Fibroblast-specific PRMT5 deficiency suppresses cardiac fibrosis and left ventricular dysfunction in male mice.


Anserine, a Histidine-Containing Dipeptide, Suppresses Pressure Overload-Induced Systolic Dysfunction by Inhibiting Histone Acetyltransferase Activity of p300 in Mice.

International Journal of Molecular Sciences


Effects of D-allose on ATP production and cell viability in neonatal rat cardiomyocytes.

2-Deoxy-d-glucose (2DG) induces anticancer effects through glycolytic inhibition but it may raise the risk of arrhythmia. The rare monosaccharide d-allose also has anticancer properties, but its cardiac effects are unknown. We examined the effects of d-allose on adenosine triphosphate (ATP) production in neonatal rat cardiomyocytes. We showed that 25 mM d-allose selectively reduced glycolytic ATP, but had minimal impact on mitochondrial ATP, while 1 mM 2DG strongly inhibited both. Furthermore, d-allose had less impact on cell viability and was less cytotoxic than 2DG; neither compound caused apoptosis. Thus, d-allose selectively diminished glycolytic ATP production with no apparent effects on cardiomyocytes.


Impact of smoking initiation age on nicotine dependency and cardiovascular risk factors: a retrospective cohort study in Japan.


CA9 and PRELID2; hypoxia-responsive potential therapeutic targets for pancreatic ductal adenocarcinoma as per bioinformatics analyses.

A strong hypoxic environment has been observed in pancreatic ductal adenocarcinoma (PDAC) cells, which contributes to drug resistance, tumor progression, and metastasis. Therefore, we performed bioinformatics analyses to investigate potential targets for the treatment of PDAC. To identify potential genes as effective PDAC treatment targets, we selected all genes whose expression level was related to worse overall survival (OS) in The Cancer Genome Atlas (TCGA) database and selected only the genes that matched with the genes upregulated due to hypoxia in pancreatic cancer cells in the dataset obtained from the Gene Expression Omnibus (GEO) database. Although the extracted 107 hypoxia-responsive genes included the genes that were slightly enriched in angiogenic factors, TCGA data analysis revealed that the expression level of endothelial cell (EC) markers did not affect OS. Finally, we selected CA9 and PRELID2 as potential targets for PDAC treatment and elucidated that a CA9 inhibitor, U-104, suppressed pancreatic cancer cell growth more effectively than 5-fluorouracil (5-FU) and PRELID2 siRNA treatment suppressed the cell growth stronger than CA9 siRNA treatment. Thus, we elucidated that specific inhibition of PRELID2 as well as CA9, extracted via exhaustive bioinformatic analyses of clinical datasets, could be a more effective strategy for PDAC treatment.


TJ-17 (Goreisan) mitigates renal fibrosis in a mouse model of folic acid-induced chronic kidney disease.

TJ-17 may have a novel preventive effect against inflammation, oxidative stress, and fibrosis, contributing to innovation in the treatment of CKD.

We the preventive action of TJ-17 against acute kidney injury (AKI) transition to CKD in vivo using a folic acid (FA)-induced mouse model. Mice were treated with food containing TJ-17 at 48 h after FA intraperitoneal injection (AKI phase).


6-Shogaol, an Active Component of Ginger, Inhibits p300 Histone Acetyltransferase Activity and Attenuates the Development of Pressure-Overload-Induced Heart Failure.


Auraptene, a citrus peel-derived natural product, prevents myocardial infarction-induced heart failure by activating PPARα in rats.

Auraptene has beneficial effects on MI-induced cardiac hypertrophy and left ventricular systolic dysfunction in rats, at least partly due to PPARα activation. Further clinical studies are required to evaluate the efficacy of auraptene in patients with HF.


Effects of high-absorption curcumin for the prevention of hypertensive heart disease: a double-blind, placebo-controlled, randomized clinical study.

' ratio, rather it significantly inhibited the increase in plasma BNP levels in patients with initial signs of hypertensive heart disease.


Pyrazole-Curcumin Suppresses Cardiomyocyte Hypertrophy by Disrupting the CDK9/CyclinT1 Complex.

The intrinsic histone acetyltransferase (HAT), p300, has an important role in the development and progression of heart failure. Curcumin (CUR), a natural p300-specific HAT inhibitor, suppresses hypertrophic responses and prevents deterioration of left-ventricular systolic function in heart-failure models. However, few structure-activity relationship studies on cardiomyocyte hypertrophy using CUR have been conducted. To evaluate if prenylated pyrazolo curcumin (PPC) and curcumin pyrazole (PyrC) can suppress cardiomyocyte hypertrophy, cultured cardiomyocytes were treated with CUR, PPC, or PyrC and then stimulated with phenylephrine (PE). PE-induced cardiomyocyte hypertrophy was inhibited by PyrC but not PPC at a lower concentration than CUR. Western blotting showed that PyrC suppressed PE-induced histone acetylation. However, an in vitro HAT assay showed that PyrC did not directly inhibit p300-HAT activity. As Cdk9 phosphorylates both RNA polymerase II and p300 and increases p300-HAT activity, the effects of CUR and PyrC on the kinase activity of Cdk9 were examined. Phosphorylation of p300 by Cdk9 was suppressed by PyrC. Immunoprecipitation-WB showed that PyrC inhibits Cdk9 binding to CyclinT1 in cultured cardiomyocytes. PyrC may prevent cardiomyocyte hypertrophic responses by indirectly suppressing both p300-HAT activity and RNA polymerase II transcription elongation activity via inhibition of Cdk9 kinase activity.


The novel preventive effect of a Japanese ethical Kampo extract formulation TJ-90 (Seihaito) against cisplatin-induced nephrotoxicity


The polyunsaturated fatty acids, EPA and DHA, ameliorate myocardial infarction-induced heart failure by inhibiting p300-HAT activity in rats.

While the cardioprotective functions of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and omega-3 unsaturated fatty acids have been previously demonstrated, little is known about their effects on cardiomyocyte hypertrophy. In this study, we compared the effects of EPA and DHA on hypertrophic responses in cardiomyocytes and development of heart failure in rats with myocardial infarction (MI). Both EPA and DHA significantly suppressed phenylephrine- and p300-induced cardiomyocyte hypertrophy, transcription of hypertrophy response genes, and acetylation of histone H3K9 in cardiomyocytes. EPA and DHA directly inhibited p300-histone acetyltransferase activity (IC50: 37.8 and 30.6 μM, respectively). Further, EPA- and DHA-induced allosteric inhibition of histones and competitive inhibition of acetyl-CoA, and significantly prevented p300-induced hypertrophic responses. Rats with moderate MI (left ventricular fractional shortening [FS] <40%) were randomly assigned to three groups, namely, vehicle (saline), EPA (1 g/kg), and DHA (1 g/kg). One week after the operation, rats were orally administrated with test agents for 6 weeks. Echocardiographic analysis demonstrated that both EPA and DHA treatments preserved FS and prevented MI-induced left ventricular remodeling. Furthermore, EPA and DHA significantly suppressed the MI-induced increase in myocardial cell diameter, perivascular fibrosis, mRNA levels of hypertrophic markers, fibrosis, and acetylation of histone H3K9. The effects on hypertrophic responses and the development of heart failure were not different between EPA and DHA groups. Both EPA and DHA suppressed hypertrophic responses and the development of heart failure to the same extent through the inhibition of p300-HAT activity.


ANGPTL4 Expression Is Increased in Epicardial Adipose Tissue of Patients with Coronary Artery Disease.

Epicardial adipose tissue (EAT) is known to affect atherosclerosis and coronary artery disease (CAD) pathogenesis, persistently releasing pro-inflammatory adipokines that affect the myocardium and coronary arteries. Angiopoietin-like 4 (ANGPTL4) is a protein secreted from adipose tissue and plays a critical role in the progression of atherosclerosis. Here, the expression of ANGPTL4 in EAT was investigated in CAD subjects. Thirty-four consecutive patients (13 patients with significant CAD; 21 patients without CAD) undergoing elective open-heart surgery were recruited. EAT and pericardial fluid were obtained at the time of surgery. mRNA expression and ANGPTL4 and IL-1β levels were evaluated by qRT-PCR and ELISA. The expression of ANGPTL4 (p = 0.0180) and IL-1β (p < 0.0001) in EAT significantly increased in the CAD group compared to that in the non-CAD group and positively correlated (p = 0.004). Multiple regression analysis indicated that CAD is a contributing factor for ANGPTL4 expression in EAT. IL-1β level in the pericardial fluid was significantly increased in patients with CAD (p = 0.020). Moreover, the expression of ANGPTL4 (p = 0.004) and IL-1β (p < 0.001) in EAT was significantly increased in non-obese patients with CAD. In summary, ANGPTL4 expression in EAT was increased in CAD patients.


Okamura Extract Suppresses Myocardial Infarction-Induced Left Ventricular Systolic Dysfunction by Inhibiting p300-HAT Activity.

Ecklonia stolonifera Okamura extract (ESE) has been reported to have various bioactive effects, but its effects on cardiovascular disease have not yet been investigated. First, primary neonatal rat cultured cardiomyocytes were treated with ESE and stimulated with phenylephrine (PE) for 48 h. ESE (1000 µg/mL) significantly suppressed PE-induced cardiomyocyte hypertrophy, hypertrophy-related gene transcription, and the acetylation of histone H3K9. An in vitro p300-HAT assay indicated that ESE directly inhibited p300-HAT activity. Next, one week after myocardial infarction (MI) surgery, rats (left ventricular fractional shortening (LVFS) < 40%) were randomly assigned to three groups: vehicle (saline, n = 9), ESE (0.3 g/kg, n = 10), or ESE (1 g/kg, n = 10). Daily oral administration was carried out for 8 weeks. After treatment, LVFS was significantly higher in the ESE (1 g/kg) group than in the vehicle group. The ESE treatments also significantly suppressed MI-induced increases in myocardial cell diameter, perivascular fibrosis, hypertrophy- and fibrosis-related gene transcription, and the acetylation of histone H3K9. These results suggest that ESE suppressed both hypertrophic responses in cardiomyocytes and the development of heart failure in rats by inhibiting p300-HAT activity. Thus, this dietary extract is a potential novel therapeutic strategy for heart failure in humans.


Extract Ameliorates Doxorubicin-Induced Cardiotoxicity by Decreasing Apoptosis.


Multimerization of the GATA4 transcription factor regulates transcriptional activity and cardiomyocyte hypertrophic response.

International Journal of Biological Sciences


The Selective Serotonin 2A Receptor Antagonist Sarpogrelate Prevents Cardiac Hypertrophy and Systolic Dysfunction via Inhibition of the ERK1/2-GATA4 Signaling Pathway

Drug repositioning has recently emerged as a strategy for developing new treatments at low cost. In this study, we used a library of approved drugs to screen for compounds that suppress cardiomyocyte hypertrophy. We identified the antiplatelet drug sarpogrelate, a selective serotonin-2A (5-HT) receptor antagonist, and investigated the drug's anti-hypertrophic effect in cultured cardiomyocytes and its effect on heart failure in vivo. Primary cultured cardiomyocytes pretreated with sarpogrelate were stimulated with angiotensin II, endothelin-1, or phenylephrine. Immunofluorescence staining showed that sarpogrelate suppressed the cardiomyocyte hypertrophy induced by each of the stimuli. Western blotting analysis revealed that 5-HT receptor level was not changed by phenylephrine, and that sarpogrelate suppressed phenylephrine-induced phosphorylation of ERK1/2 and GATA4. C57BL/6J male mice were subjected to transverse aortic constriction (TAC) surgery followed by daily oral administration of sarpogrelate for 8 weeks. Echocardiography showed that 5 mg/kg of sarpogrelate suppressed TAC-induced cardiac hypertrophy and systolic dysfunction. Western blotting revealed that sarpogrelate suppressed TAC-induced phosphorylation of ERK1/2 and GATA4. These results indicate that sarpogrelate suppresses the development of heart failure and that it does so at least in part by inhibiting the ERK1/2-GATA4 signaling pathway.


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


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


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


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


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

The Journal of International Medical Research


Gingival bleeding and pocket depth among smokers and the related changes after short-term smoking cessation

Smoking is associated with the deteriorating health of the gingiva and periodontium. The long-term beneficial effects of smoking cessation on oral health are well known. However, the effects of short-term smoking cessation on gingival bleeding and periodontal pocket depth are unknown. The purpose of the present study was to determine the effects of short-term smoking cessation on gingival bleeding and periodontal pocket depth. Dentate smokers with a mean age of 56.9 ± 14.4 years at an outpatient smoking cessation clinic participated in this study. A professional dentist checked the periodontal pocket depth and gingival bleeding. Patients visited the smoking cessation clinic on their first visit and 2, 4, 8, and 12 weeks (three months). The gingival assessment was re-performed in those who succeeded in smoking cessation 3 months after the baseline. The baseline data of 83 patients showed that an increase in pocket depth was associated with increasing age and the amount of smoking. A significant increase in gingival bleeding ( = .031) and increase in pocket depth ( = .046) were observed 3 months after the baseline in patients who successfully quit smoking ( = 14). Short-term smoking cessation increased periodontal pocket depth and gingival bleeding. These findings may reflect healing processes that occur in the healthy gingiva. Study findings will be useful to advise patients during smoking cessation programs. Dentists can inform patients that an initial increase in gingival bleeding and pocket depth could be associated with smoking cessation. Such advice will prevent patients from any apprehension that may cause them to recommence smoking.


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

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.

International Journal of Molecular Sciences


Clinically Administered Doses of Pitavastatin and Rosuvastatin.

Clinical studies have indicated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, can potentially inhibit chronic heart failure. In the Stat-LVDF study, a difference was noted in terms of the effect of lipophilic pitavastatin (PTV) and hydrophilic rosuvastatin (RSV) on plasma BNP, suggesting that statin lipophilicity and pharmacokinetics change the pleiotropic effect on heart failure in humans. Therefore, we assessed the beneficial effects of PTV on hypertrophy in cardiac myocytes compared with RSV at clinically used doses. Cultured cardiomyocytes were stimulated with 30 μM phenylephrine (PE) in the presence of PTV (250 nM) or RSV (50 nM). These doses were calculated based on the maximum blood concentration of statins used in clinical situations in Japan. The results showed that PTV, but not RSV, significantly inhibits the PE-induced increase in cell size and leucine incorporation without causing cell toxicity. In addition, PTV significantly suppressed PE-induced mRNA expression of hypertrophic response genes. PE-induced ERK phosphorylation was inhibited by PTV, but not by RSV. Furthermore, PTV significantly suppressed the angiotensin-II-induced proline incorporation in primary cultured cardiac fibroblasts. In conclusion, a clinical dose of PTV was noted to directly inhibit cardiomyocyte hypertrophy and cardiac fibrosis, suggesting that lipophilic PTV can be a potential drug candidate against chronic heart failure.


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

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.


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


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


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.


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


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


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


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


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


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

International Journal of Chronic Obstructive Pulmonary Disease


Tyrosine phosphorylation of RACK1 triggers cardiomyocyte hypertrophy by regulating the interaction between p300 and GATA4.


Colloidal submicron-particle curcumin exhibits high absorption efficiency-a double-blind, 3-way crossover study.

Journal of Nutritional Science and Vitaminology


Effects of Statins on Left Ventricular Diastolic Function in Patients with Dyslipidemia and Diastolic Dysfunction (Stat-LVDF Study).


Optimal dose-setting study of curcumin for improvement of left ventricular systolic function after myocardial infarction in rats.