Effect of Saxagliptin on Endothelial Function in Patients with Type 2 Diabetes : A Prospective Multicenter Study

The dipeptidyl peptidase-4 inhibitor saxagliptin is a widely used antihyperglycemic agent in patients with type 2 diabetes. The purpose of this study was to evaluate the effects of saxagliptin on endothelial function in patients with type 2 diabetes. This was a prospective, multicenter, interventional study. A total of 34 patients with type 2 diabetes were enrolled at four university hospitals in Japan. Treatment of patients was initially started with saxagliptin at a dose of 5 mg daily. Assessment of endothelial function assessed by flow-mediated vasodilation (FMD) and measurement of stromal cell-derived factor-1α (SDF-1α) were conducted at baseline and at 3 months after treatment with saxagliptin. A total of 31 patients with type 2 diabetes were included in the analysis. Saxagliptin significantly increased FMD from 3.1 ± 3.1% to 4.2 ± 2.4% (P = 0.032) and significantly decreased total cholesterol from 190 ± 24 mg/dL to 181 ± 25 mg/dL (P = 0.002), glucose from 160 ± 53 mg/dL to 133 ± 25 mg/dL (P < 0.001), HbA1c from 7.5 ± 0.6% to 7.0 ± 0.6% (P < 0.001), urine albumin-to-creatinine ratio from 63.8 ± 134.2 mg/g to 40.9 ± 83.0 mg/g (P = 0.043), and total SDF-1α from 2108 ± 243 pg/mL to 1284 ± 345 pg/mL (P < 0.001). These findings suggest that saxagliptin is effective for improving endothelial function

EGUIDE project and treatment guidelines

Aim: Although treatment guidelines for pharmacological therapy for schizophrenia and major depressive disorder have been issued by the Japanese Societies of Neuropsychopharmacology and Mood Disorders, these guidelines have not been well applied by psychiatrists throughout the nation. To address this issue, we developed the ‘Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE)’ integrated education programs for psychiatrists to disseminate the clinical guidelines. Additionally, we conducted a systematic efficacy evaluation of the programs. Methods: Four hundred thirteen out of 461 psychiatrists attended two 1‐day educational programs based on the treatment guidelines for schizophrenia and major depressive disorder from October 2016 to March 2018. We measured the participants’ clinical knowledge of the treatment guidelines using self‐completed questionnaires administered before and after the program to assess the effectiveness of the programs for improving knowledge. We also examined the relation between the participants’ demographics and their clinical knowledge scores. Results: The clinical knowledge scores for both guidelines were significantly improved after the program. There was no correlation between clinical knowledge and participant demographics for the program on schizophrenia; however, a weak positive correlation was found between clinical knowledge and the years of professional experience for the program on major depressive disorder. Conclusion: Our results provide evidence that educational programs on the clinical practices recommended in guidelines for schizophrenia and major depressive disorder might effectively improve participants’ clinical knowledge of the guidelines. These data are encouraging to facilitate the standardization of clinical practices for psychiatric disorders

Monitoring Thermoresponsive Morphological Changes in Individual Hydrogel Microspheres

Real-time morphology/structure changes in individual hydrogel microspheres (microgels) were directly visualized at high spatiotemporal resolution using high-speed atomic force microscopy (HS-AFM) under temperature control ranging from room temperature to ∼40 °C. The recorded HS-AFM movies demonstrate that the size and morphology of thermoresponsive poly­(N-isopropyl acrylamide)-based microgels change with increasing temperature at the individual microgel level. Specifically, the height of the microgels gradually decreases and domain structures appeared even below the volume phase transition temperature. Moreover, the domain structure is retained, even after the microgels have fully collapsed. The present study thus demonstrates that temperature-controlled HS-AFM is a useful tool for monitoring stimulus-responsiveness of microgels. In the near future, it should furthermore be possible to extend this temperature-controlled HS-AFM to other stimulus-responsive materials, including autonomously oscillating microgels

Unique coupling of mono- and dioxygenase chemistries in a single active site promotes heme degradation

Bacterial pathogens must acquire host iron for survival and colonization. Because free iron is restricted in the host, numerous pathogens have evolved to overcome this limitation by using a family of monooxygenases that mediate the oxidative cleavage of heme into biliverdin, carbon monoxide, and iron. However, the etiological agent of tuberculosis, Mycobacterium tuberculosis, accomplishes this task without generating carbon monoxide, which potentially induces its latent state. Here we show that this unusual heme degradation reaction proceeds through sequential mono- and dioxygenation events within the single active center of MhuD, a mechanism unparalleled in enzyme catalysis. A key intermediate of the MhuD reaction is found to be meso-hydroxyheme, which reacts with O2 at an unusual position to completely suppress its monooxygenation but to allow ring cleavage through dioxygenation. This mechanistic change, possibly due to heavy steric deformation of hydroxyheme, rationally explains the unique heme catabolites of MhuD. Coexistence of mechanistically distinct functions is a previously unidentified strategy to expand the physiological outcome of enzymes, and may be applied to engineer unique biocatalysts

Prediction of dynamic allostery for the transmembrane domain of the sweet taste receptor subunit, TAS1R3

Molecular dynamics simulations and functional assays of the transmembrane domain of the sweet taste receptor subunit, TAS1R3 reveal mechanisms on the allostery of sweet receptor activation or inactivation and pH-dependent sensitivity to saccharin

Heme Degradation by <i>Staphylococcus aureus</i> IsdG and IsdI Liberates Formaldehyde Rather Than Carbon Monoxide

IsdG and IsdI from <i>Staphylococcus aureus</i> are novel heme-degrading enzymes containing unusually nonplanar (ruffled) heme. While canonical heme-degrading enzymes, heme oxygenases, catalyze heme degradation coupled with the release of CO, in this study we demonstrate that the primary C1 product of the <i>S. aureus</i> enzymes is formaldehyde. This finding clearly reveals that both IsdG and IsdI degrade heme by an unusual mechanism distinct from the well-characterized heme oxygenase mechanism as recently proposed for MhuD from <i>Mycobacterium tuberculosis</i>. We conclude that heme ruffling is critical for the drastic mechanistic change for these novel bacterial enzymes

Small-Angle X‑ray Scattering Study on Internal Microscopic Structures of Poly(<i>N</i>‑isopropylacrylamide-<i>co</i>-tris(2,2′-bipyridyl))ruthenium(II) Complex Microgels

Internal microscopic structures of poly­(<i>N</i>-isopropylacrylamide-<i>co</i>-tris­(2,2′-bipyridyl))­ruthenium­(II) complex microgels were investigated using small-angle X-ray scattering (SAXS) in the extended <i>q</i>-range of 0.07 ≤ <i>q</i>/nm^–1 ≤ 20. The microgels were prepared by aqueous free-radical precipitation polymerization, resulting in formation of monodispersed, submicrometer-sized microgels, which was confirmed by transmission electron microscopy and dynamic light scattering. To reveal the changes in the microscopic structures of the microgels during swelling/deswelling or dispersing/flocculating oscillation, the redox state of Ru­(bpy)₃ complexes was fixed in the microgels using Ce­(IV) or Ce­(III) ions under high ionic strength (1.5 M) during the SAXS measurements. The scattering intensity of the microgels manifested five different structural features. In particular, the correlation length (ξ), which was obtained from the fitting analysis using the Ornstein–Zernike equation, of the microgels both in the reduced and oxidized Ru­(bpy)₃ states exhibited divergent-like behavior. In addition, a low-<i>q</i> peak centered at <i>q</i> ≈ 5 nm^–1 did not appear clearly in both the reduced [Ru­(bpy)₃]²⁺ and oxidized [Ru­(bpy)₃]³⁺ states, indicating that the formation of a polymer-rich domain was suppressed; thus, Ru­(bpy)₃ complexes can be active even though the microgels are deswollen or flocculated during the oscillation reaction

Self-Organization of Soft Hydrogel Microspheres during the Evaporation of Aqueous Droplets

The unique drying behavior of aqueous droplets that contain soft hydrogel microspheres (microgels) upon evaporation was systematically investigated. Compared to the ring-shaped deposits that are obtained from drying solid microsphere dispersions, we have previously reported that uniformly ordered thin films are obtained from drying ∼1.2 μm-sized poly­(<i>N</i>-isopropyl acrylamide) microgel dispersions. In the present study, we thoroughly investigated several hitherto unexplored aspects of this self-organization, such as the effect of the size, chemical structure, and “softness” of the microgels (or rigid microspheres). For the macro- and microscopic observation of the drying behavior of various microsphere dispersions, an optical microscope and a digital camera were employed. The results suggested that the convection in the aqueous droplets plays an important role for the transportation of the microgels to the air/water interface, where the softness and surface activity of the microgels strongly affects the adsorption of the microgels. On the basis of these discoveries, a design concept for the rapid formation of uniform thin films of soft microgels was proposed

Self-Organization of Soft Hydrogel Microspheres during the Evaporation of Aqueous Droplets

The unique drying behavior of aqueous droplets that contain soft hydrogel microspheres (microgels) upon evaporation was systematically investigated. Compared to the ring-shaped deposits that are obtained from drying solid microsphere dispersions, we have previously reported that uniformly ordered thin films are obtained from drying ∼1.2 μm-sized poly­(<i>N</i>-isopropyl acrylamide) microgel dispersions. In the present study, we thoroughly investigated several hitherto unexplored aspects of this self-organization, such as the effect of the size, chemical structure, and “softness” of the microgels (or rigid microspheres). For the macro- and microscopic observation of the drying behavior of various microsphere dispersions, an optical microscope and a digital camera were employed. The results suggested that the convection in the aqueous droplets plays an important role for the transportation of the microgels to the air/water interface, where the softness and surface activity of the microgels strongly affects the adsorption of the microgels. On the basis of these discoveries, a design concept for the rapid formation of uniform thin films of soft microgels was proposed