SCGB1C1 Plays a Critical Role in Suppression of Allergic Airway Inflammation through the Induction of Regulatory T Cell Expansion.

The nanosized vesicles secreted from various cell types into the surrounding extracellular space are called extracellular vesicles (EVs). Although mesenchymal stem cell-derived EVs are known to have immunomodulatory effects in asthmatic mice, the role of identified pulmonary genes in the suppression of allergic airway inflammation remains to be elucidated. Moreover, the major genes responsible for immune regulation in allergic airway diseases have not been well documented. This study aims to evaluate the immunomodulatory effects of secretoglobin family 1C member 1 (SCGB1C1) on asthmatic mouse models. C57BL/6 mice were sensitized to ovalbumin (OVA) using intraperitoneal injection and were intranasally challenged with OVA. To evaluate the effect of SCGB1C1 on allergic airway inflammation, 5 µg/50 µL of SCGB1C1 was administrated intranasally before an OVA challenge. We evaluated airway hyperresponsiveness (AHR), total inflammatory cells, eosinophils in the bronchoalveolar lavage fluid (BALF), lung histology, serum immunoglobulin (Ig), the cytokine profiles of BALF and lung-draining lymph nodes (LLN), and the T cell populations in LLNs. The intranasal administration of SCGB1C1 significantly inhibited AHR, the presence of eosinophils in BALF, eosinophilic inflammation, goblet cell hyperplasia in the lung, and serum total and allergen-specific IgE. SCGB1C1 treatment significantly decreased the expression of interleukin (IL)-5 in the BALF and IL-4 in the LLN, but significantly increased the expression of IL-10 and transforming growth factor (TGF)-ß in the BALF. Furthermore, SCGB1C1 treatment notably increased the populations of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in asthmatic mice. The intranasal administration of SCGB1C1 provides a significant reduction in allergic airway inflammation and improvement of lung function through the induction of Treg expansion. Therefore, SCGB1C1 may be the major regulator responsible for suppressing allergic airway inflammation.

Free-Living Amoeba Vermamoeba vermiformis Induces Allergic Airway Inflammation.

The high percentage of Vermamoeba was found in tap water in Korea. This study investigated whether Vermamoeba induced allergic airway inflammation in mice. We selected 2 free-living amoebas (FLAs) isolated from tap water, which included Korean FLA 5 (KFA5; Vermamoeba vermiformis) and 21 (an homolog of Acanthamoeba lugdunensis KA/ E2). We axenically cultured KFA5 and KFA21. We applied approximately 1 × 106 to mice's nasal passages 6 times and investigated their pathogenicity. The airway resistance value was significantly increased after KFA5 and KFA21 treatments. The eosinophil recruitment and goblet cell hyperplasia were concomitantly observed in bronchial alveolar lavage (BAL) fluid and lung tissue in mice infected with KFA5 and KFA21. These infections also activated the Th2-related interleukin 25, thymic stromal lymphopoietin, and thymus and activation-regulated chemokines gene expression in mouse lung epithelial cells. The CD4+ interleukin 4+ cell population was increased in the lung, and the secretion of Th2-, Th17-, and Th1-associated cytokines were upregulated during KFA5 and KFA21 infection in the spleen, lung-draining lymph nodes, and BAL fluid. The pathogenicity (allergenicity) of KFA5 and KFA21 might not have drastically changed during the long-term in vitro culture. Our results suggested that Vermamoeba could elicit allergic airway inflammation and may be an airway allergen.

Association between atherogenic index of plasma and coronary artery calcification progression in Korean adults.

BACKGROUND: Dyslipidemia is a well-known risk factor for cardiovascular disease (CVD). Recently, atherogenic index of plasma (AIP) has been proposed as a novel predictive marker for CVD, and few cross sectional studies have demonstrated a relationship between AIP and coronary artery disease. The present study investigated the association between AIP and the progression of coronary artery calcification (CAC) in Korean adults without CVD. METHODS: A total of 1124 participants who had undergone CAC measurement at least twice by multi-detector computed tomography (CT) at a health check-up center were enrolled. Their anthropometric measurements and various cardiovascular risk factors were assessed. AIP was defined as the base 10 logarithm of the ratio of the concentration of triglyceride (TG) to high-density lipoprotein-cholesterol (HDL-C). CAC progression was defined as either incident CAC in a CAC-free population at baseline, or an increase of ≥2.5 units between the square roots of the baseline and follow-up coronary artery calcium scores (CACS) in subjects with detectable CAC at baseline. RESULTS: CAC progression was observed in 290 subjects (25.8%) during the mean follow-up of 4.2 years. All subjects were stratified into three groups according to AIP. There were significant differences in cardiovascular parameters among groups at baseline. The follow-up CAC and the incidence of CAC progression increased gradually with rising AIP tertiles. In logistic regression analysis, the odds ratio for CAC progression was 2.27 when comparing the highest to the lowest tertile of AIP (95% CI: 1.61-3.19; P for trend < 0.01). However, this association was attenuated after adjustment for multiple risk factors (P for trend = 0.67). CONCLUSIONS: There is a significant correlation between AIP and the progression of CAC in subjects without CVD. Although AIP was not an independent predictor of CAC progression, AIP should be considered when estimating the current as well as future CVD risk, along with other traditional risk factors.

Therapeutic effects of Echinococcus granulosus cystic fluid on allergic airway inflammation.

Previous studies showed that Echinococcus granulosus infection reduces allergic airway inflammation in experimentally infected hosts and the cystic fluid of E. granulosus is known to activate regulatory T (CD4+CD25+Foxp3+T, Treg) cells. To evaluate the effects of cystic fluid of E. granulosus on allergic airway inflammation, we investigated the regulation of the inflammatory reaction by cystic fluid using an allergic airway inflammation animal model. Cystic fluid was administered to C57BL/6 mice seven times every other day, after which allergic airway inflammation was induced using ovalbumin and aluminum. The airway resistance, number of eosinophils and other immune cells in the bronchoalveolar lavage fluid, and levels of Th2 and Th17-related cytokines were significantly reduced by cystic fluid pre-treatment in allergic airway inflammation-induced mice. The number IL-4+CD4+ T cells decreased, the number of Treg cells increased in the lung-draining lymph nodes and spleen of cystic fluid pre-treated mice. In conclusion, E. granulosus-derived cystic fluid may alleviate the Th2 allergic airway inflammatory response via Treg cells. Further studies of the immune regulation of cystic fluid may lead to the development of therapeutic agents for immune disorders.

Association between triglyceride glucose index and arterial stiffness in Korean adults.

BACKGROUND: The triglyceride glucose (TyG) index has been suggested as a simple surrogate marker of insulin resistance. However, there are limited data regarding the association between the TyG index and arterial stiffness in adults. Therefore, we evaluated the relationship between the TyG index and arterial stiffness as measured based on brachial ankle pulse wave velocity (baPWV) in Korean adults. METHODS: A total of 3587 subjects were enrolled in this study. Anthropometric and cardiovascular risk factors were measured. The TyG index was calculated as ln[fasting triglycerides(mg/dl) × fasting glucose(mg/dl)/2], and the insulin resistance index of homeostasis model assessment (HOMA-IR) was estimated. Arterial stiffness was determined by measuring baPWV. RESULTS: The subjects were stratified into four groups based on the TyG index. There were significant differences in cardiovascular parameters among the groups; the mean baPWV increased significantly with increasing TyG index. According to the logistic regression analysis after adjusting for multiple risk factors, the odds ratio (95% CI) for increased baPWV (> 75th percentile) for the highest and lowest quartiles of the TyG index was 2.92 (1.92-4.44) in men and 1.84 (1.15-2.96) in women, and the odds ratio for increased baPWV for the highest and lowest quartiles of the HOMA-IR was 1.80 (1.17-2.78) in men and 1.46 (1.06-2.47) in women, respectively. CONCLUSION: The TyG index is more independently associated with increased arterial stiffness than HOMA-IR in Korean adults.

ß-cell serotonin production is associated with female sex, old age, and diabetes-free condition.

Serotonin is known to be present in pancreatic ß-cells and to play several physiological roles, including insulin secretion, ß-cell proliferation, and paracrine inhibition of α-cells. However, the serotonin production of different cell lines and islets has not been compared based on age, sex, and diabetes related conditions. Here, we directly compared the serotonin concentrations in ßTC and MIN6 cell lines, as well as in islets from mice using ultra-performance liquid chromatography tandem mass spectrometry. The average serotonin concentration was 5-10 ng/mg protein in the islets of male and non-pregnant female mice. The serotonin level was higher in females than males at 8 weeks, although there was no difference at 1 year. Furthermore, we observed serotonin by immunofluorescence staining in the pancreatic tissues of mice and human. Serotonin was detected by immunofluorescence staining in a portion of ß-cells from islets of old female mice, but not of male or young female mice. A similar pattern was observed in human pancreas as well. In humans, serotonin production in ß-cells was associated with a diabetes-free condition. Thus, serotonin production in ß-cells was associated with old age, female sex, and diabetes-free condition.

Relationship between the triglyceride glucose index and coronary artery calcification in Korean adults.

BACKGROUND: The triglyceride glucose (TyG) index has been considered a simple surrogate marker of insulin resistance. However, few studies have investigated the relationship between the TyG index and coronary artery calcification (CAC). Thus, we investigated the relationship between the TyG index and CAC in healthy Korean adults. METHODS: In total, 4319 participants who underwent cardiac computed tomography (CT) in a health promotion center were enrolled. Anthropometric profiles and multiple cardiovascular risk factors were measured. The TyG index was calculated as ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2], and the insulin resistance index of homeostasis model assessment (HOMA-IR) was estimated. The CAC was measured using multidetector CT, and CAC presence was defined as an Agatston score of >0. RESULTS: All subjects were stratified into four groups based on their TyG indices. Significant differences were observed in cardiovascular parameters among the groups, and the prevalence of CAC significantly increased with increasing TyG index. In the logistic regression analysis after adjustment for multiple risk factors, the odds ratio for the prevalence of CAC, when comparing the highest and lowest quartiles of the TyG index was 1.95 (95% CI 1.23-3.11; P for trend = 0.01); the odds ratio for the prevalence of CAC, when comparing the highest and lowest quartiles of HOMA-IR was 1.64 (95% CI 1.12-2.40; P for trend = 0.04). In the receiver operating characteristics analysis, the TyG index was superior to HOMA-IR in predicting CAC. CONCLUSION: The TyG index is more independently associated with the presence of coronary artery atherosclerosis than is HOMA-IR in healthy Korean adults.

BNIP3 is essential for mitochondrial bioenergetics during adipocyte remodelling in mice.

AIMS/HYPOTHESIS: Adipose tissue is a highly versatile system in which mitochondria in adipocytes undergo significant changes during active tissue remodelling. BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) is a mitochondrial protein and a known mitochondrial quality regulator. In this study, we investigated the role of BNIP3 in adipocytes, specifically under conditions of peroxisome proliferator-activated receptor-γ (PPARγ)-induced adipose tissue remodelling. METHODS: The expression of BNIP3 was evaluated in 3T3-L1 adipocytes in vitro, C57BL/6 mice fed a high-fat diet and db/db mice in vivo. Mitochondrial bioenergetics was investigated in BNIP3-knockdown adipocytes after rosiglitazone treatment. A putative peroxisome proliferator hormone responsive element (PPRE) was characterised by promoter assay and electrophoretic mobility shift assay (EMSA). RESULTS: The protein BNIP3 was more abundant in brown adipose tissue than white adipose tissue. Furthermore, BNIP3 expression was upregulated by 3T3-L1 pre-adipocyte differentiation, starvation and rosiglitazone treatment. Conversely, BNIP3 expression in adipocytes decreased under various conditions associated with insulin resistance. This downregulation of BNIP3 was restored by rosiglitazone treatment. Knockdown of BNIP3 in adipocytes inhibited rosiglitazone-induced mitochondrial biogenesis and function, partially mediated by the 5' AMP-activated protein kinase (AMPK)-peroxisome proliferator-activated receptor γ, co-activator 1 α (PGC1α) signalling pathway. Rosiglitazone treatment increased the transcription level of Bnip3 in the reporter assay and the presence of the PPRE site in the Bnip3 promoter was demonstrated by EMSA. CONCLUSIONS/INTERPRETATION: The protein BNIP3 contributes to the improvement of mitochondrial bioenergetics that occurs on exposure to rosiglitazone. It may be a novel therapeutic target for restoring mitochondrial dysfunction under insulin-resistant conditions.

The effect of soluble E-selectin on tumor progression and metastasis.

BACKGROUND: Distant metastasis resulting from vascular dissemination of cancer cells is the primary cause of mortality from breast cancer. We have previously reported that E-selectin expression on the endothelial cell surface mediates shear-resistant adhesion and migration of circulating cancer cells via interaction with CD44. As a result of shedding, soluble E-selectin (sE-selectin) from the activated endothelium is present in the serum. In this study, we aimed to understand the role of sE-selectin in tumor progression and metastasis. METHODS: We investigated the effect of sE-selectin on shear-resistant adhesion and migration of metastatic breast cancer cells and leukocytes in vitro and in vivo. RESULTS: We found that sE-selectin promoted migration and shear-resistant adhesion of CD44(+) (/high) breast cancer cell lines (MDA-MB-231 and MDA-MB-468) to non-activated human microvessel endothelial cells (ES-HMVECs), but not of CD44(-/low) breast cancer cell lines (MCF-7 and T-47D). This endothelial E-selectin independent, sE-selectin-mediated shear-resistant adhesion was also observed in a leukocyte cell line (HL-60) as well as human peripheral blood mononuclear cells (PBMCs). Additionally, the incubation of MDA-MB-231 cells with sE-selectin triggered FAK phosphorylation and shear-resistant adhesion of sE-selectin-treated cells resulted in increased endothelial permeabilization. However, CD44 knockdown in MDA-MB-231 and HL-60 cells resulted in a significant reduction of sE-selectin-mediated shear-resistant adhesion to non-activated HMVECs, suggesting the involvement of CD44/FAK. Moreover, functional blockade of ICAM-1 in non-activated HMVECs resulted in a marked reduction of sE-selectin-mediated shear-resistant adhesion. Finally, the pre-incubation of CD44(+) 4 T1 murine breast cancer cells with sE-selectin augmented infiltration into the lung in E-selectin K/O mice and infusion of human PBMCs pre-incubated with sE-selectin stimulated MDA-MB-231 xenografted breast tumor growth in NSG mice. CONCLUSIONS: Our data suggest that circulating sE-selectin stimulates a broad range of circulating cells via CD44 and mediates pleiotropic effects that promote migration and shear-resistant adhesion in an endothelial E-selectin independent fashion, in turn accelerating tissue infiltration of leukocytes and cancer cells.

Serum ferritin levels are associated with arterial stiffness in healthy Korean adults.

Although an association between serum ferritin and atherosclerosis has been suggested, limited epidemiologic data are available regarding the association between ferritin and arterial stiffness in healthy adults. A total of 2932 healthy subjects were enrolled in this study. Anthropometric and biochemical profiles including ferritin were measured. The arterial stiffness was measured using brachial-ankle pulse wave velocity (baPWV). Serum ferritin levels were classified into quartiles and baPWV values gradually increased with each ferritin quartile. Multiple regression analysis showed that ferritin levels were independently correlated with baPWV. After adjusting for multiple risk factors, as compared with the lowest quartile, the odds ratios for high baPWV (>75(th) percentile) were 1.15 (0.84-1.56), 1.37 (0.97-1.73), and 1.46 (1.29-2.17) among men (p for trend < 0.05) and 1.24 (0.87-1.79), 1.53 (1.09-2.16), and 1.80 (1.25-2.82) among women (p for trend < 0.05), for the second, third, and fourth quartiles of ferritin, respectively. In conclusion, serum ferritin levels are independently associated with arterial stiffness in healthy Korean adults.

Blocking the adhesion cascade at the premetastatic niche for prevention of breast cancer metastasis.

Shear-resistant adhesion and extravasation of disseminated cancer cells at the target organ is a crucial step in hematogenous metastasis. We found that the vascular adhesion molecule E-selectin preferentially promoted the shear-resistant adhesion and transendothelial migration of the estrogen receptor (ER)(-)/CD44(+) hormone-independent breast cancer cells, but not of the ER(+)/CD44(-/low) hormone-dependent breast cancer cells. Coincidentally, CD44(+) breast cancer cells were abundant in metastatic lung and brain lesions in ER(-) breast cancer, suggesting that E-selectin supports hematogenous metastasis of ER(-)/CD44(+) breast cancer. In an attempt to prevent hematogenous metastasis through the inhibition of a shear-resistant adhesion of CD44(+) cancer cells to E-selectin-expressing blood vessels on the premetastatic niche, an E-selectin targeted aptamer (ESTA) was developed. We demonstrated that a single intravenous injection of ESTA reduced metastases to a baseline level in both syngeneic and xenogeneic forced breast cancer metastasis models without relocating the site of metastasis. The effect of ESTA was absent in E-selectin knockout mice, suggesting that E-selectin is a molecular target of ESTA. Our data highlight the potential application of an E-selectin antagonist for the prevention of hematogenous metastasis of ER(-)/CD44(+) breast cancer.

Normal-weight obesity is associated with increased risk of subclinical atherosclerosis.

BACKGROUND: Subjects with normal body mass index (BMI) but elevated amounts of body fat (normal-weight obesity; NWO) show cardiometabolic dysregulation compared to subjects with normal BMI and normal amounts of body fat (normal-weight lean; NWL). In this study, we aimed to evaluate whether NWO individuals have higher rates of subclinical atherosclerosis compared to NWL subjects. METHODS: From a large-scale health checkup system, we identified 2078 normal weight (18.5 ≤ BMI < 25 kg/m(2)) subjects with no previous history of coronary artery disease who underwent analysis of atherosclerosis using coronary computed tomography angiography (CCTA) and pulse wave velocity (PWV). NWO was defined as normal BMI and highest tertile of body fat percentage by sex (men ≥ 25. 4 % and women ≥ 31.4 %). CCTA was performed using a 64-detector row CT. A plaque was defined as a structure >1 mm(2) within and/or adjacent to the vessel lumen and classified according to the presence/proportion of intraplaque calcification. RESULTS: NWO subjects (n = 283) demonstrated metabolic dysregulation compared to NWL individuals (n = 1795). After adjusting for age, sex, and smoking, NWO individuals showed higher PWV values than NWL individuals (1474.0 ± 275.4 vs. 1380.7 ± 234.3 cm/s, p = 0.006 by ANCOVA). Compared with NWL subjects, NWO subjects had a higher prevalence of soft plaques even after age, sex, and smoking adjustment (21.6% vs. 14.5%, p = 0.039 by ANCOVA). The PWV value and the log{(number of segments with plaque) + 1} showed a positive correlation with numerous parameters such as age, systolic blood pressure, visceral fat, fasting glucose level, serum triglyceride level, and C-reactive protein (CRP) in contrast to the negative correlation with high-density lipoprotein-cholesterol level. The visceral fat was an independent determinant of log{(number of segments with plaque) + 1} (ß = 0.027, SE = 0.011, p = 0.016) even after adjustment for other significant factors. Most importantly, NWO was an independent risk factor for the presence of soft plaques (odds ratio 1.460, 95 % confidence interval 1.027-2.074, p = 0.035) even after further adjustment for multiple factors associated with atherosclerosis (blood pressure, blood glucose, lipid level, CRP, medication, smoking status, physical activity). CONCLUSIONS: NWO individuals carry a higher incidence of subclinical atherosclerosis compared with NWL individuals, regardless of other clinical risk factors for atherosclerosis.

Safety evaluation of intravenously administered mono-thioated aptamer against E-selectin in mice.

The medical applications of aptamers have recently emerged. We developed an antagonistic thioaptamer (ESTA) against E-selectin. Previously, we showed that a single injection of ESTA at a dose of 100µg inhibits breast cancer metastasis in mice through the functional blockade of E-selectin. In the present study, we evaluated the safety of different doses of intravenously administered ESTA in single-dose acute and repeat-dose subacute studies in ICR mice. Our data indicated that intravenous administration of up to 500µg ESTA did not result in hematologic abnormality in either study. Additionally, intravenous injection of ESTA did not affect the levels of plasma cytokines (IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, GM-CSF, IFN-γ, and TNF-α) or complement split products (C3a and C5a) in either study. However, repeated injections of ESTA slightly increased plasma ALT and AST activities, in accordance with the appearance of small necrotic areas in the liver. In conclusion, our data demonstrated that intravenous administration of ESTA does not cause overt hematologic, organs, and immunologic responses under the experimental conditions.

Subclinical vascular inflammation in subjects with normal weight obesity and its association with body fat: an 18 F-FDG-PET/CT study.

BACKGROUND: Although body mass index (BMI) is the most widely accepted parameter for defining obesity, recent studies have indicated a unique set of patients who exhibit normal BMI and excess body fat (BF), which is termed as normal weight obesity (NWO). Increased BF is an established risk factor for atherosclerosis. However, it is unclear whether NWO subjects already have a higher degree of vascular inflammation compared to normal weight lean (NWL) subjects; moreover, the association of BF with vascular inflammation in normal weight subjects is largely unknown. METHODS: NWO and NWL subjects (n = 82 in each group) without any history of significant vascular disease were identified from a 3-year database of consecutively recruited patients undergoing 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG-PET/CT) at a self-referred Healthcare Promotion Program. The degree of subclinical vascular inflammation was evaluated using the mean and maximum target-to-background ratios (TBRmean and TBRmax) of the carotid artery, which were measured by 18 F-FDG-PET/CT (a noninvasive tool for assessing vascular inflammation). RESULTS: We found that metabolically dysregulation was greater in NWO subjects than in NWL subjects, with a significantly higher blood pressure, higher fasting glucose level, and worse lipid profile. Moreover, NWO subjects exhibited higher TBR than NWL subjects (TBRmean: 1.33 ± 0.16 versus 1.45 ± 0.19, p < 0.001; TBRmax: 1.52 ± 0.23 versus 1.67 ± 0.25, p < 0.001). TBR was significantly associated with total BF (TBRmean: r = 0.267, p = 0.001; TBRmax: r = 0.289, p < 0.001), age (TBRmean: r = 0.170, p = 0.029; TBRmax: r = 0.165, p = 0.035), BMI (TBRmean: r = 0.184, p = 0.018; TBRmax: r = 0.206, p = 0.008), and fasting glucose level (TBRmean: r = 0.157, p = 0.044; TBRmax: r = 0.182, p = 0.020). In multiple linear regression analysis, BF was an independent determinant of TBRmean and TBRmax, after adjusting for age, BMI, and fasting glucose level (TBRmean: regression coefficient = 0.020, p = 0.008; TBRmax: regression coefficient = 0.028, p = 0.005). Compared to NWL, NWO was also independently associated with elevated TBRmax values, after adjusting for confounding factors (odds ratio = 2.887, 95% confidence interval 1.206-6.914, p = 0.017). CONCLUSIONS: NWO is associated with a higher degree of subclinical vascular inflammation, of which BF is a major contributing factor. These results warrant investigations for subclinical atherosclerosis in NWO patients.

Discovery of (E)-5-(benzylideneamino)-1H-benzo[d]imidazol-2(3H)-one derivatives as inhibitors for PTK6.

A lead compound 1, which inhibits the catalytic activity of PTK6, was selected from a chemical library. Derivatives of compound 1 were synthesized and analyzed for inhibitory activity against PTK6 in vitro and at the cellular level. Selected compounds were analyzed for cytotoxicity in human foreskin fibroblasts using MTT assays and for selectivity towards PTK members in HEK 293 cells. Compounds 20 (in vitro IC50=0.12µM) and 21 (in vitro IC50=0.52µM) showed little cytotoxicity, excellent inhibition of PTK6 in vitro and at the cellular level, and selectivity for PTK6. Compounds 20 and 21 inhibited phosphorylation of specific PTK6 substrates in HEK293 cells. Thus, we have identified novel PTK6 inhibitors that may be used as treatments for PTK6-positive carcinomas, including breast cancer.

Adipose-derived stem cells ameliorate allergic airway inflammation by inducing regulatory T cells in a mouse model of asthma.

Although several studies have demonstrated that mesenchymal stem cells derived from adipose tissue (ASCs) can ameliorate allergic airway inflammation, the immunomodulatory mechanism of ASCs remains unclear. In this study, we investigated whether regulatory T cells (Tregs) induction is a potential mechanism in immunomodulatory effects of ASCs on allergic airway disease and how these induced Tregs orchestrate allergic inflammation. Intravenous administration of ASCs significantly reduced allergic symptoms and inhibited eosinophilic inflammation. Airway hyperresponsiveness, total immune cell and eosinophils in the bronchoalveolar lavage fluid, mucus production, and serum allergen-specific IgE and IgG1 were significantly reduced after ASCs administration. ASCs significantly inhibited Th2 cytokines (IL-4, IL-5, and IL-13) and enhanced Th1 cytokine (IFN-γ) and regulatory cytokines (IL-10 and TGF-ß) in the bronchoalveolar lavage fluid and lung draining lymph nodes. Furthermore, levels of IDO, TGF-ß, and PGE2 were significantly increased after ASCs administration. Interestingly, this upregulation was accompanied by increased Treg populations. In conclusion, ASCs ameliorated allergic airway inflammation and improved lung function through the induction of Treg expansion. The induction of Treg by ASCs involves the secretion of soluble factors such as IDO, TGF-ß, and PGE2 and Treg might be involved in the downregulation of Th2 cytokines and upregulation of Th1 cytokines production.

Efficacy and Safety of IDegAsp in a Real-World Korean Population with Type 2 Diabetes Mellitus.

Background: This study investigated the real-world efficacy and safety of insulin degludec/insulin aspart (IDegAsp) in Korean adults with type 2 diabetes mellitus (T2DM), whose insulin treatment was switched to IDegAsp. Methods: This was a multicenter, retrospective, observational study comprising two 26-week treatment periods, before and after switching to IDegAsp, respectively. Korean adults with uncontrolled T2DM treated with basal or premix insulin (±oral antidiabetic drugs) were enrolled. The primary objective was to compare the degree of glycosylated hemoglobin (HbA1c) change in each 26-week observation period. The analyses included changes in HbA1c, fasting plasma glucose (FPG), body weight, proportion of participants achieving HbA1c <7.0%, hypoglycemic events, and total daily insulin dose (ClinicalTrials.gov, number NCT04656106). Results: In total, 196 adults (mean age, 65.95 years; mean T2DM duration, 18.99 years) were analyzed. The change in both HbA1c and FPG were significantly different between the pre-switching and the post-switching period (0.28% vs. -0.51%, P<0.001; 5.21 mg/dL vs. -23.10 mg/dL, P=0.005), respectively. After switching, the rate of achieving HbA1c <7.0% was significantly improved (5.10% at baseline vs. 11.22% with IDegAsp, P=0.012). No significant differences (before vs. after switching) were observed in body weight change, and total daily insulin dose. The rates of overall and severe hypoglycemia were similar in the two periods. Conclusion: In real-world clinical practice in Korea, the change of insulin regimen to IDegAsp was associated with an improvement in glycemic control without increase of hypoglycemia, supporting the use of IDegAsp for patients with T2DM uncontrolled with basal or premix insulin.

PTK6 promotes degradation of c-Cbl through PTK6-mediated phosphorylation.

PTK6 (also known as Brk) is an intracellular tyrosine kinase which induces proliferation, anti-apoptosis, migration, and anchorage-independent growth. Herein we report that PTK6 phosphorylates and down-regulates E3 ubiquitin ligase c-Cbl. Tyr(700), Tyr(731), and Tyr(774) residues in the C-terminal domain of c-Cbl are major phosphorylation sites targeted by PTK6. The phosphorylated c-Cbl is subjected to auto-ubiquitination and degraded through the ubiquitin-proteasome pathway. These results provide evidence for a novel mechanism demonstrating the oncogenic potential of PTK6 through degradation of c-Cbl, which is an E3 ligase important in down-regulation of oncoproteins.

Hsp90 rescues PTK6 from proteasomal degradation in breast cancer cells.

PTK6 [protein tyrosine kinase 6; also known as Brk (breast tumour kinase)] is a non-receptor tyrosine kinase, closely related to Src, but evolutionarily distinct, that is up-regulated in various cancers, including breast cancer. Hsp90 (heat-shock protein 90) was identified as a PTK6-interacting protein in HEK (human embryonic kidney)-293 cells overexpressing PTK6. Hsp90 interacted with the PTK6 tyrosine kinase catalytic domain, but catalytic activity was not required for the interaction. Geldanamycin, an Hsp90 inhibitor, significantly decreased the PTK6 protein level through proteasome-dependent degradation, but did not affect the level of Src. Geldanamycin treatment also decreased phosphorylation of PTK6 substrates due to reduced amounts of PTK6. Moreover, overexpression of CHIP [C-terminus of Hsc70 (heat-shock cognate 70)-interacting protein], a chaperone-dependent E3 ligase, enhanced proteosomal degradation of PTK6. Geldanamycin increased the interaction of PTK6 with CHIP, but decreased the interaction of PTK6 with Hsp90. We also found that endogenous PTK6 associated with Hsp90 and geldanamycin decreased expression of endogenous PTK6 in breast carcinoma cells. Finally, we report that silencing endogenous CHIP expression in breast carcinoma cells inhibited geldanamycin-induced PTK6 reduction. These results demonstrate that Hsp90 plays an essential role in regulating PTK6 stability and suggest that Hsp90 inhibitors may be useful as therapeutic drugs for PTK6-positive cancers, including breast cancer.

Dyslipidemia Fact Sheet in South Korea, 2022.

BACKGRUOUND: This study aimed to investigate the prevalence and status of dyslipidemia management among South Korean adults, as performed by the Korean Society of Lipid and Atherosclerosis under the name Dyslipidemia Fact Sheet 2022. METHODS: We analyzed the lipid profiles, age-standardized and crude prevalence, management status of hypercholesterolemia and dyslipidemia, and health behaviors among Korean adults aged ≥20 years, using the Korea National Health and Nutrition Examination Survey data between 2007 and 2020. RESULTS: In South Korea, the crude prevalence of hypercholesterolemia (total cholesterol ≥240 mg/dL or use of a lipid-lowering drug) in 2020 was 24%, and the age-standardized prevalence of hypercholesterolemia more than doubled from 2007 to 2020. The crude treatment rate was 55.2%, and the control rate was 47.7%. The crude prevalence of dyslipidemia-more than one out of three conditions (low-density lipoprotein cholesterol ≥160 or the use of a lipid-lowering drug, triglycerides ≥200, or high-density lipoprotein cholesterol [HDL-C] [men and women] <40 mg/dL)-was 40.2% between 2016 and 2020. However, it increased to 48.2% when the definition of hypo-HDL-cholesterolemia in women changed from <40 to <50 mg/dL. CONCLUSION: Although the prevalence of hypercholesterolemia and dyslipidemia has steadily increased in South Korea, the treatment rate remains low. Therefore, continuous efforts are needed to manage dyslipidemia through cooperation between the national healthcare system, patients, and healthcare providers.