RESUMEN
AIM: Nocturia impairs the quality of life in patients with type 2 diabetes mellitus. Although sodium glucose co-transporter 2 inhibitors (SGLT2i) such as tofogliflozin increase urine volume, their impact on nocturia, in conjunction with dietary salt restriction, is less clear. MATERIALS AND METHODS: This multicenter, open-label, randomized, parallel-group trial included 80 subjects with type 2 diabetes and nocturia. The patients were divided into two groups: one receiving tofogliflozin, the shortest half-life, without salt restriction, and the other receiving both tofogliflozin and dietary salt restriction. The primary endpoint was nocturia frequency at 12 weeks. The secondary outcomes included changes in daytime urination frequency, urine volume, and home blood pressure. RESULTS: At 12 weeks, there were no significant differences in nocturia changes between both groups. Nocturia frequency did not change in the tofogliflozin without salt restriction group from 1.5 ± 0.8 to 1.3 ± 1.1 times per night (P = 0.297), and significantly decreased from 1.6 ± 1.0 to 1.3 ± 0.7 times per night in the tofogliflozin and dietary salt restriction group (P = 0.049). There was a trend toward increased urine volume and frequency during the daytime in the group with salt restriction, indicating a time-shift effect of the short half-life tofogliflozin and salt restriction on urinary time. CONCLUSIONS: The frequency of nocturia after tofogliflozin did not increase. Tofogliflozin reduced nocturia when combined with salt restriction. Furthermore, daytime urine volume and frequency showed an increasing trend, suggesting a shift in urine production to daytime hours due to the short half-life of tofogliflozin. Dietary modifications can enhance the therapeutic benefits of tofogliflozin in managing nocturia in people with type 2 diabetes.
RESUMEN
The discovery of polypyrazolylborate ligands allowed the development of various chemical fields and these ligands are an alternative to cyclopentadienyl, because both ligands have the same charge and donate the same number of electrons, as well as adopting the same facial geometry. Easy control of the bulkiness of polypyrazolylborate ligands is possible by modification of the substituents in the 3- and 5-positions of the pyrazolyl rings. The title complex, bis[tetrakis(3-methyl-1H-pyrazol-1-yl)borato]samarium(II), [Sm(C16H20BN8)2], was synthesized from the reaction of SmI2 with potassium tetrakis(3-methyl-1H-pyrazol-1-yl)borate, denoted K[B(3-Mepz)4], in tetrahydrofuran. The X-ray structure analysis revealed an unusual side-on coordination mode of a 3-methylpyrazolyl group through an N=N group in the B(3-Mepz)4 ligand. The distortion is defined by the B-N-N-Sm torsion angle [85.5â (4)°]. This is in contrast to the structure of the similar divalent samarium complex [Sm(TpMe2 is tris(3,5-dimethylpyrazol-1-yl)borate], which displays normal κ3-bonding modes of the TpMe2 ligands.
RESUMEN
Heteropolynuclear Pt(II) complexes with 3,5-diphenylpyrazolate [Pt(2)Ag(4)(µ-Cl)(2)(µ-Ph(2)pz)(6)] (3), [Pt(2)Ag(2)Cl(2)(µ-Ph(2)pz)(4)(Ph(2)pzH)(2)] (4), [Pt(2)Cu(2)Cl(2)(µ-Ph(2)pz)(4)(Ph(2)pzH)(2)] (5), [Pt(2)Ag(4)(µ-Cl)(µ-Me(2)pz)(µ-Ph(2)pz)(6)] (7), and [Pt(2)Ag(4)(µ-Me(2)pz)(2)(µ-Ph(2)pz)(6)] (8) have been prepared and structurally characterized. These complexes are luminescent except for 5 in the solid state at an ambient temperature with emissions of red-orange (3), orange (4), yellow-orange (7), and green (8) light, respectively. Systematic red shift of the emission energies with the number of chloride ligands was observed for 3, 7, and 8. DFT calculations indicate that the highest occupied molecular orbital (HOMO) as well as HOMO-1 of the heterohexanuclear complexes, 3, 7, and 8, having Pt(2)Ag(4) core, mainly consist of dδ orbital of Pt(II) and π orbitals of Ph(2)pz ligands, while the lowest unoccupied molecular orbital (LUMO) of these complexes mainly consists of in-phase combination of 6p of two Pt(II) centers and 5p of four Ag(I) centers. It is likely that the emissions of 3, 7, and 8 are attributed to emissive states derived from the Pt(2)(d)/π â Pt(2)Ag(4) transitions, the emission energy of which depends on the ratio of chloride ligands to pyrazolate ligands.
RESUMEN
Diastereomeric geminate pairs of chiral bis(2-oxazoline) ruthenium complexes with bipyridyl-type N-heteroaromatics, Λ- and Δ-[Ru(L-L)(2)(iPr-biox)](2+) (iPr-biox=(4S,4'S)-4,4'-diisopropyl-2,2'-bis(2-oxazoline); L-L=2,2'-bipyridyl (bpy) for 1Λ and 1Δ, 4,4'-dimethyl-2,2'-bipyridyl (dmbpy) for 2Λ and 2Δ, and 1,10-phenanthroline (phen) for 3Λ and 3Δ), were separated as BF(4) and PF(6) salts and were subjected to the comparative studies of their stereochemical and photochemical characterization. DFT calculations of 1Λ and 1Δ electronic configurations for the lowest triplet excited state revealed that their MO-149 (HOMO) and MO-150 (lower SOMO) characters are interchanged between them and that the phosphorescence-emissive states are an admixture of a Ru-to-biox charge-transfer state and an intraligand excited state within the iPr-biox. Furthermore, photoluminescence properties of the two Λ,Δ-diastereomeric series are discussed with reference to [Ru(bpy)(3)](2+).
RESUMEN
The hydroxido-bridged dinuclear ruthenium complex 4, which is supported by Tp ligands, has been prepared from protonation of the oxido-bridged dinuclear ruthenium complex 3. Additional protonation of 4, affording the aqua-bridged dinuclear ruthenium complex 5 in situ, and subsequent treatment with NO gave rise to the dicationic dinitrosyl complex 2. These indicate completion of the NO reduction cycle on the dinuclear ruthenium complex.
Asunto(s)
Complejos de Coordinación/química , Óxido Nítrico/química , Compuestos Organometálicos/química , Protones , Rutenio/química , Cationes/química , Ligandos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Oxidación-ReducciónRESUMEN
Vinylidene ruthenium complexes were prepared from trichloronitrosylbis(phosphine)rutheniums and terminal alkynes, subsequent cycloaddition of methyl propiolate to the vinylidene complexes giving rise to unusual ruthenacyclobutene species; in these transformations, an interesting electrostructurally-flexible behaviour of the NO ligand was observed.
RESUMEN
Swap the coins! The Pt(2)Au(2), Pt(2)Au(2)Cu(2), and Pt(2)Au(2)Ag(2) complexes of 3,5-dimethylpyrazolate exhibit yellow-green, orange, and sky-blue luminescence, respectively (see figure). The emission energies of Pt(2)Au(2)M(2) complexes can be controlled by the change of the third coinage metal ions M. The Pt(2)Au(2)M(2) complexes take the cis configuration with respect to the Au(2)M(2) plane.
RESUMEN
The N-C coupling of ligating NO with 2-vinylpyridines, affording nitrosovinyl complexes, was found. This is of significance since the reaction process involves a C-H activation of the vinyl moiety and subsequent C-N bond formation. Furthermore, we show that the resulting nitrosovinyl complexes are chemically versatile and potentially valuable species. Protonation of the resulting nitrosovinyl complexes in refluxing alcohol afforded the alcohol-incorporated complexes, as well as the ketoimine species. It is interesting to note that a proton-induced reaction with PPh3 trapped their intermediates, leading to the explication of these reaction mechanisms.
RESUMEN
The platinum dimer and heteropolynuclear platinum complexes of 3,5-dimethylpyrazolate, [Pt2M4(mu-Me2pz)8] [M = H (1), Ag (2), Cu (3)], were synthesized and structurally characterized. They exhibit yellow, sky-blue, and orange luminescence, respectively, in the solid state. The absorption bands of 2 and 3 are mainly assigned to the combination of the metal-metal-to-ligand charge-transfer and [Pt2 --> Pt2M4] transitions by the time-dependent density functional theory (DFT) method. DFT calculations also indicate that the emissive states of 2 and 3 are 3[Pt2 --> Pt2Ag4] and 3[Cu(d) --> Pt2Cu4], respectively.
RESUMEN
Symmetrically disubstituted bis(3-hydroxyalkynyl) complex [TpRu{C[triple chemical bond]CCPh(2)(OH)}(2)(NO)] (1) (Tp = BH(pyrazol-1-yl)(3)) and unsymmetrically mixed (arylalkynyl)(3-hydroxyalkynyl) congener [TpRu(C[triple chemical bond]CC(6)H(4)Me){C[triple chemical bond]CCPh(2)(OH)}(NO)] (2) were newly prepared. Treatment of 1 or 2 with p-toluenesulfonic acid monohydrate was carried out to give unusual four-membered metallacyclic complexes [TpRu{C(=C=CPh(2))C(O)C(=CPh(2))}(NO)] (3) and [TpRu{C(=C=CPh(2))C(O)CH(C(6)H(4)Me)}(NO)] (5), respectively, as major products. Formation mechanism of 3 and 5 would involve insertion of the generated allenylidene group (Ru=C=C=CPh(2)) into the other Ru--C(alkynyl) bond, followed by hydration of the resulting alpha-alkynyl--allenyl fragment. With regards to the chemical reactivity of their four-membered metallacycles, treatment with aq. HCl in MeOH afforded the ring-opened one-HCl adducts, [TpRuCl{C(=C=CPh(2))C(O)CH=CPh(2)}(NO)] (7) and [TpRuCl{C(=C=CPh(2))C(O)CH(2)(C(6)H(4)Me)}(NO)] (8). On the other hand, the use of CH(2)Cl(2) and THF as the reaction solvent gave another type of one-HCl adducts [TpRu{CH(C(Cl)=CPh(2))C(O)C(==CPh(2))}(NO)] (9 a/9 b) and [TpRu{CH(C(Cl)=CPh(2))C(O)CH(C(6)H(4)Me)}(NO)] (11 a/11 b) as diastereomeric pairs, still retaining the four-membered ring structure. Moreover, their kinetically controlled products 9 b and 11 b were treated with aq. HCl to afford the ring-opened two-HCl adducts [TpRuCl{C(C(Cl)=CPh(2))(H)C(O)CH=CPh(2)}(NO)] (10) and [TpRuCl{CH(C(6)H(4)Me)C(O)CH(2)(C(Cl)=CPh(2))}(NO)] (12), respectively. In 10 and 12, each one Ru--C bond is cleaved at mutually different positions in the ring. Protonation on the carbonyl group would trigger the formation of 7-12.
RESUMEN
The oxidation of the pyrazolate bridged cyclic PtII trimer, [Pt3(mu-pz)6] (1), in the presence of bromide ion gave a deep blue mixed-valent Pt(II,III,III) complex, [Pt3Br2(mu-pz)6] (2). The structural analysis of 2 disclosed that the complex has localized Pt--Pt bond. Our theoretical calculations revealed that the HOMO and LUMO of Pt3 (II,III,III) species mainly consists of (dsigma-dsigma) and (dsigma-dsigma)* orbitals, respectively, and the origin of deep blue color of the bromo complex, 2, arises from the (dsigma-dsigma)-->(dsigma-dsigma)* transition. Unique fluxional behavior was observed due to valence-detrapping of 2 in solution. The activation parameters of the valence-detrapping of 2 obtained by Eyring analyses were DeltaH(not equal)=37(2) kJ mol(-1) and DeltaS(not equal)=-67(7) J mol(-1) K(-1).
RESUMEN
The heteropolynuclear complexes [Pd(2)M'(2)(mu-pz)(6)] (M'=Ag (1), Au (2); pzH=pyrazole), HT-[Pd(2)M'(2)(mu-3-tBupz)(6)] (M'=Ag (3 a), Au (4 a); 3-tBupzH=3-tert-butylpyrazole), and HH-[Pd(2)Au(2)(mu-3-tBupz)(6)] (4 b) have been prepared and some of them were structurally characterized. When 3-tert-butylpyrazolate was employed as a bridging ligand, two linkage isomers (head-to-tail (HT) and head-to-head (HH)) arise from the difference in orientation of the substituent groups on the pyrazolate bridges between the two Pd atoms. (1)H NMR spectroscopy has been used to identify and to follow the reversible stereochemical rearrangement of the HH isomer of [Pd(2)Ag(2)(mu-3-tBupz)(6)] (3 b) to form the HT isomer 3 a in CDCl(3) and the HT isomer of [Pd(2)Au(2)(mu-3-tBupz)(6)] (4 a) to form the HH isomer 4 b in C(6)D(6). Kinetic studies of the reaction have established the rate law to be -d(HH)/dt=d(HT)/dt=k(2)[HH]-k(1)[HT] for 3 b and -d(HT)/dt=d(HH)/dt=k(1)[HT]-k(2)[HH] for 4 a, where k(1) and k(2) denote the rate of isomerization from the HT to the HH isomer and that from the HH to the HT isomer, respectively. For typical runs at 50 degrees C in C(6)D(6), k(1)=13.8x10(-5) s(-1), k(2)=18.6x10(-5) s(-1), and K(eq)=k(2)/k(1)=1.24 for 3 b, and k(1)=1.26x10(-5) s(-1), k(2)=3.52x10(-5) s(-1), and K(eq)=k(1)/k(2)=0.36 for 4 a. Temperature-dependent rate measurements reveal DeltaH(not equal) and DeltaS(not equal) to be 100(1) kJ mol(-1) and 0(3) J mol(-1) K(-1) for 3 b and 112(5) kJ mol(-1) and 20(17) J mol(-1) K(-1) for 4 a, respectively. The rate of isomerization is essentially unaffected by the concentration of the complex or by the presence of neutral bridging ligands. These data and observations imply that the isomerization involves an intramolecular exchange process.
RESUMEN
Recently we cloned the Hanp1 cDNA that encodes a histone H1-like haploid germ cell-specific nuclear protein in the mouse. Homozygous Hanp1 mutant male mice were infertile, while females were fertile. Although a substantial number of sperm were recovered from the epididymis, their shape and function were abnormal. Hanp1 protein is essential for nuclear formation in functional spermatozoa, and is specifically involved in the replacement of histones with protamines during spermiogenesis. To investigate the roles of human HANP1 (h-HANP1) and its relation to male infertility, we isolated h-HANP1 cDNA from a human cDNA plasmid library using mouse Hanp1 cDNA as a probe. h-HANP1 is expressed in the testes and its genomic construct also intronless as mouse Hanp1. We found that the h-HANP1 coding region have 5 single-nucleotide polymorphisms in Japanese men.
Asunto(s)
Núcleo Celular/metabolismo , Histonas/genética , Polimorfismo de Nucleótido Simple , Testículo/metabolismo , Secuencia de Aminoácidos , Secuencia de Bases , Estudios de Casos y Controles , Línea Celular , Expresión Génica , Histonas/química , Histonas/metabolismo , Humanos , Infertilidad Masculina/genética , Masculino , Datos de Secuencia Molecular , ARN Mensajero/metabolismo , Homología de Secuencia , Distribución Tisular , Transcripción Genética , TransfecciónRESUMEN
We retrospectively investigated the effects of adding glimepiride in patients with type 2 diabetes showing suboptimal control by insulin therapy. Of 63 patients with poorly controlled insulin-treated type 2 diabetes (baseline HbA1c, 8.4 +/- 0.6%), 32 were treated with insulin alone and 31 were given glimepiride in addition to insulin. HbA1c values, daily insulin dose, body weight, blood pressure, plasma lipid concentrations, and the number of hypoglycemic events were recorded at weeks 0, 12, 24, 36, 48, 60, and 72. HbA1c decreased by 1.1%, from 8.5 +/- 0.6% to 7.4 +/- 0.8% (P<0.0001) in patients treated with insulin plus glimepiride at 12 weeks, and improved glycemic control continued throughout the study. Required insulin dose was reduced significantly in patients treated with insulin plus glimepiride (from 29.4 +/- 14.5 to 22.3 +/- 12.1 units/day, P = 0.0187). Body weight increased significantly in patients treated with insulin plus glimepiride (from 57.0 +/- 8.7 to 59.5 +/- 9.2 kg, P = 0.0232). Adding glimepiride showed little effect on blood pressure, plasma total cholesterol, triglyceride, or HDL-cholesterol. Serum C peptide concentrations increased significantly in patients treated with insulin plus glimepiride (from 1.01 +/- 0.71 to 1.28 +/- 0.65 ng/ml, P = 0.0367). The number of hypoglycemic events did not differ between groups. Adding glimepiride to insulin therapy resulted in sustained improvement of glycemic control in patients with poorly controlled type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insulina/uso terapéutico , Compuestos de Sulfonilurea/uso terapéutico , Anciano , Glucemia/metabolismo , Péptido C/sangre , Quimioterapia Combinada , Femenino , Hemoglobina Glucada/análisis , Humanos , Insulina/administración & dosificación , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
We cloned a testis-specific cDNA from mice that encodes a histone H1-like, haploid germ cell-specific nuclear protein designated HANP1/H1T2. The HANP1/H1T2 protein was specifically localized to the nuclei of murine spermatids during differentiation steps 5 to 13 but not to the nuclei of mature sperm. HANP1/H1T2 contains an arginine-serine-rich domain and an ATP/GTP binding site, and it binds to DNA, ATP, and protamine. To investigate the physiological role of HANP1/H1T2, we generated Hanp1/H1T2-disrupted mutant mice. Homozygous Hanp1/H1T2 mutant males were infertile, but females were fertile. Although a substantial number of sperm were recovered from the epididymides, their shape and function were abnormal. During sperm morphogenesis, the formation of nuclei was disturbed and protamine-1 and -2 were only weakly detectable in the nuclei. The chromatin packaging was aberrant, as demonstrated by electron microscopy and biochemical analysis. The mutant sperm exhibited deficient motility and were not competent to fertilize eggs under in vitro fertilization conditions; however, they were capable of fertilizing eggs via intracytoplasmic sperm injection that resulted in the birth of healthy progeny. Thus, we found that HANP1/H1T2 is essential for nuclear formation in functional spermatozoa and is specifically involved in the replacement of histones with protamines during spermiogenesis. At the time of submission of the manuscript, we found an independent publication by Martianov et al. (I. Martianov, S. Brancorsini, R. Catena, A. Gansmuller, N. Kotaja, M. Parvinen, P. Sassone-Corsi, and I. Davidson, Proc. Natl. Acad. Sci. USA 102:2808-2813, 2005) that reported similar results.
Asunto(s)
Núcleo Celular/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/fisiología , Fertilidad , Histonas/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Espermatozoides/metabolismo , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Secuencia de Aminoácidos , Animales , Arginina/química , Secuencia de Bases , Sitios de Unión , Diferenciación Celular , Cromatina/metabolismo , ADN/metabolismo , ADN Complementario/metabolismo , Proteínas de Unión al ADN/química , Relación Dosis-Respuesta a Droga , Epidídimo/metabolismo , Femenino , Fertilización , Vectores Genéticos , Guanosina Trifosfato/química , Haploidia , Heterocigoto , Homocigoto , Masculino , Ratones , Ratones Noqueados , Microscopía Electrónica , Modelos Genéticos , Datos de Secuencia Molecular , Mutación , Proteínas Nucleares/química , Filogenia , Protaminas/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Homología de Secuencia de Aminoácido , Espermátides/metabolismo , Testículo/metabolismo , Factores de Tiempo , Distribución TisularRESUMEN
Promoters, including neither TATA box nor initiator, have been frequently found in testicular germ cell-specific genes in mice. These investigations imply that unique forms of the polymerase II transcription initiation machinery play a role in selective activation of germ cell-specific gene expression programs during spermatogenesis. However, there is little information about testis-specific core promoters, because useful germ cell culture system is not available. In this study, we characterize the regulatory region of the haploid-specific Oxct2b gene in detail by using in vivo transient transfection assay in combination with a transgenic approach, with electrophoretic mobility shift and chromatin immunoprecipitation assays. Expression studies using mutant constructs demonstrate that a 34 bp region, which extends from -49 to -16, acts as a core promoter in an orientation-dependent manner. This promoter region includes the cAMP-responsive element (CRE)-like sequence TGACGCAG, but contains no other motifs, such as a TATA box or initiator. The CRE-like element is indispensable for the core promoter activity, but not for activator in testicular germ cells, through the binding of a testis-specific CRE modulator transcription factor. These results indicate the presence of alternative transcriptional initiation machinery for cell-type-specific gene expression in testicular germ cells.
Asunto(s)
Coenzima A Transferasas/genética , Proteínas de Unión al ADN/metabolismo , Regiones Promotoras Genéticas , Elementos de Respuesta , Testículo/metabolismo , Factores de Transcripción/metabolismo , Región de Flanqueo 5' , Animales , Secuencia de Bases , Sitios de Unión , Coenzima A Transferasas/biosíntesis , AMP Cíclico/metabolismo , Modulador del Elemento de Respuesta al AMP Cíclico , Electroporación , Haploidia , Masculino , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Alineación de Secuencia , Espermátides/metabolismo , TATA Box , Transcripción Genética , TransfecciónRESUMEN
A nitrosylruthenium alkynyl complex of TpRuCl(C[triple bond]CPh)(NO)(1a) was reacted with PPh3 in the presence of HBF4.Et2O at room temperature to give a beta-phosphonio-alkenyl complex (E)-[TpRuCl{CH=C(PPh3)Ph}(NO)]BF4(2.BF4). On the other hand, for gamma-hydroxyalkynyl complexes TpRuCl{C[triple bond]CC(R)2OH}(NO)(R = Me (1b), Ph (1c), H (1d)), similar treatments with PPh3 were found to give gamma-phosphonio-alkynyl [TpRuCl{C[triple bond]CC(Me)2PPh3}(NO)]BF4(3.BF4),alpha-phosphonio-allenyl [TpRuCl{C(PPh3)=C=CPh2}(NO)]BF4(4.BF4), and a novel product of gamma-hydroxy-beta-phosphonio-alkenyl (E)-[TpRuCl{CH=C(PPh3)CH2OH}(NO)]BF4(5.BF4), respectively. Dominant factors for the selectivity in affording 3-5 were associated with the steric congestion and electronic properties at the gamma-carbons, along with those around the metal fragment. From the bis(alkynyl) complex TpRu(C[triple bond]CPh)2(NO)6, a bis(beta-phosphonio-alkenyl)(E,E)-[TpRu{CH=C(PPh3)Ph}2(NO)](BF4)2{7.(BF4)2} was produced at room temperature. However, similar reactions at 0 degrees C gave an alkynyl beta-phosphonio-alkenyl complex (E)-[TpRu(C[triple bondCPh){CH=C(PPh3)Ph}(NO)]BF4(8.BF4) as a sole product, of which additional hydration in the presence of HBF4.Et2O afforded a [small beta]-phosphonio-alkenyl ketonyl (E)-[TpRu{CH2C(O)Ph}{CH=C(PPh3)Ph}(NO)]BF(.9BF4). Five complexes, 2-5 and 7 were crystallographically characterized.