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BMC Nephrology Oct 2019Heavy metal poisoning can cause debilitating illness if left untreated, and its management in anuric patients poses challenges. Literature with which to guide clinical... (Review)
Review
BACKGROUND
Heavy metal poisoning can cause debilitating illness if left untreated, and its management in anuric patients poses challenges. Literature with which to guide clinical practice in this area is rather scattered.
CASE PRESENTATION
We present a case of symptomatic lead and arsenic poisoning from use of Ayurvedic medicine in a 28-year-old man with end-stage kidney disease on chronic hemodialysis. We describe his treatment course with chelating agents and extracorporeal blood purification, and review the relevant literature to provide general guidance.
CONCLUSION
Cumulative clinical experience assists in identifying preferred chelators and modalities of extracorporeal blood purification when managing such patients. However, a larger body of real-world or clinical trial evidence is necessary to inform evidence-based guidelines for the management of heavy metal poisoning in anuric patients.
Topics: Adult; Animals; Anuria; Arsenic Poisoning; Chelating Agents; Continuous Renal Replacement Therapy; Dimercaprol; Edetic Acid; Humans; Kidney Failure, Chronic; Lead Poisoning; Male; Renal Dialysis; Succimer; Unithiol
PubMed: 31623560
DOI: 10.1186/s12882-019-1561-1 -
International Journal of Molecular... Feb 2022The increasing antibiotic resistance is a clinical problem worldwide. Numerous Gram-negative bacteria have already become resistant to the most widely used class of...
The increasing antibiotic resistance is a clinical problem worldwide. Numerous Gram-negative bacteria have already become resistant to the most widely used class of antibacterial drugs, β-lactams. One of the main mechanisms is inactivation of β-lactam antibiotics by bacterial β-lactamases. Appearance and spread of these enzymes represent a continuous challenge for the clinical treatment of infections and for the design of new antibiotics and inhibitors. Drug repurposing is a prospective approach for finding new targets for drugs already approved for use. We describe here the inhibitory potency of known detoxifying antidote 2,3-dimercaptopropane-1-sulfonate (unithiol) against metallo-β-lactamases. Unithiol acts as a competitive inhibitor of meropenem hydrolysis by recombinant metallo-β-lactamase NDM-1 with the K of 16.7 µM. It is an order of magnitude lower than the K for l-captopril, the inhibitor of angiotensin-converting enzyme approved as a drug for the treatment of hypertension. Phenotypic methods demonstrate that the unithiol inhibits natural metallo-β-lactamases NDM-1 and VIM-2 produced by carbapenem-resistant and bacterial strains. The 3D full atom structures of unithiol complexes with NDM-1 and VIM-2 are obtained using QM/MM modeling. The thiol group is located between zinc cations of the active site occupying the same place as the catalytic hydroxide anion in the enzyme-substrate complex. The sulfate group forms both a coordination bond with a zinc cation and hydrogen bonds with the positively charged residue, lysine or arginine, responsible for proper orientation of antibiotics upon binding to the active site prior to hydrolysis. Thus, we demonstrate both experimentally and theoretically that the unithiol is a prospective competitive inhibitor of metallo-β-lactamases and it can be utilized in complex therapy together with the known β-lactam antibiotics.
Topics: Carbapenems; Drug Repositioning; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Enzymologic; Klebsiella pneumoniae; Models, Molecular; Protein Conformation; Pseudomonas aeruginosa; Quantitative Structure-Activity Relationship; Unithiol; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 35163756
DOI: 10.3390/ijms23031834 -
The Journal of Biological Chemistry Mar 2017Neuroinflammation and oxidative stress are hallmarks of various neurological diseases. However, whether and how the redox processes control neuroinflammation is...
Neuroinflammation and oxidative stress are hallmarks of various neurological diseases. However, whether and how the redox processes control neuroinflammation is incompletely understood. We hypothesized that increasing cellular glutathione (GSH) levels would inhibit neuroinflammation. A series of thiol compounds were identified to elevate cellular GSH levels by a novel approach ( post-translational activation of glutamate cysteine ligase (GCL), the rate-limiting enzyme in GSH biosynthesis). These small thiol-containing compounds were examined for their ability to increase intracellular GSH levels in a murine microglial cell line (BV2), of which dimercaprol (2,3-dimercapto-1-propanol (DMP)) was found to be the most effective compound. DMP increased GCL activity and decreased LPS-induced production of pro-inflammatory cytokines and inducible nitric-oxide synthase induction in BV2 cells in a concentration-dependent manner. The ability of DMP to elevate GSH levels and attenuate LPS-induced pro-inflammatory cytokine production was inhibited by buthionine sulfoximine, an inhibitor of GCL. DMP increased the expression of GCL holoenzyme without altering the expression of its subunits or Nrf2 target proteins (NQO1 and HO-1), suggesting a post-translational mechanism. DMP attenuated LPS-induced MAPK activation in BV2 cells, suggesting the MAPK pathway as the signaling mechanism underlying the effect of DMP. Finally, the ability of DMP to increase GSH via GCL activation was observed in mixed cerebrocortical cultures and N27 dopaminergic cells. Together, the data demonstrate a novel mechanism of GSH elevation by post-translational activation of GCL. Post-translational activation of GCL offers a novel targeted approach to control inflammation in chronic neuronal disorders associated with impaired adaptive responses.
Topics: Animals; Cell Line; Cytokines; Dimercaprol; Enzyme Activation; Glutamate-Cysteine Ligase; Glutathione; Inflammation; MAP Kinase Signaling System; Mice; Nervous System; Oxidation-Reduction; Rats; Sulfhydryl Compounds
PubMed: 28202547
DOI: 10.1074/jbc.M116.723700 -
Proteins Jul 2017The molecular details of the association between the human Fyn-SH3 domain, and the fragment of 18.5-kDa myelin basic protein (MBP) spanning residues S38-S107 (denoted as...
Docking and molecular dynamics simulations of the Fyn-SH3 domain with free and phospholipid bilayer-associated 18.5-kDa myelin basic protein (MBP)-Insights into a noncanonical and fuzzy interaction.
The molecular details of the association between the human Fyn-SH3 domain, and the fragment of 18.5-kDa myelin basic protein (MBP) spanning residues S38-S107 (denoted as xα2-peptide, murine sequence numbering), were studied in silico via docking and molecular dynamics over 50-ns trajectories. The results show that interaction between the two proteins is energetically favorable and heavily dependent on the MBP proline-rich region (P93-P98) in both aqueous and membrane environments. In aqueous conditions, the xα2-peptide/Fyn-SH3 complex adopts a "sandwich""-like structure. In the membrane context, the xα2-peptide interacts with the Fyn-SH3 domain via the proline-rich region and the β-sheets of Fyn-SH3, with the latter wrapping around the proline-rich region in a form of a clip. Moreover, the simulations corroborate prior experimental evidence of the importance of upstream segments beyond the canonical SH3-ligand. This study thus provides a more-detailed glimpse into the context-dependent interaction dynamics and importance of the β-sheets in Fyn-SH3 and proline-rich region of MBP. Proteins 2017; 85:1336-1350. © 2017 Wiley Periodicals, Inc.
Topics: Amino Acid Sequence; Animals; Binding Sites; Dimyristoylphosphatidylcholine; Humans; Lipid Bilayers; Mice; Molecular Docking Simulation; Molecular Dynamics Simulation; Myelin Basic Protein; Peptides; Phosphorylcholine; Proline; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Structure, Tertiary; Proto-Oncogene Proteins c-fyn; Thermodynamics; Unithiol; Water; src Homology Domains
PubMed: 28380689
DOI: 10.1002/prot.25295 -
Langmuir : the ACS Journal of Surfaces... Nov 2021Dopamine (DA), a naturally occurring neurotransmitter, plays a crucial role in the function of the mammalian nervous system. DA-lipid-membrane interaction is inevitable...
Dopamine (DA), a naturally occurring neurotransmitter, plays a crucial role in the function of the mammalian nervous system. DA-lipid-membrane interaction is inevitable during the neurotransmission process. In this report, we have studied the interaction of DA with anionic 1,2-dimyristoyl--glycero-3-phospho-l-serine (DMPS), neutral (zwitterionic) 1,2-dimyristoyl--glycero-3-phosphocholine (DMPC), and synaptic membrane-mimicking mixed DMPC/DMPS (3:1 molar ratio) model multilamellar vesicle (MLV) membranes. Differential scanning calorimetry (DSC) studies suggest a strong specific interaction of DA with the anionic DMPS membrane, a weak interaction with the zwitterionic DMPC membrane, and a moderate interaction with the mixed DMPC/DMPS (3:1) membrane. The intrinsic fluorescence of DA was used as a new approach to gain a molecular-level understanding of DA-lipid-membrane interaction. Toward this end, a detailed photophysical study of DA, including its steady-state fluorescence anisotropy and fluorescence lifetime, was undertaken for the first time. The partition coefficient, location, and distribution of DA in the DMPS and DMPC model membranes were studied by employing intrinsic fluorescence. The effect of DA on the phase transition of the model membranes was also examined using the intrinsic fluorescence of DA. Zeta potential studies suggest a strong electrostatic interaction of DA with the anionic DMPS membrane and a nonspecific, relatively weak interaction of DA with the zwitterionic DMPC membrane. In addition, we observed cholesterol-induced DA expulsion from both DMPS and DMPC membranes. We believe that this work will provide a more in-depth understanding of DA-membrane interaction at a molecular level.
Topics: Anions; Dimyristoylphosphatidylcholine; Dopamine; Lipid Bilayers; Unithiol
PubMed: 34732050
DOI: 10.1021/acs.langmuir.1c02184 -
Medicine Dec 2018Both Wilson disease (WD) and Oculocutaneous Albinism (OCA) are rare autosomal recessive disorders that are caused by mutations on chromosome 13 and chromosome 11,...
RATIONALE
Both Wilson disease (WD) and Oculocutaneous Albinism (OCA) are rare autosomal recessive disorders that are caused by mutations on chromosome 13 and chromosome 11, respectively. Here, we report on a patient with coexisting WD and OCA, initially presenting episodes of tremors.
PATIENT CONCERNS
WD is a disorder of copper metabolism. The main sites of copper accumulation are the liver and the brain, resulting in hepatic symptoms. OCA is a disorder of melanin biosynthesis, characterized by a generalized reduction in pigmentation of the eyes (oculo-), skin (-cutaneous), and hair.
DIAGNOSIS
The diagnosis of WD was confirmed by neurological symptoms, metabolism tests, and MRI scans. Interestingly, the patient also had very light skin color, blond hair and eyebrows, and dark brown eyelashes and irises. Because the association of dermatologic signs in WD has rarely been reported, OCA was highly suspected based on these clinical findings. Genetic analysis was subsequently conducted, and the results revealed the p. (Arg778Leu) mutation in 1 allele and the p. (Asn1270Ser) mutation in the other allele of the ATP7B gene, confirming the diagnosis of WD; the p. (D456fs) mutation in 1 allele and the p. (R299H) mutation in the other allele of the TYR gene, confirming the diagnosis of OCA. The family history was positive for WD with a 14-year-old younger brother also being diagnosed with it. Her parents are negative for OCA and WD.
INTERVENTIONS
Sodium dimercaptopropanesulfonate (DMPS) was given during hospitalization. D-penicillamine and zinc sulfate treatment was initiated after discharge for long-term control.
OUTCOMES
Postural and intention tremor disappeared, and other symptoms and signs markedly improved after treatment.
LESSONS
In this study, we reported on the first case of a child who simultaneously presented WD and OCA, bringing up the possibility of a presumable link between these 2 rare diseases.
Topics: Albinism, Oculocutaneous; Asian People; Astringents; Chelating Agents; Female; Hepatolenticular Degeneration; Humans; Magnetic Resonance Imaging; Mutation; Penicillamine; Treatment Outcome; Unithiol; Young Adult; Zinc Sulfate
PubMed: 30558096
DOI: 10.1097/MD.0000000000013744 -
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 -
Environmental Toxicology and... May 2022The reaction between 2,3-dimercaptopropane-1-sulfonate (DMPS, unithiol) and four phenylarsonic(V) acids, i.e. phenylarsonic acid (PAA), 4-hydroxy-3-nitrophenylarsonic...
The reaction between 2,3-dimercaptopropane-1-sulfonate (DMPS, unithiol) and four phenylarsonic(V) acids, i.e. phenylarsonic acid (PAA), 4-hydroxy-3-nitrophenylarsonic acid (HNPAA), 2-aminophenylarsonic acid (o-APAA) and 4-aminophenylarsonic acid (p-APAA), is investigated in aqueous solution. The pentavalent arsenic compounds are reduced by DMPS to their trivalent analogs and instantly chelated by the vicinal dithiol, forming covalent As-S bonds within a five-membered chelate ring. The different types and positions of polar substituents at the aromatic ring of the arsonic acids influence the reaction rates in the same way as observed for reaction with glutathione (GSH), as well as the syn/anti molar ratio of the diastereomeric products, which was analyzed using time- and temperature-dependent nuclear magnetic resonance (NMR) spectroscopy. Addition of DMPS to the conjugate formed by a phenylarsonic(V) acid and the biologically relevant tripeptide GSH showed the immediate replacement of GSH by chelating DMPS, underlining the importance of dithiols as detoxifying agent.
Topics: Arsenicals; Chelating Agents; Glutathione; Magnetic Resonance Spectroscopy; Oxidation-Reduction; Unithiol; X-Ray Diffraction
PubMed: 35248761
DOI: 10.1016/j.etap.2022.103837 -
The Brazilian Journal of Infectious... 2023COVID-19-Associated Pulmonary Aspergillosis (CAPA) is a relatively common complication in patients with severe forms of the disease caused by the SARS-CoV-2 virus....
COVID-19-Associated Pulmonary Aspergillosis (CAPA) is a relatively common complication in patients with severe forms of the disease caused by the SARS-CoV-2 virus. Diagnosing and confirming CAPA is challenging. In this study, Aspergillus spp. isolation in respiratory specimens from patients with COVID-19 was evaluated for identifying cases of CAPA. In 2020‒2021, 17 Aspergillus spp. were isolated from 15 COVID-19 patients admitted to a university hospital in Brazil. Patient records were retrospectively reviewed to obtain clinical-epidemiological data and other markers of Aspergillus spp. infection and then compared with the ECMM/ISHAM criteria for defining CAPA. Probable CAPA was defined in 5/10 patients, who had Aspergillus spp. isolated from Bronchoalveolar Lavage (BAL) or a positive galactomannan blood test. Additionally, anti-Aspergillus antibodies were detected in two of these patients, during active or follow-up phases of CAPA. In another seven patients with Aspergillus spp. isolated from tracheobronchial aspirate or sputum, CAPA was presumed, mainly due to deterioration of clinical conditions and new lung imaging suggestive of fungal infection. Antifungal agents to control CAPA, particularly voriconazole, were used in 9/15 cases. In cases of probable CAPA and remaining patients, clinical conditions and comorbidities were similar, with lethality being high, at 60% and 71%, respectively. The number of CAPA cases defined by scientific criteria was lower than that assumed in the clinical context. This was largely due to the lack of BAL collection for fungal culture and the non-intensive use of other markers of invasive aspergillosis. The isolation of Aspergillus spp. in different respiratory specimens should alert clinicians to the diagnosis of CAPA.
Topics: Humans; Retrospective Studies; COVID-19; SARS-CoV-2; Aspergillosis; Aspergillus; Pulmonary Aspergillosis; Dimercaprol
PubMed: 37507102
DOI: 10.1016/j.bjid.2023.102793 -
Nanoscale Jul 2021A novel nanomaterial is synthesized based on the functionalization of graphene quantum dot with dimercaprol (GQD-DMC). Fourier transform infrared spectroscopy (FTIR),...
A novel nanomaterial is synthesized based on the functionalization of graphene quantum dot with dimercaprol (GQD-DMC). Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and high-resolution transmission electron microscopy (TEM) are used to approve the successful synthesis of GQD-DMC. The synthesized nanomaterial is used as an electrode modifier for the sensitive and selective determination of mercury(ii) ions in real water samples. The method of evaluation is based on the pre-concentration of mercury ions on the GQD-DMC modified glassy carbon electrode, reduction of Hg(ii), and anodic stripping voltammetric measurement of these reduced ions in a buffer solution. The pre-concentration of mercury ions is driven by the affinity interaction between the surface containing functional groups of DMC and Hg(ii) ions. The GQD-DMC modified glassy carbon electrode (GQD-DMC/GCE) shows extra sensitivity and selectivity for mercury(ii) detection, which is assumed to be due to the increased surface area as well as the presence of sulfur-containing functional groups on the modified structure.
PubMed: 34160516
DOI: 10.1039/d1nr00076d