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Colloids and Surfaces. B, Biointerfaces Dec 2017GM has generally been considered as the major receptor that binds to cholera toxin subunit B (CTB) due to its low dissociation constant. However, using a unique nanocube...
GM has generally been considered as the major receptor that binds to cholera toxin subunit B (CTB) due to its low dissociation constant. However, using a unique nanocube sensor technology, we have shown that CTB can also bind to other glycolipid receptors, fucosyl-GM and GDb. Additionally, we have demonstrated that GM can contribute to CTB binding if present in a glycolipid mixture with a strongly binding receptor (GM/fucosyl-GM/GDb). This hetero-multivalent binding result was unintuitive because the interaction between CTB and pure GM is negligible. We hypothesized that the reduced dimensionality of CTB-GM binding events is a major cause of the observed CTB binding enhancement. Once CTB has attached to a strong receptor, subsequent binding events are confined to a 2D membrane surface. Therefore, even a weak GM receptor could now participate in second or higher binding events because its surface reaction rate can be up to 10 times higher than the bulk reaction rate. To test this hypothesis, we altered the surface reaction rate by modulating the fluidity and heterogeneity of the model membrane. Decreasing membrane fluidity reduced the binding cooperativity between GM and a strong receptor. Our findings indicated a new protein-receptor binding assay, that can mimic complex cell membrane environment more accurately, is required to explore the inherent hetero-multivalency of the cell membrane. We have thus developed a new membrane perturbation protocol to efficiently screen receptor candidates involved in hetero-multivalent protein binding.
Topics: Binding Sites; Carbohydrate Sequence; Cell Membrane; Cholera Toxin; Dimyristoylphosphatidylcholine; G(M1) Ganglioside; G(M2) Ganglioside; Kinetics; Lipid Bilayers; Metal Nanoparticles; Phosphatidylcholines; Phosphatidylserines; Protein Binding; Silicon Dioxide; Thermodynamics; Unithiol
PubMed: 28946063
DOI: 10.1016/j.colsurfb.2017.09.035 -
Journal of Pharmacological Sciences Jun 2017Previously, we reported that specific lower dose of sodium 2,3-dimercapto-1-propanesulfonic acid (DMPS) which is an antidote to heavy metal intoxication, inversely...
The effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) on the nephrotoxicity in the mouse during repeated cisplatin (CDDP) treatments.
Previously, we reported that specific lower dose of sodium 2,3-dimercapto-1-propanesulfonic acid (DMPS) which is an antidote to heavy metal intoxication, inversely enhanced cisplatin (CDDP)-induced antitumor activity to S-180 cell-bearing mouse. This activity was only weak with meso-2,3-dimercaptosuccinic acid (DMSA), however. This study investigated the effects of lower doses of DMPS or DMSA on the nephrotoxicity and kinetics of CDDP. Kidney and blood isolated from female mice which received CDDP with or without DMPS or DMSA once daily for 4 days were provided for measuring levels of blood urea nitrogen (BUN) and transporter proteins (OCT2: organic cation transporter; MATE1: multidrug and toxin extrusion) mRNA, and CDDP-originated platinum, and TUNEL staining of renal tubular cells. DMPS or DMSA reduced effectively CDDP-induced BUN, and caused a moderate reduction of platinum in kidney. Additionally, both dimercapto-compounds restored the CDDP-reduced mRNA levels of transporter proteins (OCT2 and MATE1), and apparently suppressed the CDDP-induced apoptosis. These results suggest that DMPS, as well as DMSA, at approximate 17-fold dose (μmol/kg) of CDDP, has an enough potential to reverse the CDDP nephrotoxicity, and concomitant use of DMPS considering both dose and timing for administration is potentially useful for preventing nephrotoxicity and enhancing antitumor activity during CDDP chemotherapy.
Topics: Animals; Antineoplastic Agents; Cisplatin; Dose-Response Relationship, Drug; Female; Kidney; Kidney Diseases; Mice; Organic Cation Transport Proteins; Organic Cation Transporter 2; RNA, Messenger; Succimer; Unithiol
PubMed: 28648300
DOI: 10.1016/j.jphs.2017.05.006 -
Complementary Medicine Research 2017Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to death within 3-5 years in most cases. New approaches to treating this disease are needed. Here,...
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to death within 3-5 years in most cases. New approaches to treating this disease are needed. Here, we report a successful therapy.
CASE REPORT
In a 49-year-old male patient suffering from muscle weakness and fasciculations, progressive muscular atrophy, a variant of ALS, was diagnosed after extensive examinations ruling out other diseases. Due to supposed mercury exposure from residual amalgam, the patient's teeth were restored. Then, the patient received sodium 2,3-dimercaptopropanesulfate (DMPS; overall 86 × 250 mg in 3 years) in combination with α-lipoic acid and followed by selenium. In addition, he took vitamins and micronutrients and kept a vegetarian diet. The excretion of metals was monitored in the urine. The success of the therapy was followed by scoring muscle weakness and fasciculations and finally by electromyography (EMG) of the affected muscles. First improvements occurred after the dental restorations. Two months after starting therapy with DMPS, the mercury level in the urine was increased (248.4 µg/g creatinine). After 1.5 years, EMG confirmed the absence of typical signs of ALS. In the course of 3 years, the patient recovered completely.
CONCLUSIONS
The therapy described here is a promising approach to treating some kinds of motor neuron disease and merits further evaluation in rigorous trials.
Topics: Amyotrophic Lateral Sclerosis; Dental Amalgam; Dental Restoration, Permanent; Environmental Exposure; Humans; Male; Mercury; Middle Aged; Muscular Atrophy, Spinal; Selenium; Thioctic Acid; Treatment Outcome; Unithiol
PubMed: 28641283
DOI: 10.1159/000477397 -
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 -
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 -
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 -
Basic & Clinical Pharmacology &... Jun 2017The efficacy of treatment for intravenous elemental mercury intoxication has not been fully studied with regard to clinical outcome, and treatment recommendations vary....
The efficacy of treatment for intravenous elemental mercury intoxication has not been fully studied with regard to clinical outcome, and treatment recommendations vary. We treated a 41-year-old man with a history of drug abuse and depression who attempted suicide using 1 mL (13.53 g) metallic Hg i.v. He was admitted to the hospital 2 months later for dyspnoea and thoracic pain and was diagnosed with pneumonia. Hg deposits were seen in the lungs and extra-pulmonary organs. His blood level (372 μg/L) exceeded the population level of 5 μg/L by more than 70 times. Dimercaptopropane sulphonate sodium (DMPS; 600 mg/day orally) was administered for 14 days. One year later, the patient presented with dyspnoea on exertion, fatigue, depression and impaired sleep. His chest X-ray showed multiple opacities (size up to 2.8 cm), and psychological testing revealed a selective cognitive deficit in the area of visual attentiveness, flexibility, source memory and impairment of the motor speed of the dominant upper extremity. Mercury blood level was 158 μg/L and mercury urine output was 1380 μg/24 hr. DMPS (800 mg/day orally) was administered for 40 days; the patient eliminated up to 18 mg Hg/day. His Hg blood level and Hg urine output belong to the highest among reported cases. In spite of the therapy, the patient's blood Hg, complaints and psychological tests showed no improvement. This case report confirms that DMPS does not effectively remove intravenous deposits of metallic Hg.
Topics: Adult; Chelation Therapy; Humans; Injections, Intravenous; Male; Mercury Poisoning; Suicide, Attempted; Unithiol
PubMed: 27911474
DOI: 10.1111/bcpt.12725 -
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