Structure-Activity Relationship of Synthetic Ginkgolic Acid Analogs for Treating Type 2 Diabetes by PTPN9 Inhibition.

Ginkgolic acid (C13:0) (GA), isolated from Ginkgo biloba, is a potential therapeutic agent for type 2 diabetes. A series of GA analogs were designed and synthesized for the evaluation of their structure-activity relationship with respect to their antidiabetic effects. Unlike GA, the synthetic analog 1e exhibited improved inhibitory activity against PTPN9 and significantly stimulated glucose uptake via AMPK phosphorylation in differentiated 3T3-L1 adipocytes and C2C12 myotubes; it also induced insulin-dependent AKT activation in C2C12 myotubes in a concentration-dependent manner. Docking simulation results showed that 1e had a better binding affinity through a unique hydrophobic interaction with a PTPN9 hydrophobic groove. Moreover, 1e ameliorated palmitate-induced insulin resistance in C2C12 cells. This study showed that 1e increases glucose uptake and suppresses palmitate-induced insulin resistance in C2C12 myotubes via PTPN9 inhibition; thus, it is a promising therapeutic candidate for treating type 2 diabetes.

High-dose intraoperative remifentanil infusion increases early postoperative analgesic consumption: a prospective, randomized, double-blind controlled study.

PURPOSE: The purpose of this study was to determine whether intraoperative infusion of remifentanil induces acute tolerance to opioids, and compare the postoperative pain and opioid consumption by the effect site concentrations of remifentanil. METHODS: One hundred and ninety-eight patients undergoing gastrectomy were randomly assigned to maintain target effect site concentrations of remifentanil at 0 (Group 1, n = 39), 2 (Group 2, n = 40), 4 (Group 3, n = 39), 8 (Group 4, n = 40), or 12 ng/ml (Group 5, n = 40) during operation. Postoperative pain intensities and fentanyl requirement were recorded at postoperative 2, 6, 24, and 48 h. RESULTS: Fentanyl requirement for postoperative 2 h was significantly greater in Group 5 compared to Group 1 (376 ± 116 vs. 283 ± 129 µg, P = 0.03). However, there were no differences in fentanyl requirements among the groups after postoperative 2 h. Also, total fentanyl consumption for 48 h was similar in all groups (Group 1; 3106 ± 629, Group 2; 2970 ± 705, Group 3; 3017 ± 555, Group 4; 3151 ± 606, and Group 5; 2984 ± 443 µg, P = 0.717). Pain scores at rest and during deep breathing were comparable in all groups at the time of each examination. CONCLUSION: Intraoperative infusion of remifentanil with 12 ng/ml of effect site concentration in patients undergoing gastrectomy increases early postoperative fentanyl requirement. Acute opioid tolerance would be developed by higher concentration of remifentanil than dosage of common anesthetic practice.

Measurements of the length and diameter of main bronchi on three-dimensional images in Asian adult patients in comparison with the height of patients.

OBJECTIVE: To measure the length and diameter of the main bronchus using the three-dimensional reconstruction images from the spiral chest computerized tomography scans in Asian adult patients, and to evaluate the relationship between the height of patients and the length and diameter of main bronchi. DESIGN: Prospective observational study. SETTING: Academic, tertiary care hospital. PARTICIPANTS: Two hundred Asian adults undergoing a chest spiral computerized tomography scan. INTERVENTION: No intervention. MEASUREMENTS AND MAIN RESULTS: The authors measured the anteroposterior and transverse diameters of the mid-portion of the right main bronchus and 2 cm below the carina of the left main bronchus. In addition, the length of both main bronchi was also measured. The length of the left main bronchus was about 3-4 times greater than its right counterpart. The main bronchus of women was oval-shape, with a large anteroposterior diameter, but the main bronchus of men was round-shape. There was no significant correlation between the measurements of main bronchi and the height of patients. CONCLUSIONS: The results showed that there is no direct relationship between the length and diameter of main bronchi and the height of patients. The height is not the criterion for choosing DLT size. Therefore, the authors proposed that 3-D images be used to determine the size of the main bronchi. The diameter of main bronchus using the 3-D images can be used to determine the optimal size of the DLT in a clinical setting, although further studies are needed.

Exploring the Anti-Diabetic Potential of Quercetagitrin through Dual Inhibition of PTPN6 and PTPN9.

Protein tyrosine phosphatases (PTPs) are pivotal contributors to the development of type 2 diabetes (T2DM). Hence, directing interventions towards PTPs emerges as a valuable therapeutic approach for managing type 2 diabetes. In particular, PTPN6 and PTPN9 are targets for anti-diabetic effects. Through high-throughput drug screening, quercetagitrin (QG) was recognized as a dual-target inhibitor of PTPN6 and PTPN9. We observed that QG suppressed the catalytic activity of PTPN6 (IC50 = 1 µM) and PTPN9 (IC50 = 1.7 µM) in vitro and enhanced glucose uptake by mature C2C12 myoblasts. Additionally, QG increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and insulin-dependent phosphorylation of Akt in mature C2C12 myoblasts. It further promoted the phosphorylation of Akt in the presence of palmitic acid, suggesting the attenuation of insulin resistance. In summary, our results indicate QG's role as a potent inhibitor targeting both PTPN6 and PTPN9, showcasing its potential as a promising treatment avenue for T2DM.