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Redox Biology Nov 2023Glutathione (GSH) depletion, and impaired redox homeostasis have been observed in experimental animal models and patients with epilepsy. Pleiotropic strategies that...
Glutathione (GSH) depletion, and impaired redox homeostasis have been observed in experimental animal models and patients with epilepsy. Pleiotropic strategies that elevate GSH levels via transcriptional regulation have been shown to significantly decrease oxidative stress and seizure frequency, increase seizure threshold, and rescue certain cognitive deficits. Whether elevation of GSH per se alters neuronal hyperexcitability remains unanswered. We previously showed that thiols such as dimercaprol (DMP) elevate GSH via post-translational activation of glutamate cysteine ligase (GCL), the rate limiting GSH biosynthetic enzyme. Here, we asked if elevation of cellular GSH by DMP altered neuronal hyperexcitability in-vitro and in-vivo. Treatment of primary neuronal-glial cerebrocortical cultures with DMP elevated GSH and inhibited a voltage-gated potassium channel blocker (4-aminopyridine, 4AP) induced neuronal hyperexcitability. DMP increased GSH in wildtype (WT) zebrafish larvae and significantly attenuated convulsant pentylenetetrazol (PTZ)-induced acute 'seizure-like' swim behavior. DMP treatment increased GSH and inhibited convulsive, spontaneous 'seizure-like' swim behavior in the Dravet Syndrome (DS) zebrafish larvae (scn1Lab). Furthermore, DMP treatment significantly decreased spontaneous electrographic seizures and associated seizure parameters in scn1Lab zebrafish larvae. We investigated the role of the redox-sensitive mammalian target of rapamycin (mTOR) pathway due to the presence of several cysteine-rich proteins and their involvement in regulating neuronal excitability. Treatment of primary neuronal-glial cerebrocortical cultures with 4AP or l-buthionine-(S,R)-sulfoximine (BSO), an irreversible inhibitor of GSH biosynthesis, significantly increased mTOR complex I (mTORC1) activity which was rescued by pre-treatment with DMP. Furthermore, BSO-mediated GSH depletion oxidatively modified the tuberous sclerosis protein complex (TSC) consisting of hamartin (TSC1), tuberin (TSC2), and TBC1 domain family member 7 (TBC1D7) which are critical negative regulators of mTORC1. In summary, our results suggest that DMP-mediated GSH elevation by a novel post-translational mechanism can inhibit neuronal hyperexcitability both in-vitro and in-vivo and a plausible link is the redox sensitive mTORC1 pathway.
Topics: Animals; Humans; Zebrafish; Glutathione; Glutamate-Cysteine Ligase; TOR Serine-Threonine Kinases; Mechanistic Target of Rapamycin Complex 1; Seizures; Buthionine Sulfoximine; Mammals
PubMed: 37769522
DOI: 10.1016/j.redox.2023.102895 -
Clinics in Chest Medicine Mar 2024Sarcoidosis is a multisystem inflammatory disorder with unclear etiology and can often pose a diagnostic challenge. A tissue diagnosis is often necessary to illustrate... (Review)
Review
Sarcoidosis is a multisystem inflammatory disorder with unclear etiology and can often pose a diagnostic challenge. A tissue diagnosis is often necessary to illustrate the non-caseating granulomas on histopathology. This review aims to synthesize current evidence related to tissue diagnosis of sarcoidosis using various bronchoscopic techniques. We start by discussing standard bronchoscopic techniques which have remained the cornerstone of diagnostic workup such as bronchoalveolar lavage (BAL), endobronchial biopsy (EBB), conventional transbronchial needle aspiration (cTBNA) and transbronchial lung biopsy (TBLB) followed by newer modalities that incorporate real-time image guidance using endobronchial and endoscopic ultrasound. Although BAL, EBB, and TBLB have been employed as a diagnostic tool for several decades, their sensitivity and diagnostic yield is inferior to ultrasound-based endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). More recently, convincing evidence has also emerged to support the diagnostic accuracy and tissue yield of transbronchial lung cryobiopsy which will also be discussed in this review. These advances in bronchoscopic equipment and techniques over the last 2 decades have made it possible to obtain tissue samples using minimally invasive techniques thus avoiding invasive open lung biopsy and the risks that inherently follow. Up-to-date knowledge of these modalities is imperative for ensuring evidence-based medicine and improving patient-centric outcomes.
Topics: Humans; Bronchoscopy; Sarcoidosis, Pulmonary; Sarcoidosis; Lung; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Dimercaprol; Lymph Nodes
PubMed: 38245368
DOI: 10.1016/j.ccm.2023.08.001 -
Archives of Toxicology Dec 2017This article reviews the clinical use of the metal chelators sodium 2,3-dimercapto-1-propanesulfonate (DMPS), meso-2,3-dimercaptosuccinic acid (DMSA), and calcium... (Review)
Review
This article reviews the clinical use of the metal chelators sodium 2,3-dimercapto-1-propanesulfonate (DMPS), meso-2,3-dimercaptosuccinic acid (DMSA), and calcium disodium edetate (CaEDTA, calcium EDTA) in overexposure and poisonings with salts of lead (Pb), mercury (Hg), and arsenic (As). DMSA has considerably lower toxicity than the classic heavy metal antagonist BAL (2,3-dimercaptopropanol) and is also less toxic than DMPS. Because of its adverse effects, CaEDTA should be replaced by DMSA as the antidote of choice in treating moderate Pb poisoning. Combination therapy with BAL and CaEDTA was previously recommended in cases of severe acute Pb poisoning with encephalopathy. We suggest that BAL in such cases acted as a shuttling Pb transporter from the intra- to the extracellular space. The present paper discusses if a combination of the extracellularly distributed DMSA with the ionophore, Monensin may provide a less toxic combination for Pb mobilization by increasing both the efflux of intracellularly deposited Pb and the urinary Pb excretion. Anyhow, oral therapy with DMSA should be continued with several intermittent courses. DMPS and DMSA are also promising antidotes in Hg poisoning, whereas DMPS seems to be a more efficient agent against As poisoning. However, new insight indicates that a combination of low-dosed BAL plus DMPS could be a preferred antidotal therapy to obtain mobilization of the intracerebral deposits into the circulation for subsequent rapid urinary excretion.
Topics: Arsenic Poisoning; Chelating Agents; Edetic Acid; Humans; Lead Poisoning, Nervous System; Mercury Poisoning, Nervous System; Monensin; Succimer; Unithiol
PubMed: 29063135
DOI: 10.1007/s00204-017-2100-0 -
Journal of Visualized Experiments : JoVE Feb 2023Acute respiratory distress syndrome (ARDS) causes acute lung injury, characterized by rapid alveolar damage and severe hypoxemia. This, in turn, leads to high morbidity...
Acute respiratory distress syndrome (ARDS) causes acute lung injury, characterized by rapid alveolar damage and severe hypoxemia. This, in turn, leads to high morbidity and mortality. Currently, there are no pre-clinical models that recapitulate the complexity of human ARDS. However, infectious models of pneumonia (PNA) can replicate the main pathophysiological features of ARDS. Here, we describe a model of PNA induced by the intratracheal instillation of live Streptococcus pneumoniae and Klebsiella pneumoniae in C57BL6 mice. In order to evaluate and characterize the model, after inducing injury, we carried out serial measurements of body weight and bronchoalveolar lavage (BAL) for measuring markers of lung injury. Additionally, we harvested lungs for cell count and differentials, BAL protein quantification, cytospin, bacterial colony-forming unit counts, and histology. Lastly, high dimensional flow cytometry was performed. We propose this model as a tool to understand the immune landscape during the early and late resolution phases of lung injury.
Topics: Animals; Mice; Humans; Mice, Inbred C57BL; Pneumonia; Streptococcus pneumoniae; Acute Lung Injury; Dimercaprol; Models, Theoretical
PubMed: 36876955
DOI: 10.3791/63925 -
Annals of the New York Academy of... Aug 2016Arsenicals are highly reactive inorganic and organic derivatives of arsenic. These chemicals are very toxic and produce both acute and chronic tissue damage. On the... (Review)
Review
Arsenicals are highly reactive inorganic and organic derivatives of arsenic. These chemicals are very toxic and produce both acute and chronic tissue damage. On the basis of these observations, and considering the low cost and simple methods of their bulk syntheses, these agents were thought to be appropriate for chemical warfare. Among these, the best-known agent that was synthesized and weaponized during World War I (WWI) is Lewisite. Exposure to Lewisite causes painful inflammatory and blistering responses in the skin, lung, and eye. These chemicals also manifest systemic tissue injury following their cutaneous exposure. Although largely discontinued after WWI, stockpiles are still known to exist in the former Soviet Union, Germany, Italy, the United States, and Asia. Thus, access by terrorists or accidental exposure could be highly dangerous for humans and the environment. This review summarizes studies that describe the biological, pathophysiological, toxicological, and environmental effects of exposure to arsenicals, with a major focus on cutaneous injury. Studies related to the development of novel molecular pathobiology-based antidotes against these agents are also described.
Topics: Animals; Arsenic Poisoning; Arsenicals; Chemical Warfare; Chemical Warfare Agents; Dimercaprol; Environmental Exposure; Humans; Oxidative Stress; Reactive Oxygen Species
PubMed: 27636894
DOI: 10.1111/nyas.13214 -
Technology in Cancer Research &... 2021To investigate the efficacy of a formula comprising arsenic trioxide and dimercaprol (BAL-ATO) as a radiosensitizing agent in model mice with pancreatic cancer...
OBJECTIVE
To investigate the efficacy of a formula comprising arsenic trioxide and dimercaprol (BAL-ATO) as a radiosensitizing agent in model mice with pancreatic cancer xenografts.
METHODS
Female BALB/c nude mice bearing SW1990 human pancreatic cancer xenografts were divided into four treatment arms, including control, radiotherapy (RT), BAL-ATO, and RT + BAL-ATO groups. Survival and tumor volume were analyzed. We also assessed apoptosis in tumor samples by live imaging and detected hypoxia by confocal laser microscope observation. We further investigated the mechanisms of BAL-ATO action in RT by detecting affected proteins by western blot and immunohistochemistry assays.
RESULTS
Median survival was significantly longer in the RT + BAL-ATO group (64.5 days) compared with the control (49.5 days), RT (39 days), and BAL-ATO (48 days) groups ( 0.001). RT + BAL-ATO inhibited the growth of tumors in mice by 73% compared with the control group, which was significantly higher than the rate of inhibition following RT alone (59%) ( < 0.01). Further analysis showed an improved microenvironment in terms of hypoxia in tumors treated with BAL-ATO alone or RT + BAL-ATO. Expression of signaling molecules associated with pancreatic cancer stem cells, including CD24, CD44, ALDH1A1, Gli-1, and Nestin, was detected in tumors treated with BAL-ATO alone or in combination with RT.
CONCLUSION
These data suggest that BAL-ATO function as a radiosensitizer in mice with pancreatic cancer xenografts, via mechanisms involving hypoxia reduction and inhibition of signaling pathways associated with pancreatic cancer stem cells. BAL-ATO may thus be a promising radiosensitizing agent in patients with pancreatic cancer.
Topics: Animals; Antineoplastic Agents; Arsenic Trioxide; Biomarkers; Cell Line, Tumor; Cell Proliferation; Dimercaprol; Disease Models, Animal; Drug Combinations; Drug Compounding; Female; Humans; Mice; Pancreatic Neoplasms; Prognosis; Radiation Tolerance; Radiation-Sensitizing Agents; Signal Transduction; Treatment Outcome; Xenograft Model Antitumor Assays
PubMed: 34433326
DOI: 10.1177/15330338211036324 -
Journal of Infusion Nursing : the... 2016
Topics: American Nurses' Association; Humans; Infusions, Intravenous; Nurse's Role; Patient Safety; Practice Guidelines as Topic; Safety Management; Unithiol
PubMed: 27074988
DOI: 10.1097/NAN.0000000000000171 -
Italian Journal of Pediatrics Sep 2023There are relatively few studies investigating C-C motif chemokine ligand 2 (CCL2) level in bronchoalveolar lavage fluid (BALF) in children with Mycoplasma pneumoniae...
BACKGROUND
There are relatively few studies investigating C-C motif chemokine ligand 2 (CCL2) level in bronchoalveolar lavage fluid (BALF) in children with Mycoplasma pneumoniae pneumonia (MPP), and the relationship between CCL2 level in BALF and refractory mycoplasma pneumoniae pneumonia (RMPP) is unclear. This study aims to explore the relationship between chemokine CCL2 level in BALF and clinical characteristics and clinical outcome in children with MPP.
METHODS
A total of 51 children with confirmed acute MPP and requiring bronchoalveolar lavage in Department of Pediatrics, Huanghe Sanmenxia Hospital and The First Clinical College of Xinxiang Medical University from October 2021 to February 2023 were selected as the study group. And 11 children with bronchial foreign body were selected as the control group. The study group was divided into the non-refractory mycoplasma pneumoniae pneumonia (NRMPP) group and the RMPP group based on the response to treatment. BALF and clinical data of the patients were collected. And CCL2 levels were tested in the patients. Differences in CCL2 level in BALF and clinical characteristics were tested and compared.
RESULTS
The CCL2 level in BALF of the study group was higher than that of the control group, with significant difference (P < 0.05). With ROC curve, the area under the curve (AUC) of CCL2 in BALF predicting RMPP was 0.94, the cut-off value was 0.645 ng/ml, the sensitivity was 85%, and the specificity was 94%, and the diagnostic value was better than that of serum CRP and LDH. Logistic regression analysis was used to build the RMPP prediction model, and CCL2 showed good predictive value.
CONCLUSION
The level of CCL2 in BALF was high in children with MPP and had a high predictive value for RMPP. CCL2 can be used as one of the biomarkers for predicting RMPP.
Topics: Humans; Child; Bronchoalveolar Lavage Fluid; Pneumonia, Mycoplasma; Chemokines; Dimercaprol; Foreign Bodies
PubMed: 37740208
DOI: 10.1186/s13052-023-01528-2 -
Frontiers in Immunology 2023Low-dose radiation therapy (LDRT) can suppress intractable inflammation, such as that in rheumatoid arthritis, and is used for treating more than 10,000 rheumatoid...
Low-dose radiation therapy (LDRT) can suppress intractable inflammation, such as that in rheumatoid arthritis, and is used for treating more than 10,000 rheumatoid arthritis patients annually in Europe. Several recent clinical trials have reported that LDRT can effectively reduce the severity of coronavirus disease (COVID-19) and other cases of viral pneumonia. However, the therapeutic mechanism of LDRT remains unelucidated. Therefore, in the current study, we aimed to investigate the molecular mechanism underlying immunological alterations in influenza pneumonia after LDRT. Mice were irradiated to the whole lung 1 day post-infection. The changes in levels of inflammatory mediators (cytokines and chemokines) and immune cell populations in the bronchoalveolar lavage (BALF), lungs, and serum were examined. LDRT-treated mice displayed markedly increased survival rates and reduced lung edema and airway and vascular inflammation in the lung; however, the viral titers in the lungs were unaffected. Levels of primary inflammatory cytokines were reduced after LDRT, and transforming growth factor-β (TGF-β) levels increased significantly on day 1 following LDRT. Levels of chemokines increased from day 3 following LDRT. Additionally, M2 macrophage polarization or recruitment was increased following LDRT. We found that LDRT-induced TGF-β reduced the levels of cytokines and polarized M2 cells and blocked immune cell infiltration, including neutrophils, in BALF. LDRT-induced early TGF-β production was shown to be a key regulator involved in broad-spectrum anti-inflammatory activity in virus-infected lungs. Therefore, LDRT or TGF-β may be an alternative therapy for viral pneumonia.
Topics: Animals; Mice; COVID-19; Pneumonia, Viral; Inflammation; Cytokines; Arthritis, Rheumatoid; Dimercaprol; Transforming Growth Factors
PubMed: 37304302
DOI: 10.3389/fimmu.2023.1182927 -
The Journal of Pediatric Pharmacology... Jun 2024The study aims to describe drug shortages affecting lead chelators in the United States from 2001 through 2022.
OBJECTIVE
The study aims to describe drug shortages affecting lead chelators in the United States from 2001 through 2022.
METHODS
Drug shortage data were retrieved from the University of Utah Drug Information Service from January 1, 2001, through December 31, 2022. Shortages of first- and second-line lead chelators were analyzed. Drug class, formulation, administration route, shortage reason, shortage duration, generic status, single-source status, and presence of temporally overlapping shortages were examined. Total shortage months, percentages of study period on shortage, and median shortage durations were calculated.
RESULTS
Thirteen lead chelator shortages were reported during the study period. Median duration was 7.4 months and the longest shortage (24.8 months) involved calcium disodium edetate. Calcium disodium edetate and dimercaprol had the greatest number of shortages, 4 each, and 61.5% of shortages involved parenteral medications. Median shortage duration was 14.2 months for parenteral agents and 2.2 months for non-parenteral agents. All shortages involved generic, single-source products. Supply/demand and manufacturing problems were the most common shortage reasons provided. Overlapping shortages occurred for 3.7% of the study period. Median shortage duration increased from 3 to 11 months in the second half of the study period, and 61.5% of shortages occurred in the second half of the study period.
CONCLUSIONS
All chelators experienced multiple shortages, which became increasingly frequent and prolonged over time. Concurrent shortages occurred, potentially hampering substitution between different agents. Health care stakeholders must build supply chain resilience and develop guidelines regarding how to modify chelation therapy based on shortage conditions.
PubMed: 38863853
DOI: 10.5863/1551-6776-29.3.306