-
Toxicon: X Jun 2022Snakebite envenoming affects more than 250,000 people annually in sub-Saharan Africa. Envenoming by (boomslang) results in venom-induced consumption coagulopathy...
Snakebite envenoming affects more than 250,000 people annually in sub-Saharan Africa. Envenoming by (boomslang) results in venom-induced consumption coagulopathy (VICC), whereby highly abundant prothrombin-activating snake venom metalloproteinases (SVMPs) consume clotting factors and deplete fibrinogen. The only available treatment for envenoming is the monovalent SAIMR Boomslang antivenom. Treatment options are urgently required because this antivenom is often difficult to source and, at US$6000/vial, typically unaffordable for most snakebite patients. We therefore investigated the and preclinical efficacy of four SVMP inhibitors to neutralise the effects of venom; the matrix metalloproteinase inhibitors marimastat and prinomastat, and the metal chelators dimercaprol and DMPS The venom of exhibited an SVMP-driven procoagulant phenotype . Marimastat and prinomastat demonstrated equipotent inhibition of the SVMP-mediated procoagulant activity of the venom , whereas dimercaprol and DMPS showed considerably lower potency. However, when tested in preclinical murine models of envenoming using mixed sex CD1 mice, DMPS and marimastat demonstrated partial protection against venom lethality, demonstrated by prolonged survival times of experimental animals, whereas dimercaprol and prinomastat failed to confer any protection at the doses tested. The preclinical results presented here demonstrate that DMPS and marimastat show potential as novel small molecule-based therapeutics for snakebite envenoming. These two drugs have been previously shown to be effective against VICC in preclinical models, and thus we conclude that marimastat and DMPS should be further explored as potentially valuable early intervention therapeutics to broadly treat VICC following snakebite envenoming in sub-Saharan Africa.
PubMed: 35321116
DOI: 10.1016/j.toxcx.2022.100118 -
BMJ Case Reports Sep 2021A 38-year-old man presented at the emergency department with abdominal pain, vomiting, generalised weakness and altered consciousness. He had been ingesting opioids for...
A 38-year-old man presented at the emergency department with abdominal pain, vomiting, generalised weakness and altered consciousness. He had been ingesting opioids for over 5 years and had several past hospital admissions for abdominal pain. His investigations showed deranged liver function tests, anaemia and basophilic stippling on the peripheral blood smear. Further investigations revealed a significant increase in the serum lead level. We started chelation with peroral penicillamine 250 mg every 6 hours for 2 days and switched to intramuscular dimercaprol 4 mg/kg every 12 hours and intravenous calcium ethylenediamine tetraacetic acid 50 mg/kg in two divided doses daily for the next 5 days. We then discharged him home; he had become clinically stable by that time. We repeated his lead level and followed him up in the clinic. In this report, we emphasise the consideration of lead toxicity in opioid abusers and bring to attention a rare way of lead chelation in resource-limited settings.
Topics: Abdominal Pain; Adult; Analgesics, Opioid; Brain Diseases; Humans; Lead; Lead Poisoning; Male
PubMed: 34544696
DOI: 10.1136/bcr-2020-240977 -
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 -
Translational Neurodegeneration Apr 2021The mechanisms underlying lesions of dopaminergic (DA) neurons, an essential pathology of Parkinson's disease (PD), are largely unknown, although oxidative stress is...
BACKGROUND
The mechanisms underlying lesions of dopaminergic (DA) neurons, an essential pathology of Parkinson's disease (PD), are largely unknown, although oxidative stress is recognized as a key factor. We have previously shown that the pro-oxidative aldehyde acrolein is a critical factor in PD pathology, and that acrolein scavenger hydralazine can reduce the elevated acrolein, mitigate DA neuron death, and alleviate motor deficits in a 6-hydroxydopamine (6-OHDA) rat model. As such, we hypothesize that a structurally distinct acrolein scavenger, dimercaprol (DP), can also offer neuroprotection and behavioral benefits.
METHODS
DP was used to lower the elevated levels of acrolein in the basal ganglia of 6-OHDA rats. The acrolein levels and related pathologies were measured by immunohistochemistry. Locomotor and behavioral effects of 6-OHDA injections and DP treatment were examined using the open field test and rotarod test. Pain was assessed using mechanical allodynia, cold hypersensitivity, and plantar tests. Finally, the effects of DP were assessed in vitro on SK-N-SH dopaminergic cells exposed to acrolein.
RESULTS
DP reduced acrolein and reversed the upregulation of pain-sensing transient receptor potential ankyrin 1 (TRPA1) channels in the substantia nigra, striatum, and cortex. DP also mitigated both motor and sensory deficits typical of PD. In addition, DP lowered acrolein and protected DA-like cells in vitro. Acrolein's ability to upregulate TRPA1 was also verified in vitro using cell lines.
CONCLUSIONS
These results further elucidated the acrolein-mediated pathogenesis and reinforced the critical role of acrolein in PD while providing strong arguments for anti-acrolein treatments as a novel and feasible strategy to combat neurodegeneration in PD. Considering the extensive involvement of acrolein in various nervous system illnesses and beyond, anti-acrolein strategies may have wide applications and broad impacts on human health.
Topics: Acrolein; Animals; Behavior, Animal; Cerebral Cortex; Dimercaprol; Dopaminergic Neurons; Hydroxydopamines; Male; Motor Activity; Neostriatum; Neuroprotective Agents; Pain; Pain Measurement; Parkinson Disease, Secondary; Rats; Rats, Sprague-Dawley; Substantia Nigra; TRPA1 Cation Channel
PubMed: 33910636
DOI: 10.1186/s40035-021-00239-0 -
Neurotoxicity Research Oct 2022Ferroptosis is a necrotic cell death caused by lipid oxidation that may be responsible for neural degeneration in Parkinson's disease. We assessed whether three neuronal...
Ferroptosis is a necrotic cell death caused by lipid oxidation that may be responsible for neural degeneration in Parkinson's disease. We assessed whether three neuronal cell lines are sensitive to killing by ferroptosis. Ferroptosis inducer erastin killed LUHMES neurons at sub-micromolar concentrations, whereas neuronal cells derived from SH-SY5Y cells or neural stem cells were at least 50-fold less sensitive. LUHMES differentiated neurons were likewise sensitive to killing by RSL3 or ML210, inhibitors of the glutathione peroxidase 4 enzyme (GPX4) that consumes GSH to detoxify lipid peroxides. Additional assays showed that erastin, RSL3, and ML210 increased lipid peroxide levels, and that LUHMES neurons were protected from both peroxide accumulation and cell death by ferrostatin-1. A possible role of iron was assessed by evaluating the effects of five metal chelators on cytotoxicity of erastin and RSL3. LUHMES neurons were protected from RSL3 by three of the chelators, 2,3-dimercapto-1-propanesulfonic acid (DMPS), deferoxiprone (DFX), and deferiprone (DFP). Collectively, these results demonstrate the vulnerability of LUHMES neurons to ferroptosis by chemical treatments that disrupt glutathione synthesis, lipid peroxide detoxification, or iron metabolism. The same vulnerabilities may occur in CNS neurons, which reportedly generate low levels of GSH and metallothioneins, limiting their ability to neutralize oxidative stresses and toxic metals. These results suggest a rationale and methods to search for environmental toxicants that may exploit these vulnerabilities and promote neurodegenerative diseases.
Topics: Humans; Carbolines; Chelating Agents; Deferiprone; Dopaminergic Neurons; Ferroptosis; Glutathione; Iron; Lipid Peroxides; Neuroblastoma; Phospholipid Hydroperoxide Glutathione Peroxidase; Unithiol
PubMed: 35922689
DOI: 10.1007/s12640-022-00538-y -
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 -
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 -
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 -
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