Toll-Like Receptor 2 Attenuates the Formation and Progression of Angiotensin II-Induced Abdominal Aortic Aneurysm in ApoE-/- Mice.

INTRODUCTION: We demonstrated Toll-like receptor (TLR) 4 in the pathogenesis of angiotensin II (AngII)-mediated abdominal aortic aneurysm (AAA) formation. Here, we study TLR2 in the AAA formation. METHODS: Male ApoE-/- and ApoE-/-TLR2-/- mice were treated with AngII. Mice were injected with the TLR2 agonist Pam3CSK4. The incidence and severity of AAA were determined. MCP-1, MCP-5, RANTES, CXCL10, CCR5, and CXCR3 were analyzed. M1 and M2 macrophages in the aorta were detected by flow cytometry. RESULTS: These studies demonstrated an increase in AAA formation in TLR2-/- mice and a decrease by Pam3CSK4. Pam3CSK4 decreased the ratio of M1/M2 and the levels of RANTES, CXCL10, CCR5, and CXCR3. Furthermore, Pam3CSK4 treatment 1 week following AngII retarded the progression of AAA. CONCLUSION: These data demonstrated a protective effect of TLR2 signaling on AAA in association with a decrease in the ratio of M1 to M2 macrophages and the expression of chemokines and their receptors. Furthermore, the treatment of Pam3CSK4 after AngII demonstrated a marked retardation of lesion progression. Given the fact that most AAA patients are detected late in the disease process, these findings suggest that TLR2 stimulation may play a therapeutic role in retarding disease progression.

Enantiomeric CopA3 dimer peptide suppresses cell viability and tumor xenograft growth of human gastric cancer cells.

The CopA3 dimer peptide is a coprisin analog that has an anticancer effect against human cancer cells in vitro. In this study, we investigated the anticancer activity of the enantiomeric CopA3 dimer peptide in human gastric cancer cell lines as well as in an in vivo tumor xenograft model. Enantiomeric CopA3 reduced gastric cancer cell viability and exhibited cytotoxicity against cancer cells. Enantiomeric CopA3-induced cell death was mediated by specific interactions with phosphatidylserine and phosphatidylcholine, membrane components that are enriched in cancer cells, in a calcein leakage assay. Moreover, acridine orange/ethidium bromide staining, flow cytometric analysis, and Western blot analysis showed that enantiomeric CopA3 induced apoptotic and necrotic gastric cancer cell death. The antitumor effect was also observed in a mouse tumor xenograft model in which intratumoral inoculation of the peptide resulted in a significant decrease in the SNU-668 gastric cancer tumor volume. In addition, periodic acid-Schiff and hematoxylin staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay revealed apoptotic and necrotic cell death in tumor masses treated with greater than 150 µg CopA3. Collectively, these results indicate that the enantiomeric CopA3 dimer peptide induces apoptosis and necrosis of gastric cancer cells in vitro and in vivo, indicating that the peptide is a potential candidate for the treatment of gastric cancer, which is a common cause of cancer and cancer deaths worldwide.

Angiotensin II-induced TLR4 mediated abdominal aortic aneurysm in apolipoprotein E knockout mice is dependent on STAT3.

Abdominal Aortic Aneurysm (AAA) is a major cause of mortality and morbidity in men over 65 years of age. Male apolipoprotein E knockout (ApoE(-/-)) mice infused with angiotensin II (AngII) develop AAA. Although AngII stimulates both JAK/STAT and Toll-like receptor 4 (TLR4) signaling pathways, their involvement in AngII mediated AAA formation is unclear. Here we used the small molecule STAT3 inhibitor, S3I-201, the TLR4 inhibitor Eritoran and ApoE(-/-)TLR4(-/-) mice to evaluate the interaction between STAT3 and TLR4 signaling in AngII-induced AAA formation. ApoE(-/-) mice infused for 28 days with AngII developed AAAs and increased STAT3 activation and TLR4 expression. Moreover, AngII increased macrophage infiltration and the ratio of M1 (pro-inflammatory)/M2 (healing) macrophages in aneurysmal tissue as early as 7-10 days after AngII infusion. STAT3 inhibition with S3I-201 decreased the incidence and severity of AngII-induced AAA formation and decreased MMP activity and the ratio of M1/M2 macrophages. Furthermore, AngII-mediated AAA formation, MMP secretion, STAT3 phosphorylation and the ratio of M1/M2 macrophages were markedly decreased in ApoE(-/-)TLR4(-/-) mice, and in Eritoran-treated ApoE(-/-) mice. TLR4 and pSTAT3 levels were also increased in human aneurysmal tissue. These data support a role of pSTAT3 in TLR4 dependent AAA formation and possible therapeutic roles for TLR4 and/or STAT3 inhibition in AAA.

Curcumol metabolized by rat liver S9 fraction and orally administered in mouse suppressed the proliferation of colon cancer in vitro and in vivo.

Following 3R (reduction, refinement, and replacement) principles, we employed the rat liver S9 fraction to mimic liver metabolism of curcumol having high in vitro IC50 on cancer cells. In HCT116 and HT29 colon cancer cells, the metabolites of curcumol by S9 fraction exerted more enhanced activity in inducing cell cycle arrest and apoptosis via regulating the expression of cyclin D1, CDK1, p21, PARP and Bcl-2 than curcumol. In addition, oral administration of curcumol at 4 mg/kg BW significantly suppressed the development of colon tumor induced by azoxymethane/dextran sulfate sodium, and induced cell cycle arrest and apoptosis in tumor tissues. In mass analysis, curcumenol and curzerene were identified as the metabolites of curcumol by S9 fraction metabolism. Taken together, curcumol metabolites showed the enhanced suppressive effect on colon cancer, suggesting that S9 fraction can be considered as simple, fast, and bio-mimicking platform for the screening of chemical libraries on different chronic diseases.

Increased inducibility of ventricular tachycardia and decreased heart rate variability in a mouse model for type 1 diabetes: effect of pravastatin.

Although a reduction in the high-frequency (HF) component of heart rate variability (HRV) is a major complication of diabetes and a risk factor for sudden death, its relationship to ventricular tachycardia (VT) is unknown. We developed a mouse model for the study of VT and its relationship to changes in HRV in the Akita type 1 diabetic mouse. Programmed ventricular stimulation of anesthetized mice demonstrated that Akita mice were more inducible for VT compared with wild-type mice: 78.6% versus 28.6% (P = 0.007). Optical mapping of perfused hearts demonstrated multifocal breakthroughs that occasionally gave rise to short-lived rotors consistent with focal initiation and maintenance of VT. Treatment of Akita mice with pravastatin, which had been previously shown clinically to decrease ventricular ectopy and to increase HRV, decreased the inducibility of VT: 36.8% compared with 75.0% with placebo treatment (P = 0.022). The HF fraction of HRV was reduced in Akita mice (48.6 ± 5.2% vs. 70.9 ± 4.8% in wild-type mice, P = 0.005) and was increased compared with placebo treatment in pravastatin-treated mice. Pretreatment of Akita mice with the muscarinic agonist carbamylcholine or the ß-adrenergic receptor blocker propranolol decreased the inducibility of VT (P = 0.001). In conclusion, the increased inducibility of focally initiated VT and reduced HF fraction in Akita mice were partially reversed by both pravastatin treatment and pharmacologic reversal of parasympathetic dysfunction. In this new animal model for the study of the pathogenesis of VT in type 1 diabetes, pravastatin may play a role in the prevention of VT by attenuating parasympathetic dysfunction.

Oronasal fistula reconstruction using tongue flap with simultaneous iliac bone graft: a case report.

The ultimate goal of cleft palate repair is to achieve an intact palate with the separation of the oral and nasal cavities. However, some patients develop an oronasal fistula in the secondary palate after palatoplasty. Postoperatively, a secondary palatal oronasal fistula may develop, leading to functional problems. In this study, we describe a patient with recurrent oronasal fistula and alveolar cleft with multiple failed previous reconstructions at another clinic. The oronasal fistula and alveolar cleft were repaired using a tongue flap and an iliac bone graft, respectively. The patient demonstrated excellent clinical progress with no recurrence of the oronasal fistula at the 1-year follow-up.

Comprehensive Evaluation System for Post-Metabolic Activity of Potential Thyroid-Disrupting Chemicals.

Endocrine-disrupting chemicals (EDCs) are compounds that disturb hormonal homeostasis by binding to receptors. EDCs are metabolized through hepatic enzymes, causing altered transcriptional activities of hormone receptors, and thus necessitating the exploration of the potential endocrine-disrupting activities of EDC-derived metabolites. Accordingly, we have developed an integrative workflow for evaluating the post-metabolic activity of potential hazardous compounds. The system facilitates the identification of metabolites that exert hormonal disruption through the integrative application of an MS/MS similarity network and predictive biotransformation based on known hepatic enzymatic reactions. As proof-of-concept, the transcriptional activities of 13 chemicals were evaluated by applying the in vitro metabolic module (S9 fraction). Identified among the tested chemicals were three thyroid hormone receptor (THR) agonistic compounds that showed increased transcriptional activities after phase I+II reactions (T3, 309.1 ± 17.3%; DITPA, 30.7 ± 1.8%; GC-1, 160.6 ± 8.6% to the corresponding parents). The metabolic profiles of these three compounds showed common biotransformation patterns, particularly in the phase II reactions (glucuronide conjugation, sulfation, GSH conjugation, and amino acid conjugation). Data-dependent exploration based on molecular network analysis of T3 profiles revealed that lipids and lipid-like molecules were the most enriched biotransformants. The subsequent subnetwork analysis proposed 14 additional features, including T4 in addition to 9 metabolized compounds that were annotated by prediction system based on possible hepatic enzymatic reaction. The other 10 THR agonistic negative compounds showed unique biotransformation patterns according to structural commonality, which corresponded to previous in vivo studies. Our evaluation system demonstrated highly predictive and accurate performance in determining the potential thyroid-disrupting activity of EDC-derived metabolites and for proposing novel biotransformants.

Correction to: 1,3,5,8­Tetrahydroxyxanthone suppressed adipogenesis via activating Hedgehog signaling in 3T3­L1 adipocytes.

[This corrects the article DOI: 10.1007/s10068-022-01130-y.].

Correction to: Capsicum annuum L. cv. DANGJO ameliorated hyperglycemia in type 2 diabetes animal model induced by high-fat diet and streptozotocin.

[This corrects the article DOI: 10.1007/s10068-022-01068-1.].

Age-specific characteristics of road traffic injuries among children and adolescents in South Korea.

OBJECTIVE: Road traffic injuries (RTIs) are the leading cause of mortality among children and adolescents. This study aimed to identify and compare the age-specific epidemiology, clinical characteristics and factors related to severe RTIs among children and adolescents who had RTIs. METHODS: This multicenter cross-sectional study was conducted using data collected between January 2011 and December 2018 in the Emergency Department-based Injury In-depth Surveillance registry in South Korea. A total of 66,632 participants younger than 19 years who presented with RTIs to emergency departments (EDs) were classified under three age groups: preschoolers (age 0-6 years, n = 18,694), elementary school student (age 7-12 years, n = 21,251), and middle and high school student (age 13-18 years, n = 26,687). Data on demographic and injury-related factors were analyzed, and multivariate logistic regression was used to determine the factors related to severe RTIs, which were defined as the Excess Mortality Ratio-based Injury Severity Score ≥16. RESULTS: RTIs among children and adolescents were more common in boys (71.0%), during weekdays (39.7%), in the summer (31.1%), and between 12 noon and 6 pm (47.9%). The most common type of road users were passengers (preschoolers, 46.4%) and cyclists (age 7-12 years and age 13-18 years, 50.1% and 36.2%, respectively). The proportion of head injury was highest in the preschoolers group (57.3%). The length of ED stay, Excess Mortality Ratio-adjusted Injury Severity Score, and the proportion of intensive care unit admission increased with age. Nighttime (0-6 am), vulnerable road users (motorcyclists, bicyclists, and pedestrians), and use of emergency medical services were significantly associated with severe injury. CONCLUSIONS: The three age groups of patients younger than 19 years with RTIs differed in the types of road user, proportions of injured body regions, and clinical outcomes. In an effort to reduce RTIs to children and adolescents, age-specific focused intervention should be considered. Additionally, the injury severity was found to be associated with nighttime occurrence, vulnerable road users, ED visit through emergency medical services, and nonuse of safety devices across all age group.

Perilla oil and α-linolenic acid ameliorated thrombosis in rats induced by collagen and epinephrine.

Perilla frutescens is an annual herbaceous plant widely cultivated for oil production in China, Japan, and Korea. In this study, we investigated the effect of perilla oil (PO) on thrombosis induced by collagen and epinephrine (CE) in rats. The oral administration of PO significantly increased prothrombin time (PT) and activated partial thromboplastin time (aPTT) in the blood plasma and inhibited the expression of cells adhesion markers (CAMs) such as intercellular CAM-1 (ICAM-1), vascular CAM (VCAM-1), E-selectin and P-selectin in the aorta tissue. Furthermore, pulmonary occlusion induced by CE in rats was suppressed by PO. α-Linolenic acid (ALA) was quantified at 60.14 ± 2.50 g/100 g of PO, and its oral administration at the same concentration with that in PO exerted the similar effect on PT, aPTT, ICAM-1, VCAM-1, E-selectin and P-selectin in CE-induced thrombosis rats. Taken together, PO and ALA significantly ameliorated thrombosis by regulating CAMs.

Prevalence and clinical characteristics of primary headaches among school children in South Korea: a nationwide survey.

OBJECTIVES: To determine the 1-year prevalence of headache and clinical characteristics of primary headaches among school children in South Korea. BACKGROUND: Many population-based studies have estimated the 1-year prevalence of headache, migraine, and tension-type headache (TTH). The results of those studies vary in terms of race and region. There have been few epidemiological population-based studies of headache in children and adolescents in Korea. METHODS: We conducted a cross-sectional school-based study of a randomized and proportional sample of 5360 boys and girls. All 180 sampled schools participated in this study. The questionnaires collected demographic data in addition to specific questions about headache according to the International Classification of Headache Disorder criteria, 2nd Edition. Valid questionnaires were returned by 94.1% of the sample population. Modified criteria changed the "duration" of migraine (>1 hour instead of 4 hours). RESULTS: The prevalence of headache among school children was 29.1% (1465/5039) in South Korea. The prevalence of headache in girls (33.4%) was significantly higher than in boys (24.4%) (P<.001). The mean age of students with headaches (14.02±3.03) was significantly higher than students without headaches (12.73±3.36) (P <.001). The prevalence of headache according to region was 30.7% among students in urban, 31.2% in suburban, and 21.6% in rural areas. The prevalence of headache according to age was 20.8% among students ∼6-12 years, 32.0% ∼13-15 years, and 38.2% ∼16-18 years. The prevalence according to headache types was 8.7% (boys 7.0%, girls 10.3%) in migraine, 13.7% (boys 10.7%, girls 16.3%) in TTH, and 6.7% in others. The mean frequency, severity of headache, and duration of symptoms were significantly higher in girls than in boys (P<.001). CONCLUSIONS: Recurrent primary headaches are quite prevalent among school-aged children and adolescents in South Korea, and the prevalence rates are similar to those reported elsewhere. TTH was more common than migraine. The prevalence of migraine headache increased with age. The prevalence rate of headache in students in urban and suburban areas was significantly higher than the rate of students in rural areas.

Garcinone C Suppresses Tumorsphere Formation and Invasiveness by Hedgehog/Gli1 Signaling in Colorectal Cancer Stem-like Cells.

Hyperactivation of hedgehog signaling occurs in colorectal cancer stem-like cells (CSCs), a rare subpopulation, potentially involved in metastasis, chemotherapy resistance, and cancer relapse. Garcinone C, a xanthone isolated from mangosteen (Garcinia mangostana), suppresses colorectal cancer in vivo and in vitro by inhibiting Gli1-dependent noncanonical hedgehog signaling. Herein, we investigated the effect of garcinone C on cancer stemness and invasiveness in colorectal cancer; Gli1 was noted as pivotal in maintaining stemness and invasiveness in HCT116 and HT29 CSCs. Garcinone C inhibited the proliferation and self-renewal of HCT116 and HT29 CSCs. Colon cancer stemness markers such as CD44, CD133, ALDH1, and Nanog were significantly decreased by garcinone C. Computational studies showed that garcinone C showed a high affinity with the Gli1 protein ZF domain by forming hydrogen bonds with amino acid residues of ASP244, ARG223, and ASP216. Besides, MG132 blocked the effects of garcinone C on Gli1. Thus, garcinone C suppressed colorectal CSCs by binding to Gli1 and enhancing its degradation. MMP2 and MMP9 levels, invasive-related markers, were increased in HCT116 CSCs but decreased by garcinone C. E-cadherin level was reduced in HCT116 CSCs, while the presence of garcinone C was restored. Garcinone C inhibited the proliferation and invasiveness of colorectal CSCs by targeting Gli1-dependent Hh signaling. Garcinone C may be a potent natural agent against colorectal cancer relapse.

1,3,5,8-Tetrahydroxyxanthone suppressed adipogenesis via activating Hedgehog signaling in 3T3-L1 adipocytes.

In this study, we investigated the effect of 1,3,5,8-tetrahydroxyxanthone (THX) on the adipogenesis of 3T3-L1 adipocytes. THX, a xanthone isolated from Gentianella acuta, inhibited lipid accumulation in 3T3-L1 adipocytes and reduced the protein levels of the key adipogenic transcriptional factors, peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), in a dose-dependent manner. In addition, THX enhanced the transcriptional activity of Gli1 known as the key indicator of Hedgehog (Hh) signaling activity and increased the expression of Gli1 and its upstream regulator Smo. The Smo activator SAG exerted the similar effect with THX on regulating Gli1, Smo, PPARγ and C/EBPα expression, which led to the suppression of fat formation in 3T3-L1 adipocytes. Furthermore, we found that the inhibitory effect of THX on adipogenesis was derived from regulation of the early stage of adipogenesis. These results suggest that THX suppresses the differentiation of adipocyte through Hh signaling and may be considered as a potent agent for the prevention of obesity.

Suppression of Adipogenesis and Fat Accumulation by Vitexin Through Activation of Hedgehog Signaling in 3T3-L1 Adipocytes.

Many studies have demonstrated that adipogenesis is associated with obesity, and the Hedgehog (Hh) signaling pathway regulates adipogenesis and obesity. Following the screening study of the chemical library evaluating the effect of vitexin on Gli1 transcriptional activity, vitexin was chosen as a candidate for antiadipogenic efficacy. Vitexin significantly reduced lipid accumulation and suppressed C/EBPα (CCAAT/enhancer-binding protein α) and PPARγ (peroxisome proliferator-activated receptor γ) expression, which are known as key adipogenic factors in the early stages of adipogenesis by activating Hh signaling. Furthermore, Hh inhibitor GANT61 reversed the effect of AMP-activated protein kinase (AMPK) activator AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), indicating that Hh signaling is an upstream regulator of AMPK in 3T3-L1 cells. Vitexin suppressed adipogenesis by regulating Hh signaling and phosphorylation of AMPK, leading to the inhibition of fat formation. These results suggest that vitexin can be considered a potent dietary agent in alleviating lipid accumulation and obesity.

Clinical Application of 3D-Printed Patient-Specific Polycaprolactone/Beta Tricalcium Phosphate Scaffold for Complex Zygomatico-Maxillary Defects.

(1) Background: In the present study, we evaluated the efficacy of a 3D-printed, patient-specific polycaprolactone/beta tricalcium phosphate (PCL/ß-TCP) scaffold in the treatment of complex zygomatico-maxillary defects. (2) Methods: We evaluated eight patients who underwent immediate or delayed maxillary reconstruction with patient-specific PCL implants between December 2019 and June 2021. The efficacy of these techniques was assessed using the volume and density analysis of computed tomography data obtained before surgery and six months after surgery. (3) Results: Patients underwent maxillary reconstruction with the 3D-printed PCL/ß-TCP scaffold based on various reconstructive techniques, including bone graft, fasciocutaneous free flaps, and fat graft. In the volume analysis, satisfactory volume conformity was achieved between the preoperative simulation and actual implant volume with a mean volume conformity of 79.71%, ranging from 70.89% to 86.31%. The ratio of de novo bone formation to total implant volume (bone volume fraction) was satisfactory with a mean bone fraction volume of 23.34%, ranging from 7.81% to 66.21%. Mean tissue density in the region of interest was 188.84 HU, ranging from 151.48 HU to 291.74 HU. (4) Conclusions: The combined use of the PCL/ß-TCP scaffold with virtual surgical simulation and 3D printing techniques may replace traditional non-absorbable implants in the future owing to its accuracy and biocompatible properties.

Capsicum annuum L. cv. DANGJO ameliorated hyperglycemia in type 2 diabetes animal model induced by high-fat diet and streptozotocin.

In this study, it was evaluated the effect of freeze-dried powder of Capsicum annuum L. cv. DANGJO (DJ) on ameliorating hyperglycemia in type 2 diabetes rat model induced by high-fat diet (HFD) and streptozotocin (STZ). Oral administration of DJ significantly reduced non-fasting blood glucose (NFBG) and insulin levels, as well as glycated hemoglobin (HbA1c) level, a representative marker for diabetes, in HFD/STZ treated rats whereas the administration of green hot pepper (GHP) and green sweet pepper (GSP) did not show the significant effect. Quercitrin was quantified (40.97 mg/100 g of DJ) by HPLC, and administration of the same amount of quercitrin with DJ exerted the significant reduction of blood glucose level, strongly supporting that quercitrin is the key component in ameliorating the hyperglycemia of DJ in HFD/STZ treated rats. These results suggest that DJ can be considered as a potent functional food in preventing hyperglycemia in type 2 diabetes mellitus.

Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP.

Parasympathetic stimulation of the heart, which provides protection from arrhythmias and sudden death, involves activation of the G protein-coupled inward rectifying K+ channel GIRK1/4 and results in an acetylcholine-sensitive K+ current, I KACh. We describe a unique relationship between lipid homeostasis, the lipid-sensitive transcription factor SREBP-1, regulation of the cardiac parasympathetic response, and the development of ventricular arrhythmia. In embryonic chick atrial myocytes, lipid lowering by culture in lipoprotein-depleted serum increased SREBP-1 levels, GIRK1 expression, and I KACh activation. Regulation of the GIRK1 promoter by SREBP-1 and lipid lowering was dependent on interaction with 2 tandem sterol response elements and an upstream E-box motif. Expression of dominant negative SREBP-1 (DN-SREBP-1) reversed the effect of lipid lowering on I KACh and GIRK1. In SREBP-1 knockout mice, both the response of the heart to parasympathetic stimulation and the expression of GIRK1 were reduced compared with WT. I KACh, attenuated in atrial myocytes from SREBP-1 knockout mice, was stimulated by SREBP-1 expression. Following myocardial infarction, SREBP-1 knockout mice were twice as likely as WT mice to develop ventricular tachycardia in response to programmed ventricular stimulation. These results demonstrate a relationship between lipid metabolism and parasympathetic response that may play a role in arrhythmogenesis.

Role of SREBP-1 in the development of parasympathetic dysfunction in the hearts of type 1 diabetic Akita mice.

RATIONALE: Diabetic autonomic neuropathy (DAN), a major complication of diabetes mellitus, is characterized, in part, by impaired cardiac parasympathetic responsiveness. Parasympathetic stimulation of the heart involves activation of an acetylcholine-gated K+ current, I(KAch), via a (GIRK1)2/(GIRK4)2 K+ channel. Sterol regulatory element binding protein-1 (SREBP-1) is a lipid-sensitive transcription factor. OBJECTIVE: We describe a unique SREBP-1-dependent mechanism for insulin regulation of cardiac parasympathetic response in a mouse model for DAN. METHODS AND RESULTS: Using implantable EKG transmitters, we demonstrated that compared with wild-type, Ins2(Akita) type I diabetic mice demonstrated a decrease in the negative chronotropic response to carbamylcholine characterized by a 2.4-fold decrease in the duration of bradycardia, a 52+/-8% decrease in atrial expression of GIRK1 (P<0.01), and a 31.3+/-2.1% decrease in SREBP-1 (P<0.05). Whole-cell patch-clamp studies of atrial myocytes from Akita mice exhibited a markedly decreased carbamylcholine stimulation of I(KAch) with a peak value of -181+/-31 pA/pF compared with -451+/-62 pA/pF (P<0.01) in cells from wild-type mice. Western blot analysis of extracts of Akita mice demonstrated that insulin treatment increased the expression of GIRK1, SREBP-1, and I(KAch) activity in atrial myocytes from these mice to levels in wild-type mice. Insulin treatment of cultured atrial myocytes stimulated GIRK1 expression 2.68+/-0.12-fold (P<0.01), which was reversed by overexpression of dominant negative SREBP-1. Finally, adenoviral expression of SREBP-1 in Akita atrial myocytes reversed the impaired I(KAch) to levels in cells from wild-type mice. CONCLUSIONS: These results support a unique molecular mechanism for insulin regulation of GIRK1 expression and parasympathetic response via SREBP-1, which might play a role in the pathogenesis of DAN in response to insulin deficiency in the diabetic heart.

Freeze-Dried Powder of Rubus coreanus Miquel Ameliorates Isoproterenol-Induced Oxidative Stress and Tissue Damage in Rats.

Rubus coreanus Miquel (bokbunja), Korean black raspberry, is known to possess various phytochemicals that exert antioxidative, anti-inflammatory, and anti-cancer effects. However, most studies on Rubus coreanus Miquel have been performed with the solvent extracts and/or a single component to demonstrate the efficacy, while studies evaluating the effect of the whole fructus of Rubus coreanus Miquel are limited. In this study, therefore, we employed the isoproterenol (IPN)-induced myocardial infarction model and investigated the effect of freeze-dried powder of Rubus coreanus Miquel (RCP) on oxidative stress and prevention of organ damage. Oral administration of RCP reduced the level of toxicity markers, alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) without affecting body weight and diet intake. The oxidative stress marker glutathione (GSH) increased about 45% and malonaldehyde (MDA) decreased about 27% compared to the IPN group with RCP-H (3%) administration. By histological analysis, IPN induced significant myocardial damage in the heart and vascular injury in the liver, and RCP administration ameliorated the damages in a dose-dependent manner. Taken together, RCP activated the antioxidant system leading to prevention of damage to organs by IPN in rats, making it possible to expect beneficial efficacies by consuming the whole fructus of Rubus coreanus Miquel.