Terminalin from African Mango (Irvingia gabonensis) Stimulates Glucose Uptake through Inhibition of Protein Tyrosine Phosphatases.

Protein tyrosine phosphatases (PTPs), along with protein tyrosine kinases, control signaling pathways involved in cell growth, metabolism, differentiation, proliferation, and survival. Several PTPs, such as PTPN1, PTPN2, PTPN9, PTPN11, PTPRS, and DUSP9, disrupt insulin signaling and trigger type 2 diabetes, indicating that PTPs are promising drug targets for the treatment or prevention of type 2 diabetes. As part of an ongoing study on the discovery of pharmacologically active bioactive natural products, we conducted a phytochemical investigation of African mango (Irvingia gabonensis) using liquid chromatography-mass spectrometry (LC/MS)-based analysis, which led to the isolation of terminalin as a major component from the extract of the seeds of I. gabonensis. The structure of terminalin was characterized by spectroscopic methods, including one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) and high-resolution (HR) electrospray ionization (ESI) mass spectroscopy. Moreover, terminalin was evaluated for its antidiabetic property; terminalin inhibited the catalytic activity of PTPN1, PTPN9, PTPN11, and PTPRS in vitro and led to a significant increase in glucose uptake in differentiated C2C12 muscle cells, indicating that terminalin exhibits antidiabetic effect through the PTP inhibitory mechanism. These findings suggest that terminalin derived from African mango could be used as a functional food ingredient or pharmaceutical supplement for the prevention of type 2 diabetes.

Entelon® (Vitis vinifera Seed Extract) Prevents Cancer Metastasis via the Downregulation of Interleukin-1 Alpha in Triple-Negative Breast Cancer Cells.

Interleukin-1 (IL1) is a proinflammatory cytokine and promotes cancer cell proliferation and invasiveness in a diversity of cancers, such as breast and colon cancer. Here, we focused on the pharmacological effect of Entelon® (ETL) on the tumorigenesis of triple-negative breast cancer (TNBC) cells by IL1-alpha (IL1A). IL1A enhanced the cell growth and invasiveness of TNBC cells. We observed that abnormal IL1A induction is related with the poor prognosis of TNBC patients. IL1A also increased a variety of chemokines such as CCL2 and IL8. Interestingly, IL1A expression was reduced by the ETL treatment. Here, we found that ETL significantly decreased the MEK/ERK signaling pathway in TNBC cells. IL1A expression was reduced by UO126. Lastly, we studied the effect of ETL on the metastatic potential of TNBC cells. Our results showed that ETL significantly reduced the lung metastasis of TNBC cells. Our results showed that IL1A expression was regulated by the MEK/ERK- and PI3K/AKT-dependent pathway. Taken together, ETL inhibited the MEK/ERK and PI3K/AKT signaling pathway and suppressing the lung metastasis of TNBC cells through downregulation of IL1A. Therefore, we propose the possibility of ETL as an effective adjuvant for treating TNBC.

A Randomized, Noninferiority Trial Comparing ICS + LABA with ICS + LABA + LAMA in Asthma-COPD Overlap (ACO) Treatment: The ACO Treatment with Optimal Medications (ATOMIC) Study.

BACKGROUND: Current guidelines for the treatment of asthma and chronic obstructive pulmonary disease overlap (ACO) recommend initial treatment using inhaled corticosteroids (ICSs) plus 1 or more bronchodilators. OBJECTIVE: To clarify which therapeutic effect is better between the ICS + long-acting ß2 agonist (LABA) and ICS + LABA + long-acting muscarinic antagonist (LAMA) treatment in patients with ACO. METHODS: We conducted a multicenter, 48-week, randomized, noninferiority trial. Patients with ACO were enrolled if they were treated with a moderate to high dose of ICS + LABA. In total, 303 patients were involved in the present trial, with 149 receiving ICS + LABA + LAMA. The primary end point was the time to first exacerbation. Secondary outcomes included changes in FEV1, forced vital capacity, FEV1/forced vital capacity ratio, asthma control, blood eosinophil count, and fractional exhaled nitric oxide. RESULTS: In the ICS + LABA treatment group, 29 of 154 patients (18.83%) experienced exacerbation, whereas 28 of 149 patients (18.79%) experienced exacerbation in the ICS + LABA + LAMA treatment group. The results of this noninferiority study were ultimately inconclusive (hazard ratio, 1.1; 95% CI, 0.66-1.84). However, the patients treated with the addition of LAMA showed significant improvements in FEV1 and forced vital capacity (P < .001). Asthma control did not improve in either group. CONCLUSIONS: Although this study was unable to conclude that ICS + LABA treatment is not inferior to ICS + LABA + LAMA in terms of exacerbation, it is obvious that the ICS + LABA + LAMA treatment group had improved lung function in ACO.

Genkwadaphnin promotes leukocyte migration by increasing CD44 expression via PKD1/NF-κB signaling pathway.

Genkwadaphnin (GD), an extract from the flower buds of Daphne genkwa Siebold & Zucc. (Thymelaeaceae) has been reported a significant anti-leukemic activity. However, its functional mechanism has not been defined well. To study the biological mechanism of GD function, we have investigated whether GD affects CD44 expression, which has a role in the regulation of immune cell motilities, and identified the related signaling pathways. GD treatment induced the increase of CD44 expression in a time- and concentration-dependent manner, which was specific for immune cells. GD activated PKD1/NF-κB signaling to induce CD44 expression, and resulted in the increased migration of K562 cells. In invasion assay, cell migratory ability was induced by GD and the transfection with CD44-specific short hairpin RNA resulted in reduction of its cell migration. GD treated human peripheral blood mononuclear cell (PBMC) were also shown the increased CD44 expression and migration. These data suggest that the induction of CD44 expression by GD treatment promotes immune cell transmigration resulting in the enhanced innate immunity.

Effect of pregnancy in asthma on health care use and perinatal outcomes.

BACKGROUND: It is generally known that pregnancy in asthmatic patients increases the risk of asthma exacerbations and poor perinatal outcomes. However, the effect of pregnancy in asthmatic patients on health care use is not known well. In addition, its effect on perinatal outcomes is still controversial because of study limitations caused by ethical issues. National Health Insurance claim data are an ideal resource for studying real-world health care use patterns of asthma. OBJECTIVE: We sought to evaluate the effect of pregnancy on asthma in terms of asthma-related health care use and prescription patterns in concert with the effect of asthma exacerbations on adverse pregnancy outcomes. METHODS: Among all asthmatic patients in the Korean National Health Insurance claim database from January 2009 to December 2013, pregnant women who delivered in 2011 with pre-existing asthma were enrolled. Analyses included asthma-related health care use and prescription patterns compared between pregnant asthmatic women and nonpregnant female asthmatic control subjects, as well as within the pregnant subjects from before pregnancy throughout postpartum periods. In addition, the association between asthma exacerbation during pregnancy and adverse pregnancy outcomes was assessed. RESULTS: A total of 3,357 pregnant asthmatic patients were compared with 50,355 nonpregnant asthmatic patients, and 10,311 pregnant patients were included to determine the effect of asthma exacerbations on adverse pregnancy outcome in the study. Pregnant asthmatic patients underwent more asthma-related hospitalizations (1.3% vs 0.8%, P = .005) but had significantly fewer outpatient visits and prescriptions for most asthma medications than nonpregnant asthmatic patients. The proportion of patients ever hospitalized gradually increased throughout pregnancy (first trimester, 0.2%; second trimester, 0.5%; and third trimester, 0.7%; P = .018). The prevalence of asthma exacerbation during pregnancy was 5.3%, and the patients who had acute exacerbation during pregnancy had significantly higher asthma-related health care use in terms of hospitalization, intensive care unit admission, and emergency department and outpatient visits within 1 year before delivery than those who had not. However, asthma exacerbation during pregnancy was not significantly related to adverse perinatal outcomes, except for cesarean section (27.1% vs 18.9%, P < .001). All exacerbations were managed with systemic corticosteroids, and the patients who ever experienced acute exacerbations maintained asthma medications, including inhaled corticosteroid-based inhalers, throughout the pregnancy period. CONCLUSION: Pregnancy profoundly affects asthma-related health care use but to a different degree depending on whether the patient experienced an exacerbation. Asthma exacerbation during pregnancy is not associated with adverse pregnancy outcomes while managed appropriately with systemic corticosteroids. However, further studies are needed to clarify the effect of asthma control on perinatal outcome and delivery method.

Anti-fatigue activity of Hovenia dulcis on a swimming mouse model through the inhibition of stress hormone expression and antioxidation.

Hovenia dulcis (H. dulcis) Thunb., which is distributed in Korea, China, and Japan, has been known to show hepatoprotective and free radical scavenging effects and enhance physical activity. Therefore, the objectives of this present study were to determine the anti-fatigue activity of hot-water extract from H. dulcis peduncle, and to find the reason why H. dulcis extract (HDE)-ingested mice had enhanced physical activity against swimming performance. The mice orally administrated with HDE (HDE-mice) dramatically enhanced their swimming time compared to the control mice. HDE significantly decreased serum levels of stress hormones, such as cortisol and adrenocorticotropic hormone (ACTH) in mice. The levels of thiobarbituric acid reactive substances (TBARS) were dramatically decreased in gastrocnemius muscle from both 100 mg/kg of HDE (LHDE) and 200 mg/kg of HDE (HHDE)-ingested mice compared to the control mice. The liver activities of superoxide dismutase (SOD) were significantly increased in HHDE-mice with increasing tendency in LHDE-mice. In addition, HHDE-mice significantly decreased the levels of blood glucose, total cholesterol (T-Chol), and triglyceride (TG). These results suggest that HDE had a significant anti-fatigue effect via its anti-stress and antioxidant activities, and thereby enhanced physical activity in swimming performance.