Efficacy of Additional Canagliflozin Administration to Type 2 Diabetes Patients Receiving Insulin Therapy: Examination of Diurnal Glycemic Patterns Using Continuous Glucose Monitoring (CGM)

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Probucol attenuates hyperoxia-induced lung injury in mice

<div><p>Hyperoxic lung injury is pathologically characterized by alveolar edema, interlobular septal edema, hyaline membrane disease, lung inflammation, and alveolar hemorrhage. Although the precise mechanism by which hyperoxia causes lung injury is not well defined, oxidative stress, epithelial cell death, and proinflammatory cytokines are thought to be involved. Probucol—a commercially available drug for treating hypercholesterolemia—has been suggested to have antioxidant and antiapoptotic effects. This study aimed to assess whether probucol could attenuate hyperoxic lung injury in mice. Mice were exposed to 95% O₂ for 72 h, with or without pre-treatment with 130 μg/kg probucol intratracheally. Probucol treatment significantly decreased both the number of inflammatory cells in the bronchoalveolar lavage fluid and the degree of lung injury in hyperoxia-exposed mice. Probucol treatment reduced the number of cells positive for 8-hydroxyl-2′-deoxyguanosine or terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and suppressed NF-κB activation, Bax expression, and caspase-9 activation in lung tissues from hyperoxia-exposed mice. These results suggest that probucol can reduce oxidative DNA damage, apoptotic cell death, and inflammation in lung tissues. Intratracheal administration of probucol may be a novel treatment for lung diseases induced by oxidative stress, such as hyperoxic lung injury and acute respiratory distress syndrome.</p></div

Probucol ameliorates apoptosis in hyperoxic lung injury.

<p>(A-D) The effect of probucol on TUNEL staining. (A) No positive signals for TUNEL were observed in lung tissues of room-air-exposed mice treated with probucol. (B) There were some TUNEL-positive cells (arrows in F) in the lung tissues of hyperoxia-exposed mice. (C) Probucol treatment decreased the number of TUNEL-positive cells in hyperoxia-exposed mice. (D) Quantitative result of the number of TUNEL-positive cells in lung tissues. Original magnifications: ×200. Data are shown as the mean ± SEM from four mice in each group. **<i>p</i> < 0.01.</p

Effect of probucol on BALF and the histological findings in hyperoxic lung injury.

<p>(A) The results of cell count and level of IL-6 in BALF. Each bar shows mean ± SEM of the ten mice in each group. (B-E) Hematoxylin and eosin staining. In room-air-exposed mice without probucol treatment (B) and room-air-exposed mice treated with probucol (C), no abnormalities were observed. In the lung tissue of hyperoxia-exposed mice without probucol treatment (D), invasion of inflammatory cells, pulmonary edema, and alveolar hemorrhage were observed. In hyperoxia-exposed mice treated with probucol (E), those findings were improved. In the pathological grading, each circle corresponds to one mouse (F). Original magnifications: ×200. **<i>P</i> < 0.01, *<i>p</i> < 0.05.</p

Western blot analysis for p47^phox, phospho-ERK1/2, NF-κB (p65), Bcl-X_L, Bax (6A7), cleaved caspase-9, and β-tubulin.

<p>(A) Each lane corresponds to the data from one mouse. (B) Relative band intensities from western blot analysis. Optical density values for each individual band were normalized to β-tubulin expression from the same tissue. Data are means ± SEM from three mice. **<i>p</i> < 0.01.</p

Probucol ameliorates oxidative stress and apoptosis in hyperoxic lung injury.

<p>(A-D) The results of immunohistochemistry for 8-OHdG. (A) In room-air-exposed mice treated with probucol, expression of 8-OHdG was not detected. (B) In hyperoxia-exposed mice without probucol treatment, 8-OHdG was strongly expressed in nuclei of lung epithelial cells due to the tissue damage. (C) In hyperoxia-exposed mice treated with probucol, signal of 8-OHdG was decreased. (D) The immunostaining grade for 8-OHdG was significantly decreased by probucol treatment. Original magnifications: ×200. Data are shown as the mean ± SEM from four mice in each group. (E) Western blot analysis for p47^phox. Each lane corresponds to the data from one mouse. (F) Relative band intensities from western blot analysis. Optical density values for each individual band were normalized to β-tubulin expression from the same tissue. Data are means ± SEM from three mice. **<i>p</i> < 0.01.</p

Probucol treatment increases Bcl-X_L expression in the lung tissues.

<p>(A) There was no detectable expression of Bcl-X_L in room-air-exposed mice (A). In both room-air-exposed mice and hyperoxia-exposed mice, probucol treatment increased Bcl-X_L expression in lung epithelial cells (B, D). In hyperoxia-exposed mice without probucol treatment, there was a low-level expression of Bcl-X_L (C). Original magnifications: ×200.</p