Efficacy and safety of cetagliptin as monotherapy in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled phase 3 trial.

AIM: To assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor, cetagliptin, as monotherapy in Chinese patients with type 2 diabetes (T2D) and inadequate glycaemic control. MATERIALS AND METHODS: In total, 504 eligible patients with T2D were enrolled and randomized to cetagliptin 50 mg once daily, cetagliptin 100 mg once daily or placebo at a ratio of 2:2:1 for 24 weeks of double-blind treatment, then all patients received cetagliptin 100 mg once daily for 28 weeks of open-label treatment. The primary efficacy endpoint was the change in HbA1c level from baseline at week 24. RESULTS: After 24 weeks, HbA1c from baseline was significantly reduced with cetagliptin 50 mg (-1.08%) and cetagliptin 100 mg (-1.07%) compared with placebo (-0.35%). The placebo-subtracted HbA1c reduction was -0.72% with cetagliptin 50 mg and 100 mg. Patients with a baseline HbA1c of 8.5% or higher had a greater HbA1c reduction with cetagliptin than those patients with a baseline HbA1c of less than 8.5%. Both doses studied led to a significantly higher proportion of patients (42.3% with 100 mg and 45.0% with 50 mg) achieving an HbA1c of less than 7.0% compared with placebo (12.9%). Cetagliptin also significantly lowered fasting plasma glucose and 2-hour postmeal plasma glucose relative to placebo. The incidence of adverse experiences was similar between cetagliptin and placebo. No drug-related hypoglycaemia was reported. CONCLUSIONS: Cetagliptin monotherapy was effective and well tolerated in Chinese patients with T2D who had inadequate glycaemic control on exercise and diet.

Silenced CHOP protects pancreatic B-cell function by targeting peroxisome proliferator-activated receptor-γ coactivator-1α through nuclear factor-κB signaling pathway in diabetes mellitus.

AIMS: Diabetes mellitus (DM) is one of the most common metabolic diseases worldwide characterized by insulin resistance and pancreatic ß-cell dysfunction. In the previous study, endoplasmic reticulum (ER) stress could increase the C/EBP homologous protein (CHOP) expression through inhibiting C/EBß transcriptional activity. However, the role of CHOP and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in pancreatic ß-cell dysfunction remains unknown. The aim of the study was to investigate the effect of CHOP and PGC-1α in pancreatic ß-cell dysfunction and the potential mechanisms underlying its actions. METHODS: We established the pancreatic ß-cell dysfunction model to identify the biological features and functions of CHOP. Apoptosis was detected using Western blot analysis and real-time polymerase chain reaction (RT-PCR). RESULTS: Our results showed that high glucose (HG) increases CHOP and inhibits PGC-1α expression and ameliorates apoptosis in pancreatic ß cells. Silenced CHOP elevates the PGC-1α expression and ameliorates HG-induced apoptosis in pancreatic ß cells. Furthermore, upregulation of the PGC-1α alleviates HG-induced apoptosis in pancreatic ß cells. We also expounded that HG-activated phosphorylation of nuclear factor-κB through increasing PGC-1α expression. CONCLUSION: We verified the function and mechanism of CHOP and provide evidence that CHOP and PGC-1α may serve as potential candidates for the clinical treatment of DM.

Magnesia-stabilised zirconia solid electrolyte assisted electrochemical investigation of iron ions in a SiO2-CaO-MgO-Al2O3 molten slag at 1723 K.

Production of metallic iron through molten oxide electrolysis using inert electrodes is an alternative route for fast ironmaking without CO2 emissions. The fact that many inorganic oxides melt at ultrahigh temperatures (>1500 K) challenges conventional electro-analytical techniques used in aqueous, organic and molten salt electrolytes. However, in order to design a feasible and effective electrolytic process, it is necessary to best understand the electrochemical properties of iron ions in molten oxide electrolytes. In this work, a magnesia-stabilised zirconia (MSZ) tube with a closed end was used to construct an integrated three-electrode cell with a "MSZ|Pt|O2 (air)" assembly functioning as the solid electrolyte, the reference electrode and also the counter electrode. Electrochemical reduction of iron ions was systematically investigated on an iridium (Ir) wire working electrode in a SiO2-CaO-MgO-Al2O3 molten slag at 1723 K by cyclic voltammetry (CV), square wave voltammetry (SWV), chronopotentiometry (CP) and potentiostatic electrolysis (PE). The results show that the electroreduction of the Fe2+ ion to Fe on the Ir electrode in the molten slag follows a single two-electron transfer step, and the rate of the process is diffusion controlled. The peak current on the obtained CVs is proportional to the concentration of the Fe2+ ion in the molten slag and the square root of scan rate. The diffusion coefficient of Fe2+ ions in the molten slag containing 5 wt% FeO at 1723 K was derived to be (3.43 ± 0.06) × 10-6 cm2 s-1 from CP analysis. However, a couple of subsequent processes, i.e. alloy formation on the Ir electrode surface and interdiffusion, were found to affect the kinetics of iron deposition. An ECC mechanism is proposed to account for the CV observations. The findings from this work confirm that zirconia-based solid electrolytes can play an important role in electrochemical fundamental research in high temperature molten slag electrolytes.

Chronic Ca2+ imaging of cortical neurons with long-term expression of GCaMP-X.

Dynamic Ca2+ signals reflect acute changes in membrane excitability, and also mediate signaling cascades in chronic processes. In both cases, chronic Ca2+ imaging is often desired, but challenged by the cytotoxicity intrinsic to calmodulin (CaM)-based GCaMP, a series of genetically-encoded Ca2+ indicators that have been widely applied. Here, we demonstrate the performance of GCaMP-X in chronic Ca2+ imaging of cortical neurons, where GCaMP-X by design is to eliminate the unwanted interactions between the conventional GCaMP and endogenous (apo)CaM-binding proteins. By expressing in adult mice at high levels over an extended time frame, GCaMP-X showed less damage and improved performance in two-photon imaging of sensory (whisker-deflection) responses or spontaneous Ca2+ fluctuations, in comparison with GCaMP. Chronic Ca2+ imaging of one month or longer was conducted for cultured cortical neurons expressing GCaMP-X, unveiling that spontaneous/local Ca2+ transients progressively developed into autonomous/global Ca2+ oscillations. Along with the morphological indices of neurite length and soma size, the major metrics of oscillatory Ca2+, including rate, amplitude and synchrony were also examined. Dysregulations of both neuritogenesis and Ca2+ oscillations became discernible around 2-3 weeks after virus injection or drug induction to express GCaMP in newborn or mature neurons, which were exacerbated by stronger or prolonged expression of GCaMP. In contrast, neurons expressing GCaMP-X were significantly less damaged or perturbed, altogether highlighting the unique importance of oscillatory Ca2+ to neural development and neuronal health. In summary, GCaMP-X provides a viable solution for Ca2+ imaging applications involving long-time and/or high-level expression of Ca2+ probes.

[Changes of granulocyte distribution induced by thyroxin and epinephrine: experiment with rabbits].

OBJECTIVE: To investigate the distribution of granulocyte during thyrotoxicosis and the relation of granulopenia and the gathering of circulating granulocytes into the marginal pool. METHODS: Forty-five rabbits were randomly divided into 3 equal groups: epinephrine group fed with levo-thyroxin (LT4) for 14 days, injected subcutaneously with epinephrine 0.07 mg/kg, and undergoing collection of peripheral blood samples for white blood cell and granulocyte counts, free blood triiodothyroxine (FT3) and free blood thyroxine (FT4), electrocardiography, and body weight measurement; labeled group fed with LT4 for 14 days, injected subcutaneously with 131I-labeled anti-human granulocyte monoclonal antibody, and killed 6 hours later to calculate the ratio of radioactivity of heart, liver, spleen, and muscle tissues to blood (CPM/g), and control group, not fed with L-T4 but injected with 131I-labeled anti-human granulocyte monoclonal antibody on the day 14, and killed 6 hours later to calculate the ratio of radioactivity of tissues to blood. RESULTS: After 14-day feeding of L-T4, the heart rates of the epinephrine and labeled groups were significantly higher than those before injection, and the FT3 and FT4 levels were significantly increased;the venous WBC and granulocyte counts were significantly reduced. But the granulocyte count of 13 of the 15 rabbits in the epinephrine group increased 20 minutes after the injection of epinephrine, even becoming 2-4.8 times as high as those before the injection in 7 rabbits. The heart, liver, spleen, and muscle tissues to blood CPM/g ratios of the labeled group were all significantly higher than those of the control group (all P<0.01). CONCLUSION: During thyrotoxicosis the circulating granulocytes are reduced and the distribution of circulating granulocytes is abnormal with a gathering phenomenon of the granulocytes into the marginal pool.