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Redox Biology Apr 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.
PubMed: 38714094
DOI: 10.1016/j.redox.2024.103168 -
Journal of Postgraduate Medicine Apr 2024Arsenic compounds are colorless and odorless and toxicity can occur either acutely following ingestion of arsenicals with gastrointestinal disturbances or due to chronic...
Arsenic compounds are colorless and odorless and toxicity can occur either acutely following ingestion of arsenicals with gastrointestinal disturbances or due to chronic exposure usually presenting with dermatologic lesions and peripheral neuropathy. We report a young couple who presented with signs and symptoms of painful sensorimotor peripheral neuropathy in a typical "stocking and glove" pattern. They had raised urinary arsenic levels with normal blood levels and thus, a diagnosis of chronic arsenic poisoning due to contaminated water intake was made after detecting elevated arsenic levels in their home water supply. Both patients underwent chelation therapy with dimercaprol for 14 days and reported subjective and objective improvement in symptoms with the reduction in urinary arsenic levels at the end of therapy.
Topics: Humans; Arsenic Poisoning; Peripheral Nervous System Diseases; Male; Female; Adult; Dimercaprol; Chelating Agents; Arsenic; Treatment Outcome; Chronic Disease; Chelation Therapy
PubMed: 38629272
DOI: 10.4103/jpgm.jpgm_708_23 -
Heliyon Apr 2024Mercury's neurotoxic effects have prompted the development of advanced control and remediation methods to meet stringent measures for industries with high-mercury... (Review)
Review
Mercury's neurotoxic effects have prompted the development of advanced control and remediation methods to meet stringent measures for industries with high-mercury feedstocks. Industries with significant Hg emissions, including artisanal and small-scale gold mining (ASGM)-789.2 Mg year, coal combustion-564.1 Mg year, waste combustion-316.1 Mg year, cement production-224.5 Mg year, and non-ferrous metals smelting-204.1 Mg year, use oxidants and adsorbents capture Hg from waste streams. Oxidizing agents such as O, Cl, HCl, CaBr, CaCl, and NHCl oxidize Hg to Hg for easier adsorption. To functionalize adsorbents, carbonaceous ones use S, SO, and NaS, metal-based adsorbents use dimercaprol, and polymer-based adsorbents are grafted with acrylonitrile and hydroxylamine hydrochloride. Adsorption capacities span 0.2-85.6 mg g for carbonaceous, 0.5-14.8 mg g for metal-based, and 168.1-1216 mg g for polymer-based adsorbents. Assessing Hg contamination in soils and sediments uses bioindicators and stable isotopes. Remediation approaches include heat treatment, chemical stabilization and immobilization, and phytoremediation techniques when contamination exceeds thresholds. Achieving a substantially Hg-free ecosystem remains a formidable challenge, chiefly due to the ASGM industry, policy gaps, and Hg persistence. Nevertheless, improvements in adsorbent technologies hold potential.
PubMed: 38571637
DOI: 10.1016/j.heliyon.2024.e28253 -
Frontiers in Immunology 2024Influenza A viruses (IAVs) infect the respiratory tract of mainly humans, poultry, and pigs. Co-infections with pathogenic lung bacteria are a common event and...
INTRODUCTION
Influenza A viruses (IAVs) infect the respiratory tract of mainly humans, poultry, and pigs. Co-infections with pathogenic lung bacteria are a common event and contribute to the severity of disease progression. Neutrophils are a major cell type of the innate immune system and are rapidly recruited to the site of infection. They have several effector functions to fight invading pathogens such as the secretion of reactive oxygen species (ROS) or the release of neutrophil extracellular traps (NETs). NETs are known to promote the growth of bacteria, especially if degraded by nucleases.
METHODS
In this study, bronchoalveolar lavage fluid (BALF) from 45 field-infected pigs was analyzed for 1) NET markers, 2) influence on growth of lung bacteria, and 3) impact on neutrophil functions. BALF samples from 21 IAV-positive pigs and 24 lung diseased but IAV-negative pigs were compared.
RESULTS
Here, we show that neutrophils in the lungs of IAV-positive pigs release vesicular NETs. Several NET markers were increased in the BALF of IAV-positive pigs compared with the BALF from IAV-negative pigs. The amount of NET markers positively correlated with the viral load of the IAV infection. Interestingly, the BALF of IAV-positive pigs enhanced the growth of bacteria belonging to the family of Pasteurellaceae as potential coinfecting bacteria. These effects were weaker with the BALF derived from IAV-negative pigs with other lung infections. The intensity of oxidative burst in neutrophils was significantly decreased by BALF from IAVpositive pigs, indicating impaired antimicrobial activity of neutrophils. Finally, the lung milieu reflected by IAV-positive BALF does not enable neutrophils to kill but rather enhances its growth.
DISCUSSION
In summary, our data show that an IAV infection is affecting neutrophil functions, in particular the release of NETs and ROS. Furthermore, IAV infection seems to provide growth-enhancing factors for especially coinfecting Pasteurellaceae and reduces the killing efficiency of neutrophils.
Topics: Humans; Animals; Swine; Neutrophils; Reactive Oxygen Species; Bronchoalveolar Lavage; Bacteria; Dimercaprol; Influenza A virus
PubMed: 38449874
DOI: 10.3389/fimmu.2024.1325269 -
Journal of Applied Biomaterials &... 2024To evaluate the antitumor and antimicrobial properties of an alginate-based membrane (ABM) loaded with bismuth lipophilic nanoparticles (BisBAL NPs) and cetylpyridinium...
OBJECTIVE
To evaluate the antitumor and antimicrobial properties of an alginate-based membrane (ABM) loaded with bismuth lipophilic nanoparticles (BisBAL NPs) and cetylpyridinium chloride (CPC) on clinically isolated bacteria and a pancreatic cancer cell line.
MATERIAL AND METHODS
The BisBAL NP-CPC ABM was characterized using optical and scanning electron microscopy (SEM). The antimicrobial potential was measured using the disk-diffusion assay, and antibiofilm activity was determined through the live/dead assay and fluorescence microscopy. The antitumor activity was analyzed on the pancreatic cell line (Panc 03.27) using the MTT assay and live/dead assay with fluorescence microscopy.
RESULTS
After a 24-h exposure (37°C, aerobic conditions), 5 µM BisBAL NP reduced the growth of by 77.9%, while 2.5 µM BisBAL NP inhibited the growth of , and by 82.9%, 82.6%, and 78%, respectively (). The BisBAL NPs-CPC ABM (at a ratio of 10:1; 500 and 50 µM, respectively) inhibited the growth of all isolated bacteria, producing inhibition halos of 9.5, 11.2, 7, and 10.3 mm for , and , respectively, in contrast to the 6.5, 9.5, 8.5, and 9.8 mm obtained with 100 µM ceftriaxone (). The BisBAL NPs-CPC ABM also reduced bacterial biofilms, with 81.4%, 74.5%, 97.1%, and 79.5% inhibition for , and , respectively. Furthermore, the BisBAL NPs-CPC ABM decreased Panc 03.27 cell growth by 76%, compared to 18% for drug-free ABM. GEM-ABM reduced tumoral growth by 73%. The live/dead assay confirmed that BisBAL NPs-CPC-ABM and GEM-ABM were cytotoxic for the turmoral Panc 03.27 cells.
CONCLUSION
An alginate-based membrane loaded with BisBAL NP and CPC exhibits dual antimicrobial and antitumoral efficacy. Therefore, it could be applied in cancer treatment and to diminish the occurrence of surgical site infections.
Topics: Bismuth; Cetylpyridinium; Anti-Infective Agents; Alginates; Klebsiella pneumoniae; Dimercaprol; Organometallic Compounds
PubMed: 38444166
DOI: 10.1177/22808000241236590 -
Advances in Respiratory Medicine Dec 2023Hospitalized patients with a high suspicion of pulmonary tuberculosis (HS-PTB) are isolated until a definite diagnosis can be determined. If doubt remains after negative...
Hospitalized patients with a high suspicion of pulmonary tuberculosis (HS-PTB) are isolated until a definite diagnosis can be determined. If doubt remains after negative sputum samples, bronchoscopy with bronchoalveolar lavage (BAL) is often sought. Still, evidence of the added value of BAL in this patient population is scarce. To address this issue, we included consecutive HS-PTB patients with negative sputum samples who underwent BAL between 2017 and 2018. Chest X-rays (CXR) and CT scans were evaluated by a chest radiologist blind to the final diagnosis. Independent predictors for PTB were assessed by multivariate regression, using all positive PTB patients between 2017 and 2019 (by sputum or BAL) as a control group ( = 41). Overall, 42 HS-PTB patients were included (mean age 51 ± 9, 36% female). BAL was a viable diagnostic for PTB in three (7%) cases and for other clinically relevant pathogens in six (14%). Independent predictors for PTB were ≥2 sub-acute symptoms (adjusted OR 3.18, 95% CI 1.04-9.8), CXR upper-lobe consolidation (AOR 8.70, 95% CI 2.5-29), and centrilobular nodules in chest CT (AOR 3.96, 95% CI 1.20-13.0, = 0.02). In conclusion, bronchoscopy with BAL in hospitalized patients with HS-PTB had a 7% added diagnostic value after negative sputum samples. Our findings highlight specific predictors for PTB diagnosis that could be used in future controlled studies to personalize the diagnostic evaluation.
Topics: Humans; Female; Adult; Middle Aged; Male; Mycobacterium tuberculosis; Sputum; Bronchoalveolar Lavage Fluid; Sensitivity and Specificity; Tuberculosis, Pulmonary; Bronchoalveolar Lavage; Dimercaprol
PubMed: 38392033
DOI: 10.3390/arm92010003 -
Frontiers in Pharmacology 2023Snakebite envenoming results in ∼100,000 deaths per year, with close to four times as many victims left with life-long sequelae. Current antivenom therapies have...
Snakebite envenoming results in ∼100,000 deaths per year, with close to four times as many victims left with life-long sequelae. Current antivenom therapies have several limitations including high cost, variable cross-snake species efficacy and a requirement for intravenous administration in a clinical setting. Next-generation snakebite therapies are being widely investigated with the aim to improve cost, efficacy, and safety. In recent years several small molecule drugs have shown considerable promise for snakebite indication, with oral bioavailability particularly promising for community delivery rapidly after a snakebite. However, only two such drugs have entered clinical development for snakebite. To offset the risk of attrition during clinical trials and to better explore the chemical space for small molecule venom toxin inhibitors, here we describe the first high throughput drug screen against snake venom metalloproteinases (SVMPs)-a pathogenic toxin family responsible for causing haemorrhage and coagulopathy. Following validation of a 384-well fluorescent enzymatic assay, we screened a repurposed drug library of 3,547 compounds against five geographically distinct and toxin variable snake venoms. Our drug screen resulted in the identification of 14 compounds with pan-species inhibitory activity. Following secondary potency testing, four SVMP inhibitors were identified with nanomolar ECs comparable to the previously identified matrix metalloproteinase inhibitor marimastat and superior to the metal chelator dimercaprol, doubling the current global portfolio of SVMP inhibitors. Following analysis of their chemical structure and ADME properties, two hit-to-lead compounds were identified. These clear starting points for the initiation of medicinal chemistry campaigns provide the basis for the first ever designer snakebite specific small molecules.
PubMed: 38273820
DOI: 10.3389/fphar.2023.1328950 -
Zhongguo Dang Dai Er Ke Za Zhi =... Jan 2024To study the efficacy of bronchoalveolar lavage (BAL) combined with prone positioning in children with pneumonia (MPP) and atelectasis and its effect on pulmonary... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To study the efficacy of bronchoalveolar lavage (BAL) combined with prone positioning in children with pneumonia (MPP) and atelectasis and its effect on pulmonary function.
METHODS
A prospective study was conducted on 94 children with MPP and atelectasis who were hospitalized in Ordos Central Hospital of Inner Mongolia from November 2020 to May 2023. The children were randomly divided into a treatment group and a control group, with 47 children in each group. The children in the treatment group were given conventional treatment, BAL, and prone positioning, and those in the control group were given conventional treatment and BAL. The two groups were compared in terms of fever, pulmonary signs, length of hospital stay, lung recruitment, and improvement in pulmonary function.
RESULTS
Compared with the control group, the treatment group had significantly shorter time to improvement in pulmonary signs and length of hospital stay and a significantly higher rate of lung recruitment on day 7 of hospitalization, on the day of discharge, and at 1 week after discharge (<0.05). Compared with the control group, the treatment group had significantly higher levels of forced vital capacity (FVC) as a percentage of the predicted value, forced expiratory volume (FEV) in 1 second as a percentage of the predicted value, ratio of FEV in 1 second to FVC, forced expiratory flow at 50% of FVC as a percentage of the predicted value, forced expiratory flow at 75% of FVC as a percentage of the predicted value, and maximal mid-expiratory flow as a percentage of the predicted value on the day of discharge and at 1 week after discharge (<0.05). There was no significant difference in the time for body temperature to return to normal between the two groups (>0.05).
CONCLUSIONS
In the treatment of children with MPP and atelectasis, BAL combined with prone positioning can help to shorten the time to improvement in pulmonary signs and the length of hospital stay and promote lung recruitment and improvement in pulmonary function.
Topics: Child; Humans; Prospective Studies; Mycoplasma pneumoniae; Prone Position; Pulmonary Atelectasis; Pneumonia, Mycoplasma; Bronchoalveolar Lavage; Dimercaprol
PubMed: 38269456
DOI: 10.7499/j.issn.1008-8830.2308013 -
BMC Pulmonary Medicine Jan 2024Flexible bronchoscopy procedures require detailed anatomical knowledge and advanced technical skills. Simulation-based training offers a patient-safe training...
BACKGROUND
Flexible bronchoscopy procedures require detailed anatomical knowledge and advanced technical skills. Simulation-based training offers a patient-safe training environment that can be more efficient than patient-based training. Physical models are cheaper than virtual reality simulators and allow trainees to be acquainted with the equipment used in the clinic. The choice of a physical model for training depends on the local context. The aim of this study was to compare four different bronchoscopy models for flexible bronchoscopy training.
METHODS
The BronchoBoy manikin, the Koken manikin, a human cadaver, and a preserved porcine lung were included in the study. Seven physicians experienced in bronchoscopy performed a bronchoscopic airway inspection, bronchoalveolar lavage (BAL), and tissue sampling on all four models with performance evaluated by observation and participant evaluation of models by questionnaire.
RESULTS
Nineteen segments were identified in all human anatomy models, and the only significant difference found was that only the Thiel embedded cadaver allowed all participants to enter RB1 with an instrument in the working channel (p = 0.001). The Thiel embedded cadaver and the BronchoBoy manikin had low fluid return on BAL (22 and 52 ml), whereas the Koken manikin and the preserved porcine lung had high return (132 and 134 ml), (p = 0.017). Tissue samplings were only completed in the preserved porcine lung and the Thiel embedded cadaver (p < 0.001).
CONCLUSIONS
An anatomically correct bronchoscopy is best simulated with the Koken manikin or the Thiel embedded cadaver. Bronchoalveolar lavage should be simulated with the Koken manikin or the preserved porcine lung. Tissue sampling procedures are best simulated using the Thiel embedded cadaver or the preserved porcine lung.
Topics: Swine; Animals; Humans; Bronchoscopy; Bronchoalveolar Lavage; Cadaver; Dimercaprol; Manikins
PubMed: 38195463
DOI: 10.1186/s12890-024-02846-9 -
Proceedings of the National Academy of... Nov 2023Cobalt-containing alloys are useful for orthopedic applications due to their low volumetric wear rates, corrosion resistance, high mechanical strength, hardness, and...
Cobalt-containing alloys are useful for orthopedic applications due to their low volumetric wear rates, corrosion resistance, high mechanical strength, hardness, and fatigue resistance. Unfortunately, these prosthetics release significant levels of cobalt ions, which was only discovered after their widespread implantation into patients requiring hip replacements. These cobalt ions can result in local toxic effects-including peri-implant toxicity, aseptic loosening, and pseudotumor-as well as systemic toxic effects-including neurological, cardiovascular, and endocrine disorders. Failing metal-on-metal (MoM) implants usually necessitate painful, risky, and costly revision surgeries. To treat metallosis arising from failing MoM implants, a synovial fluid-mimicking chelator was designed to remove these metal ions. Hyaluronic acid (HA), the major chemical component of synovial fluid, was functionalized with British anti-Lewisite (BAL) to create a chelator (BAL-HA). BAL-HA effectively binds cobalt and rescues in vitro cell vitality (up to 370% of cells exposed to IC levels of cobalt) and enhances the rate of clearance of cobalt in vivo ( from 48 h to 6 h). A metallosis model was also created to investigate our therapy. Results demonstrate that BAL-HA chelator system is biocompatible and capable of capturing significant amounts of cobalt ions from the hip joint within 30 min, with no risk of kidney failure. This chelation therapy has the potential to mitigate cobalt toxicity from failing MoM implants through noninvasive injections into the joint.
Topics: Humans; Hip Prosthesis; Hyaluronic Acid; Dimercaprol; Chelation Therapy; Prosthesis Failure; Arthroplasty, Replacement, Hip; Metals; Cobalt; Chelating Agents; Ions
PubMed: 37903261
DOI: 10.1073/pnas.2309156120