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Liriope platyphyllahas been reported to possess various biological activities, including anti-asthma, anti-inflammation, anti-diabetes, and neuriotogenic properties. In this study, we evaluated the effects of prosapogenin III isolated from the roots ofL. platyphylla(Liriopis Tuber) on inflammatory responses in lipopolysaccharide (LPS) stimulated RAW264.7 mouse macrophages. We investigated LPS-induced production/expression of inflammatory mediators such as nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxigenase-2 (COX-2), and proinflammatory cytokines, including interleukin-1β (IL-1β) and interleukin (IL)-6 in RAW264.7 cells. We also performed Western blot analysis for determination of the phosphorylation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK) 1/2, p38, and c-Jun N-terminal kinase (JNK), and nuclear translocation of nuclear factor-κB (NF-κB) in LPS-stimulated cells. Treatment with prosapogenin III resulted in significant inhibition of NO production in LPS-stimulated Raw264.7 cells through suppression of iNOS expression. Treatment with prosapogenin III resulted in a significant decrease in expressions of COX-2, IL-1β, and IL-6 through down-regulation of their mRNA or protein in LPS-stimulated cells. In addition, treatment with prosapogenin III resulted in potently inhibited phosphorylation of three MAPKs, including ERK1/2, p38, and JNK in LPS-stimulated cells. Treatment with prosapogenin III also resulted in suppression of the nuclear translocation of NF-κB in LPS-stimulated cells. These results indicate that prosapogenin III of Liriopis Tuber has anti-inflammatory effects in activated macrophages through inhibition of production of inflammatory mediators by blockade of the MAPK/NF-κB pathway. [ABSTRACT FROM PUBLISHER]

Objectives: To directly compare the effectiveness of HbA1c reduction between two distinct SGLT2 inhibitors, Empagliflozin (EMPA, 25 mg/day) and Dapagliflozin (DAPA, 10 mg/day), as part of a quadruple OAD drug regimen. Research Design and Methods: This study was an open-labeled, prospective, observational, 52-week study conducted in a clinical practice. T2D patients (HbA1c, 7.5-12.0%) with three different OADs (metformin, glimepiride, and dipeptidyl peptidase-4 inhibitors) were enrolled to either EMPA or DAPA. The outcome measures included changes in HbA1c, fasting plasma glucose (FPG), and cardiometabolic variables at week 52 and the safety outcomes of treatment-emergent adverse events. Results: In total, 350 patients were enrolled with EMPA (N=176) and DAPA (N=174), respectively. After 52 weeks, both groups showed significant reductions (P <0.001) in HbA1c and FPG, but the reduction was greater in the EMPA group. In addition, both groups showed decreased blood pressure and body weight with improved liver function, and high-density lipoprotein cholesterol levels were significantly increased in the EMPA (1.9 ± 5.7 mg/dl, P <0.001 and 0.6 ± 4.5 mg/dl, P = 0.157, respectively) (between groups, P = 0.035). Both groups were well tolerated with overall similar safety profiles. Conclusions: Our present study demonstrated that SGLT2 inhibitors can be safely and effectively used as a fourth OAD in T2D patients who are already being treated with three other OADs to control their hyperglycemia. More specifically, Empagliflozin was more effective in reducing HbA1c and improving other cardiometabolic parameters affecting patient health in T2D. Our findings show that 4 different OADs can be used as a viable therapeutic regimen to treat T2D, especially in patients who are unwilling to use injectable therapies as their alternate method to control blood glucose. Disclosure: E. Ku: None. D. Lee: None. H. Jeon: None. T. Oh: None. [ABSTRACT FROM AUTHOR]

Background: Diabetes is recognized as a risk factor for various inflammatory conditions, including periodontitis. There exists a bidirectional relationship between glycemic control and oral health in individuals with diabetes. This study aimed to analyze the link between glycemic control and oral health status among Korean patients with diabetes., Methods: Using data from a population-based nationwide survey conducted between 2007 and 2019, we identified 70,554 adults with diabetes-related information. The study population included 9,090 individuals diagnosed with diabetes and 61,164 healthy controls. The association between glycemic control, defined by mean glycated hemoglobin (HbA1c) values, and various oral health measures, such as tooth brushing frequency, periodontitis, denture wearing, Decayed, Missing, and Filled Teeth (DMFT) index, number of remaining teeth, and past-year dental clinic visits, was evaluated using multivariate logistic regression analyses., Results: Compared to the control group, patients with diabetes exhibited a higher prevalence of periodontitis (88.6% vs. 73.3%), complete dentures (5.0% vs. 1.5%), and elevated DMFT index (33.2% vs. 26.7%) (all P < 0.001). Multivariate analyses revealed significant associations between diabetes and several oral health factors: denture status (No denture: adjusted odds ratio [aOR], 0.784; 95% confidence interval [CI], 0.627-0.979), and having fewer permanent teeth (0-19) (aOR, 1.474; 95% CI, 1.085-2.003). Additionally, a positive correlation was found between higher HbA1c levels and the risk of having fewer remaining teeth (0-19) (HbA1c < 6.5%: aOR, 1.129; 95% CI, 0.766-1.663; 6.5% ≤ HbA1c < 8.0%: aOR, 1.590; 95% CI, 1.117-2.262; HbA1c ≥ 8%: aOR, 1.910; 95% CI, 1.145-3.186) ( P for trends = 0.041)., Conclusion: We found a positive association between diabetes and poor oral health, as well as a noteworthy relationship between reduced permanent teeth (≤ 19) and glycemic control. These insights emphasize the critical role of oral health management in diabetic care and underscore the importance of maintaining effective glycemic control strategies for overall health and well-being in patients with diabetes., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Background: Adrenal venous sampling (AVS) is performed to distinguish the subtype of primary aldosteronism (PA). The clinical implication of contralateral suppression (CS; aldosterone/cortisolnondominant0.26 after adjusting for other factors., Conclusion: CS may not predict postoperative clinical and biochemical outcomes in subjects with unilateral aldosterone excess, but it is associated with postsurgical deterioration of renal function in subjects over 50 years with CSI ≤0.26.

Introduction: Monogenic diabetes is attributed to genetic variations in a single gene. Maturity-onset diabetes of the young (MODY) is the most common phenotype associated with monogenic diabetes, but is frequently misdiagnosed as either type 1 or type 2 diabetes. Increasing our basic understanding of genetic variations in MODY may help to improve the accuracy of providing the correct diagnosis and personalize subsequent treatment regimens in different racial populations. For this reason, this study was designed to identify nucleotide variants in early onset diabetes patients with clinically suspected MODY in a Korean population., Research Design and Methods: Among 2908 Korean patients diagnosed with diabetes, we selected 40 patients who were diagnosed before 30 years old and were clinically suspected of MODY. Genetic testing was performed using a targeted gene sequencing panel that included 30 known monogenic diabetes genes. The pathogenicity of the identified variants was assessed according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG-AMP) guidelines., Results: A total of six rare missense variants (p.Ala544Thr in HNF1A, p.Val601Ile and p.His103Tyr in ABCC8, p.Pro33Ala in PDX1, p.Gly18Glu in INS, and p.Arg164Gln in PAX4) in five distinct MODY genes were identified in five patients. In addition, a variant was identified in mitochondrial DNA at 3243A>G in one patient. The identified variants were either absent or detected at a rare frequency in the 1000 Genomes Project. These variants were classified as uncertain significance using the ACMG-AMP guidelines., Conclusion: Using a targeted gene sequencing panel, we identified seven variants in either MODY genes or mitochondrial DNA using a Korean patient population with early onset diabetes who were clinically suspected of MODY. This genetic approach provides the ability to compare distinct populations of racial and ethnic groups to determine whether specific gene is involved in their diagnosis of MODY., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: A psychometric analysis on type 2 diabetic (T2D) patients was performed to assess whether glycated hemoglobin (HbA1c) levels were dependent upon either the psychologic or economic attitude toward the use of insulin as a treatment for their diabetic condition., Methods: A cross-sectional study was designed using 271 patients with T2D who regularly visited a tertiary referral hospital in South Korea from June 2019 to December 2019. Each patient enrolled in this protocol was treated with insulin for at least 6 months, had recordings of their plasma HbA1c measurement, and completed validated questionnaires consisting of items focusing on patient attitudes toward insulin use [Insulin Treatment Appraisal Scale (ITAS)] and cost-related issues related to diabetic supply purchase. Multiple regression analyses were performed to determine the association between their HbA1c and each item on the questionnaires., Results: In both males and females, there was a significant association (P < 0.05) between HbA1c levels and multiple items on the ITAS questionnaire, which are generally regarded as a negative perception (ITAS 1 "personal failure" and ITAS 2 "illness severity" in males and ITAS 12 "expected harm" and ITAS 15 "restrictiveness" in females). In females, however, not all perceptions were negative, since one item (ITAS 8 "anticipated effect") was correlated with the measurement of a lower HbA1c level (- 0.495 ± 0.211, P < 0.05). There was no association between the levels of HbA1c and the cost of insulin or associated diabetic supplies. Since only a few patients in this study chose to reduce their drug dosing because of cost, the resistance to using insulin is likely not driven by economic reasons., Conclusion: The psychometric results of the ITAS suggested that HbA1c levels were directly associated with a positive attitude of the patient to willingly use insulin for therapy. The cost of the insulin therapy was not associated with HbA1c levels. These findings in the Korean population suggest that continued education is needed to ensure that T2D patients have a reinforced positive psychology toward the use of insulin in the control of their glycemia.

The tuberous roots of Liriope platyphylla (Liriopis Tuber; LT) is traditionally used in Korean Medicine for treating colds, cough, and sputum production. In this study, we investigated the effect of spicatoside A isolated from LT methanol extract on ovalbumin (OVA)-sensitized/challenged asthmatic mice. For induction of allergic asthma, BALB/c mice were sensitized with OVA by an intraperitoneal injection at three times a week, and then challenged into the nasal cavities using a nebulizer. Spicatoside A at dose of 1mg/kg body weight was treated in mice with an oral administration once daily for a week during OVA challenge. The concentrations of OVA-specific IgE, IL-4, IL-5 and IL-13 were measured in the sera or bronchoalveolar lavage fluids (BALF) of mice by enzyme-linked immunosorbent assay (ELISA). The numbers of total cells, macrophages, lymphocytes, neutrophils and eosinophils were counted in BALFs using Diff-Quik staining, and histopathological changes of lung tissues were observed by hematoxylin and eosin (H&E), Periodic acid Schiff (PAS) and Masson's trichrome staining. The purity of spicatoside A was 98.1% with a white powder (yield: 465.6mg). The treatment of spicatoside A in asthmatic mice significantly decreased the production of allergic mediator, OVA-specific IgE and Th2 cytokines, IL-4, IL-5 and IL-13 in sera and BALF. The numbers of inflammatory cells such as macrophages, lymphocytes, neutrophils and eosinophils in BALF of asthmatic mice were significantly reduced by the treatment of spicatoside A. Furthermore, the treatment of spicatoside A in asthmatic mice inhibited the structural damages of lung tissues with thickened bronchiolar epithelium and infiltration of inflammatory cells, the accumulation of mucus by the goblet cells hyperplasia and collagen in the bronchioles. These results suggest that spicatoside A of LT has a preventive effect on allergic asthma through the inhibition of lung inflammation and allergic response.

Background: Diabetic nephropathy (DN) is the most serious microvascular complication of diabetes mellitus and is one of the leading causes of end stage renal failure. In previous studies, the contribution of genetic susceptibility to DN showed inconsistent results. In this study, we investigated the association between the solute carrier family 2 facilitated glucose transporter member 1 (SLC2A1) HaeIII polymorphism and DN in Korean patients with type 2 diabetes mellitus (T2DM) according to disease duration., Methods: A total of 846 patients with T2DM (mean age, 61.3 ± 12.3 years; mean duration of T2DM, 10.3 ± 7.9 years; 55.3% men) who visited the Chungbuk National University Hospital were investigated. The HaeIII polymorphism of the SLC2A1 gene was determined by the real time polymerase chain reaction method. Genotyping results were presented as GG, AG, or AA. A subgroup analysis was performed according to duration of T2DM (≤ 10 years, > 10 years)., Results: The AG + AA genotype showed a significantly higher risk of DN compared with the GG genotype in patients with a type 2 DM duration less than 10 years (12.4% vs. 4.2%; P < 0.001). No significant differences were observed in terms of other diabetic complications, including retinopathy, peripheral neuropathy, cardiovascular disease, cerebrovascular disease or peripheral artery disease, according to the genotypes of the SLC2A1 HaeIII polymorphism., Conclusion: The SLC2A1 HaeIII polymorphism was associated with DN in Korean patients with T2DM, particularly in the group with a relatively short disease duration., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2019 The Korean Academy of Medical Sciences.)

Aims: To directly compare the effectiveness and safety between two distinct sodium-glucose co-transporter 2 (SGLT2) inhibitors, empagliflozin and dapagliflozin, as part of a quadruple oral antidiabetic agents (OADs) in patients with inadequately controlled type 2 diabetes (T2D)., Methods: This study was an open-labeled, prospective, 52-week study conducted in T2D patients with glycated hemoglobin (HbA 1c ) ranging 7.5-12.0% with metformin, glimepiride and dipeptidyl peptidase-4 inhibitors. Patients were divided into either empagliflozin (25 mg/day) or dapagliflozin (10 mg/day). The outcome measures included changes in HbA 1c , fasting plasma glucose (FPG), and cardiometabolic variables and the safety profiles., Results: In total, 350 patients were enrolled with empagliflozin (n = 176) and dapagliflozin (n = 174), respectively. After 52 weeks, both groups showed significant reductions in HbA 1c and FPG, but the reduction was greater in the empagliflozin group (P < 0.001). Both groups showed significantly decreased blood pressure and body weight and high-density lipoprotein cholesterol levels were increased in the empagliflozin (between groups, P = 0.035). Both groups showed similar safety profiles., Conclusions: Our study demonstrated that SGLT2 inhibitors can be effectively used as a fourth OAD in T2D patients who are treated with three other OADs. More specifically, empagliflozin was more effective in reducing HbA 1c and improving other cardiometabolic parameters than dapagliflozin. Clinical Trial Number NCT03748810 (ClinicalTrials.gov)., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In response to genotoxic stress, the tumor suppressor protein p73 induces apoptosis and cell cycle arrest. Despite extensive studies on p73-mediated apoptosis, little is known about the cytoplasmic apoptotic function of p73. Here, using H1299 lung cancer cells and diverse biochemical approaches, including colony formation, DNA fragmentation, GST pulldown, and apoptosis assays along with NMR spectroscopy, we show that p73 induces transcription-independent apoptosis via its transactivation domain (TAD) through a mitochondrial pathway and that this apoptosis is mediated by the interaction between p73-TAD and the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-X L or BCL2L1). This binding disrupted an interaction between Bcl-X L and the pro-apoptotic protein BH3-interacting domain death agonist (Bid). In particular, we found that a 16-mer p73-TAD peptide motif (p73-TAD16) mediates transcription-independent apoptosis, accompanied by cytochrome c release from the mitochondria, by interacting with Bcl-X L Interestingly, the structure of the Bcl-X L -p73-TAD16 peptide complex revealed a novel mechanism of Bcl-X L recognition by p73-TAD. We observed that the α-helical p73-TAD16 peptide binds to a noncanonical site in Bcl-X L , comprising the BH1, BH2, and BH3 domains in an orientation opposite to those of pro-apoptotic BH3 peptides. Taken together, our results indicate that the cytoplasmic apoptotic function of p73 is mediated through a noncanonical mode of Bcl-X L recognition. This finding sheds light on a critical transcription-independent, p73-mediated mechanism for apoptosis induction, which has potential implications for anticancer therapy., (© 2018 Yoon et al.)

Background: Symptoms and signs of thyrotoxicosis are nonspecific and assessing its clinical status is difficult with conventional physical examinations and history taking. Increased heart rate (HR) is one of the easiest signs to quantify this, and current wearable devices can monitor HR., Objective: We assessed the association between thyroid function and resting HR measured by a wearable activity tracker (WD-rHR) and evaluated the clinical feasibility of using this method in patients with thyrotoxicosis., Methods: Thirty patients with thyrotoxicosis and 10 controls were included in the study. Participants were instructed to use the wearable activity tracker during the study period so that activity and HR data could be collected. The primary study outcomes were verification of changes in WD-rHR during thyrotoxicosis treatment and associations between WD-rHR and thyroid function. Linear and logistic model generalized estimating equation analyses were performed and the results were compared to conventionally obtained resting HR during clinic visits (on-site resting HR) and the Hyperthyroidism Symptom Scale., Results: WD-rHR was higher in thyrotoxic patients than in the control groups and decreased in association with improvement of thyrotoxicosis. A one standard deviation-increase of WD-rHR of about 11 beats per minute (bpm) was associated with the increase of serum free T4 levels (beta=.492, 95% CI 0.367-0.616, P<.001) and thyrotoxicosis risk (odds ratio [OR] 3.840, 95% CI 2.113-6.978, P<.001). Although the Hyperthyroidism Symptom Scale showed similar results with WD-rHR, a 1 SD-increase of on-site rHR (about 16 beats per minute) showed a relatively lower beta and OR (beta=.396, 95% CI 0.204-0.588, P<.001; OR 2.114, 95% CI 1.365-3.273, P<.001) compared with WD-rHR., Conclusions: Heart rate data measured by a wearable device showed reasonable predictability of thyroid function. This simple, easy-to-measure parameter is clinically feasible and has the potential to manage thyroid dysfunction., Trial Registration: ClinicalTrials.gov NCT03009357; https://clinicaltrials.gov/ct2/show/NCT03009357 (Archived by WebCite at http://www.webcitation.org/70h55Llyg)., (©Jie-Eun Lee, Dong Hwa Lee, Tae Jung Oh, Kyoung Min Kim, Sung Hee Choi, Soo Lim, Young Joo Park, Do Joon Park, Hak Chul Jang, Jae Hoon Moon. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 13.07.2018.)

Background and Objectives: This study aimed to evaluate malnutrition prevalence and usefulness of the body mass index (BMI) in the assessment of malnutrition in hospitalized elderly patients with adrenal insufficiency (AI)., Methods and Study Design: 318 hospitalized AI patients were diagnosed by a rapid ACTH stimulation test with a history of steroid treatment and compared with 374 control patients. Nutrition was assessed using the Malnutrition Universal Screening Tool (MUST). Nutritional status was evaluated using the Mini Nutritional Assessment short form (MNA-SF) and BMI., Results: There was no difference in nutritional screening between the AI and control groups. Nutritional assessments indicated that 31.2% of all elderly patients suffered from malnutrition and 33.8% of patients were at risk of malnutrition. Less than half of the patients (34.9%) were identified as well nourished. In this study, 33.6% vs 29.1% of patients were malnourished in the AI and control group, respectively. Overall, prevalence of malnutrition was higher in the AI group than the control group. In the AI group, patients with low basal cortisol had a higher incidence of malnutrition than those with high basal cortisol. The BMI of patients in the AI group was higher than in the control group. According to BMI criteria, 64.3% of malnourished patients were overweight or obese in the AI group., Conclusions: Elderly AI patients are prone to develop malnutrition despite being overweight or obese. Therefore, more extensive nutritional assessment of elderly patients with AI is required regardless of BMI.

Objectives: The relationship between the renin-angiotensin system (RAS) and diabetes has been studied for many years. However, studies that assessed RAS components comprehensively were limited. We hypothesized that serum RAS components, especially the effector peptide angiotensin-II, might be closely associated with glucose metabolism status and diabetic complications., Methods: We investigated the association of individual RAS component with albuminuria in 407 subjects with normal glucose metabolism (NGM), prediabetes, or type 2 diabetes mellitus (T2DM). Anthropometric and biochemical parameters, including glucose homeostasis, albuminuria, and RAS-related parameters such as plasma renin activity (PRA), aldosterone, angiotensin-converting enzyme (ACE), and angiotensin-II levels, were measured., Results: The mean±standard deviation (SD) age and body mass index were 57.1±11.1years and 24.7±3.3kg/m 2 , respectively. There were 54 subjects with NGM, 102 with prediabetes, and 251 with T2DM. The mean±SD angiotensin-II levels in these groups were 9.32±6.89, 12.89±10.39, and 17.00±15.28pg/mL, and the respective urinary albumin-to-creatinine ratios (ACRs) were 8.1±5.3, 13.3±17.3, and 30.7±51.9mg/g, which were significantly different among the groups. The serum angiotensin-II levels were correlated with levels of PRA, insulin resistance, C-reactive protein, and urinary ACR. Among RAS-related parameters, only the angiotensin-II level was significantly associated with urinary ACR after adjusting for relevant risk factors., Conclusions: Angiotensin-II may play an important role in the development of albuminuria, particularly in subjects with impaired glucose metabolism., (Copyright © 2017 Elsevier Inc. All rights reserved.)

There have been few reports on changes in bone geometry in asymptomatic patients with primary hyperparathyroidism (PHPT) not treated surgically. We reviewed the records concerning biochemical parameters, bone mineral density (BMD), and hip geometry in 119 PHPT patients who did not undergo parathyroidectomy, followed up at one of three hospitals affiliated to Seoul National University from 1997 to 2013. We examined biochemical parameters over 7 years and BMD and hip geometry over 5 years of follow-up. We further compared hip geometry and BMD derived from dual-energy X-ray absorptiometry (DXA) between patients and age- and sex-matched controls. The median follow-up duration of 56 patients for whom surgery was not indicated was 33.9 months (range 11.2-131.2 months), and 19.6 % of these patients had disease progression during follow-up. Serum calcium levels remained stable for 7 years in all 119 patients. From a comparison of the PHPT patients for whom surgery was not indicated with controls, both male and postmenopausal female patients had significantly lower hip axis length (P < 0.001), cross-sectional moment of inertia (P < 0.001), cross-sectional area (P < 0.001), and section modulus (P < 0.001). In addition, cortical thickness was significantly decreased at 5 years compared with individual baseline values (P = 0.003). However, there was no significant change in BMD for the duration of the 5-year follow-up. DXA-derived geometry can detect skeletal change in asymptomatic PHPT patients for whom surgery is not indicated, supporting the concept that even mild PHPT can eventually compromise the cortical bones. Hip geometry is a potential tool for monitoring skeletal complication in asymptomatic PHPT patients.

Aims: Enhancement of glucagon-like peptide-1 (GLP-1) reduces glucose levels and preserves pancreatic β-cell function, but its effect against restenosis is unknown., Methods and Results: We investigated the effect of subcutaneous injection of exenatide or local delivery of a recombinant adenovirus expressing GLP-1 (rAd-GLP-1) into carotid artery, in reducing the occurrence of restenosis following balloon injury. As a control, we inserted β-galactosidase cDNA in the same vector (rAd-βGAL). Otsuka Long-Evans Tokushima rats were assigned to three groups (n = 12 each): (1) normal saline plus rAd-βGAL delivery (NS + rAd-βGAL), (2) exenatide plus rAd-βGAL delivery (Exenatide + rAd-βGAL), and (3) normal saline plus rAd-GLP-1 delivery (NS + rAd-GLP-1). Normal saline or exenatide were administered subcutaneously from 1 week before to 2 weeks after carotid injury. After 3 weeks, the NS + rAd-βGAL group showed the highest intima-media ratio (IMR; 3.73 ± 0.90), the exenatide + rAd-βGAL treatment was the next highest (2.80 ± 0.51), and NS + rAd-GLP-1 treatment showed the lowest IMR (1.58 ± 0.48, P < 0.05 vs. others). The proliferation and migration of vascular smooth muscle cells and monocyte adhesion were decreased significantly after rAd-GLP-1 treatment, showing the same overall patterns as the IMR. In injured vessels, the apoptosis was greater and MMP2 expression was less in the NS + rAd-GLP-1 than in the exenatide or rAd-βGAL groups. In vitro expressions of matrix metalloproteinases-2 and monocyte chemoattractant protein-1 and nuclear factor-kappa-B-p65 translocation were decreased more in the NS + rAd-GLP-1 group than in the other two groups (all P < 0.05)., Conclusion: Direct GLP-1 overexpression showed better protection against restenosis after balloon injury via suppression of vascular smooth muscle cell migration, increased apoptosis, and decreased inflammatory processes than systemic exenatide treatment. This has potential therapeutic implications for treating macrovascular complications in diabetes., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions, please email: journals.permissions@oup.com.)

Aims/hypothesis: A recent large clinical study has shown that empagliflozin has a lower rate of cardiovascular and all-cause mortality when compared with placebo in patients with type 2 diabetes. We investigated the effect of empagliflozin (compared with glimepiride) on the progression of atherosclerosis, and its possible mechanisms of action., Methods: Forty-eight 5-week-old male ApoE -/- mice were fed a western diet for 20 weeks and divided into four groups: control (saline, 154 mmol/l NaCl), glimepiride 0.1 mg/kg, empagliflozin 1 mg/kg and empagliflozin 3 mg/kg (n = 12/group). Plaque size and composition in the aortic arch/valve areas and cardiovascular risk variables in the blood and tissues were evaluated. Insulin resistance was estimated by HOMA and adiponectin levels. Body composition was determined using dual-energy x-ray absorptiometry., Results: After 8 weeks of treatment, the empagliflozin and glimepiride groups exhibited decreased blood glucose levels. Atherosclerotic plaque areas in the aortic arch/valve were significantly smaller in the empagliflozin groups than in the control or glimepiride groups. Insulin resistance and circulating concentrations of TNF-α, IL-6, monocyte chemoattractant protein-1 (MCP-1), serum amyloid A and urinary microalbumin decreased after empagliflozin treatment, and this significantly correlated with plaque size. Empagliflozin treatment reduced weight and fat mass, lipid droplets in the liver, fat cell size, mRNA expression of Tnf, Il6 and Mcp-1 (also known as Ccl2) and the infiltration of inflammatory cells in plaque and adipose tissue compared with the control or glimepiride group. Empagliflozin treatment increased adiponectin levels., Conclusions/interpretation: Improvements in inflammation and insulin resistance seem to be mechanisms involved in the mitigation of atherosclerosis by empagliflozin.

Background: Early detection of atherogenic dyslipidemia is crucial. We investigated lipoprotein subfraction parameters according to glucose metabolism status., Methods: We recruited 1255 lipid-lowering drug-naïve subjects with normal fasting glucose (NFG; n=200, 15.9%), impaired fasting glucose (IFG; n=443, 35.3%), or type 2 diabetes (T2D; n=612, 48.8%). Lipoprotein subfractions (1-7) were determined by polyacrylamide gel electrophoresis, separating low-density lipoprotein (LDL) into large buoyant LDL (lbLDL, LDL1-2) and small dense LDL (sdLDL, LDL3-7). Lipoprotein subfraction parameters including the sdLDL% (LDL3-7/LDL1-7), the sdLDL/lbLDL ratio (LDL3-7/LDL1-2), and weighted LDL subfraction (LDLSF) scores, were compared between groups. Their associations with insulin resistance, estimated using the homeostasis model assessment of insulin resistance, were examined., Results: The concentrations of sdLDL particles were significantly higher in subjects with T2D and IFG than in those with NFG (15.78±13.47mg/dl and 14.60±14.33mg/dl, respectively, vs. 12.22±12.31mg/dl). Compared with those with NFG, subjects with IFG or T2D had significantly a higher sdLDL% (15.98±15.26% vs. 19.50±16.21% or 21.46±16.81%, respectively), a higher sdLDL/lbLDL ratio (0.24±0.30 vs. 0.31±0.37 or 0.35±0.39), and a higher LDLSF score (2.08±0.91 vs. 2.30±1.14 or 2.36±1.17). These lipoprotein subfraction parameters had stronger associations with insulin resistance compared to conventional lipid profiles in the IFG and T2D groups., Conclusions: Atherogenic dyslipidemia is initiated in an early stage of impaired glucose metabolism, when early intervention might be required., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To compare the accuracy of abdominal visceral fat area (VFA) measurements between abdominal dual bioelectrical impedance analysis (BIA) and whole-body BIA referenced to computed tomography (CT) measures., Methods: Abdominal VFAs were measured in 102 individuals: 59 men and 43 women with a mean age of 44.2 ± 16.3 years (range 21 - 76), body mass index 23.9 ± 7.8 kg/m(2) (range 18 - 35) using a DUALSCAN HDS-2000 machine (dual abdominal BIA) and an InBody720 machine (whole-body BIA). The VFA values from each machine were compared with those from CT under various conditions., Results: Mean abdominal VFAs were 116 ± 69 cm(2) by CT, 89 ± 47 cm(2) by dual abdominal BIA, and 84 ± 33 cm(2) by whole-body BIA. The former measure showed a higher correlation with the CT measure than the latter (r=0.89 vs. r=0.64, P<0.001). Both BIA methods tended to underestimate abdominal VFAs compared with CT scans when CT VFA was not small. The dual abdominal BIA had less bias than the whole-body BIA in the assessment of VFAs. The whole-body BIA was affected by subcutaneous fat area., Conclusions: Dual BIA was more accurate in assessing abdominal VFA than whole-body BIA., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The molecular interaction between tumor suppressor p53 and the anti-apoptotic Bcl-2 family proteins plays an essential role in the transcription-independent apoptotic pathway of p53. In this study, we investigated the binding of p53 DNA-binding domain (p53DBD) with the anti-apoptotic Bcl-2 family proteins, Bcl-w, Mcl-1, and Bcl-2, using GST pull-down assay and NMR spectroscopy. The GST pull-down assays and NMR experiments demonstrated the direct binding of the p53DBD with Bcl-w, Mcl-1, and Bcl-2. Further, NMR chemical shift perturbation data showed that Bcl-w and Mcl-1 bind to the positively charged DNA-binding surface of p53DBD. Noticeably, the refined structural models of the complexes between p53DBD and Bcl-w, Mcl-1, and Bcl-2 showed that the binding mode of p53DBD is highly conserved among the anti-apoptotic Bcl-2 family proteins. Furthermore, the chemical shift perturbations on Bcl-w, Mcl-1, and Bcl-2 induced by p53DBD binding occurred not only at the p53DBD-binding acidic region but also at the BH3 peptide-binding pocket, which suggests an allosteric conformational change similar to that observed in Bcl-XL. Taken altogether, our results revealed a structural basis for a conserved binding mechanism between p53DBD and the anti-apoptotic Bcl-2 family proteins, which shed light on to the molecular understanding of the transcription-independent apoptosis pathway of p53.

Monoclonal antibodies are currently the most important pharmaceutical proteins, and the economic production of functional immunoglobulin G (IgG) is an important issue in biotechnology. Recent successes in the development of aglycosylated IgG variants that do not require glycosylation for effector functions have increased the use of Escherichia coli as an alternative host for economic production of IgG, instead of traditional mammalian host expression systems. Here, we have developed a new E. coli host-vector system for the high-level production of full-length IgG1 by examining (1) E. coli strains, (2) modification of 5' untranslated region sequences, and (3) co-expression of periplasmic foldase. With the engineered host-vector system, fed-batch cultivations were conducted at two different conditions, and under optimized conditions, up to 362 mg/L of full-length IgG1 could be produced in a relatively short-time (22 h) cultivation. The fully assembled IgG1 from fed-batch cultivation was purified with high purity and yield. With the purified IgG1, the specific bindings to an antigen, anthrax toxin PA, and to human neonatal Fc receptor were successfully demonstrated.

Breast cancer frequently spreads to bone. The interaction between bone metastases and microenvironment, referred as the "vicious cycle", increases both tumor burden and bone destruction. Therefore, inhibition at any point in this "vicious cycle" can reduce malignant osteolytic lesions in patients with advanced breast cancer. In this study, we evaluated whether tetrahydrofurofuran-type lignans derived from Magnoliae Flos, commonly used in traditional Asian medicine to treat inflammatory diseases, could block breast cancer-mediated bone loss. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin at noncytotoxic concentrations suppressed mRNA expression and secretion of osteolytic factor PTHrP in MDA-MB-231 metastatic human breast cancer cells. Fargesin inhibited TGF-β-stimulated cell viability, migration, and invasion and decreased TGF-β-induced PTHrP production in MDA-MB-231 cells. In addition, these lignans reduced RANKL/OPG ratio in PTHrP-treated hFOB1.19 human osteoblastic cells and inhibited RANKL-mediated osteoclast differentiation in mouse bone marrow macrophages. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin substantially reduced bone-resorbing activity of osteoclasts by inhibiting MMP-9 and cathepsin K activities. Furthermore, orally administered fargesin inhibited tumor growth and cancer-mediated bone destruction in mice with MDA-MB-231 cells injected into calvarial tissues. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin blocked initiation and progression of the "vicious cycle" between breast cancer metastases and bone microenvironment by inhibiting PTHrP production in breast cancer cells and osteoclastic bone resorption. Therefore, these tetrahydrofurofuran-type lignans have the potential to serve as beneficial agents to prevent and treat cancer-induced bone destruction in breast cancer patients.

In this study, we investigated the anticancer mechanism of akebia saponin PA (AS), a natural product isolated from Dipsacus asperoides in human gastric cancer cell lines. It was shown that AS-induced cell death is caused by autophagy and apoptosis in AGS cells. The apoptosis-inducing effect of AS was characterized by annexin V/propidium (PI) staining, increase of sub-G1 phase and caspase-3 activation, while the autophagy-inducing effect was indicated by the formation of cytoplasmic vacuoles and microtubule-associated protein 1 light chain-3 II (LC3-II) conversion. The autophagy inhibitor bafilomycin A1 (BaF1) decreased AS-induced cell death and caspase-3 activation, but caspase-3 inhibitor Ac-DEVD-CHO did not affect LC3-II accumulation or AS-induced cell viability, suggesting that AS induces autophagic cell death and autophagy contributes to caspase-3-dependent apoptosis. Furthermore, AS activated p38/c-Jun N-terminal kinase (JNK), which could be inhibited by BaF1, and caspase-3 activation was attenuated by both SB202190 and SP600125, indicating that AS-induced autophagy promotes mitogen-activated protein kinases (MAPKs)-mediated apoptosis. Taken together, these results demonstrate that AS induces autophagic and apoptotic cell death and autophagy plays the main role in akebia saponin PA-induced cell death., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Activators of PPAR have been demonstrated to inhibit the induction of VCAM-1 but not ICAM-1 in human endothelial cells (EC). During the screening of anti-inflammatory activity of traditional herbs, we found 7,8-didehydrocimigenol (7,8-DHC), one of active triterpenoids of Cimicifugae rhizoma (C. rhizoma) increases PPAR-γ expression in EC in a time- and dose-dependent manner. Therefore, we asked whether 7,8-DHC selectively inhibits the expression of VCAM-1 but not ICAM-1 in TNF-α-activated EC via upregulation of PPAR-γ. Treatment with 7,8-DHC or PPAR-γ agonists (GW1929, troglitazone) inhibited the expression of VCAM-1 but not ICAM-1. Furthermore, the selective inhibition of VCAM-1 expression was inhibited by PPAR-γ antagonist, GW9662, or siPPAR-γ-transfected cells. 7,8-DHC significantly inhibited NF-kB activity via inhibition of phosphorylation of IkB and it also inhibited phosphorylation of ERK1/2 and Akt but not PKC. Finally, attachment of monocytes (U937) to EC by TNF-α was significantly reduced by 7,8-DHC. These results indicate that upregualtion of PPAR-γ by 7,8-DHC in EC inhibits NF-kB activity of TNF-α-activated EC which leads to selective inhibition of VCAM-1 expression. In addition, ERK1/2 and Akt signal pathways are involved in differential regulation by 7,8-DHC. We concluded that 7,8-DHC can be used for the treatment of cardiovascular disorders such as atherosclerosis., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Previously, we reported the cognitive enhancing effects of oroxylin A in unimpaired mice and its memory ameliorating activity in various memory impaired mice. To elucidate the mechanism mediating the cognitive effects of oroxylin A, this study examined the consequences of oroxylin A administration on neurogenesis in the hippocampal dentate gyrus using immunostaining for 5-bromo-2-deoxyuridine (BrdU) incorporation. In addition, we determined whether the new cells adopted a neuronal or glial fate by examining the co-localization of BrdU staining with neuronal or glial markers. Administration of oroxylin A in a dose-dependent and time-dependent manner increased the number of BrdU-incorporating cells. Moreover, the percentage of BrdU-incorporating cells co-localized with neuronal markers, neuronal nuclei, was significantly increased by the oroxylin A administration. These results suggest that the increased neurogenesis induced by the administration of oroxylin A could be, at least in part, associated with its positive effects on cognitive processing.