One-Pot Self-Assembly of Dinuclear,Tetranuclear, and H-Bonding-Directed Polynuclear Cobalt(II), Cobalt(III), and Mixed-Valence Co(II)/Co(III) Complexes of Schiff Base Ligands with Incomplete Double Cubane Core

The reaction of 2,6-diformyl-4-methylphenol (DFMF) with 1-amino-2-propanol (AP) and tris(hydroxymethyl)aminomethane (THMAM) was investigated in the presence of Cobalt(II) salts, (X = ClO₄⁻, CH₃CO₂⁻, Cl⁻, NO₃⁻), sodium azide (NaN₃), and triethylamine (TEA). In one pot, the variation in Cobalt(II) salt results in the self-assembly of dinuclear, tetranuclear, and H-bonding-directed polynuclear coordination complexes of Cobalt(III), Cobalt(II), and mixed-valence Co^IICo^III: [Co₂^III(H₂L⁻¹)₂(AP⁻¹)(N₃)](ClO₄)₂ (1), [Co₄(H₂L⁻¹)₂(µ₃-1,1,1-N₃)₂(µ-1,1-N₃)₂Cl₂(CH₃OH)₂]·4CH₃OH (2), [Co₂^IICo₂^III(HL⁻²)₂(µ-CH₃CO₂)₂(µ₃-OH)₂](NO₃)₂·2CH₃CH₂OH (3), and [Co₂^IICo₂^III (H₂L1²⁻)₂(THMAM⁻¹)₂](NO₃)₄ (4). In 1, two cobalt(III) ions are connected via three single atom bridges; two from deprotonated ethanolic oxygen atoms in the side arms of the ligands and one from the1-amino-2-propanol moiety forming a dinuclear unit with a very short (2.5430(11) Å) Co-Co intermetallic separation with a coordination number of 7, a rare feature for cobalt(III). In 2, two cobalt(II) ions in a dinuclear unit are bridged through phenoxide O and μ₃-1,1,1-N₃ azido bridges, and the two dinuclear units are interconnected by two μ-1,1-N₃ and two μ₃-1,1,1-N₃ azido bridges generating tetranuclear cationic [Co₄(H₂L⁻¹)₂(µ₃-1,1,1-N₃)₂(µ-1,1-N₃)₂Cl₂(CH₃OH)₂]²⁺ units with an incomplete double cubane core, which grow into polynuclear 1D-single chains along the a-axis through H-bonding. In 3, HL²⁻ holds mixed-valent Co(II)/Co(III) ions in a dinuclear unit bridged via phenoxide O, μ-1,3-CH₃CO₂⁻, and μ₃-OH⁻ bridges, and the dinuclear units are interconnected through two deprotonated ethanolic O in the side arms of the ligands and two μ₃-OH⁻ bridges generating cationic tetranuclear [Co₂^IICo₂^III(HL⁻²)₂(µ-CH₃CO₂)₂(µ_3-OH)₂]²⁺ units with an incomplete double cubane core. In 4, H₂L1⁻² holds mixed-valent Co(II)/Co(III) ions in dinuclear units which dimerize through two ethanolic O (μ-RO⁻) in the side arms of the ligands and two ethanolic O (μ₃-RO⁻) of THMAM bridges producing centrosymmetric cationic tetranuclear [Co₂^IICo₂^III (H₂L1⁻²)₂(THMAM⁻¹)₂]⁴⁺ units which grow into 2D-sheets along the bc-axis through a network of H-bonding. Bulk magnetization measurements on 2 demonstrate that the magnetic interactions are completely dominated by an overall ferromagnetic coupling occurring between Co(II) ions.     

Crystal Structure,Spectroscopic Characterization,Antioxidant and Cytotoxic Activity of New Mg(II) and Mn(II)/Na(I) Complexes of Isoferulic Acid

The Mg(II) and heterometallic Mn(II)/Na(I) complexes of isoferulic acid (3-hydroxy-4-methoxycinnamic acid, IFA) were synthesized and characterized by infrared spectroscopy FT-IR, FT-Raman, electronic absorption spectroscopy UV/VIS, and single-crystal X-ray diffraction. The reaction of MgCl₂ with isoferulic acid in the aqueous solutions of NaOH resulted in synthesis of the complex salt of the general formula of [Mg(H₂O)₆]⋅(C₁₀H₉O₄)₂⋅6H₂O. The crystal structure of this compound consists of discrete octahedral [Mg(H₂O)₆]²⁺ cations, isoferulic acid anions and solvent water molecules. The hydrated metal cations are arranged among the organic layers. The multiple hydrogen-bonding interactions established between the coordinated and lattice water molecules and the functional groups of the ligand stabilize the 3D architecture of the crystal. The use of MnCl₂ instead of MgCl₂ led to the formation of the Mn(II)/Na(I) complex of the general formula [Mn₃Na₂(C₁₀H₇O₄)₈(H₂O)₈]. The compound is a 3D coordination polymer composed of centrosymmetric pentanuclear subunits. The antioxidant activity of these compounds was evaluated by assays based on different antioxidant mechanisms of action, i.e., with ^•OH, DPPH^• and ABTS^•+ radicals as well as CUPRAC (cupric ions reducing power) and lipid peroxidation inhibition assays. The pro-oxidant property of compounds was measured as the rate of oxidation of Trolox. The Mg(II) and Mn(II)/Na(I) complexes with isoferulic acid showed higher antioxidant activity than ligand alone in DPPH (IFA, IC₅₀ = 365.27 μM, Mg(II) IFA IC₅₀ = 153.50 μM, Mn(II)/Na(I) IFA IC₅₀ = 149.00 μM) and CUPRAC assays (IFA 40.92 μM of Trolox, Mg(II) IFA 87.93 μM and Mn(II)/Na(I) IFA 105.85 μM of Trolox; for compounds’ concentration 10 μM). Mg(II) IFA is a better scavenger of ^•OH than IFA and Mn(II)/Na(I) IFA complex. There was no distinct difference in ABTS^•+ and lipid peroxidation assays between isoferulic acid and its Mg(II) complex, while Mn(II)/Na(I) complex showed lower activity than these compounds. The tested complexes displayed only slight antiproliferative activity tested in HaCaT human immortalized keratinocyte cell line within the solubility range. The Mn(II)/Na(I) IFA (16 μM in medium) caused an 87% (±5%) decrease in cell viability, the Mg salt caused a comparable, i.e., 87% (±4%) viability decrease in a concentration of 45 μM, while IFA caused this level of cell activity attenuation (87% ± 5%) at the concentration of 1582 μM (significant at α = 0.05).     

Two Luminescent Iridium Complexes with Phosphorous Ligands and Their Photophysical Comparison in Solution,Solid and Electrospun Fibers: Decreased Aggregation-Caused Emission Quenching by Steric Hindrance

In this paper, we prepared two phosphorescent Ir complexes with ligands of 2-phenyl pyridine (ppy), and two phosphorous ligands with large steric hindrance, hoping to allow enough time for the transformation of the highly phosphorescent ³MLLCT (metal-to-ligand-ligand-charge-transfer) excited state. Their large steric hindrance minimized the π-π interaction between complex molecules, so that the aggregation-induced phosphorescence emission (AIPE) influence could be minimized. Their single crystals indicated that they took a distorted octahedral coordination mode. Photophysical comparison between these Ir complexes in solution, in the solid state and in electrospun fibers was performed to confirm the realization of limited aggregation-caused quenching (ACQ). The potential surface crossing and energy transfer from ³ML_BPECT/³ML_BPEL_ppyCT to ³ML_ppyCT in these Ir complexes were revealed by density functional theory calculation and temperature-dependent emission. It was confirmed that these two phosphorous ligands offered large steric hindrance, which decreased the ACQ effect, allowing the efficient emissive decay of the ³ML_ppyCT excited state. This is one of the several luminescent Ir complexes with a high emission yield (Φ = 0.27) and long emission lifetime (0.43 μs) in the solid state.     

A model for the CO-inhibited form of [NiFe] hydrogenase: synthesis of (CO)3Fe(μ-StBu)3Ni{SC6H3-2,6-(mesityl)2} and reversible CO addition at the Ni site

A [NiFe] hydrogenase model compound having a distorted trigonal-pyramidal nickel center, (CO)₃Fe(μ-S^tBu)₃Ni(SDmp), 1 (Dmp = C₆H₃-2,6-(mesityl)₂), was synthesized from the reaction of the tetranuclear Fe-Ni-Ni-Fe complex [(CO)₃Fe(μ-S^tBu)₃Ni]₂(μ-Br)₂, 2 with NaSDmp at -40 °C. The nickel site of complex 1 was found to add CO or CN^tBu at -40 °C to give (CO)₃Fe(S^tBu)(μ-S^tBu)₂Ni(CO)(SDmp), 3, or (CO)₃Fe(S^tBu)(μ-S^tBu)₂Ni(CN^tBu)(SDmp), 4, respectively. One of the CO bands of 3, appearing at 2055 cm^-1 in the infrared spectrum, was assigned as the Ni-CO band, and this frequency is comparable to those observed for the CO-inhibited forms of [NiFe] hydrogenase. Like the CO-inhibited forms of [NiFe] hydrogenase, the coordination of CO at the nickel site of 1 is reversible, while the CN^tBu adduct 4 is more robust.     

A relation between automorphic forms on GL(2) and GL(3)

Let ρ_n denote the standard n-dimensional representation of GL(n,C) and ρ_n² its symmetric square. For each automorphic cuspidal representation π of GL(2,A) we introduce an Euler product L(s,π,ρ₂²) of degree 3 which we prove is entire. We also prove that there exists an automorphic representation II of GL(3)—“the lift of π”—with the property that L(s,II,ρ₃) = L(s,π,ρ₂²). Our results confirm conjectures described in a more general context by R. P. Langlands [(1970) Lecture Notes in Mathematics, no. 170 (Springer-Verlag, Berlin-Heidelberg-New York)].     

Synthesis,Crystal Structure and Luminescent Property of Cd (II) Complex with N-Benzenesulphonyl-L-leucine

A new trinuclear Cd (II) complex [Cd₃(L)₆(2,2-bipyridine)₃] [L = N-phenylsulfonyl-L-leucinato] has been synthesized and characterized by elemental analysis, IR and X-ray single crystal diffraction analysis. The results show that the complex belongs to the orthorhombic, space group P2₁2₁2₁ with a = 16.877(3) Å, b = 22.875(5) Å, c = 29.495(6) Å, α = β = γ = 90°, V = 11387(4) ų, Z = 4, D_c= 1.416 μg·m⁻³, μ = 0.737 mm⁻¹, F (000) = 4992, and final R₁ = 0.0390, ωR₂ = 0.0989. The complex comprises two seven-coordinated Cd (II) atoms, with a N₂O₅ distorted pengonal bipyramidal coordination environment and a six-coordinated Cd (II) atom, with a N₂O₄ distorted octahedral coordination environment. The molecules form one dimensional chain structure by the interaction of bridged carboxylato groups, hydrogen bonds and π-π interaction of 2,2-bipyridine. The luminescent properties of the Cd (II) complex and N-Benzenesulphonyl-L-leucine in solid and in CH₃OH solution also have been investigated.     

Phosphatidylinositol 4,5-bisphosphate (PIP2) stimulates the electrogenic Na/HCO3 cotransporter NBCe1-A expressed in Xenopus oocytes

Bicarbonate transporters are regulated by signaling molecules/ions such as protein kinases, ATP, and Ca²⁺. While phospholipids such as PIP₂ can stimulate Na-H exchanger activity, little is known about phospholipid regulation of bicarbonate transporters. We used the patch-clamp technique to study the function and regulation of heterologously expressed rat NBCe1-A in excised macropatches from Xenopus laevis oocytes. Exposing the cytosolic side of inside-out macropatches to a 5% CO₂/33 mM HCO₃⁻ solution elicited a mean inward current of 14 pA in 74% of macropatches attached to pipettes (−V_p = −60 mV) containing a low-Na⁺, nominally HCO₃⁻-free solution. The current was 80–90% smaller in the absence of Na⁺, approximately 75% smaller in the presence of 200 μM DIDS, and absent in macropatches from H₂O-injected oocytes. NBCe1-A currents exhibited time-dependent rundown that was inhibited by removing Mg²⁺ in the presence or absence of vanadate and F⁻ to reduce general phosphatase activity. Applying 5 or 10 μM PIP₂ (diC8) in the presence of HCO₃⁻ induced an inward current in 54% of macropatches from NBC-expressing, but not H₂O-injected oocytes. PIP₂-induced currents were HCO₃⁻-dependent and somewhat larger following more NBCe1-A rundown, 62% smaller in the absence of Na⁺, and 90% smaller in the presence of 200 μM DIDS. The polycation neomycin (250–500 μM) reduced the PIP₂-induced inward current by 69%; spermine (100 μM) reduced the current by 97%. Spermine, poly-D-lysine, and neomycin all reduced the baseline HCO₃⁻-induced inward currents by as much as 85%. In summary, PIP₂ stimulates NBCe1-A activity, and phosphoinositides are regulators of bicarbonate transporters.     

Synthesis,Crystal Structure and Luminescent Property of Mg(II) Complex with N-Benzenesulphonyl-L-Leucine and 1,10-Phenanthroline

A new complex [Mg(L)₂(phen)(H₂O)₂](phen)(H₂O)₂ [L= N-benzenesulphonyl-L-leucine] was synthesized by the reaction of magnesium chloride hexahydrate with N-benzenesulphonyl-L-leucine and 1,10-phenanthroline in the CH₃CH₂OH/H₂O (v:v = 5:1). It was characterized by elemental analysis, IR and X-ray single crystal diffraction analysis. The crystal of the title complex [Mg(L)₂(phen)(H₂O)₂](phen)(H₂O)₂ belongs to triclinic, space group P-1 with a = 0.72772(15) nm, b = 1.4279(3) nm, c = 1.4418(3) nm, α = 63.53(3)°, β = 79.75(3)°, γ = 81.83(3)°, V = 1.3163(5) nm³, Z =1, D_c= 1.258 μg·m⁻³, μ = 0.177 mm⁻¹, F(000) = 526, and final R₁ = 0.0506, ωR₂ = 0.1328. The complex comprises a six-coordinated magnesium(II) center, with a N₂O₄ distorted octahedron coordination environment. The molecules are connected by hydrogen bonds and π-π stacking to form one dimensional chain structure. The luminescent property of the Mg(II) complex has been investigated in solid.     

Isolation and bacterial expression of a sesquiterpene synthase cDNA clone from peppermint (Mentha x piperita, L.) that produces the aphid alarm pheromone (E)-β-farnesene

(E)-β-Farnesene is a sesquiterpene semiochemical that is used extensively by both plants and insects for communication. This acyclic olefin is found in the essential oil of peppermint (Mentha x piperita) and can be synthesized from farnesyl diphosphate by a cell-free extract of peppermint secretory gland cells. A cDNA from peppermint encoding (E)-β-farnesene synthase was cloned by random sequencing of an oil gland library and was expressed in Escherichia coli. The corresponding synthase has a deduced size of 63.8 kDa and requires a divalent cation for catalysis (K_m for Mg²⁺ ≈ 150 μM; K_m for Mn²⁺ ≈ 7 μM). The sesquiterpenoids produced by the recombinant enzyme, as determined by radio-GC and GC-MS, are (E)-β-farnesene (85%), (Z)-β-farnesene (8%), and δ-cadinene (5%) with the native C15 substrate farnesyl diphosphate (K_m ≈ 0.6 μM; V_rel = 100) and Mg²⁺ as cofactor, and (E)-β-farnesene (98%) and (Z)-β-farnesene (2%) with Mn²⁺ as cofactor (V_rel = 80). With the C₁₀ analog, GDP, as substrate (K_m = 1.5 μM; V_rel = 3 with Mg²⁺ as cofactor), the monoterpenes limonene (48%), terpinolene (15%), and myrcene (15%) are produced.     

Subordinate quadratic forms and their complementary forms

Theorem 1. For α, β on the range 1,..., μ, let Q(z) = ^*aαβzαzβ be a real valued, nonsingular, symmetric quadratic form. For positive integers r and s such that μ = r + s set (z₁,..., z_μ) = (u₁,..., u_r:S₁,..., S_n), Q(z) = P(u, s) and [Formula: see text] Let B = (z⁽¹⁾,..., z^(r)) be a base “over R” for points z ε π_r. For an arbitrary r-tuple ω₁,..., ω_r set [Formula: see text] index H_B(ω) = κ and nullity H_B(ω) = ν. Then [Formula: see text]     

Dendritic Iron(III) Carbazole Complexes: Structural,Optical, and Magnetic Characteristics

This paper focuses on the synthesis, structural characterization, and study of the optical, magnetic, and thermal properties of novel architectures combining metal ions as magnetoactive centers and photoactive blocks formed by carbazole units. For this purpose, a series of azomethine complexes of the composition [Fe(L)₂]X (L = 3,6-bis[(3′,6′-di-tert-butyl-9-carbazol)-9-carbazol]benzoyloxy-4-salicylidene-N′-ethyl-N-ethylenediamine, X = NO₃⁻, Cl⁻, PF₆⁻) were synthesized by the reaction of metal salts with Schiff bases in a mixture of solvents. The UV–Vis absorption properties were studied in dichloromethane and rationalized via time-dependent density functional theory (DFT) calculations. Upon excitation at 350 nm, the compounds exhibited an intense dual fluorescence with two emission bands centered at ~445 and ~485 nm, which were assigned to π_carb–π* intraligand and π_carb–d_Fe ligand-to-metal charge-transfer excited states. EPR spectroscopy and SQUID magnetometry revealed solid-state partial spin crossover in some compounds, and antiferromagnetic interactions between the neighboring Fe(III) ions.     

Unmasking the functions of the chromaffin cell α7 nicotinic receptor by using short pulses of acetylcholine and selective blockers

Methyllycaconitine (MLA), α-conotoxin ImI, and α-bungarotoxin inhibited the release of catecholamines triggered by brief pulses of acetylcholine (ACh) (100 μM, 5 s) applied to fast-superfused bovine adrenal chromaffin cells, with IC₅₀s of 100 nM for MLA and 300 nM for α-conotoxin ImI and α-bungarotoxin. MLA (100 nM), α-conotoxin ImI (1 μM), and α-bungarotoxin (1 μM) halved the entry of ⁴⁵Ca²⁺ stimulated by 5-s pulses of 300 μM ACh applied to incubated cells. These supramaximal concentrations of α₇ nicotinic receptor blockers depressed by 30% (MLA), 25% (α-bungarotoxin), and 50% (α-conotoxin ImI) the inward current generated by 1-s pulses of 100 μM ACh, applied to voltage-clamped chromaffin cells. In Xenopus oocytes expressing rat brain α₇ neuronal nicotinic receptor for acetylcholine nAChR, the current generated by 1-s pulses of ACh was blocked by MLA, α-conotoxin ImI, and α-bungarotoxin with IC₅₀s of 0.1 nM, 100 nM, and 1.6 nM, respectively; the current through α₃β₄ nAChR was unaffected by α-conotoxin ImI and α-bungarotoxin, and weakly blocked by MLA (IC₅₀ = 1 μM). The functions of controlling the electrical activity, the entry of Ca²⁺, and the ensuing exocytotic response of chromaffin cells were until now exclusively attributed to α₃β₄ nAChR; the present results constitute the first evidence to support a prominent role of α₇ nAChR in controlling such functions, specially under the more physiological conditions used here to stimulate chromaffin cells with brief pulses of ACh.     

Fatty acids suppress voltage-gated Na+ currents in HEK293t cells transfected with the α-subunit of the human cardiac Na+ channel

Studies have shown that fish oils, containing n-3 fatty acids, have protective effects against ischemia-induced, fatal cardiac arrhythmias in animals and perhaps in humans. In this study we used the whole-cell voltage-clamp technique to assess the effects of dietary, free long-chain fatty acids on the Na⁺ current (I_Na,α) in human embryonic kidney (HEK293t) cells transfected with the α-subunit of the human cardiac Na⁺ channel (hH1_α). Extracellular application of 0.01 to 30 μM eicosapentaenoic acid (EPA, C20:5n-3) significantly reduced I_Na,α with an IC₅₀ of 0.51 ± 0.06 μM. The EPA-induced suppression of I_Na,α was concentration- and voltage-dependent. EPA at 5 μM significantly shifted the steady-state inactivation relationship by −27.8 ± 1.2 mV (n = 6, P < 0.0001) at the V_1/2 point. In addition, EPA blocked I_Na,α with a higher “binding affinity” to hH1_α channels in the inactivated state than in the resting state. The transition from the resting state to the inactivated state was markedly accelerated in the presence of 5 μM EPA. The time for 50% recovery from the inactivation state was significantly slower in the presence of 5 μM EPA, from 2.1 ± 0.8 ms for control to 34.8 ± 2.1 ms (n = 5, P < 0.001). The effects of EPA on I_Na,α were reversible. Furthermore, docosahexaenoic acid (C22:6n-3), α-linolenic acid (C18:3n-3), conjugated linoleic acid (C18:2n-7), and oleic acid (C18:1n-9) at 5 μM and all-trans-retinoic acid at 10 μM had similar effects on I_Na,α as EPA. Even 5 μM of stearic acid (C18:0) or palmitic acid (C16:0) also significantly inhibited I_Na,α. In contrast, 5 μM EPA ethyl ester did not alter I_Na,α (8 ± 4%, n = 8, P > 0.05). The present data demonstrate that free fatty acids suppress I_Na,α with high “binding affinity” to hH1_α channels in the inactivated state and prolong the duration of recovery from inactivation.     

Specific binding of phorbol ester tumor promoters

[20-³H]Phorbol 12,13-dibutyrate bound to particulate preparations from chicken embryo fibroblasts in a specific, saturable, reversible fashion. Equilibrium binding occurred with a K_d of 25 nM; this value is very close to the 50% effective dose (ED₅₀), 50 nM, previously determined for the biological response (induction of fibronectin loss) in growing chicken embryo fibroblasts. At saturation, 1.4 pmol of [20-³H]phorbol 12,13-dibutyrate was bound per mg of protein (approximately 7 × 10⁴ molecules per cell). Binding was inhibited by phorbol 12-myristate 13-acetate (K_i = 2 nM), mezerein (K_i = 180 nM), phorbol 12,13-dibenzoate (K_i = 180 nM), phorbol 12,13-diacetate (K_i = 1.7 μM), phorbol 12,13,20-triacetate (K_i = 39 μM), and phorbol 13-acetate (K_i = 120 μM). The measured K_i values are all within a factor of 3.5 of the ED₅₀ values of these derivatives for inducing loss of fibronectin in intact cells. Binding was not inhibited by the inactive compounds phorbol (10 μg/ml) and 4α-phorbol 12,13-didecanoate (10 μg/ml) or by the inflammatory but nonpromoting phorbol-related diterpene esters resiniferatoxin (100 ng/ml) and 12-deoxyphorbol 13-isobutyrate 20-acetate (100 ng/ml). These data suggest that biological responses to the phorbol esters in chicken embryo fibroblasts are mediated by this binding activity and that the binding activity corresponds to the phorbol ester target in mouse skin involved in tumor promotion. Binding was not inhibited by the nonphorbol promoters anthralin (1 μM), phenol (1 mM), iodoacetic acid (1.7 μM), and cantharidin (75 μM), or by epidermal growth factor (100 ng/ml), dexamethasone acetate (2 μM), retinoic acid (10 μM), or prostaglandin E₂ (1 μM). These agents thus appear to act at a target distinct from that of the phorbol esters.     

Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY): A Randomized Trial

Background and objectives

The generation of key uremic nephrovascular toxins, indoxyl sulfate (IS), and p-cresyl sulfate (PCS), is attributed to the dysbiotic gut microbiota in CKD. The aim of our study was to evaluate whether synbiotic (pre- and probiotic) therapy alters the gut microbiota and reduces serum concentrations of microbiome–generated uremic toxins, IS and PCS, in patients with CKD.

Design, setting, participants, & measurements

Predialysis adult participants with CKD (eGFR=10–30 ml/min per 1.73 m²) were recruited between January 5, 2013 and November 12, 2013 to a randomized, double–blind, placebo–controlled, crossover trial of synbiotic therapy over 6 weeks (4-week washout). The primary outcome was serum IS. Secondary outcomes included serum PCS, stool microbiota profile, eGFR, proteinuria-albuminuria, urinary kidney injury molecule-1, serum inflammatory biomarkers (IL-1β, IL-6, IL-10, and TNF-α), serum oxidative stress biomarkers (F₂-isoprostanes and glutathione peroxidase), serum LPS, patient-reported health, Gastrointestinal Symptom Score, and dietary intake. A prespecified subgroup analysis explored the effect of antibiotic use on treatment effect.

Results

Of 37 individuals randomized (age =69±10 years old; 57% men; eGFR=24±8 ml/min per 1.73 m²), 31 completed the study. Synbiotic therapy did not significantly reduce serum IS (−2 μmol/L; 95% confidence interval [95% CI], −5 to 1 μmol/L) but did significantly reduce serum PCS (−14 μmol/L; 95% CI, −27 to −2 μmol/L). Decreases in both PCS and IS concentrations were more pronounced in patients who did not receive antibiotics during the study (n=21; serum PCS, −25 μmol/L; 95% CI, −38 to −12 μmol/L; serum IS, −5 μmol/L; 95% CI, −8 to −1 μmol/L). Synbiotics also altered the stool microbiome, particularly with enrichment of Bifidobacterium and depletion of Ruminococcaceae. Except for an increase in albuminuria of 38 mg/24 h (P=0.03) in the synbiotic arm, no changes were observed in the other secondary outcomes.

Conclusion

In patients with CKD, synbiotics did not significantly reduce serum IS but did decrease serum PCS and favorably modified the stool microbiome. Large–scale clinical trials are justified.     

Effects of non-steroidal anti-inflammatory drugs and prostaglandins on alkali secretion by rabbit gastric fundus in vitro

The effects of non-steroidal anti-inflammatory drugs and prostaglandins E₂ and F_2α on the secretory and electrical activity of isolated rabbit fundic mucosa have been studied. Spontaneous acid secretion was inhibited by serosal side application of sodium thiocyanate (6×10⁻²M) and the resulting alkali secretion measured by pH stat tiration. Serosal side application of indomethacin (10⁻⁵M) or aspirin (3×10⁻³M) inhibited alkali secretion (0·55±0·06 to 0·12±0·06 μmol/cm²/h, n=6, p<0·01 and 0·28±0·06 to 0·11±0·03 μmol/cm²/h, n=7, p<0·02 respectively). Mucosal or serosal side prostaglandin E₂ (10⁻⁵ to 10⁻¹⁰M) and F_2α (10⁻⁴ to 10⁻¹⁰M) failed to alter the rate of alkalinisation but secretion was significantly increased by serosal side 16,16-dimethyl-prostaglandin E₂ (10⁻⁶M) (0·90±0·20 to 1·50±0·30 μmol/cm²/h, n=6, p<0·01). Serosal side application of 10⁻⁶M prostaglandin E₂ to fundic mucosae pretreated with either aspirin (5×10⁻³M) or indomethacin (10⁻⁵M), to reduce endogenous E₂ formation, also failed to alter alkali secretion. Pretreatment of the mucosa with 16,16-dimethyl-E₂ (10⁻⁶M) abolished the inhibitory effect of indomethacin (10⁻⁵M) on alkali secretion (n=6) but did not modify the secretory response to aspirin (3×10⁻³M) (fall in alkali secretion with aspirin = 81±11% and with aspirin plus 16,16-dimethyl-E₂ = 72±10%, n=7). In the doses used, none of the prostaglandins or non-steroidal anti-inflammatory drugs altered transmucosal potential difference or electrical resistance. These results show that the damaging agents, aspirin and indomethacin, both inhibit gastric alkali secretion but that modes of action may differ. The observation that prostaglandins, E₂ and F_2α failed to increase alkali production suggests that their protective activity against a variety of damaging agents as shown by others, may be mediated by another mechanism.     

The effects of cyclooxygenase and nitric oxide synthase inhibition on cardiodynamic parameters and coronary flow in isolated rat hearts

BACKGROUND:

Despite the widespread clinical use of cyclooxygenase (COX) inhibitors, dilemmas regarding the potential impact of these drugs on the cardiovascular system persist.

OBJECTIVE:

To estimate the effects of different COX inhibitors (meloxicam, acetylsalicylic acid [ASA] and SC-560) on cardiac function and coronary flow in isolated rat hearts, with special focus on the L-arginine/nitric oxide system.

METHODS:

The hearts of eight-week-old male Wistar albino rats (n=72; 12 rats per group; body mass 180 g to 200 g) were retrogradely perfused according to the Langendorff technique at gradually increased perfusion pressure (40 cmH₂O to 120 cmH₂O). After control experiments, the hearts were perfused with the following drugs: 100 μM ASA, alone or in combination with 30 μM N(ω)-nitro-L-arginine monomethyl ester (L-NAME), 0.3 μM meloxicam with or without 30 μM L-NAME, 3 μM meloxicam with or without 30 μM L-NAME, 30 μM L-NAME and 0.25 μM SC-560. In the control and experimental groups, the following parameters of heart function were continuously recorded: maximum rate of left ventricular pressure development, minimum rate of left ventricular pressure development, systolic left ventricular pressure, diastolic left ventricular pressure, heart rate and mean blood pressure. Coronary flow was measured flowmetrically. The amount of released NO₂⁻ was determined spectrophotometrically in coronary venous effluent.

RESULTS:

While meloxicam and SC-560 were found to have an adverse influence on cardiac function and coronary perfusion, ASA did not negatively affect the intact model of the heart.

CONCLUSION:

It appeared that interaction between COX and the L-arginine/nitric oxide system truly exists in coronary circulation and may explain the causes of the observed effects.     

An attempt to distinguish between the actions of neuromuscular blocking drugs on the acetylcholine receptor and on its associated ionic channel

The effects of lobeline and tubocurarine on the voltage-clamped endplates of frog sartorius and cutaneous pectoris muscles were examined at room temperature (20-23°C). Like tubocurarine, lobeline causes nondepolarizing neuromuscular blockade. The half-time of decay (t_½) of endplate currents (e.p.c.s) recorded at a holding potential (V_m) of -90 mV was significantly shorter in endplates treated with lobeline (50 μM; mean t_½ ± SEM = 0.41 ± 0.02 ms) or tubocurarine (11.4 μM; t_½ = 0.64 ± 0.04 ms) than in those treated with Mg²⁺ (13 mM; t_½ = 1.39 ± 0.11 ms) or a low concentration of tubocurarine (3 μM; t_½ = 0.87 ± 0.05 ms). Similarly, lobeline (10 μM) shortened the t_½ of untreated miniature e.p.c.s by 35%; tubocurarine, however, abolished miniature e.p.c.s at the concentration required to observe its actions on e.p.c. decay kinetics. The t_½ of e.p.c.s recorded from preparations treated with Mg²⁺ (13 mM), tubocurarine at low concentrations (3 μM), or untreated miniature e.p.c.s was logarithmically related to V_m, being slower at more hyperpolarized values. By contrast, the t_½s of e.p.c.s recorded in either lobeline (50 μM) or tubocurarine (11.4 μM) were independent of voltage in the range -150 to -80 mV. The ability of lobeline to shorten t_½ and to remove the voltage dependence of t_½ was partially antagonized by Mg²⁺ (13 mM). As expected, when lobeline or tubocurarine was removed from the bath or when acetylcholine release from the motor nerve terminals was increased by 4-aminopyridine (20 μM) and Ca²⁺ (10 mM) (in the presence of lobeline or tubocurarine), the amplitude of e.p.c.s increased as a function of time. However, the t_½ of the decay phase of the e.p.c.s remained shortened (i.e., unaltered from the earlier treatment). These results suggest that both tubocurarine and lobeline have at least two distinct postjunctional actions including: (i) a block of the acetylcholine receptor and (ii) a block of the ionic channel associated with the acetylcholine receptor.     

Understanding the factors affecting the activation of alkane by Cp'Rh(CO)2 (Cp' = Cp or Cp*)

Fast time-resolved infrared spectroscopic measurements have allowed precise determination of the rates of activation of alkanes by Cp′Rh(CO) (Cp^′ = η⁵-C₅H₅ or η⁵-C₅Me₅). We have monitored the kinetics of C─H activation in solution at room temperature and determined how the change in rate of oxidative cleavage varies from methane to decane. The lifetime of CpRh(CO)(alkane) shows a nearly linear behavior with respect to the length of the alkane chain, whereas the related Cp*Rh(CO)(alkane) has clear oscillatory behavior upon changing the alkane. Coupled cluster and density functional theory calculations on these complexes, transition states, and intermediates provide the insight into the mechanism and barriers in order to develop a kinetic simulation of the experimental results. The observed behavior is a subtle interplay between the rates of activation and migration. Unexpectedly, the calculations predict that the most rapid process in these Cp′Rh(CO)(alkane) systems is the 1,3-migration along the alkane chain. The linear behavior in the observed lifetime of CpRh(CO)(alkane) results from a mechanism in which the next most rapid process is the activation of primary C─H bonds (─CH₃ groups), while the third key step in this system is 1,2-migration with a slightly slower rate. The oscillatory behavior in the lifetime of Cp*Rh(CO)(alkane) with respect to the alkane’s chain length follows from subtle interplay between more rapid migrations and less rapid primary C─H activation, with respect to CpRh(CO)(alkane), especially when the CH₃ group is near a gauche turn. This interplay results in the activation being controlled by the percentage of alkane conformers.     

Thermal Stability and Sublimation Pressures of Some Ruthenocene Compounds

We set out to study the use of a series of ruthenocenes as possible and promising sources for ruthenium and/or ruthenium oxide film formation.The thermal stability of a series of ruthenocenes, including (η⁵-C₅H₄R)(η⁵-C₅H₄R´)Ru (1), R = R´ = H (3), R = H, R´ = CH₂NMe₂ (5), R = H, R´= C(O)Me (6), R = R´ = C(O)Me (7), R = H, R´ = C(O)(CH₂)₃CO₂H (8), R = H, R´ = C(O)(CH₂)₂CO₂H (9), R = H, R´ = C(O)(CH₂)₃CO₂Me (10), R = H, R´= C(O)(CH₂)₂CO₂Me (11), R = R´ = SiMe₃), (η⁵-C₄H₃O-2,4-Me₂)₂Ru (2), and (η⁵-C₅H₅-2,4-Me₂)₂Ru (4) was studied by thermogravimetry. From these studies, it could be concluded that 1–4, 6 and 9–11 are the most thermally stable molecules. The sublimation pressure of these sandwich compounds was measured using a Knudsen cell. Among these, the compound 11 shows the highest vapor pressure.