Publications by authors named "Yasufumi Katanasaka"

56 Publications

Effect of Theaflavin on Oral Bacteria in Japanese Subjects: A Randomized, Placebo-Controlled, Double-Blind Study.

J Med Food 2021 Nov 25;24(11):1186-1190. Epub 2021 Oct 25.

Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.

Black tea is a popular beverage worldwide. Theaflavins (TFs), which are active functional components of black tea, are potentially valuable for preventing and/or treating the progression of periodontal diseases. Our previous pilot study showed that TF intake decreases the number of () bacteria in the saliva. In this study, we aimed to determine whether TF intake improves periodontal disease attributed to oral bacteria in a randomized, placebo-controlled, and double-blind study. A total of 56 healthy subjects without periodontal diseases were enrolled and assigned to the placebo and TF groups ( = 28). TF intake for 6 weeks did not significantly alter the clinical evaluation of subjects. There was no significant adverse effect among the subjects. The number of and () bacteria, which was the primary endpoint in this study, was not impacted by TF intake. The change ratio of was significantly decreased by TF intake ( = .043) when compared with the placebo group. Collectively, our findings suggest that TFs have beneficial effects on oral bacteria for the prevention of periodontal disease. The study protocol was registered in the University Hospital Medical Information Network (UMIN000020049).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/jmf.2021.K.0050DOI Listing
November 2021

Alpha Mangostin Derived from Garcinia magostana Linn Ameliorates Cardiomyocyte Hypertrophy and Fibroblast Phenotypes in Vitro.

Biol Pharm Bull 2021 ;44(10):1465-1472

Division of Molecular Medicine, Graduate School of Pharmaceutical Sciences, University of Shizuoka.

Cardiac hypertrophy and fibrosis are significant risk factors for chronic heart failure (HF). Since pharmacotherapy agents targeting these processes have not been established, we investigated the effect of alpha-magostin (α-man) on cardiomyocyte hypertrophy and fibrosis in vitro. Primary cultured cardiomyocytes and cardiac fibroblasts were prepared from neonatal rats. After α-man treatment, phenylephrine (PE) and transforming growth factor-beta (TGF-β) were added to the cardiomyocytes and cardiac fibroblasts to induce hypertrophic and fibrotic responses, respectively. Hypertrophic responses were assessed by measuring the cardiomyocyte surface area and hypertrophic gene expression levels. PE-induced phosphorylation of Akt, extracellular signal-regulated kinase (ERK)1/2, and p38 was examined by Western blotting. Fibrotic responses were assessed by measuring collagen synthesis, fibrotic gene expression levels, and myofibroblast differentiation. In addition, TGF-β-induced reactive oxygen species (ROS) production was investigated. In cultured cardiomyocytes, α-man significantly suppressed PE-induced increases in the cardiomyocyte surface area, and the mRNA levels (atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP)). Treatment with α-man significantly suppressed PE-induced Akt phosphorylation, but not ERK and p38 phosphorylation. In cultured cardiac fibroblasts, α-man significantly suppressed TGF-β-induced increases in L-proline incorporation, mRNA levels (POSTN and alpha-smooth muscle actin (α-SMA)), and myofibroblast differentiation. Additionally, it significantly inhibited TGF-β-induced reduced nicotinamide adenine dinucleotide phosphate oxidase4 (NOX4) expression and ROS production in cardiac fibroblasts. Treatment with α-man significantly ameliorates hypertrophy by inhibiting Akt phosphorylation in cardiomyocytes and fibrosis by inhibiting NOX4-generating ROS in fibroblasts. These findings suggest that α-man is a possible natural product for the prevention of cardiac hypertrophy and fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/bpb.b21-00294DOI Listing
January 2021

Zerumbone prevents pressure overload-induced left ventricular systolic dysfunction by inhibiting cardiac hypertrophy and fibrosis.

Phytomedicine 2021 Nov 14;92:153744. Epub 2021 Sep 14.

Division of Molecular Medicine, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan; Clinical Research Institute, Division of Translational Research, National Hospital Organization Kyoto Medical Center, Kyoto, 612-8555, Japan; Shizuoka General Hospital, Shizuoka, Japan. Electronic address:

Background: Cardiac hypertrophy and fibrosis are hallmarks of cardiac remodeling and are involved functionally in the development of heart failure (HF). However, it is unknown whether Zerumbone (Zer) prevents left ventricular (LV) systolic dysfunction by inhibiting cardiac hypertrophy and fibrosis.

Purpose: This study investigated the effect of Zer on cardiac hypertrophy and fibrosis in vitro and in vivo.

Study Design/methods: In primary cultured cardiac cells from neonatal rats, the effect of Zer on phenylephrine (PE)-induced hypertrophic responses and transforming growth factor beta (TGF-β)-induced fibrotic responses was observed. To determine whether Zer prevents the development of pressure overload-induced HF in vivo, a transverse aortic constriction (TAC) mouse model was utilized. Cardiac function was evaluated by echocardiography. The changes of cardiomyocyte surface area were observed using immunofluorescence staining and histological analysis (HE and WGA staining). Collagen synthesis and fibrosis formation were measured by scintillation counter and picrosirius staining, respectively. The total mRNA levels of genes associated with hypertrophy (ANF and BNP) and fibrosis (Postn and α-SMA) were measured by qRT-PCR. The protein expressions (Akt and α-SMA) were assessed by western blotting.

Results: Zer significantly suppressed PE-induced increase in cell size, mRNA levels of ANF and BNP, and Akt phosphorylation in cardiomyocytes. The TGF-β-induced increase in proline incorporation, mRNA levels of Postn and α-SMA, and protein expression of α-SMA were decreased by Zer in cultured cardiac fibroblasts. In the TAC male C57BL/6 mice, echocardiography results demonstrated that Zer improved cardiac function by increasing LV fractional shortening and reducing LV wall thickness compared with the vehicle group. ZER significantly reduced the level of phosphorylated Akt both in cultured cardiomyocytes treated with PE and in the hearts of TAC. Finally, Zer inhibited the pressure overload-induced cardiac hypertrophy and cardiac fibrosis.

Conclusion: Zer ameliorates pressure overload-induced LV dysfunction, at least in part by suppressing both cardiac hypertrophy and fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phymed.2021.153744DOI Listing
November 2021

Curcumin, an Inhibitor of p300-HAT Activity, Suppresses the Development of Hypertension-Induced Left Ventricular Hypertrophy with Preserved Ejection Fraction in Dahl Rats.

Nutrients 2021 Jul 29;13(8). Epub 2021 Jul 29.

Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.

We found that curcumin, a p300 histone acetyltransferase (HAT) inhibitor, prevents cardiac hypertrophy and systolic dysfunction at the stage of chronic heart failure in Dahl salt-sensitive rats (DS). It is unclear whether curcumin suppresses the development of hypertension-induced left ventricular hypertrophy (LVH) with a preserved ejection fraction. Therefore, in this study, we randomized DS ( = 16) and Dahl salt-resistant (DR) rats ( = 10) at 6 weeks of age to either curcumin or vehicle groups. These rats were fed a high-salt diet and orally administrated with 50 mg/kg/d curcumin or its vehicle for 6 weeks. Both curcumin and vehicle treatment groups exhibited similar degrees of high-salt diet-induced hypertension in DS rats. Curcumin significantly decreased hypertension-induced increase in posterior wall thickness and LV mass index, without affecting the systolic function. It also significantly reduced hypertension-induced increases in myocardial cell diameter, perivascular fibrosis and transcriptions of the hypertrophy-response gene. Moreover, it significantly attenuated the acetylation levels of GATA4 in the hearts of DS rats. A p300 HAT inhibitor, curcumin, suppresses the development of hypertension-induced LVH, without affecting blood pressure and systolic function. Therefore, curcumin may be used for the prevention of development of LVH in patients with hypertension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu13082608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397934PMC
July 2021

Metformin suppresses phenylephrine-induced hypertrophic responses by inhibiting p300-HAT activity in cardiomyocytes.

J Pharmacol Sci 2021 Oct 6;147(2):169-175. Epub 2021 Jul 6.

Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan; Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto, 612-8555, Japan; Shizuoka General Hospital, Shizuoka, 420-8527, Japan. Electronic address:

Introduction: Heart failure is the final pathway for a wide spectrum of myocardial stress, including hypertension and myocardial infarction. However, the potential effects of metformin on cardiac hypertrophy are still unclear.

Purpose: The purpose of this study was to investigate whether metformin leads to suppression of hypertrophic responses in cardiomyocytes.

Methods And Results: To investigate whether metformin inhibited p300-histone acetyltransferase (HAT), we performed an in vitro HAT assay. Metformin directly inhibited p300-mediated acetylation of histone-H3K9. To examine the effects of metformin on hypertrophic responses, cardiomyocytes prepared from neonatal rats were treated with metformin and stimulated with saline or phenylephrine (PE), a α-adrenergic agonist for 48 h. PE stimulus showed an increase in cell size, myofibrillar organization, expression of the endogenous atrial natriuretic factor and brain natriuretic peptide genes, and acetylation of histone-H3K9 compared with saline-treated cells. These PE-induced changes were inhibited by metformin. Next, to examine the effect of metformin on p300-mediated hypertrophy, cardiomyocytes were transfected with expression vector of p300. Metformin significantly suppressed p300-induced hypertrophic responses and acetylation of histone-H3K9.

Conclusions: The study demonstrates that metformin can suppress PE-induced and p300-mediated hypertrophic responses. Metformin may be useful for the treatment of patients with diabetes and heart failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jphs.2021.07.001DOI Listing
October 2021

The Cancer Therapy-Related Clonal Hematopoiesis Driver Gene Promotes Inflammation and Non-Ischemic Heart Failure in Mice.

Circ Res 2021 Sep 28;129(6):684-698. Epub 2021 Jul 28.

Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA (Y.Y., E.M.-Y., K.-D.M., N.C., A.H.P., H.O., K.H., H.D., M.A.E., M.S., Y.W., S.S., K.W.).

[Figure: see text].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.121.319314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409899PMC
September 2021

Neutrophil/lymphocyte ratio is correlated with levels of inflammatory markers and is significantly reduced by smoking cessation.

J Int Med Res 2021 Jun;49(6):3000605211019223

Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.

Previous studies have reported that the neutrophil to lymphocyte ratio (NLR) is associated with onset and prognosis of cardiovascular disease (CVD). Smoking is a major risk factor for CVD and smoking cessation significantly reduces CVD risk. However, the effects of smoking cessation on the NLR remain unknown. Among smokers visiting our smoking cessation clinics, we examined changes in the NLR and CVD biomarkers before and after smoking cessation. A total of 389 individuals (301 men and 88 women) were enrolled in the study. The median NLR was significantly reduced after successful smoking cessation (before: 1.8, interquartile range [IQR] 1.5, 2.5; after: 1.7, IQR 1.3, 2.4). In a linear regression model adjusted for sex, percent change in NLR comparing before and after smoking cessation was significantly and positively correlated with percent changes in C-reactive protein (β = 0.260), α1-antitrypsin-low density lipoprotein (β = 0.151,  < 0.05), and serum amyloid A-low density lipoprotein (β = 0.325). Our study demonstrated for the first time that smoking cessation significantly reduces the NLR in tandem with markers of inflammation and oxidative stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/03000605211019223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258763PMC
June 2021

Histone Acetylation Domains Are Differentially Induced during Development of Heart Failure in Dahl Salt-Sensitive Rats.

Int J Mol Sci 2021 Feb 10;22(4). Epub 2021 Feb 10.

Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, Japan.

Histone acetylation by epigenetic regulators has been shown to activate the transcription of hypertrophic response genes, which subsequently leads to the development and progression of heart failure. However, nothing is known about the acetylation of the histone tail and globular domains in left ventricular hypertrophy or in heart failure. The acetylation of H3K9 on the promoter of the hypertrophic response gene was significantly increased in the left ventricular hypertrophy stage, whereas the acetylation of H3K122 did not increase in the left ventricular hypertrophy stage but did significantly increase in the heart failure stage. Interestingly, the interaction between the chromatin remodeling factor BRG1 and p300 was significantly increased in the heart failure stage, but not in the left ventricular hypertrophy stage. This study demonstrates that stage-specific acetylation of the histone tail and globular domains occurs during the development and progression of heart failure, providing novel insights into the epigenetic regulatory mechanism governing transcriptional activity in these processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22041771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916721PMC
February 2021

Cacao Bean Polyphenols Inhibit Cardiac Hypertrophy and Systolic Dysfunction in Pressure Overload-induced Heart Failure Model Mice.

Planta Med 2020 Nov 9;86(17):1304-1312. Epub 2020 Jul 9.

Division of Molecular Medicine, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.

Pathological stresses such as pressure overload and myocardial infarction induce cardiac hypertrophy, which increases the risk of heart failure. Cacao bean polyphenols have recently gained considerable attention for their beneficial effects on cardiovascular diseases. This study investigated the effect of cacao bean polyphenols on the development of cardiac hypertrophy and heart failure. Cardiomyocytes from neonatal rats were pre-treated with cacao bean polyphenols and then stimulated with 30 µM phenylephrine. C57BL/6j male mice were subjected to sham or transverse aortic constriction surgery and then orally administered with vehicle or cacao bean polyphenols. Cardiac hypertrophy and function were examined by echocardiography. In cardiomyocytes, cacao bean polyphenols significantly suppressed phenylephrine-induced cardiomyocyte hypertrophy and hypertrophic gene transcription. Extracellular signal-regulated kinase 1/2 and GATA binding protein 4 phosphorylation induced by phenylephrine was inhibited by cacao bean polyphenols treatment in the cardiomyocytes. Cacao bean polyphenols treatment at 1200 mg/kg significantly ameliorated left ventricular posterior wall thickness, fractional shortening, hypertrophic gene transcription, cardiac hypertrophy, cardiac fibrosis, and extracellular signal-regulated kinase 1/2 phosphorylation induced by pressure overload. In conclusion, these findings suggest that cacao bean polyphenols prevent pressure overload-induced cardiac hypertrophy and systolic dysfunction by inhibiting the extracellular signal-regulated kinase 1/2-GATA binding protein 4 pathway in cardiomyocytes. Thus, cacao bean polyphenols may be useful for heart failure therapy in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1191-7970DOI Listing
November 2020

The Synthetic Curcumin Analogue GO-Y030 Effectively Suppresses the Development of Pressure Overload-induced Heart Failure in Mice.

Sci Rep 2020 04 28;10(1):7172. Epub 2020 Apr 28.

Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan.

Curcumin is a naturally occurring p300-histone acetyltransferase (p300-HAT) inhibitor that suppresses cardiomyocyte hypertrophy and the development of heart failure in experimental animal models. To enhance the therapeutic potential of curcumin against heart failure, we produced a series of synthetic curcumin analogues and investigated their inhibitory activity against p300-HAT. The compound with the strongest activity was further evaluated to determine its effects on cardiomyocyte hypertrophy and pressure overload-induced heart failure in mice. We synthesised five synthetic curcumin analogues and found that a compound we have named GO-Y030 most strongly inhibited p300-HAT activity. Furthermore, 1 μM GO-Y030, in a manner equivalent to 10 µM curcumin, suppressed phenylephrine-induced hypertrophic responses in cultured cardiomyocytes. In mice undergoing transverse aortic constriction surgery, administration of GO-Y030 at a mere 1% of an equivalently-effective dose of curcumin significantly attenuated cardiac hypertrophy and systolic dysfunction. In addition, this low dose of GO-Y030 almost completely blocked histone H3K9 acetylation and eliminated left ventricular fibrosis. A low dose of the synthetic curcumin analogue GO-Y030 effectively inhibits p300-HAT activity and markedly suppresses the development of heart failure in mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-64207-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188884PMC
April 2020

Kosen-cha, a Polymerized Catechin-Rich Green Tea, as a Potential Functional Beverage for the Reduction of Body Weight and Cardiovascular Risk Factors: A Pilot Study in Obese Patients.

Biol Pharm Bull 2020 ;43(4):675-681

Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka.

Previous studies have shown that green tea catechins (GTCs) have beneficial effects on obesity and metabolic syndromes. In this study, we prepared kosen-cha from green tea using high pressure extraction, to reduce the astringent taste of the green tea. We identified a large quantity of polymerized GTCs in kosen-cha. To investigate the effects of kosen-cha containing polymerized GTCs in obese Japanese patients, we designed an open-label pilot study in which 6 obese subjects (body mass index (BMI) >25 kg/m) were administered kosen-cha (5 g/L/d) for 12 weeks. Body composition, serum lipids, insulin resistance, vascular functions, and cardiac hypertrophy were measured before and 12 weeks after kosen-cha administration. Kosen-cha showed no significant adverse effects on the patients. Body weights, BMI, waist circumferences, serum triglyceride (TG) levels, and homeostasis model assessment as an index of insulin resistance (HOMA-IR) levels were significantly decreased after the 12 weeks of administration. Flow-mediated dilation (FMD) (p = 0.0214), brachial-ankle pulse wave velocity (baPWV)(p = 0.0141), left ventricular mass indexes (p = 0.0120), and plasma brain natriuretic peptide (BNP) (p = 0.0144) were significantly improved. Overall, kosen-cha reduced obesity and improved insulin resistance, vascular function, and cardiac hypertrophy, indicating its preventive potential in obesity and metabolic syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/bpb.b19-00921DOI Listing
November 2020

Effects of Highly Absorbable Curcumin in Patients with Impaired Glucose Tolerance and Non-Insulin-Dependent Diabetes Mellitus.

J Diabetes Res 2019 23;2019:8208237. Epub 2019 Nov 23.

Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.

Oxidative stress is enhanced by various mechanisms. Serum oxidized low-density lipoprotein (LDL) is a useful prognostic marker in diabetic patients with coronary artery disease. To examine the effects of Theracurmin®, a highly absorbable curcumin preparation, on glucose tolerance, adipocytokines, and oxidized LDL, we conducted a double-blind placebo-controlled parallel group randomized trial in patients with impaired glucose tolerance or non-insulin-dependent diabetes mellitus. We randomly divided the patients with impaired glucose tolerance or non-insulin-dependent diabetes mellitus and stable individuals into the placebo group and the Theracurmin® (180 mg daily for 6 months) group. Of the 33 patients analyzed, 18 (14 males and 4 females) were administered placebo and 15 (9 males and 6 females) were administered Theracurmin®. The patient characteristics did not differ between the two groups. The primary endpoint, HbA1c, did not differ significantly between the two groups. However, the level of 1-antitrypsin-low-density lipoprotein (AT-LDL), the oxidized LDL, significantly increased ( = 0.024) in the placebo group from the beginning of the trial up to 6 months, although there was no such change in the Theracurmin® group. The percentage change in BMI from the beginning of the trial up to 6 months tended to be higher in the Theracurmin® group than in the placebo group. Patients in the Theracurmin® group tended to have a larger percentage change in adiponectin and LDL-C than those in the placebo group. Patients in the Theracurmin® group showed a smaller percentage change in AT-LDL than those in the placebo group. This study suggests that the highly absorbable curcumin could potentially inhibit a rise in oxidized LDL in patients with impaired glucose tolerance or non-insulin-dependent diabetes mellitus. This trial is registered with UMIN000007361.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/8208237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906884PMC
June 2020

Serum Cystatin C, a Sensitive Marker of Renal Function and Cardiovascular Disease, Decreases After Smoking Cessation.

Circ Rep 2019 Nov 30;1(12):623-627. Epub 2019 Nov 30.

Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka Shizuoka Japan.

Smoking exerts detrimental effects during the progression of atherosclerotic vascular disease. Serum cystatin C is useful in the evaluation of early renal dysfunction and serves as a cardiovascular prognostic marker. This study measured changes in serum cystatin C after smoking cessation (SC). In this study, patients who visited the SC clinic for the first time and succeeded in SC for 1 year were enrolled. In the entire cohort of 86 patients, body mass index (BMI, P<0.001) and waist circumference (WC, P<0.001) increased significantly at 3 months after SC compared with baseline. These values were further increased significantly (BMI, P<0.001; WC, P<0.001) from 3 months to 1 year after SC. Serum cystatin C decreased significantly at 3 months (P=0.045) after SC, and remained unchanged (P=0.482) from 3 months to 1 year after SC. Percent change from baseline to 3 months after SC in serum cystatin C was correlated with the percent change in serum monocyte chemoattractant protein 1 (P=0.047). Serum cystatin C, a marker of chronic kidney disease, was significantly reduced at 3 months after SC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1253/circrep.CR-19-0052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897701PMC
November 2019

-Mediated Clonal Hematopoiesis Accelerates Pathological Remodeling in Murine Heart Failure.

JACC Basic Transl Sci 2019 Oct 18;4(6):684-697. Epub 2019 Sep 18.

Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia.

Janus kinase 2 (valine to phenylalanine at residue 617) ( ) mutations lead to myeloproliferative neoplasms associated with elevated myeloid, erythroid, and megakaryocytic cells. Alternatively these same mutations can lead to the condition of clonal hematopoiesis with no impact on blood cell counts. Here, a model of myeloid-restricted expression from lineage-negative bone marrow cells was developed and evaluated. This model displayed greater cardiac inflammation and dysfunction following permanent left anterior descending artery ligation and transverse aortic constriction. These data suggest that mutations arising in myeloid progenitor cells may contribute to cardiovascular disease by promoting the proinflammatory properties of circulating myeloid cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacbts.2019.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834960PMC
October 2019

Anti-inflammatory Action of Curcumin and Its Use in the Treatment of Lifestyle-related Diseases.

Eur Cardiol 2019 Jul 11;14(2):117-122. Epub 2019 Jul 11.

Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka Shizuoka, Japan.

Chronic inflammation plays a significant role in lifestyle-related diseases, such as cardiovascular diseases and obesity/impaired glucose tolerance. Curcumin is a natural extract that possesses numerous physiological properties, as indicated by its anti-inflammatory action. The mechanisms underlying these effects include the inhibition of nuclear factor-kappaB and Toll-like receptor 4-dependent signalling pathways and the activation of a peroxisome proliferator-activated receptor-gamma pathway. However, the bioavailability of curcumin is very low in humans. To resolve this issue, several drug delivery systems have been developed and a number of clinical trials have reported beneficial effects of curcumin in the management of inflammation-related diseases. It is expected that evidence regarding the clinical application of curcumin in lifestyle-related diseases associated with chronic inflammation will accumulate over time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15420/ecr.2019.17.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659038PMC
July 2019

Wnt5a-Mediated Neutrophil Recruitment Has an Obligatory Role in Pressure Overload-Induced Cardiac Dysfunction.

Circulation 2019 08 7;140(6):487-499. Epub 2019 Jun 7.

Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville (Y. Wang, S.S., M.S., Y.Y., C.J., K.W.).

Background: Although the complex roles of macrophages in myocardial injury are widely appreciated, the function of neutrophils in nonischemic cardiac pathology has received relatively little attention.

Methods: To examine the regulation and function of neutrophils in pressure overload-induced cardiac hypertrophy, mice underwent treatment with Ly6G antibody to deplete neutrophils and then were subjected to transverse aortic constriction.

Results: Neutrophil depletion diminished transverse aortic constriction-induced hypertrophy and inflammation and preserved cardiac function. Myeloid deficiency of Wnt5a, a noncanonical Wnt, suppressed neutrophil infiltration to the hearts of transverse aortic constriction-treated mice and produced a phenotype that was similar to the neutropenic conditions. Conversely, mice overexpressing Wnt5a in myeloid cells displayed greater hypertrophic growth, inflammation, and cardiac dysfunction. Neutrophil depletion reversed the Wnt5a overexpression-induced cardiac pathology and eliminated differences in cardiac parameters between wild-type and myeloid-specific Wnt5a transgenic mice.

Conclusions: These findings reveal that Wnt5a-regulated neutrophil infiltration has a critical role in pressure overload-induced heart failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.118.038820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684855PMC
August 2019

[Noble Heart Failure Therapy Using Food Compositions].

Yakugaku Zasshi 2018 ;138(10):1263-1269

Division of Translational Research, Kyoto Medical Center, National Hospital Organization.

 Hemodynamic stresses, including hypertension and myocardial infarction, activate neurohumoral factors such as the sympathetic nervous system and the renin-angiotensin system, and can lead to the progression of heart failure. Established pharmacological agents such as angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, and β-blockers target extra-cellular molecules and receptors on the cell membrane. These agents have shown some efficacy for the treatment of heart failure, but the long-term survival rate of patients with heart failure remains low. Additional effective pharmacological approaches are urgently required. Our previous studies have demonstrated that curcumin, a natural polyphenol derived from the root of Curcuma longa, prevented the development of heart failure in rat models of myocardial infarction and hypertensive heart disease. However, until recently curcumin's poor water solubility and extremely low bioavailability have presented serious challenges to its clinical applicability. In recent years, highly absorbable curcumin preparations have been developed using methods such as nanoparticle formation and micellization, and there are now high expectations for their wide clinical application. Our group has developed a highly absorbable curcumin formulation called Theracurmin using nanoparticulation and surface processing techniques. Our preliminary data indicated that Theracurmin may improve left ventricular diastolic function. Furthermore, we have already completed and are currently carrying out several clinical trials using Theracurmin against heart failure-related diseases. This paper summarizes and discusses the potential clinical applications of curcumin, focusing on our highly absorbable curcumin formulation, Theracurmin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/yakushi.18-00091-2DOI Listing
October 2018

CRISPR-Mediated Gene Editing to Assess the Roles of Tet2 and Dnmt3a in Clonal Hematopoiesis and Cardiovascular Disease.

Circ Res 2018 07 4;123(3):335-341. Epub 2018 May 4.

From the Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville (S.S., Y.W., K.W.)

Rationale: Clonal hematopoiesis has been associated with increased mortality and cardiovascular disease. This condition can arise from somatic mutations in preleukemic driver genes within hematopoietic stem/progenitor cells. Approximately 40 candidate driver genes have been identified, but mutations in only 1 of these genes, TET2 (ten-eleven translocation-2), has been shown to casually contribute to cardiovascular disease in murine models.

Objective: To develop a facile system to evaluate the disease characteristics of different clonal hematopoiesis driver genes using lentivirus vector and CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) methodology. Using this methodology, evaluate whether Dnmt3a (DNA [cytosine-5]-methyltransferase 3a)-a commonly occurring clonal hematopoiesis driver gene-causally contributes to cardiovascular disease.

Methods And Results: Lentivirus vectors were used to deliver Cas9 and guide RNA to introduce inactivating mutations in Tet2 and Dnmt3a in lineage-negative bone marrow cells. After implantation into lethally irradiated mice, these cells were engrafted and gave rise to labeled blood cell progeny. When challenged with an infusion of Ang II (angiotensin II), mice with inactivating mutations in Tet2 or Dnmt3a displayed greater cardiac hypertrophy, diminished cardiac function, and greater cardiac and renal fibrosis. In comparison with Tet2, inactivation of Dnmt3a did not lead to detectable expansion of the mutant hematopoietic cells during the time course of these experiments. Tet2 inactivation promoted the expression of IL (interleukin) 1β, IL-6, and Ccl5, whereas Dnmt3a inactivation promoted the expression of Cxcl1 (CXC chemokine ligand), Cxcl2, IL-6, and Ccl5 in a lipopolysaccharide-stimulated macrophage cell line.

Conclusions: Experiments using lentivirus vector/CRISPR methodology provided evidence suggesting that inactivating DNMT3A mutations in hematopoietic cells contributes to cardiovascular disease. Comparative analyses showed that inactivation of Tet2 and Dnmt3 was similar in their ability to promote Ang II-induced cardiac dysfunction and renal fibrosis in mice. However, gene-specific actions were indicated by differences in kinetics of hematopoietic stem/progenitor cell expansion and different patterns of inflammatory gene expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.118.313225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054544PMC
July 2018

Curcumin and its demethoxy derivatives possess p300 HAT inhibitory activity and suppress hypertrophic responses in cardiomyocytes.

J Pharmacol Sci 2018 Apr 13;136(4):212-217. Epub 2018 Mar 13.

Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan; Shizuoka General Hospital, Shizuoka 420-8527, Japan; Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto 612-8555, Japan. Electronic address:

The natural compound, curcumin (CUR), possesses several pharmacological properties, including p300-specific histone acetyltransferase (HAT) inhibitory activity. In our previous study, we demonstrated that CUR could prevent the development of cardiac hypertrophy by inhibiting p300-HAT activity. Other major curcuminoids isolated from Curcuma longa including demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) are structural analogs of CUR. In present study, we first confirmed the effect of these three curcuminoid analogs on p300-HAT activity and cardiomyocyte hypertrophy. Our results showed that DMC and BDMC inhibited p300-HAT activity and cardiomyocyte hypertrophy to almost the same extent as CUR. As the three compounds have structural differences in methoxy groups at the 3-position of their phenol rings, our results suggest that these methoxy groups are not involved in the inhibitory effects on p300-HAT activity and cardiac hypertrophy. These findings provide useful insights into the structure-activity relationship and biological activity of curcuminoids for p300-HAT activity and cardiomyocyte hypertrophy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jphs.2017.12.013DOI Listing
April 2018

Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome.

J Am Coll Cardiol 2018 02;71(8):875-886

Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts. Electronic address:

Background: Recent studies have shown that hematopoietic stem cells can undergo clonal expansion secondary to somatic mutations in leukemia-related genes, thus leading to an age-dependent accumulation of mutant leukocytes in the blood. This somatic mutation-related clonal hematopoiesis is common in healthy older individuals, but it has been associated with an increased incidence of future cardiovascular disease. The epigenetic regulator TET2 is frequently mutated in blood cells of individuals exhibiting clonal hematopoiesis.

Objectives: This study investigated whether Tet2 mutations within hematopoietic cells can contribute to heart failure in 2 models of cardiac injury.

Methods: Heart failure was induced in mice by pressure overload, achieved by transverse aortic constriction or chronic ischemia induced by the permanent ligation of the left anterior descending artery. Competitive bone marrow transplantation strategies with Tet2-deficient cells were used to mimic TET2 mutation-driven clonal hematopoiesis. Alternatively, Tet2 was specifically ablated in myeloid cells using Cre recombinase expressed from the LysM promoter.

Results: In both experimental heart failure models, hematopoietic or myeloid Tet2 deficiency worsened cardiac remodeling and function, in parallel with increased interleukin-1beta (IL-1β) expression. Treatment with a selective NLRP3 inflammasome inhibitor protected against the development of heart failure and eliminated the differences in cardiac parameters between Tet2-deficient and wild-type mice.

Conclusions: Tet2 deficiency in hematopoietic cells is associated with greater cardiac dysfunction in murine models of heart failure as a result of elevated IL-1β signaling. These data suggest that individuals with TET2-mediated clonal hematopoiesis may be at greater risk of developing heart failure and respond better to IL-1β-NLRP3 inflammasome inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2017.12.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828038PMC
February 2018

Effects of Products Containing Bacillus subtilis var. natto on Healthy Subjects with Neck and Shoulder Stiffness, a Double-Blind, Placebo-Controlled, Randomized Crossover Study.

Biol Pharm Bull 2018 Apr 6;41(4):504-509. Epub 2018 Feb 6.

Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka.

Neck and shoulder stiffness is a typical subjective symptom in developed countries. This stiffness is caused by factors such as muscle tension and poor blood flow, leading to reduce work efficiency and diminish QOL. NKCP, a natto-derived dietary food supplement whose main component is bacillopeptidase F, has antithrombotic, fibrinolytic, and blood viscosity-lowering effects. Here, we investigated the effect of NKCP on neck and shoulder stiffness in a double-blind placebo-controlled randomized crossover study. Thirty subjects with neck and shoulder stiffness were randomly divided into 2 groups and ingested 250 mg of NKCP or placebo daily for 4 weeks. Headache score significantly improved in the NKCP group compared to the placebo group. Moreover, NKCP significantly improved the score of visual analogue scale for neck and shoulder stiffness and pain, reduced muscle stiffness of the neck, and increased the skin surface temperature of neck and shoulders, compared to before ingestion. No adverse effects were observed during this study. These results suggest that NKCP may alleviate headaches and chronic neck and shoulder stiffness and pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/bpb.b17-00780DOI Listing
April 2018

[Development of Targeted Pharmacotherapy for Cardiovascular Disease].

Yakugaku Zasshi 2017 ;137(11):1349-1353

Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka.

 Heart and cardiovascular diseases are the leading causes of death in the world. Heart failure (HF) in particular is becoming a serious widespread medical issue, especially following various stresses such as myocardial infarction and hemodynamic overload. One pathological cardiac change in HF is left ventricular hypertrophy (LVH). LVH is associated with increased risk for HF; however, no drug therapy for LVH has yet been developed. During the development of LVH, gene expression is altered in cardiomyocytes through transcription factors, co-activators, and histone modifications. A zinc-finger protein and cardiac-specific transcription factor, GATA4, forms a large complex with functional proteins, including an intrinsic histone acetyltransferase, p300. p300 serves as a co-activator of GATA4 and is required for GATA4-dependent gene transcription. Although the p300/GATA4 pathway is involved in pathological cardiac hypertrophy, the remaining signal transduction pathways involved in pathological cardiac changes remain unclear. To identify therapeutic targets for preventing HF, GATA4-binding proteins have been analyzed, and 73 proteins were identified by tandem affinity purification and mass spectrometry. Here, we describe a receptor for activated protein kinase C1 (RACK1) as a novel GATA4-binding protein. RACK1 inhibited phenylephrine (PE)-induced cell hypertrophy and hypertrophy-associated gene transcription in cultured cardiomyocytes. Tyrosine phosphorylation of RACK1 was enhanced, and binding between GATA4 and RACK1 was disrupted in cardiomyocytes of hypertensive rats. In addition, tyrosine phosphorylation of RACK1 disrupted the RACK1/GATA4 complex. These findings suggest that clarification of nuclear signal pathways in cardiomyocytes would help to identify therapeutic targets for HF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/yakushi.17-00171DOI Listing
January 2018

Regulation of Cardiac Transcription Factor GATA4 by Post-Translational Modification in Cardiomyocyte Hypertrophy and Heart Failure.

Int Heart J 2016 Dec 4;57(6):672-675. Epub 2016 Nov 4.

Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka.

Heart failure is a leading cause of cardiovascular mortality in industrialized countries. During development and deterioration of heart failure, cardiomyocytes undergo maladaptive hypertrophy, and changes in the cellular phenotype are accompanied by reinduction of the fetal gene program. Gene expression in cardiomyocytes is regulated by various nuclear transcription factors, co-activators, and co-repressors. The zinc finger protein GATA4 is one such transcription factor involved in the regulation of cardiomyocyte hypertrophy. In response to hypertrophic stimuli such as those involving the sympathetic nervous and renin-angiotensin systems, changes in protein interaction and/or post-translational modifications of GATA4 cause hypertrophic gene transcription in cardiomyocytes. In this article, we focus on cardiac nuclear signaling molecules, especially GATA4, that are promising as potential targets for heart failure therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1536/ihj.16-404DOI Listing
December 2016

Effect of statins on atherogenic serum amyloid A and α1-antitrypsin low-density lipoprotein complexes.

Int J Cardiol 2016 Dec 3;225:332-336. Epub 2016 Oct 3.

Division of Molecular Medicine, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; Shizuoka General Hospital, Shizuoka, Japan; Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan. Electronic address:

Purpose: HMG-CoA reductase inhibitors, also termed statins, are used to reduce the risk of coronary artery disease. Two oxidatively modified low-density lipoprotein (LDL) complexes, serum amyloid A-LDL (SAA-LDL) and α1-antitrypsin-LDL (AT-LDL), serve as atherosclerotic, inflammatory, and cardiovascular risk markers. In this study, we examined the effects of hydrophilic rosuvastatin (RSV) and lipophilic pitavastatin (PTV) on these markers in patients with hypercholesterolemia.

Methods: The present study was a sub-analysis of our previous STAT-LVDF study. The subjects were treated with RSV or PTV for 24weeks. Changes in glucose-lipid metabolism, serum levels of SAA-LDL and AT-LDL, and C-reactive protein (CRP) level were assessed.

Results: In total, 53 patients were analyzed in the present study. RSV and PTV significantly decreased SAA-LDL (RSV: p=0.003, PTV: p=0.012) and AT-LDL levels (RSV: p=0.013, PTV: p=0.037). Changes in SAA-LDL level were significantly and positively correlated with those in CRP in both the RSV (r=0.549, p=0.003) and PTV (r=0.576, p=0.004) groups. Moreover, a positive correlation between changes of SAA-LDL levels and those of HbA1c levels was observed in the PTV group (r=0.442, p=0.030) but not in the RSV group (r=-0.100, p=0.611).

Conclusions: Both hydrophilic rosuvastatin and lipophilic pitavastatin reduce serum levels of atherosclerotic and inflammatory markers. These findings also indicate differential effects of RSV and PTV on glucose tolerance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2016.09.116DOI Listing
December 2016

Highly absorptive curcumin reduces serum atherosclerotic low-density lipoprotein levels in patients with mild COPD.

Int J Chron Obstruct Pulmon Dis 2016 26;11:2029-34. Epub 2016 Aug 26.

Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka; Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto; Shizuoka General Hospital, Shizuoka.

Purpose: COPD is mainly caused by tobacco smoking and is associated with a high frequency of coronary artery disease. There is growing recognition that the inflammation in COPD is not only confined to the lungs but also involves the systemic circulation and can impact nonpulmonary organs, including blood vessels. α1-antitrypsin-low-density lipoprotein (AT-LDL) complex is an oxidatively modified LDL that accelerates atherosclerosis. Curcumin, one of the best-investigated natural products, is a powerful antioxidant. However, the effects of curcumin on AT-LDL remain unknown. We hypothesized that Theracurmin(®), a highly absorptive curcumin with improved bioavailability using a drug delivery system, ameliorates the inflammatory status in subjects with mild COPD.

Patients And Methods: This is a randomized, double-blind, parallel-group study. Subjects with stages I-II COPD according to the Japanese Respiratory Society criteria were randomly assigned to receive 90 mg Theracurmin(®) or placebo twice a day for 24 weeks, and changes in inflammatory parameters were evaluated.

Results: There were no differences between the Theracurmin(®) and placebo groups in terms of age, male/female ratio, or body mass index in 39 evaluable subjects. The percent changes in blood pressure and hemoglobin A1c and LDL-cholesterol, triglyceride, or high-density lipoprotein-cholesterol levels after treatment were similar for the two groups. However, the percent change in the AT-LDL level was significantly (P=0.020) lower in the Theracurmin(®) group compared with the placebo group.

Conclusion: Theracurmin(®) reduced levels of atherosclerotic AT-LDL, which may lead to the prevention of future cardiovascular events in mild COPD subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/COPD.S104490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008445PMC
August 2017
-->