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Immunity, Inflammation and Disease Aug 2023A systemic and local inflammatory immune imbalance is thought to be the cause of traumatic tracheal stenosis (TS). However, with CD4 T lymphocytes being the predominant...
A systemic and local inflammatory immune imbalance is thought to be the cause of traumatic tracheal stenosis (TS). However, with CD4 T lymphocytes being the predominant immune cells in TS, the mechanism of action and recruitment has not been described. In our research, using flow cytometry, ELISA, immunofluorescence, and Transwell chamber assays, the expression, distribution, and potential chemotactic function of CD4 T cells in TS patients were examined before and after treatment. The results showed that the untreated group had significantly more CD4 T cells and their secreted TGF-β1 than the treated group. Additionally, the untreated group's CD4 T cells showed a significant rise in CCL22 and CCL1, as well as a larger proportion of CCR4 and CCR8. CD4 T cells and CD68 macrophages located in TS also expressed CCL1 and CCL22. In vitro, anti-CCL1 and anti-CCL22 can partially block the chemoattractant effect of TS bronchoalveolar lavage (BAL) on purified CD4 T cells. The findings of this study indicated that TS contained unbalanced CD4 immune cells that were actively recruited locally by CCR4/CCL22 and CCR8/CCL1. As a result, it is anticipated that CD4 immune rebalancing can serve as a novel treatment for TS.
Topics: Humans; Tracheal Stenosis; Biological Assay; CD4-Positive T-Lymphocytes; Dimercaprol; Enzyme-Linked Immunosorbent Assay
PubMed: 37647429
DOI: 10.1002/iid3.916 -
Prague Medical Report 2023Acute eosinophilic pneumonia (AEP) is a rare cause of respiratory failure. It is primarily a disease of smokers, either a new smoker or an existing one with a recent...
Acute eosinophilic pneumonia (AEP) is a rare cause of respiratory failure. It is primarily a disease of smokers, either a new smoker or an existing one with a recent increase in cigarette consumption. Other risk factors include toxic gas exposure, inhalational illicit drugs, and smoking marijuana. AEP has also been reported in patients with e-cigarette or vaping associated lung injury (EVALI). We present the case of a 20-year-old male who presented to the hospital with acute respiratory failure. The patient has been vaping heavily for the past three months and started smoking three days before presenting to the emergency department. He was hypertensive, tachycardic, tachypneic, and required high-flow nasal cannula to maintain SpO2 > 92%. His condition deteriorated in the first 24 hours following hospitalization requiring noninvasive positive pressure ventilation. Bronchoalveolar lavage revealed an eosinophil count of 36%. Bronchoalveolar lavage (BAL) cytology revealed lipid-laden macrophages. He was diagnosed with AEP due to EVALI, and the patient was treated with high dose corticosteroid with subsequent improvement. Before the bronchoscopic evaluation, the clinical and radiologic findings were consistent with COVID-19, and the patient was tested twice for SARS-CoV-2 PCR. In the appropriate clinical setting, AEP should be considered in the differential diagnoses of community-acquired pneumonia, acute respiratory distress syndrome (ARDS), and COVID-19, especially in this pandemic era.
Topics: Male; Humans; Young Adult; Adult; COVID-19; Pulmonary Eosinophilia; Vaping; Electronic Nicotine Delivery Systems; Lung Injury; SARS-CoV-2; Dimercaprol
PubMed: 37736951
DOI: 10.14712/23362936.2023.22 -
Journal of Neurochemistry Jun 2017Acrolein is one of the most toxic byproducts of lipid peroxidation, and it has been shown to be associated with multiple pathological processes in trauma and diseases,...
Acrolein is one of the most toxic byproducts of lipid peroxidation, and it has been shown to be associated with multiple pathological processes in trauma and diseases, including spinal cord injury, multiple sclerosis, and Alzheimer's disease. Therefore, suppressing acrolein using acrolein scavengers has been suggested as a novel strategy of neuroprotection. In an effort to identify effective acrolein scavengers, we have confirmed that dimercaprol, which possesses thiol functional groups, could bind and trap acrolein. We demonstrated the reaction between acrolein and dimercaprol in an abiotic condition by nuclear magnetic resonance spectroscopy. Specifically, dimercaprol is able to bind to both the carbon double bond and aldehyde group of acrolein. Its acrolein scavenging capability was further demonstrated by in vitro results that showed that dimercaprol could significantly protect PC-12 cells from acrolein-mediated cell death in a dose-dependent manner. Furthermore, dimercaprol, when applied systemically through intraperitoneal injection, could significantly reduce acrolein contents in spinal cord tissue following a spinal cord contusion injury in rats, a condition known to have elevated acrolein concentration. Taken together, dimercaprol may be an effective acrolein scavenger and a viable candidate for acrolein detoxification.
Topics: Acrolein; Animals; Body Weight; Cell Death; Dimercaprol; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Free Radical Scavengers; L-Lactate Dehydrogenase; Magnetic Resonance Spectroscopy; Male; PC12 Cells; Rats; Spinal Cord; Spinal Cord Injuries
PubMed: 28301040
DOI: 10.1111/jnc.14025 -
Acta Pharmaceutica Sinica. B Oct 2020Repurposing small molecule drugs and drug candidates is considered as a promising approach to revolutionise the treatment of snakebite envenoming. In this study, we...
Repurposing small molecule drugs and drug candidates is considered as a promising approach to revolutionise the treatment of snakebite envenoming. In this study, we investigated the inhibiting effects of the small molecules varespladib (nonspecific phospholipase A inhibitor), marimastat (broad spectrum matrix metalloprotease inhibitor) and dimercaprol (metal ion chelator) against coagulopathic toxins found in Crotalinae (pit vipers) snake venoms. Venoms from , , and were separated by liquid chromatography, followed by nanofractionation and mass spectrometry identification undertaken in parallel. Nanofractions of the venom toxins were then subjected to a high-throughput coagulation assay in the presence of different concentrations of the small molecules under study. Anticoagulant venom toxins were mostly identified as phospholipases A, while procoagulant venom activities were mainly associated with snake venom metalloproteinases and snake venom serine proteases. Varespladib was found to effectively inhibit most anticoagulant venom effects, and also showed some inhibition against procoagulant toxins. Contrastingly, marimastat and dimercaprol were both effective inhibitors of procoagulant venom activities but showed little inhibitory capability against anticoagulant toxins. The information obtained from this study aids our understanding of the mechanisms of action of toxin inhibitor drug candidates, and highlights their potential as future snakebite treatments.
PubMed: 33163338
DOI: 10.1016/j.apsb.2020.09.005 -
Redox Biology Jul 2024Glutathione (GSH) is a major endogenous antioxidant, and its depletion has been observed in several brain diseases including epilepsy. Previous studies in our laboratory...
Glutathione (GSH) is a major endogenous antioxidant, and its depletion has been observed in several brain diseases including epilepsy. Previous studies in our laboratory have shown that dimercaprol (DMP) can elevate GSH via post-translational activation of glutamate cysteine ligase (GCL), the rate limiting GSH biosynthetic enzyme and inhibit neuroinflammation in vitro. Here we determined 1) the role of cysteamine as a new mechanism by which DMP increases GSH biosynthesis and 2) its ability to inhibit neuroinflammation and neuronal injury in the rat kainate model of epilepsy. DMP depleted cysteamine in a time- and concentration-dependent manner in a cell free system. To guide the in vivo administration of DMP, its pharmacokinetic profile was determined in the plasma, liver, and brain. The results confirmed DMP's ability to cross the blood-brain-barrier. Treatment of rats with DMP (30 mg/kg) depleted cysteamine in the liver and hippocampus that was associated with increased GCL activity in these tissues. GSH levels were significantly increased (20 %) in the hippocampus 1 h after 30 mg/kg DMP administration. Following DMP (30 mg/kg) administration once daily, a marked attenuation of GSH depletion was seen in the SE model. SE-induced inflammatory markers including cytokine release, microglial activation, and neuronal death were significantly attenuated in the hippocampus with DMP treatment. Taken together, these results highlight the importance of restoring redox status with rescue of GSH depletion by DMP in post epileptogenic insults.
Topics: Animals; Rats; Glutathione; Status Epilepticus; Oxidative Stress; Neuroinflammatory Diseases; Male; Disease Models, Animal; Hippocampus; Cysteamine; Antioxidants; Glutamate-Cysteine Ligase; Liver
PubMed: 38714094
DOI: 10.1016/j.redox.2024.103168 -
Pharmaceutics Feb 2023Lipid nanoparticles (LNPs) are the commonly used delivery tools for messenger RNA (mRNA) therapy and play an indispensable role in the success of COVID-19 mRNA vaccines....
Lipid nanoparticles (LNPs) are the commonly used delivery tools for messenger RNA (mRNA) therapy and play an indispensable role in the success of COVID-19 mRNA vaccines. Ionizable cationic lipids are the most important component in LNPs. Herein, we developed a series of new ionizable lipids featuring bioreducible disulfide bonds, and constructed a library of lipids derived from dimercaprol. LNPs prepared from these ionizable lipids could be stored at 4 °C for a long term and are non-toxic toward HepG2 and 293T cells. In vivo experiments demonstrated that the best C4S18A formulations, which embody linoleoyl tails, show strong firefly luciferase (Fluc) mRNA expression in the liver and spleen via intravenous (IV) injection, or at the local injection site via intramuscular injection (IM). The newly designed ionizable lipids can be potentially safe and high-efficiency nanomaterials for mRNA therapy.
PubMed: 36839799
DOI: 10.3390/pharmaceutics15020477 -
Pharmaceutics Oct 2021Actinium-225 (Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although Ac labeling of bifunctional chelating ligands is effective, previous in vivo...
Evaluation of Aminopolycarboxylate Chelators for Whole-Body Clearance of Free Ac: A Feasibility Study to Reduce Unexpected Radiation Exposure during Targeted Alpha Therapy.
Actinium-225 (Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although Ac labeling of bifunctional chelating ligands is effective, previous in vivo studies reported that free Ac can be released from the drugs and that such free Ac is predominantly accumulated in the liver and could cause unexpected toxicity. To accelerate the clinical development of Ac TAT with a variety of drugs, preparing methods to deal with any unexpected toxicity would be valuable. The aim of this study was to evaluate the feasibility of various chelators for reducing and excreting free Ac and compare their chemical structures. Nine candidate chelators (D-penicillamine, dimercaprol, Ca-DTPA, Ca-EDTA, CyDTA, GEDTA TTHA, Ca-TTHA, and DO3A) were evaluated in vitro and in vivo. The biodistribution and dosimetry of free Ac were examined in mice before an in vivo chelating study. The liver exhibited pronounced Ac uptake, with an estimated human absorbed dose of 4.76 Sv/MBq. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, significantly reduced Ac retention in the liver (22% and 30%, respectively). Significant Ac reductions were observed in the heart and remainder of the body with both Ca-DTPA and Ca-TTHA, and in the lung, kidney, and spleen with Ca-TTHA. In vitro interaction analysis supported the in vivo reduction ability of Ca-DTPA and Ca-TTHA. In conclusion, aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, were effective for whole-body clearance of free Ac. This feasibility study provides useful information for reducing undesirable radiation exposure from free Ac.
PubMed: 34683999
DOI: 10.3390/pharmaceutics13101706 -
Science Translational Medicine May 2020Snakebite envenoming causes 138,000 deaths annually, and ~400,000 victims are left with permanent disabilities. Envenoming by saw-scaled vipers (Viperidae: ) leads to...
Snakebite envenoming causes 138,000 deaths annually, and ~400,000 victims are left with permanent disabilities. Envenoming by saw-scaled vipers (Viperidae: ) leads to systemic hemorrhage and coagulopathy and represents a major cause of snakebite mortality and morbidity in Africa and Asia. The only specific treatment for snakebite, antivenom, has poor specificity and low affordability and must be administered in clinical settings because of its intravenous delivery and high rates of adverse reactions. This requirement results in major treatment delays in resource-poor regions and substantially affects patient outcomes after envenoming. Here, we investigated the value of metal ion chelators as prehospital therapeutics for snakebite. Among the tested chelators, dimercaprol (British anti-Lewisite) and its derivative 2,3-dimercapto-1-propanesulfonic acid (DMPS) were found to potently antagonize the activity of Zn-dependent snake venom metalloproteinases in vitro. Moreover, DMPS prolonged or conferred complete survival in murine preclinical models of envenoming against a variety of saw-scaled viper venoms. DMPS also considerably extended survival in a "challenge and treat" model, where drug administration was delayed after venom injection and the oral administration of this chelator provided partial protection against envenoming. Last, the potential clinical scenario of early oral DMPS therapy combined with a delayed, intravenous dose of conventional antivenom provided prolonged protection against the lethal effects of envenoming in vivo. Our findings demonstrate that the safe and affordable repurposed metal chelator DMPS can effectively neutralize saw-scaled viper venoms in vitro and in vivo and highlight the promise of this drug as an early, prehospital, therapeutic intervention for hemotoxic snakebite envenoming.
Topics: Africa; Animals; Asia; Chelating Agents; Humans; Mice; Snake Bites; Viper Venoms
PubMed: 32376771
DOI: 10.1126/scitranslmed.aay8314 -
Journal of Veterinary Internal Medicine 2023Nonbronchoscopic bronchoalveolar lavage (nBAL) is routinely performed in calves, and airway cytology has great potential in airway disease diagnostics. A good reference...
BACKGROUND
Nonbronchoscopic bronchoalveolar lavage (nBAL) is routinely performed in calves, and airway cytology has great potential in airway disease diagnostics. A good reference framework for nBAL cytology is lacking.
OBJECTIVES
To distinguish different cytological profiles in nBAL from grouped housed calves using cluster analysis, and characterize these profiles on individual and herd levels.
ANIMALS
Three hundred thirty-eight group-housed calves from 60 herds (mainly dairy and beef ).
METHODS
Cross-sectional study. Differential counts of white blood cells were determined on nBAL fluid, followed by differentiation of cytological profiles by K-means-based cluster analysis. These profiles were characterized by reference values, decision tree analysis, and associations with clinical, ultrasonographic, bacteriological, and cytological features.
RESULTS
A normal (55.9%), a neutrophilic (41.1%), and an eosinophilic profile (3.0%) were identified. The normal profile was characterized by reference values of 2.3% to 47.4% neutrophils, 35.1% to 95.1% macrophages, 0.4 to 22.9% lymphocytes, and 0.0% to 0.9% eosinophils. The neutrophilic profile was characterized by ≥44.5% neutrophils, <1.6% eosinophils, and <11.5% lymphocytes. This profile was associated with the isolation of Pasteurella multocida, the presence of neutrophils with toxic granulation, and the presence of phagocytosed bacteria in neutrophils. The eosinophilic profile was characterized by eosinophils ≥1.6% (neutrophilia present) or ≥2.4% (neutrophilia absent), and associated with the presence of mast cells. On herd level, the neutrophilic and eosinophilic profiles were present in 85.0% and 15.0% of the herds, respectively.
CONCLUSIONS AND CLINICAL IMPORTANCE
This study provides a first step in the development of cytological guidelines, aiding the assessment of airway health and inflammation in calves through nBAL fluid cytology.
Topics: Animals; Cattle; Bronchoalveolar Lavage Fluid; Cross-Sectional Studies; Bronchoalveolar Lavage; Inflammation; Cluster Analysis; Dimercaprol; Cattle Diseases
PubMed: 37731196
DOI: 10.1111/jvim.16855 -
The American Journal of Case Reports Jul 2023BACKGROUND ThinPrep Cytolyt is a methanol-based cell preservation solution frequently used to fix tissue samples immediately following endobronchial ultrasound-guided...
BACKGROUND ThinPrep Cytolyt is a methanol-based cell preservation solution frequently used to fix tissue samples immediately following endobronchial ultrasound-guided fine-needle aspiration. Currently, no published reports describe an iatrogenic exposure to Cytolyt. We report the only known case of an accidental intraoperative administration of a methanol solution, with corresponding plasma concentrations, and successful treatment with fomepizole. CASE REPORT A 70-year-old woman with a history of stage IIIA rectal adenocarcinoma was referred for evaluation of a newly identified lung mass. During the procedure, a bronchoalveolar lavage (BAL) of the right upper lobe was performed. After BAL, the proceduralist was informed that the syringe used to instill fluid for the BAL contained Cytolyt rather than saline. The Department of Medical Toxicology was contacted immediately, and the patient received a 15 mg/kg dose of fomepizole. The first plasma methanol level, before fomepizole administration, was elevated to 21 mg/dL. The methanol level was 13 mg/dL 3 h after fomepizole treatment and even lower thereafter; therefore, no additional fomepizole was required. The patient did not develop signs of systemic toxicity and was discharged on hospital day 3. CONCLUSIONS Following methanol exposures, patients can exhibit metabolic acidosis, with potential for blindness, hemodynamic instability, and possibly death if untreated. Fomepizole (4-methylpyrazole) inhibits alcohol dehydrogenase and is a mainstay of treatment. Preventing medical errors is key in ensuring optimal patient care and decreasing adverse events. Providers using CytoLyt and any similar products should be aware of this potential error and approach the possibility of methanol toxicity as they would other routes of methanol exposure.
Topics: Female; Humans; Aged; Fomepizole; Methanol; Antidotes; Pyrazoles; Dimercaprol; Iatrogenic Disease
PubMed: 37461205
DOI: 10.12659/AJCR.937247