textiles are mostly from conventional nondegradable materials, e.g.,...
Nonwoven textiles are used extensively in the field of medicine, including wound healing, but these textiles are mostly from conventional nondegradable materials, e.g., cotton or synthetic polymers such as polypropylene. Therefore, we aimed to develop nonwoven textiles from hyaluronan (HA), a biocompatible, biodegradable and nontoxic polysaccharide naturally present in the human body. For this purpose, we used a process based on wet spinning HA into a nonstationary coagulation bath combined with the wet-laid textile technology. The obtained HA nonwoven textiles are soft, flexible and paper like. Their mechanical properties, handling and hydration depend on the microscale fibre structure, which is tuneable by selected process parameters. Cell viability testing on two relevant cell lines (3T3, HaCaT) demonstrated that the textiles are not cytotoxic, while the monocyte activation test ruled out pyrogenicity. Biocompatibility, biodegradability and their high capacity for moisture absorption make HA nonwoven textiles a promising material for applications in the field of wound healing, both for topical and internal use. The beneficial effect of HA in the process of wound healing is well known and the form of a nonwoven textile should enable convenient handling and application to various types of wounds.
Topics: 3T3 Cells; Animals; Bandages; Humans; Hyaluronic Acid; Materials Testing; Mice; Textiles; Wound Healing
PubMed: 35053164
DOI: 10.3390/biom12010016 -
BioMed Research International 2020Whilst radiopharmaceuticals have an important role to play in both imaging and treatment of patients, most notably cancer patients, nuclear medicine and radiopharmacy...
Whilst radiopharmaceuticals have an important role to play in both imaging and treatment of patients, most notably cancer patients, nuclear medicine and radiopharmacy are currently facing challenges to create innovative new drugs. Traditional radiopharmaceutical manufacture can be considered as either a routine hospital production or a large-scale industrial production. The gap between these two practices has meant that there is an inability to supply innovative radiopharmaceuticals for use at the local level for mono- or multicentric clinical trials with satisfactory quality and safety specifications. This article highlights the regulatory requirements in aseptic pharmaceutical processing and in nuclear medicine to be able to locally produce radiopharmaceuticals. We validate the proof-of-concept for an "in-house" hospital-based radiopharmacy including an on-site cyclotron, that can fulfill the conflicting requirements between radiation safety and aseptic processing. The ARRONAX in-house radiopharmacy is currently able to provide sterile and pyrogenic-free injectable radiopharmaceutical compounds for both industrial and institutional clinical trials.
Topics: Facility Design and Construction; Humans; Nuclear Medicine; Pharmacy Service, Hospital; Radiopharmaceuticals
PubMed: 32566657
DOI: 10.1155/2020/1572841 -
Cell Transplantation Feb 2018It is extremely challenging to achieve strong adhesion in soft tissues while minimizing toxicity, tissue damage, and other side effects caused by wound sealing...
It is extremely challenging to achieve strong adhesion in soft tissues while minimizing toxicity, tissue damage, and other side effects caused by wound sealing materials. In this study, flexible synthetic hydrogel sealants were prepared based on polyethylene glycol (PEG) materials. PEG is a synthetic material that is nontoxic and inert and, thus, suitable for use in medical products. We evaluated the in vitro biocompatibility tests of the dressings to assess cytotoxicity and irritation, sensitization, pyrogen toxicity, and systemic toxicity following the International Organization for Standardization 10993 standards and the in vivo effects of the hydrogel samples using Coloskin liquid bandages as control samples for potential in wound closure.
Topics: Animals; Biocompatible Materials; Hydrogels; Male; Polyethylene Glycols; Rabbits; Wound Healing
PubMed: 29637814
DOI: 10.1177/0963689717749032 -
Archives of Toxicology Dec 2016Particle sizes of E 551 products are in the micrometre range. The typical external diameters of the constituent particles (aggregates) are greater than 100 nm. E 551... (Review)
Review
Particle sizes of E 551 products are in the micrometre range. The typical external diameters of the constituent particles (aggregates) are greater than 100 nm. E 551 does not break down under acidic conditions such as in the stomach, but may release dissolved silica in environments with higher pH such as the intestinal tract. E 551 is one of the toxicologically most intensively studied substances and has not shown any relevant systemic or local toxicity after oral exposure. Synthetic amorphous silica (SAS) meeting the specifications for use as a food additive (E 551) is and has always been produced by the same two production methods: the thermal and the wet processes, resulting in E 551 products consisting of particles typically in the micrometre size range. The constituent particles (aggregates) are typically larger than 100 nm and do not contain discernible primary particles. Particle sizes above 100 nm are necessary for E 551 to fulfil its technical function as spacer between food particles, thus avoiding the caking of food particles. Based on an in-depth review of the available toxicological information and intake data, it is concluded that the SAS products specified for use as food additive E 551 do not cause adverse effects in oral repeated-dose studies including doses that exceed current OECD guideline recommendations. In particular, there is no evidence for liver toxicity after oral intake. No adverse effects have been found in oral fertility and developmental toxicity studies, nor are there any indications from in vivo studies for an immunotoxic or neurotoxic effect. SAS is neither mutagenic nor genotoxic in vivo. In intact cells, a direct interaction of unlabelled and unmodified SAS with DNA was never found. Differences in the magnitude of biological responses between pyrogenic and precipitated silica described in some in vitro studies with murine macrophages at exaggerated exposure levels seem to be related to interactions with cell culture proteins and cell membranes. The in vivo studies do not indicate that there is a toxicologically relevant difference between SAS products after oral exposure. It is noted that any silicon dioxide product not meeting established specifications, and/or produced to provide new functionality in food, requires its own specific safety and risk assessment.
Topics: Animals; Calcium Compounds; European Union; Evidence-Based Practice; Food Additives; Food Technology; Humans; Nanostructures; Particle Size; Silicates; Silicon Dioxide; Surface Properties; Toxicity Tests
PubMed: 27699444
DOI: 10.1007/s00204-016-1850-4 -
Frontiers in Oncology 2022According to the WHO, cancer is the second leading cause of death in the world. This is an important global problem and a major challenge for researchers who have been... (Review)
Review
According to the WHO, cancer is the second leading cause of death in the world. This is an important global problem and a major challenge for researchers who have been trying to find an effective anticancer therapy. A large number of newly discovered compounds do not exert selective cytotoxic activity against tumorigenic cells and have too many side effects. Therefore, research on muramyl dipeptide (MDP) analogs has attracted interest due to the urgency for finding more efficient and safe treatments for oncological patients. MDP is a ligand of the cytosolic nucleotide-binding oligomerization domain 2 receptor (NOD2). This molecule is basic structural unit that is responsible for the immune activity of peptidoglycans and exhibits many features that are important for modern medicine. NOD2 is a component of the innate immune system and represents a promising target for enhancing the innate immune response as well as the immune response against cancer cells. For this reason, MDP and its analogs have been widely used for many years not only in the treatment of immunodeficiency diseases but also as adjuvants to support improved vaccine delivery, including for cancer treatment. Unfortunately, in most cases, both the MDP molecule and its synthesized analogs prove to be too pyrogenic and cause serious side effects during their use, which consequently exclude them from direct clinical application. Therefore, intensive research is underway to find analogs of the MDP molecule that will have better biocompatibility and greater effectiveness as anticancer agents and for adjuvant therapy. In this paper, we review the MDP analogs discovered in the last 10 years that show promise for antitumor therapy. The first part of the paper compiles the achievements in the field of anticancer vaccine adjuvant research, which is followed by a description of MDP analogs that exhibit promising anticancer and antiproliferative activity and their structural changes compared to the original MDP molecule.
PubMed: 36237313
DOI: 10.3389/fonc.2022.970967 -
Microbiology Spectrum Feb 2023Three mutants individually of both staphylococcal enterotoxins B and C were prepared by site-specific mutagenesis of enterotoxin amino acids that contact host T...
Three mutants individually of both staphylococcal enterotoxins B and C were prepared by site-specific mutagenesis of enterotoxin amino acids that contact host T lymphocyte immune cell receptor sites (N23A, Q210A, and N23A/Q210A); these amino acids are shared between the two enterotoxins, and mutations reduce the interaction with the variable part of the β-chain of the T lymphocyte receptor. The mutant proteins, as expressed in Staphylococcus aureus RN4220, lacked biological toxicity as measured by the loss of (i) stimulation of rabbit splenocyte proliferation, (ii) pyrogenicity, and (iii) the ability to enhance the lethality of endotoxin shock, compared to wild-type enterotoxins. In addition, the mutants were able to vaccinate rabbits against pyrogenicity, the enhancement of endotoxin shock, and lethality in a pneumonia model when animals were challenged with methicillin-resistant S. aureus. Three vaccine injections (one primary and two boosters) protected rabbits for at least 3.5 months postvaccination when challenged with wild-type enterotoxins (last time point tested). These mutant proteins have the potential to function as toxoid vaccines against these two causes of nonmenstrual toxic shock syndrome (TSS). Toxic shock syndrome toxin 1 (TSST-1) and staphylococcal enterotoxins B and C cause the majority of cases of staphylococcal toxic shock syndrome. Previously, vaccine toxoids of TSST-1 have been prepared. In this study, vaccine toxoids of enterotoxins B and C were prepared. The toxoids lost biological toxicity but were able to vaccinate rabbits against lethal TSS.
PubMed: 36815779
DOI: 10.1128/spectrum.04446-22 -
British Journal of Clinical Pharmacology Jul 2019Drug safety is an important issue, especially in the experimental phases of development. Adverse immunostimulation (AI) is sometimes encountered following treatment with... (Review)
Review
Drug safety is an important issue, especially in the experimental phases of development. Adverse immunostimulation (AI) is sometimes encountered following treatment with biopharmaceuticals, which can be life-threatening if it results in a severe systemic inflammatory reaction. Biopharmaceuticals that unexpectedly induce an inflammatory response still enter the clinic, even while meeting all regulatory requirements. Impurities (of microbial origin) in biopharmaceuticals are an often-overlooked cause of AI. This demonstrates that the current guidelines for quality control and safety pharmacology testing are not flawless. Here, based on two case examples, several shortcomings of the guidelines are discussed. The most important of these are the lack of sensitivity for impurities, lack of testing for pyrogens other than endotoxin, and the use of insensitive animal species and biomarkers in preclinical investigations. Moreover, testing for the immunotoxicity of biopharmaceuticals is explicitly not recommended by the international guidelines. Publication of cases of AI is pivotal, both to increase awareness and to facilitate scientific discussions on how to prevent AI in the future.
Topics: Animals; Biological Products; Drug Contamination; Endotoxins; Guidelines as Topic; Humans; Immunomodulation; Pyrogens; Quality Control
PubMed: 30920013
DOI: 10.1111/bcp.13938 -
Journal of Leukocyte Biology Dec 2018Inflammation-limiting nonsteroidal pain relievers magnify myocardial infarction (MI) incidences and increase re-admission events in heart failure (HF) patients. However,...
Inflammation-limiting nonsteroidal pain relievers magnify myocardial infarction (MI) incidences and increase re-admission events in heart failure (HF) patients. However, the molecular and cellular mechanism of this provocative adverse effect is unclear. Our goal was to determine whether carprofen (CAP) impedes splenic leukocyte-directed acute inflammation-resolving response in cardiac injury. After subacute CAP treatment, mice were subjected to permanent coronary ligation maintaining MI- and naïve-controls. Spleen and left ventricle (LV) leukocytes were quantitated using flow cytometry pre- and 24 h post-MI. The inflammation resolution mediators were quantified using mass spectrometry while splenocardiac apoptosis and leukocyte phagocytosis were measured by immunofluorescence and ImageStream, respectively. Subacute CAP treatment promoted strain and cardiac dysfunction before MI and coronary occlusion showed signs of acute HF in CAP and MI-controls. Subacute CAP-injected mice had pre-activated splenic neutrophils, an over activated "don't eat me" signal (CD47) with reduced total Mϕs (F4/80 ) and reparative Mϕs (F4/80/Ly6C /CD206) compared with control in LV and spleen. Post-MI, CAP pre-activated neutrophils (Ly6G ) were intensified and reduced reparative neutrophils (Ly6G /CD206 ) and Mϕs (F4/80/Ly6C ) in LV was indicative of non-resolving inflammation compared with MI-control. Subacute CAP treatment deferred neutrophil phagocytosis functions in the spleen and LV and was more evident post-MI compared with MI-control. CAP pre-activated splenic neutrophils that tailored the Mϕ phagocytosis thereby increased splenocardiac leukocyte death. CAP over amplified COX-1 and COX-2 compared with MI-control and failed to limit prostaglandins and thromboxane in post-MI setting. Further, CAP reduced cardiac-protective epoxyeicosatrienoic acids and over amplified pyrogenic inflammatory cytokines and reduced reparative cytokines, thereby non-resolving inflammation.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Carbazoles; Cyclooxygenase 1; Cyclooxygenase 2; Eicosanoids; Heart Failure; Heart Ventricles; Inflammation; Inflammation Mediators; Leukocytes; Macrophage Activation; Membrane Proteins; Mice; Mice, Inbred C57BL; Myocardial Infarction; Neutrophil Activation; Phagocytosis; Prostaglandins; Spleen
PubMed: 30145840
DOI: 10.1002/JLB.3A0618-223R -
The American Journal of Tropical... Jan 2017Within 24 hours after antibiotic treatment of the spirochetal infections syphilis, Lyme disease, leptospirosis, and relapsing fever (RF), patients experience shaking... (Review)
Review
Within 24 hours after antibiotic treatment of the spirochetal infections syphilis, Lyme disease, leptospirosis, and relapsing fever (RF), patients experience shaking chills, a rise in temperature, and intensification of skin rashes known as the Jarisch-Herxheimer reaction (JHR) with symptoms resolving a few hours later. Case reports indicate that the JHR can also include uterine contractions in pregnancy, worsening liver and renal function, acute respiratory distress syndrome, myocardial injury, hypotension, meningitis, alterations in consciousness, seizures, and strokes. Experimental evidence indicates it is caused by nonendotoxin pyrogen and spirochetal lipoproteins. Mediation of the JHR in RF by the pro-inflammatory cytokines tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8 has been proposed, consistent with measurements in patients' blood and inhibition by anti-TNF antibodies. Accelerated phagocytosis of spirochetes by polymorphonuclear (PMN) leukocytes before rise in cytokines is responsible for removal of organisms from the blood, suggesting an early inflammatory signal from PMNs. Rarely fatal, except in neonates and in pregnancy for African women whose babies showed high perinatal mortality because of low birth weight, the JHR can be regarded as an adverse effect of antibiotics, necessary for achieving a cure of spirochetal infections.
Topics: Anti-Bacterial Agents; Cytokines; Humans; Inflammation; Spirochaetales Infections
PubMed: 28077740
DOI: 10.4269/ajtmh.16-0434