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1.
Biomed Pharmacother ; 175: 116735, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38744220

ABSTRACT

G-protein-coupled receptors are a diverse class of cell surface receptors that orchestrate numerous physiological functions. The G-protein-coupled receptors, GPR41 and GPR43, sense short-chain fatty acids (SCFAs), which are metabolites of dietary fermentation by the host's intestinal bacteria. These receptors have gained attention as potential therapeutic targets against various diseases because of their SCFA-mediated beneficial effects on the host's intestinal health. Mounting evidence has associated the activity of these receptors with chronic metabolic diseases, including obesity, diabetes, inflammation, and cardiovascular disease. However, despite intensive research using various strategies, including gene knockout (KO) mouse models, evidence about the precise roles of GPR41 and GPR43 in disease treatment remains inconsistent. Here, we comprehensively review the latest findings from functional studies of the signaling mechanisms that underlie the activities of GPR41 and GPR43, as well as highlight their multifaceted roles in health and disease. We anticipate that this knowledge will guide future research priorities and the development of effective therapeutic interventions.


Subject(s)
Receptors, G-Protein-Coupled , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/genetics , Animals , Humans , Signal Transduction , Metabolic Diseases/metabolism , Fatty Acids, Volatile/metabolism
2.
Clin Orthop Surg ; 16(1): 86-94, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38304217

ABSTRACT

Background: The lumbosacral (LS) junction has a higher nonunion rate than other lumbar segments, especially in long-level fusion. Nonunion at L5-S1 would result in low back pain, spinal imbalance, and poor surgical outcomes. Although anterior column support at L5-S1 has been recommended to prevent nonunion in long-level LS fusion, fusion length requiring additional spinopelvic fixation (SPF) in LS fusion with anterior column support at L5-S1 has not been evaluated thoroughly. This study aimed to determine the number of fused levels requiring SPF in LS fusion with anterior column support at L5-S1 by assessing the interbody fusion status using computed tomography (CT) depending on the fusion length. Methods: Patients who underwent instrumented LS fusion with L5-S1 interbody fusion without additional augmentation and CT > 1 year postoperatively were included. The fusion rates were assessed based on the number of fused segments. Patients were divided into two groups depending on the L5-S1 interbody fusion status: those with union vs. those with nonunion. Binary logistic regression analyses were performed to identify risk factors for LS junctional nonunion. Results: Fusion rates of L5-S1 interbody fusion were 94.9%, 90.3%, 80.0%, 50.0%, 52.6%, and 43.5% for fusion of 1, 2, 3, 4, 5, and ≥ 6 levels, respectively. The number of spinal levels fused ≥ 4 (p < 0.001), low preoperative bone mineral density (BMD; adjusted odds ratio [aOR], 0.667; p = 0.035), and postoperative pelvic incidence (PI) - lumbar lordosis (LL) mismatch (aOR, 1.034; p = 0.040) were identified as significant risk factors for nonunion of L5-S1 interbody fusion according to the multivariate logistic regression analysis. Conclusions: Exhibiting ≥ 4 fused spinal levels, low preoperative BMD, and large postoperative PI-LL mismatch were identified as independent risk factors for nonunion of anterior column support at L5-S1 in LS fusion without additional fixation. Therefore, SPF should be considered in LS fusion extending to or above L2 to prevent LS junctional nonunion.


Subject(s)
Lordosis , Spinal Fusion , Humans , Lumbar Vertebrae/diagnostic imaging , Lumbar Vertebrae/surgery , Retrospective Studies , Tomography, X-Ray Computed , Spinal Fusion/methods , Treatment Outcome
3.
Obesity (Silver Spring) ; 31(7): 1871-1883, 2023 07.
Article in English | MEDLINE | ID: mdl-37309717

ABSTRACT

OBJECTIVE: This study aimed to investigate the possible mechanisms by which orphan G protein-coupled receptor GPR41 activation enhances glucose uptake into C2C12 myotubes using a GPR41-selective agonist, AR420626, and to examine the ability of this agent to improve insulin sensitivity and glucose homeostasis in vivo. METHODS: Basal and insulin-stimulated glucose uptake and glucose transporter 4 translocations were measured in C2C12 myotubes. Ca2+ influx into cells was measured and GPR41-mediated signaling by AR420626 was examined. An oral glucose tolerance test was performed, and plasma insulin levels were measured in streptozotocin-treated or high-fat diet-fed diabetic mice. The glycogen content was measured in skeletal muscle tissue. RESULTS: AR420626 increased basal and insulin-stimulated glucose uptake, which was reduced by pertussis toxin, an inhibitor of Gαi -mediated signaling, and treatment with small interfering RNA for GPR41 (siGPR41). AR420626 increased intracellular Ca2+ influx and phosphorylated Ca2+ /calmodulin-dependent protein kinase type II, cyclic AMP-responsive element-binding protein, and mitogen-activated protein kinase (p38) in C2C12 myotubes, which were inhibited by treating with pertussis toxin, amlodipine (Ca2+ channel blocker), and siGPR41. AR420626 increased plasma insulin levels and skeletal muscle glycogen content and improved glucose tolerance in streptozotocin- and high-fat diet-induced diabetic mouse models. CONCLUSIONS: GPR41 activation with AR420626 increased glucose uptake mediated by Ca2+ signaling via GPR41, improving diabetes mellitus.


Subject(s)
Diabetes Mellitus, Experimental , Glucose , Animals , Mice , Diabetes Mellitus, Experimental/metabolism , Glucose/metabolism , Glycogen , Insulin/metabolism , Muscle Fibers, Skeletal/metabolism , Muscle, Skeletal/metabolism , Pertussis Toxin , Streptozocin
4.
Cells ; 12(11)2023 05 30.
Article in English | MEDLINE | ID: mdl-37296633

ABSTRACT

Astrocytes play a key role in brain functioning by providing energy to neurons. Increased astrocytic mitochondrial functions by Korean red ginseng extract (KRGE) have been investigated in previous studies. KRGE administration induces hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in astrocytes in the adult mouse brain cortex. VEGF expression can be controlled by transcription factors, such as the HIF-1α and estrogen-related receptor α (ERRα). However, the expression of ERRα is unchanged by KRGE in astrocytes of the mouse brain cortex. Instead, sirtuin 3 (SIRT3) expression is induced by KRGE in astrocytes. SIRT3 is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that resides in the mitochondria and maintains mitochondrial homeostasis. Mitochondrial maintenance requires oxygen, and active mitochondria enhance oxygen consumption, resulting in hypoxia. The effects of SIRT3 on HIF-1α-mediated mitochondria functions induced by KRGE are not well established. We aimed to investigate the relationship between SIRT3 and HIF-1α in KRGE-treated normoxic astrocyte cells. Without changing the expression of the ERRα, small interfering ribonucleic acid targeted for SIRT3 in astrocytes substantially lowers the amount of KRGE-induced HIF-1α proteins. Reduced proline hydroxylase 2 (PHD2) expression restores HIF-1α protein levels in SIRT3-depleted astrocytes in normoxic cells treated with KRGE. The translocation of outer mitochondrial membranes 22 (Tom22) and Tom20 is controlled by the SIRT3-HIF-1α axis, which is activated by KRGE. KRGE-induced Tom22 increased oxygen consumption and mitochondrial membrane potential, as well as HIF-1α stability through PHD2. Taken together, in normoxic astrocytes, KRGE-induced SIRT3 activated the Tom22-HIF-1α circuit by increasing oxygen consumption in an ERRα-independent manner.


Subject(s)
Panax , Sirtuin 3 , Mice , Animals , Mitochondrial Membranes/metabolism , Sirtuin 3/metabolism , Astrocytes/metabolism , Vascular Endothelial Growth Factor A/metabolism , Panax/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
5.
Stud Health Technol Inform ; 294: 581-582, 2022 May 25.
Article in English | MEDLINE | ID: mdl-35612154

ABSTRACT

It is very important to ensure reliable performance of deep learning model for future dataset for healthcare. This is more pronounced in the case of patient generated health data such as patient reported symptoms, which are not collected in a controlled environment. Since there has been a big difference in influenza incidence since the COVID-19 pandemic, we evaluated whether the deep learning model can maintain sufficiently robust performance against these changes. We have collected 226,655 episodes from 110,893 users since June 2020 and tested the influenza screening model, our model showed 87.02% sensitivity and 0.8670 of AUROC. The results of COVID-19 pandemic are comparable to that of before COVID-19 pandemic.


Subject(s)
Influenza, Human , Mass Screening , Patient Generated Health Data , COVID-19/epidemiology , Computer Simulation , Deep Learning , Humans , Influenza, Human/diagnosis , Influenza, Human/epidemiology , Mass Screening/methods , Pandemics , Reproducibility of Results
6.
Stud Health Technol Inform ; 294: 719-720, 2022 May 25.
Article in English | MEDLINE | ID: mdl-35612190

ABSTRACT

As the number of cases for COVID-19 continues to grow unprecedentedly, COVID-19 screening is becoming more important. In this study, we trained machine learning models from the Israel COVID-19 dataset and compared models that used surveillance indices of COVID-19 and those that did not. The AUC scores were 0.8478±0.0037 and 0.8062±0.005 with and without surveillance information, respectively, and there was significant improvement when the surveillance information was used.


Subject(s)
COVID-19 , COVID-19/epidemiology , Humans , Israel/epidemiology , Machine Learning , SARS-CoV-2
7.
Korean J Ophthalmol ; 35(4): 272-279, 2021 08.
Article in English | MEDLINE | ID: mdl-34162191

ABSTRACT

PURPOSE: To describe current cataract surgery practice patterns and trends among Korean ophthalmologists. METHODS: A survey was conducted among members of the Korean Society of Cataract and Refractive Surgery in October 2020. Of the 998 questionnaires, 262 (26.3%) were received for analysis. Data were analyzed using descriptive statistics and compared with those of previous surveys. RESULTS: The largest percentage of respondents (39%) had <5 years of practical experience, and 40% had >11 years of practical experience. The average, median, and mode monthly volumes of cataract surgeries performed by the Korean Society of Cataract and Refractive Surgery members were 31, 20, and 10 cases, respectively. Topical anesthesia was administered by 85% of the respondents. For intraocular lens (IOL) calculations, 96% of the respondents used optical biometry. The proportion of surgeons providing femtosecond laser-assisted cataract surgery increased significantly from 5% in 2018 to 29% in 2020. This increase was accompanied by an increase in the multifocal IOLs. Those who implant multifocal IOL for >10% of their cases increased from 16% (2018) to 29% (2020). Topical nonsteroidal anti-inflammatory drugs were prescribed postoperatively by 76% of the respondents. Most respondents (70%) prescribed these anti-inflammatory drugs for 4 weeks. CONCLUSIONS: This survey provided a comprehensive update on current cataract surgery practice in the Republic of Korea. The results highlighted the increasing use of premium IOLs, femtosecond laser-assisted cataract surgery, optical biometry, and topical anesthesia to better meet the patients' needs.


Subject(s)
Cataract Extraction , Cataract , Lenses, Intraocular , Phacoemulsification , Cataract/epidemiology , Humans , Lens Implantation, Intraocular , Republic of Korea/epidemiology , Surveys and Questionnaires
8.
J Pharmacol Exp Ther ; 378(1): 10-19, 2021 07.
Article in English | MEDLINE | ID: mdl-33846234

ABSTRACT

The secretion of platelet-derived growth factors (PDGFs) into vascular smooth muscle cells (VSMCs) induced by specific stimuli, such as oxidized low-density lipoprotein (LDL) cholesterol, initially increases the proliferation and migration of VSMCs, and continuous stimulation leads to VSMC apoptosis, resulting in the formation of atheroma. Autophagy suppresses VSMC apoptosis, and statins can activate autophagy. Thus, this study aimed to investigate the mechanism of the autophagy-mediated vasoprotective activity of rosuvastatin, one of the most potent statins, in VSMCs continuously stimulated with PDGF-BB, a PDGF isoform, at a high concentration (100 ng/ml) to induce phenotypic switching of VSMC. Rosuvastatin inhibited apoptosis in a concentration-dependent manner by reducing cleaved caspase-3 and interleukin-1ß (IL-1ß) levels and reduced intracellular reactive oxygen species (ROS) levels in PDGF-stimulated VSMCs. It also inhibited PDGF-induced p38 phosphorylation and increased the expression of microtubule-associated protein light chain 3 (LC3) and the conversion of LC3-I to LC3-II in PDGF-stimulated VSMCs. The ability of rosuvastatin to inhibit apoptosis and p38 phosphorylation was suppressed by treatment with 3-methyladenine (an autophagy inhibitor) but promoted by rapamycin (an autophagy activator) treatment. SB203580, a p38 inhibitor, reduced the PDGF-induced increase in intracellular ROS levels and inhibited the formation of cleaved caspase-3, indicating the suppression of apoptosis. In carotid ligation model mice, rosuvastatin decreased the thickness and area of the intima and increased the area of the lumen. In conclusion, our observations suggest that rosuvastatin inhibits p38 phosphorylation through autophagy and subsequently reduces intracellular ROS levels, leading to its vasoprotective activity. SIGNIFICANCE STATEMENT: This study shows the mechanism responsible for the vasoprotective activity of rosuvastatin in vascular smooth muscle cells under prolonged platelet-derived growth factor stimulation. Rosuvastatin inhibits p38 activation through autophagy, thereby suppressing intracellular reactive oxygen species levels, leading to the inhibition of apoptosis and reductions in the intima thickness and area. Overall, these results suggest that rosuvastatin can be used as a novel treatment to manage chronic vascular diseases such as atherosclerosis.


Subject(s)
Autophagy/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Muscle, Smooth, Vascular/drug effects , Platelet-Derived Growth Factor/toxicity , Rosuvastatin Calcium/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Apoptosis/drug effects , Apoptosis/physiology , Autophagy/physiology , Cell Survival/drug effects , Cell Survival/physiology , Cells, Cultured , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred C57BL , Muscle, Smooth, Vascular/metabolism , Rats , p38 Mitogen-Activated Protein Kinases/metabolism
9.
Life Sci ; 267: 118978, 2021 Feb 15.
Article in English | MEDLINE | ID: mdl-33412209

ABSTRACT

AIMS: Vascular smooth muscle cell (VSMC) phenotype shift is involved in the pathophysiology of vascular injury or platelet-derived growth factor (PDGF)-induced abnormal proliferation and migration of VSMCs. We aimed to investigate the underlying mechanism involved in PDGF-mediated signaling pathways and autophagy regulation followed by VSMC phenotype shift. MAIN METHODS: The proliferation, migration and apoptosis of cultured rat aortic VSMCs were measured, and cells undergoing phenotype shift and autophagy were examined. Specific inhibitors for target proteins in signaling pathways were applied to clarify their roles in regulating cell functions. KEY FINDINGS: PDGF-BB stimulation initiated autophagy activation and synthetic phenotype transition by decreasing α-smooth muscle-actin (SMA), calponin and myosin heavy chain (MHC) and increasing osteopontin (OPN) expression. However, U0126, a potent extracellular signal-regulated kinase 1/2 (Erk1/2) inhibitor, decreased PDGF-BB-induced LC3 expression, while rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), increased it. Furthermore, U0126 decreased the expresseion of autophagy-related genes (Atgs) such as beclin-1, Atg7, Atg5, and Atg12-Atg5 complex, indicating that Erk1/2 is a regulator of PDGF-BB-induced VSMC autophagy. Regardless of autophagy inhibition by U0126 or activation by rapamycin, the PDGF-BB-induced decrease in SMA, calponin and MHC and increase in OPN expression were inhibited. Furthermore, PDGF-BB-stimulated VSMC proliferation, migration and proliferating cell nuclear antigen (PCNA) expression were inhibited by U0126 and rapamycin. SIGNIFICANCE: These findings suggest that PDGF-BB-induced autophagy is strongly regulated by Erk1/2, an mTOR-independent pathway, and any approach for targeting autophagy modulation is a potential therapeutic strategy for addressing abnormal VSMC proliferation and migration.


Subject(s)
Autophagy/physiology , Becaplermin/metabolism , Muscle, Smooth, Vascular/metabolism , Animals , Becaplermin/genetics , Becaplermin/pharmacology , Calcium-Binding Proteins , Cell Movement/drug effects , Cell Proliferation/drug effects , Cells, Cultured , MAP Kinase Signaling System/physiology , Microfilament Proteins , Mitogen-Activated Protein Kinase 3/metabolism , Myocytes, Smooth Muscle/metabolism , Myosins , Phenotype , Proliferating Cell Nuclear Antigen/metabolism , Proto-Oncogene Proteins c-sis/metabolism , Rats , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Calponins
10.
Acta Pharmacol Sin ; 42(8): 1311-1323, 2021 Aug.
Article in English | MEDLINE | ID: mdl-32973326

ABSTRACT

Propionate is a short-chain fatty acid (SCFA) mainly produced from carbohydrates by gut microbiota. Sodium propionate (SP) has shown to suppress the invasion in G protein-coupled receptor 41 (GPR41) and GPR43-overexpressing breast cancer cells. In this study we investigated the effects of SP on the proliferation, apoptosis, autophagy, and antioxidant production of breast cancer cells. We showed that SP (5-20 mM) dose-dependently inhibited proliferation and induced apoptosis in breast cancer cell lines JIMT-1 (ER-negative and HER2-expressing) and MCF7 (ER-positive type), and this effect was not affected by PTX, thus not mediated by the GPR41 or GPR43 SCFA receptors. Meanwhile, we demonstrated that SP treatment increased autophagic and antioxidant activity in JIMT-1 and MCF7 breast cancer cells, which might be a compensatory mechanism to overcome SP-induced apoptosis, but were not sufficient to overcome SP-mediated suppression of proliferation and induction of apoptosis. We revealed that the anticancer effect of SP was mediated by inhibiting JAK2/STAT3 signaling which led to cell-cycle arrest at G0/G1 phase, and increasing levels of ROS and phosphorylation of p38 MAPK which induced apoptosis. In nude mice bearing JIMT-1 and MCF7 cells xenograft, administration of SP (20 mg/mL in drinking water) significantly suppressed tumor growth by regulating STAT3 and p38 in tumor tissues. These results suggest that SP suppresses proliferation and induces apoptosis in breast cancer cells by inhibiting STAT3, increasing the ROS level and activating p38. Therefore, SP is a candidate therapeutic agent for breast cancer.


Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , MAP Kinase Signaling System/drug effects , Propionates/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Female , G1 Phase Cell Cycle Checkpoints/drug effects , Humans , Mice, Nude , Propionates/pharmacology , Reactive Oxygen Species/metabolism , Xenograft Model Antitumor Assays
11.
Mater Sci Eng C Mater Biol Appl ; 114: 111042, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32993980

ABSTRACT

The incidence of rheumatoid arthritis (RA), an autoimmune inflammatory disease, is rapidly increasing in aging societies. In the current study, celecoxib (CXB) micelles were developed to improve the oral absorption and anti-inflammatory effects of CXB in cell studies and λ-carrageenan rat models, and to enhance the therapeutic effects of CXB on RA in complete Freund's adjuvant (CFA)-induced RA rat models. Moreover, CXB micelles and previously developed solid dispersion (SD6) formulations were evaluated. The physical properties of optimal CXB micelles (M3), such as crystallinity, thermal properties, and intramolecular interactions, were altered. Compared with the commercial product (Celebrex®), the M3 and SD6 formulations showed significantly improved anti-inflammatory effects in terms of nitric oxide reduction, 1.5-fold and 2.2-fold, respectively, at the cellular level. The relative bioavailability (BA) of the M3 and SD6 formulations was also significantly improved as oral bioavailability (167.2% and 219.8% respectively), compared with that of Celebrex®. In particular, M3 and SD6 significantly reduced inflammation and edema volume relative to Celebrex® in CFA-induced RA rat models. Moreover, both M3 and SD6 effectively suppressed CFA-induced pro-inflammatory cytokines (TNF-α and IL-1ß) in rat splenic tissues. In conclusion, polymeric systems improved the solubility, relative BA (%) and anti-inflammatory effects of CXB. Thus, CXB polymeric systems show potential as therapeutic agents against inflammation and RA and may need to be tested at the clinical level.


Subject(s)
Arthritis, Experimental , Arthritis, Rheumatoid , Animals , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Celecoxib/pharmacology , Celecoxib/therapeutic use , Freund's Adjuvant , Inflammation/drug therapy , Rats
12.
J Ethnopharmacol ; 239: 111912, 2019 Jul 15.
Article in English | MEDLINE | ID: mdl-31029758

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Acer tegmentosum Maxim (AT), the East Asian stripe maple, is an herb used to treat liver disease and is approved as a functional food in Korea. AT protects against hepatic disorders, atopic dermatitis, and diabetes mellitus. AIM OF THE STUDY: We explored the mechanism of the hepatoprotective effects of AT extract in in vitro and in vivo levels. MATERIALS AND METHODS: AT extract from Acer tegmentosum Maxim was extracted by hot water. Hepatoprotective effects of AT extract were confirmed using carbon tetrachloride (CCl4)- or alcohol-induced mouse model, and H2O2- or alcohol-induced HepG2 (liver hepatocellular carcinoma cell line) cells by measuring GOT, GPT, TG, and MDA levels. Hematoxylin and eosin (H&E) staining was used to observe the pathological analysis. Cytotoxicity or protective effect of AT extract was confirmed using MTT assay in HepG2 cells. Antioxidant effect of AT extract was measured using DPPH or H2DCFDA assay. Mechanism study of antioxidant and autophagy was carried out using western blotting and immunofluorescence analysis. RESULTS: AT extract increased the viability of HepG2 cells treated with H2O2 and ethanol, and protected the liver against damage induced by CCl4 and alcohol. The AT extract increased the levels of nuclear respiratory factor 2 (Nrf2) and heme oxygenase-1 (HO-1). The level of microtubule-associated protein light chain 3 (LC3)-Ⅱ, beclin-1, autophagy-related genes (Atg) such as Atg3 and Atg12-5 as markers of autophagy activation was also increased. Moreover, the AT extract increased activation of mitogen-activated protein kinase (MAPK), which regulated autophagy and HO-1. CONCLUSION: Therefore, these results indicate that the AT extract has a hepatoprotective effect by increasing antioxidant activity and inducing autophagy.


Subject(s)
Acer , Antioxidants/therapeutic use , Chemical and Drug Induced Liver Injury/drug therapy , Plant Extracts/therapeutic use , Animals , Antioxidants/pharmacology , Autophagy/drug effects , Carbon Tetrachloride , Cell Line, Tumor , Cell Survival/drug effects , Chemical and Drug Induced Liver Injury/pathology , Humans , Liver/drug effects , Liver/pathology , Male , Mice, Inbred C57BL , Mice, Inbred ICR , Mitogen-Activated Protein Kinases/metabolism , Plant Extracts/pharmacology , Plant Stems , Reactive Oxygen Species/metabolism
13.
BMC Complement Altern Med ; 19(1): 55, 2019 Mar 06.
Article in English | MEDLINE | ID: mdl-30841887

ABSTRACT

BACKGROUND: Mulberry is a Korean medicinal herb that shows effective prevention and treatment of obesity and diabetes. Bioconversion is the process of producing active ingredients from natural products using microorganisms or enzymes. METHODS: In this study, we prepared bioconverted mulberry leaf extract (BMLE) with Viscozyme L, which we tested in insulin-sensitive cells (i.e., skeletal muscle cells and adipocytes) and insulin-secreting pancreatic ß-cells, as well as obese diabetic mice induced by co-administration of streptozotocin (100 mg/kg, IP) and nicotinamide (240 mg/kg, IP) and feeding high-fat diet, as compared to unaltered mulberry leaf extract (MLE). RESULTS: BMLE increased the glucose uptake in C2C12 myotubes and 3 T3-L1 adipocytes and increased glucose-stimulated insulin secretion in HIT-T15 pancreatic ß-cells. The fasting blood glucose levels in diabetic mice treated with BMLE or MLE (300 and 600 mg/kg, PO, 7 weeks) were significantly lower than those of the vehicle-treated group. At the same concentration, BMLE-treated mice showed better glucose tolerance than MLE-treated mice. Moreover, the blood concentration of glycated hemoglobin (HbA1C) in mice treated with BMLE was lower than that in the MLE group at the same concentration. Plasma insulin levels in mice treated with BMLE or MLE tended to increase compared to the vehicle-treated group. Treatment with BMLE yielded significant improvements in insulin resistance and insulin sensitivity. CONCLUSION: These results indicate that in the management of diabetic condition, BMLE is superior to unaltered MLE due to at least, in part, high concentrations of maker compounds (trans-caffeic acid and syringaldehyde) in BMLE.


Subject(s)
Blood Glucose/drug effects , Hypoglycemic Agents/pharmacology , Morus/chemistry , Plant Extracts/pharmacology , Animals , Body Weight/drug effects , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/metabolism , Diet, High-Fat , Hypoglycemic Agents/metabolism , Insulin Resistance/physiology , Mice , Mice, Inbred C57BL , Plant Extracts/metabolism , Plant Leaves/chemistry
14.
Korean J Physiol Pharmacol ; 22(3): 349-360, 2018 May.
Article in English | MEDLINE | ID: mdl-29719457

ABSTRACT

Autophagy has been studied as a therapeutic strategy for cardiovascular diseases. However, insufficient studies have been reported concerning the influence of vascular smooth muscle cells (VSMCs) through autophagy regulation. The aim of the present study was to determine the effects of VSMCs on the regulation of autophagy under in vitro conditions similar to vascular status of the equipped microtubule target agent-eluting stent and increased release of platelet-derived growth factor-BB (PDGF-BB). Cell viability and proliferation were measured using MTT and cell counting assays. Immunofluorescence using an anti-α-tubulin antibody was performed to determine microtubule dynamic formation. Cell apoptosis was measured by cleavage of caspase-3 using western blot analysis, and by nuclear fragmentation using a fluorescence assay. Autophagy activity was assessed by microtubule-associated protein light chain 3-II (LC-II) using western blot analysis. Levels of intracellular reactive oxygen species (ROS) were measured using H2DCFDA. The proliferation and viability of VSMCs were inhibited by microtubule regulation. Additionally, microtubule-regulated and PDGF-BB-stimulated VSMCs increased the cleavage of caspase-3 more than only the microtubule-regulated condition, similar to that of LC3-II, implying autophagy. Inhibitory autophagy of microtubule-regulated and PDGF-BB-stimulated VSMCs resulted in low viability. However, enhancement of autophagy maintained survival through the reduction of ROS. These results suggest that the apoptosis of conditioned VSMCs is decreased by the blocking generation of ROS via the promotion of autophagy, and proliferation is also inhibited. Thus, promoting autophagy as a therapeutic target for vascular restenosis and atherosclerosis may be a good strategy.

15.
Br J Pharmacol ; 174(22): 4140-4154, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28832962

ABSTRACT

BACKGROUND AND PURPOSE: The proliferation and migration of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor (PDGF) are important steps in cardiovascular diseases, including neointimal lesion formation, myocardial infarction and atherosclerosis. Here, we evaluated the rubiarbonone C-mediated signalling pathways that regulate PDGF-induced VSMC proliferation and migration. EXPERIMENTAL APPROACH: Cell proliferation and migration were measured in cells treated with rubiarbonone C followed by PDGF BB using the MTT assay, [3 H]-thymidine incorporation, flow cytometry and wound-healing migration assay, MMP gelatin zymography, a fluorescence assay for F-actin. Western blotting of molecules including MAPK, focal adhesion kinase (FAK) and STAT3 and an immunofluorescence assay using anti-PCNA and -STAT3 antibodies were performed to evaluate rubiarbonone C signalling pathway(s). The medial thickness of the carotid artery was evaluated using a mouse carotid ligation model. KEY RESULTS: Rubiarbonone C inhibited PDGF-induced VSMC proliferation and migration and diminished the ligation-induced increase in medial thickness of the carotid artery. In PDGF-stimulated VSMCs rubiarbonone C decreased the following: (i) levels of cyclin-dependent kinases, cyclins, PCNA and hyperphosphorylated retinoblastoma protein; (ii) levels and activity of MMP2 and MMP9; (iii) activation of MAPK; (iv) F-actin reorganization, by reducing FAK activation; (v) activation of STAT3. CONCLUSIONS AND IMPLICATIONS: These findings suggest that rubiarbonone C inhibits the proliferation and migration of VSMCs by inhibiting the FAK, MAPK and STAT3 signalling pathways. Therefore, rubiarbonone C could be a good candidate for the treatment of cardiovascular disease.


Subject(s)
Myocytes, Smooth Muscle/drug effects , Triterpenes/pharmacology , Animals , Becaplermin , Carotid Arteries/drug effects , Carotid Arteries/pathology , Carotid Arteries/surgery , Cell Movement/drug effects , Cell Proliferation/drug effects , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Male , Mice, Inbred C57BL , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinases/metabolism , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/metabolism , Proto-Oncogene Proteins c-sis/pharmacology , Rats, Sprague-Dawley , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects
16.
J Nat Prod ; 80(7): 2018-2025, 2017 07 28.
Article in English | MEDLINE | ID: mdl-28621938

ABSTRACT

The cucurbitaceous plant Momordica charantia L., named "bitter melon", inhabits Asia, Africa, and South America and has been used as a traditional medicine. The atypical proliferation of vascular smooth muscle cells (VSMCs) plays an important role in triggering the pathogenesis of cardiovascular diseases. Platelet-derived growth factor (PDGF) is regarded as the most powerful growth factor in promoting the intimal accumulation of VSMCs. The current study features the identification of six new cucurbitane-type triterpenoids (1-6) from the fruits of M.  charantia, utilizing diverse chromatographic and spectroscopic techniques. In particular, the 2D structure of 1 was confirmed utilizing the long-range HSQMBC NMR pulse, capable of measuring heteronuclear long-range correlations (4-6JCH). The cucurbitanes were also assessed for their inhibitory activity against PDGF-induced VSMC proliferation. This current study may constitute a basis for developing those chemotypes into sensible pharmacophores alleviating cardiovascular disorders.


Subject(s)
Glycosides/pharmacology , Momordica charantia/chemistry , Muscle, Smooth, Vascular , Platelet-Derived Growth Factor/pharmacology , Triterpenes/pharmacology , Animals , Fruit/chemistry , Glycosides/chemistry , Humans , Molecular Structure , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Nuclear Magnetic Resonance, Biomolecular , Rats , Rats, Sprague-Dawley , Republic of Korea , Triterpenes/chemistry
17.
Mitochondrial DNA A DNA Mapp Seq Anal ; 27(3): 2015-7, 2016 05.
Article in English | MEDLINE | ID: mdl-25354144

ABSTRACT

The complete chloroplast genome (cpDNA) sequence of Dianthus superbus var. longicalycinus is an economically important traditional Chinese medicine was reported and characterized. The cpDNA of Dianthus superbus var. longicalycinus is 149,539 bp, with 36.3% GC content. A pair of inverted repeats (IRs) of 24,803 bp is separated by a large single-copy region (LSC, 82,805 bp) and a small single-copy region (SSC, 17,128 bp). It encodes 85 protein-coding genes, 36 tRNA genes and 8 rRNA genes. Of 129 individual genes, 13 genes encoded one intron and three genes have two introns.


Subject(s)
Dianthus/genetics , Genome, Chloroplast , Base Composition , Base Pairing/genetics , Base Sequence , DNA, Chloroplast/genetics , Open Reading Frames/genetics
18.
Korean J Ophthalmol ; 29(1): 23-30, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25646057

ABSTRACT

PURPOSE: To analyze healing changes of corneal wounds of different corneal incision sizes with or without stromal hydration in cataract surgery using anterior segment optical coherence tomography. METHODS: Cataract surgeries were performed by a single surgeon and 2.2- and 2.8-mm corneal incisions were made using a diamond blade (ME-759; Meyco, Biel-Bienne, Swiss). Patients were divided into four groups according to incision size (2.2 and 2.8 mm), and with/without stromal hydration. Fifteen eyes were assigned to each group and incision wounds were measured using anterior segment optical coherence tomography at 2 hours, 1 day, 1 week, 1 month, and 3 months postoperatively. Corneal thickness, incision length and incision angle were measured and existence of epithelial, endothelial gaping and Descemet's membrane detachment was evaluated. RESULTS: Incision thickness was greater in the group with stromal hydration than in the group without on operation day (p < 0.05). Stromal hydration exerted greater influence in the 2.2-mm incision group than in the 2.8-mm incision group. Corneal thickness decreased more rapidly in the stromal hydration group than in the group with no hydration (p = 0.022). Endothelial gaping was greater in the 2.2-mm incision group than in the 2.8-mm incision group 1 day, 1 month, and 3 months after surgery (p = 0.035, p = 0.009, and p = 0.008, respectively). No other statistical significance was observed between the two groups (2.2 and 2.8 mm) during follow-up regarding corneal thickness, epithelial gaping and Descemet's membrane detachment. CONCLUSIONS: Corneal wounds with a smaller incision could be more vulnerable to external stimuli such as stromal hydration and are less stable than those with a larger incision.


Subject(s)
Cataract Extraction/methods , Corneal Stroma/surgery , Surgical Wound Dehiscence/prevention & control , Tomography, Optical Coherence/methods , Wound Healing , Aged , Anterior Eye Segment , Corneal Stroma/pathology , Female , Humans , Male , Middle Aged , Surgical Wound Dehiscence/diagnosis
20.
Int J Oncol ; 45(6): 2569-75, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25270851

ABSTRACT

Doxorubicin (DOX) is one of the most effective chemotherapeutic agents in the treatment of a variety of tumors. However, its clinical use has been compromised by the risk of cardiotoxicity. Thus, many efforts have been focused on exploring new strategies to prevent or reverse DOX-induced cardiotoxicity. Recently, deep sea water (DSW) has drawn much scientific interest for therapeutic intervention due to its enrichment in nutrients and minerals. In this study, we investigated whether DSW has protective effects against DOX-induced cardiotoxicity. Pre-treatment with DSW significantly increased the viability of DOX-treated rat H9c2 cardiac muscle cells. This protective effect of DSW appears to be mediated through the inhibition of DNA damage rather than suppression of reactive oxygen species (ROS) production in DOX­treated H9c2 cardiac muscle cells. The inhibitory effect of DSW on DOX-induced DNA damage subsequently attenuated apoptotic signaling such as activation of cysteine-aspartic acid protease-3 (caspase-3) and fragmentation of poly(ADP-ribose) polymerase (PARP), whereas the expression of anti-apoptotic protein B-cell lymphoma-extra large (Bcl-xL) was increased. Moreover, DSW treatment rescued the activation of protein kinase B (Akt) to protect cells from DOX-triggered apoptosis. Taken together, our data showed that DSW has protective effects against DOX-induced cardiotoxicity, suggesting that DSW has some promise as a novel protective supplement for promoting the successful use of DOX in clinical regimen.


Subject(s)
Cardiotoxicity/drug therapy , Drug-Related Side Effects and Adverse Reactions/drug therapy , Myocytes, Cardiac/drug effects , Seawater , Animals , Apoptosis/drug effects , Cardiotoxicity/pathology , Caspase 3/biosynthesis , Cell Survival/drug effects , Doxorubicin/adverse effects , Drug-Related Side Effects and Adverse Reactions/pathology , Humans , Myocytes, Cardiac/pathology , Proto-Oncogene Proteins c-akt/biosynthesis , Rats , Reactive Oxygen Species/metabolism
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