Structures of voltage-gated channel with toxins suggest strategies for drug development

The asymmetric unit of the title compound {systematic name: sodium [2-({2-[(1-carboxyl­ato-2-methyl-2-sulfanidylprop­yl)amino]­eth­yl}amino)-3-methyl-3-sulf­an­idyl­butano­ato-κ4S,N,N',S']indate(III) tetra­hydrate}, Na[In(C12H20N2O4S2)]·4H2O, contains four indate(III) complex anions {[In(d-ebp)]−; d-H4ebp = N,N'-ethyelenebis(d-penicillamine)], four sodium(I) cations and sixteen water mol­ecules. The indate(III) anions and sodium cations are alternately connected through coordination bonds between Na+ ions and the carboxyl­ate groups of the complex anions, forming an infinite sixfold right-handed helix along the c-axis direction. In the crystal, the helices are linked by O—H⋯O hydrogen bonds between water mol­ecules bound to Na+ ions and carboxyl­ate groups. The crystal studied was twinned via a twofold axis about [001].

The title compound, [Na(μ-C6F5BH3)(C4H8O)2]2, represents a dimeric structure of sodium and organoborohydride, located about a centre of inversion. The Na⋯B distances of 2.7845 (19) and 2.7494 (18) Å were apparently longer than the Li⋯B distances (2.403–2.537 Å) of the lithium organotri­hydro­borates in the previous reports. Moreover, an inter­action between the sodium atom and one fluorine atom on the 2-position of the benzene ring is observed [Na—F = 2.6373 (12) Å]. In the crystal, the dimeric mol­ecules are stacked along the b-axis via a π–π inter­action between the benzene rings.

Reaction of 2-(4,4-dimethyl-2-oxazolin-2-yl)aniline (H2-L1) with one equivalent of Na[N(SiMe3)2] in toluene afforded pale-yellow crystals of tetra­meric poly[bis­[μ3-2-(4,4-dimethyl-2-oxazolin-2-yl)anilinido][μ2-2-(4,4-dimethyl-2-oxa­zolin-2-yl)aniline]tetra­sodium(I)], [Na4(C11H13N2O)4]n or [Na4(H-L1)4]n (2), in excellent yield. Subsequent reaction of [Na4(H-L1)4]n (2) with 1.33 equivalents of anhydrous YbCl3 in a 50:50 mixture of toluene–THF afforded yellow crystals of tris­[2-(4,4-dimethyl-2-oxazolin-2-yl)anilinido]ytterbium(III), [Yb(C11H13N2O)3] or Yb(H-L1)3 (3) in moderate yield. Direct reaction of three equivalents of 2-(4',4'-dimethyl-2'-oxazolin­yl)aniline (H2-L1) with Yb[N(SiMe3)2]3 in toluene resulted in elimination of hexa­methyl­disilazane, HN(SiMe3)2, and produced Yb(H-L1)3 (3) in excellent yield. The structure of 2 consists of tetra­meric Na4(H-L1)4 subunits in which each Na+ cation is bound to two H-L1 bridging bidentate ligands and these subunits are connected into a polymeric chain by two of the four oxazoline O atoms bridging to Na+ cations in the adjacent tetra­mer. This results in two 4-coordinate and two 5-coordinate Na+ cations within each tetra­meric unit. The structure of 3 consists of a distorted octa­hedron where the bite angle of ligand L1 ranges between 74.72 (11) and 77.79 (11) degrees. The oxazoline (and anilide) N atoms occupy meridional sites such that for one ligand an anilide nitro­gen is trans to an oxazoline nitro­gen while for the other two oxazoline N atoms are trans to each other. This results in a significantly longer Yb—N(oxazoline) distance [2.468 (3) Å] for the bond trans to the anilide compared to those for the oxazoline N atoms trans to one another [2.376 (3), 2.390 (3) Å].

The structure of sodium saccharinate 1.875-hydrate is presented in three- and (3+1)-dimensional space. The present model is more accurate than previously published superstructures, due to an excellent data set collected up to a high resolution of 0.89 Å−1. The present study confirms the unusual complexity of the structure comprising a very large primitive unit cell with Z' = 16. A much smaller degree of correlated disorder of parts of the unit cell is found than is present in the previously published models. As a result of pseudo-symmetry, the structure can be described in a higher-dimensional space. The X-ray diffraction data clearly indicate a (3+1)-dimensional periodic structure with stronger main reflections and weaker superstructure reflections. Furthermore, the structure is established as being commensurate. The structure description in superspace results in a four times smaller unit cell with an additional base centring of the lattice, resulting in an eightfold substructure (Z' = 2) of the 3D superstructure. Therefore, such a superspace approach is desirable to work out this high-Z' structure. The displacement and occupational modulation of the saccharinate anions have been studied, as well as their conformational variation along the fourth dimension.

Javad Fahanik-babaei, Bahareh Rezaee, Maryam Nazari, Nihad Torabi, Reza Saghiri, Remy Sauve, and Afsaneh Eliassi

We have determined the electropharmacological properties of a new potassium channel from brain mitochondrial membrane by planar lipid bilayer method. Our results showed the presence of a channel with a conductance of 150 pS at potentials between 0 and –60 mV in 200 cis/50 trans mM KCl solutions.

The channel was voltage-independent, with an open probability value ~0.6 at different voltages. ATP did not affect current amplitude and Po at positive and negative voltages. Notably, adding iberiotoxin, charybdotoxin, lidocaine, and margatoxin had no effect on the channel behavior. Similarly, no changes were observed by decreasing the cis-pH to 6. Interestingly, the channel was inhibited by adding sodium in a dose dependent manner. Our results also indicated a significant increase in mitochondrial complex IV activity and membrane potential and decrease in complex I activity and mitochondrial ROS production in the presence of sodium ions.

We propose that inhibition of mitochondrial K⁺ transport by Na ions on K⁺ channel opening may be important for cell protection and ATP synthesis.

The monoclinic crystal structure of Na2SO3(H2O)7 is characterized by an alternating stacking of (100) cationic sodium–water layers and anionic sulfite layers along [100]. The cationic layers are made up from two types of [Na(H2O)6] octa­hedra that form linear 1∞[Na(H2O)4/2(H2O)2/1] chains linked by dimeric [Na(H2O)2/2(H2O)4/1]2 units on both sides of the chains. The isolated trigonal–pyramidal sulfite anions are connected to the cationic layers through an intricate network of O—H⋯O hydrogen bonds, together with a remarkable O—H⋯S hydrogen bond, with an O⋯S donor–acceptor distance of 3.2582 (6) Å, which is about 0.05 Å shorter than the average for O—H⋯S hydrogen bonds in thio­salt hydrates and organic sulfur com­pounds of the type Y—S—Z (Y/Z = C, N, O or S). Structural relationships between monoclinic Na2SO3(H2O)7 and ortho­rhom­bic Na2CO3(H2O)7 are discussed in detail.

Combining sodium hydride with some solvents can be a bad idea, as a group of researchers from Corteva Agriscience and Dow Chemical remind the chemistry community in Organic Process Research & Development ,(2019, DOI: 10.1021/acs.oprd.9b00276). Reports of explosions from combining NaH with a polar aprotic solvent such as dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), and N,N-dimethylacetamide […]

The post Don’t mix sodium hydride with polar aprotic solvents appeared first on CENtral Science.

A new report from the National Academies of Sciences, Engineering, and Medicine reviews current evidence and updates intake recommendations known as the Dietary Reference Intakes (DRIs) for sodium and potassium that were established in 2005.

We can't seem to agree on the right amount of sodium, but these foods add up quickly.

Sodium ion batteries are cheaper and charge faster, but there are a few hurdles to their rise.

Sodium Hyaluronate, synthesized salt form of hyaluronic acid. Sodium Hyaluronate is water-soluble and has a smaller molecule structure allowing it to penetrate deeper into the skin. Hyaluronic acid cannot be absorbed by or penetrate the skin.

This invention relates to the field of preparation technology of optical pH sensor by co-intercalated fluorescein and 1-heptanesulfonic acid sodium into layered double hydroxide. The sensor is composed by conductive materials and the surface LDH films by co-interacted FLU and HES. The synthesis method is: first: synthesis of LDH colloid suspension, subsequently, the FLU and HES co-intercalated LDH colloid solution was prepared following the ion-exchange method, then the thin film of FLU-HES/LDH was spreaded on the surface of the conductive material by electrophoretic deposition, and the oriental pH sensor was synthesized. The advantages of the present invention is: first, the LDH matrix provides chromophore molecules with a confined and stable environment; the novel electrophoretic deposition strategy in this work provides a method for precise control of thickness (ranging from nanometers to micrometers), and the oriental pH sensor show good pH responsive.

The present application provides for ceramic collars and metal rings for active brazing in sodium-based thermal batteries. The ceramic collar may be an alpha-alumina collar configured for active brazing, and thereby sealing, to outer and inner Ni rings for use in NaMx cells. The portions of the alpha-alumina collar active brazed to the outer and inner Ni rings may be outwardly facing and include inwardly extending recesses. The portions of the outer and inner Ni rings active brazed to the outwardly facing portions of the collar may be inwardly facing. The alpha-alumina collar may include a greater coefficient of thermal expansion than each of the outer and inner Ni rings, and the alpha-alumina collar and outer and inner Ni rings may be configured such that a portion of the outer and inner Ni rings is deformed into the inwardly extending recesses of the alpha-alumina collar after active brazing thereof.

The present invention relates to a positive electrode active material for a sodium secondary battery, and a method for preparing the same. The positive electrode active material for the sodium secondary battery according to the present invention is structurally more stable by replacing a part of the transition metal with Li, and accordingly, the thermal stability and life characteristics of the sodium battery including the positive electrode active material are greatly improved.

The described technology relates to an electrolyte solution comprising a sulfur dioxide-based ionic liquid electrolyte, and a sodium-sulfur dioxide (Na—SO2) secondary battery having same, one purpose of the described technology being to enhance the storage characteristics of sulfur dioxide gas in an electrolyte solution. The sodium-sulfur dioxide secondary battery includes a negative electrode which is formed from an inorganic material and which contains sodium. The battery also includes a positive electrode which is formed from a carbon material and a sulfur dioxide-based inorganic electrolyte solution. Here, the electrolyte solution contains a sulfur dioxide-based ionic liquid electrolyte prepared by injecting SO2 gas in an ionic liquid.

This invention refers to a novel process to obtain magnesium hydroxide and sodium sulfate from a solid raw material, which contains sodium and magnesium soluble salts, preferably in the form of sulfates, coming from a natural source or as a byproduct of an industrial process. The process consisting in the conditioning of the raw material to guarantee the correct concentrations of sodium and magnesium sulfates that is subjected to a salting-out crystallization when mixed with sodium sulfate obtaining sodium sulfate; the resulting solution is subjected to an alkali treatment to precipitate the magnesium hydroxide and the mother liquor is fed to a regeneration stage of the alkali used in the precipitation of the magnesium hydroxide as well in the sodium sulfate solution for the crystallization. The crystallization can be performed as a multistage process countercurrent to increase the purity of sodium sulfate.

The present invention pertains to a process for producing sodium chloride comprising the steps of (i) preparing a brine comprising at least 150 g/l of sodium chloride by dissolving a sodium chloride source in water, (ii) subjecting the resulting brine to a eutectic freeze crystallization step by indirect cooling of said brine, resulting in the formation of ice, sodium chloride dihydrate, and a mother liquor, (iii) separating the sodium chloride dihydrate formed in step (ii) from the ice and optionally mother liquor at the eutectic temperature, such that a sodium chloride dihydrate-rich stream is formed, and (iv) feeding said sodium chloride dihydrate-rich stream to a recrystallizer to form sodium chloride and a mother liquor.

A process for the production of sodium carbonate and sodium bicarbonate out of trona, comprising crushing trona ore and dissolving it in a leaching tank containing a solution comprising sodium carbonate and sodium bicarbonate, and an additive selected from the group consisting of: phosphates, phospholipids, carboxylates, carboxilic acids, and combinations thereof, saturated in sodium bicarbonate, in order to produce solid particles suspended in a production solution comprising sodium carbonate, the solid particles containing insoluble impurities and at least 65% by weight of sodium bicarbonate. The solid particles are separated from the production solution containing sodium carbonate. At least part of the production solution containing sodium carbonate is taken out of the leaching tank.

The present invention pertains to a process for producing sodium chloride comprising the steps of: (i) preparing a brine having a sodium chloride concentration which is higher than the sodium chloride concentration of the eutectic point but lower than the sodium chloride concentration of a saturated brine by dissolving a sodium chloride source in water; (ii) cooling the resulting brine by indirect cooling in a self-cleaning fluidized bed heat exchanger/crystallizer to a temperature lower than 0° C. but higher than the eutectic temperature of the resulting brine, thereby forming a slurry comprising sodium chloride dihydrate and a mother liquor; (iii) feeding the sodium chloride dihydrate to a recrystallizer to form sodium chloride and a mother liquor, and (iv) recycling at least part of the mother liquor obtained in step (ii) and/or step (iii) to step (i).

A process is provided for preparing a salt product with reduced sodium content including the step of providing a concentrated brine, which is typically seawater, to which has been added potassium chloride. The mixture is transferred to a crystallizer unit where at least a portion of the mix is transferred to the crystallizer through a washing column. Liquid is evaporated from the crystallizer such that crystals form, crystals are passed from the crystallizer through said washing column to a separating unit such that in the passing through the washing column the crystals are rinsed with the brine portion being transferred as a counter current through the column. The inventive process is characterized by recycling of the brine from which the salt crystallizes, thus all main ingredients of the mixed input brine reach a steady equilibrium concentration in the mother liquor in the crystallizer. These will then precipitate as crystals, as more of the respective substances gets added to the mother liquor through inflow of mixed input brine. None of the liquor is purged out of the system as in conventional salt crystallizers. All the components in the feed are substantially contained in the product from the crystallizer either as crystalline material or soluble ingredients.

S-Palmitoylation is a reversible post-translational lipid modification that dynamically regulates protein functions. Voltage-gated sodium channels are subjected to S-palmitoylation and exhibit altered functions in different S-palmitoylation states. Our aim was to investigate whether and how S-palmitoylation regulates Nav1.6 channel function and to identify S-palmitoylation sites that can potentially be pharmacologically targeted. Acyl-biotin exchange assay showed that Nav1.6 is modified by S-palmitoylation in the mouse brain and in a Nav1.6 stable HEK 293 cell line. Using whole-cell voltage clamp, we discovered that enhancing S-palmitoylation with palmitic acid increases Nav1.6 current, whereas blocking S-palmitoylation with 2-bromopalmitate reduces Nav1.6 current and shifts the steady-state inactivation in the hyperpolarizing direction. Three S-palmitoylation sites (Cys1169, Cys1170, and Cys1978) were identified. These sites differentially modulate distinct Nav1.6 properties. Interestingly, Cys1978 is exclusive to Nav1.6 among all Nav isoforms and is evolutionally conserved in Nav1.6 among most species. Cys1978 S-palmitoylation regulates current amplitude uniquely in Nav1.6. Furthermore, we showed that eliminating S-palmitoylation at specific sites alters Nav1.6-mediated excitability in dorsal root ganglion neurons. Therefore, our study reveals S-palmitoylation as a potential isoform-specific mechanism to modulate Nav activity and neuronal excitability in physiological and diseased conditions.

S-Palmitoylation is a reversible post-translational lipid modification that dynamically regulates protein functions. Voltage-gated sodium channels are subjected to S-palmitoylation and exhibit altered functions in different S-palmitoylation states. Our aim was to investigate whether and how S-palmitoylation regulates Nav1.6 channel function and to identify S-palmitoylation sites that can potentially be pharmacologically targeted. Acyl-biotin exchange assay showed that Nav1.6 is modified by S-palmitoylation in the mouse brain and in a Nav1.6 stable HEK 293 cell line. Using whole-cell voltage clamp, we discovered that enhancing S-palmitoylation with palmitic acid increases Nav1.6 current, whereas blocking S-palmitoylation with 2-bromopalmitate reduces Nav1.6 current and shifts the steady-state inactivation in the hyperpolarizing direction. Three S-palmitoylation sites (Cys1169, Cys1170, and Cys1978) were identified. These sites differentially modulate distinct Nav1.6 properties. Interestingly, Cys1978 is exclusive to Nav1.6 among all Nav isoforms and is evolutionally conserved in Nav1.6 among most species. Cys1978 S-palmitoylation regulates current amplitude uniquely in Nav1.6. Furthermore, we showed that eliminating S-palmitoylation at specific sites alters Nav1.6-mediated excitability in dorsal root ganglion neurons. Therefore, our study reveals S-palmitoylation as a potential isoform-specific mechanism to modulate Nav activity and neuronal excitability in physiological and diseased conditions.

The prostate-specific membrane antigen (PSMA) is an excellent target for theranostic applications in prostate cancer (PCa). However, PSMA-targeted radioligand therapy can cause undesirable effects due to high accumulation of PSMA radiotracers in salivary glands and kidneys. This study assessed orally administered monosodium glutamate (MSG) as a potential means of reducing kidney and salivary gland radiation exposure using a PSMA targeting radiotracer. Methods: This prospective, double-blind, placebo-controlled study enrolled 10 biochemically recurrent PCa patients. Each subject served as his own control. [¹⁸F]DCFPyl PET/CT imaging sessions were performed 3 – 7 days apart, following oral administration of either 12.7 g of MSG or placebo. Data from the two sets of images were analyzed by placing regions of interest on lacrimal, parotid and submandibular glands, left ventricle, liver, spleen, kidneys, bowel, urinary bladder, gluteus muscle and malignant lesions. The results from MSG and placebo scans were compared by paired analysis of the ROI data. Results: A total of 142 pathological lesions along with normal tissues were analyzed. As hypothesized a priori, there was a significant decrease in maximal standardized uptake values corrected for lean body mass (SULmax) on images obtained following MSG administration in the parotids (24 ± 14%, P = 0.001), submandibular glands (35 ± 11%, P<0.001) and kidneys (23 ± 26%, P = 0.014). Significant decreases were also observed in lacrimal glands (49 ± 13%, P<0.001), liver (15 ± 6%, P<0.001), spleen (28 ± 13%, P = 0.001) and bowel (44 ± 13%, P<0.001). Mildly lower blood pool SULmean was observed after MSG administration (decrease of 11 ± 13%, P = 0.021). However, significantly lower radiotracer uptake in terms of SULmean, SULpeak, and SULmax was observed in malignant lesions on scans performed after MSG administration compared to the placebo studies (SULmax median decrease 33%, range -1 to 75%, P<0.001). No significant adverse events occurred and vital signs were stable following placebo or MSG administration. Conclusion: Orally administered MSG significantly decreased salivary gland, kidney and other normal organ PSMA radiotracer uptake in human subjects, using [¹⁸F]DCFPyL as an exemplar. However, MSG caused a corresponding reduction in tumor uptake, which may limit the benefits of this approach for diagnostic and therapeutic applications.

S-Palmitoylation is a reversible post-translational lipid modification that dynamically regulates protein functions. Voltage-gated sodium channels are subjected to S-palmitoylation and exhibit altered functions in different S-palmitoylation states. Our aim was to investigate whether and how S-palmitoylation regulates Nav1.6 channel function and to identify S-palmitoylation sites that can potentially be pharmacologically targeted. Acyl-biotin exchange assay showed that Nav1.6 is modified by S-palmitoylation in the mouse brain and in a Nav1.6 stable HEK 293 cell line. Using whole-cell voltage clamp, we discovered that enhancing S-palmitoylation with palmitic acid increases Nav1.6 current, whereas blocking S-palmitoylation with 2-bromopalmitate reduces Nav1.6 current and shifts the steady-state inactivation in the hyperpolarizing direction. Three S-palmitoylation sites (Cys1169, Cys1170, and Cys1978) were identified. These sites differentially modulate distinct Nav1.6 properties. Interestingly, Cys1978 is exclusive to Nav1.6 among all Nav isoforms and is evolutionally conserved in Nav1.6 among most species. Cys1978 S-palmitoylation regulates current amplitude uniquely in Nav1.6. Furthermore, we showed that eliminating S-palmitoylation at specific sites alters Nav1.6-mediated excitability in dorsal root ganglion neurons. Therefore, our study reveals S-palmitoylation as a potential isoform-specific mechanism to modulate Nav activity and neuronal excitability in physiological and diseased conditions.

Robert R. Henry
Dec 1, 2015; 38:2258-2265
Special Article Collection: Insulin

Bruce A. Perkins
May 1, 2014; 37:1480-1483
Novel Communications in Diabetes

OBJECTIVE

This study evaluated the ability of the Building, Relating, Assessing, and Validating Outcomes (BRAVO) risk engine to accurately project cardiovascular outcomes in three major clinical trials—BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), Canagliflozin Cardiovascular Assessment Study (CANVAS), and Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction (DECLARE-TIMI 58) trial—on sodium–glucose cotransporter 2 inhibitors (SGLT2is) to treat patients with type 2 diabetes.

Treatment of adolescent migraine remains a significant unmet medical need. In adults, the combination of sumatriptan and naproxen sodium has demonstrated superior efficacy, with similar tolerability, to its components in the acute treatment of migraine.

This study constitutes the first large-scale, placebo-controlled evidence for the acute relief of adolescent migraine pain and associated symptoms with an oral medication. (Read the full article)

High blood pressure in childhood predisposes people to hypertension in adulthood and is associated with early development of cardiovascular disease and risk for premature death. High sodium intake and overweight/obesity are recognized as risk factors for hypertension in children.

These results show that usual sodium intake was positively associated with systolic blood pressure and risk for pre-high blood pressure and high blood pressure among US children. The data indicate a synergistic interaction between sodium intake and weight status on risk for high blood pressure. (Read the full article)