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.

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

Anserine, an imidazole dipeptide, is present in the muscles of birds and fish and has various bioactivities, such as anti-inflammatory and anti-fatigue effects. However, the effect of anserine on the development of heart failure remains unknown. We cultured primary cardiomyocytes with 0.03 mM to 10 mM anserine and stimulated them with phenylephrine for 48 h. Anserine significantly suppressed the phenylephrine-induced increases in cardiomyocyte hypertrophy, ANF and BNP mRNA levels, and histone H3K9 acetylation. An in vitro histone acetyltransferase (HAT) assay showed that anserine directly suppressed p300-HAT activity with an IC50 of 1.87 mM. Subsequently, 8-week-old male C57BL/6J mice were subjected to transverse aortic constriction (TAC) and were randomly assigned to receive daily oral treatment with anserine-containing material, Marine Active® (60 or 200 mg/kg anserine) or vehicle for 8 weeks. Echocardiography revealed that anserine 200 mg/kg significantly prevented the TAC-induced increase in left ventricular posterior wall thickness and the decrease in left ventricular fractional shortening. Moreover, anserine significantly suppressed the TAC-induced acetylation of histone H3K9. These results indicate that anserine suppresses TAC-induced systolic dysfunction, at least in part, by inhibiting p300-HAT activity. Anserine may be used as a pharmacological agent for human heart failure therapy.

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

BACKGROUND AND PURPOSE: TJ-17 (Goreisan), a traditional Japanese Kampo medicine, has been generally used to treat edema, such as heart failure, due to its diuretic effect. In the present study, we investigate the effects of TJ-17 on chronic kidney disease (CKD). METHODS: 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). RESULTS: Histological analysis, as well as renal function and renal injury markers, deteriorated in mice with FA-induced CKD and were ameliorated by TJ-17 treatment. Increased levels of inflammatory cytokines and macrophage infiltration were also alleviated in mice treated with TJ-17. Renal fibrosis, a crucial factor in CKD, was induced by FA administration and inhibited by TJ-17 treatment. Pretreatment with TJ-17 did not exert an inhibitory effect on FA-induced AKI. The increase in urinary volume in FA-induced CKD mice was ameliorated by TJ-17 treatment, with a concurrent correction of reduced aquaporins expression in the kidney. CONCLUSION: TJ-17 may have a novel preventive effect against inflammation, oxidative stress, and fibrosis, contributing to innovation in the treatment of CKD.

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.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (p = .031) and increase in pocket depth (p = .046) were observed 3 months after the baseline in patients who successfully quit smoking (n = 14). CONCLUSION: Short-term smoking cessation increased periodontal pocket depth and gingival bleeding. These findings may reflect healing processes that occur in the healthy gingiva. IMPLICATIONS: 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.

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

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 α1-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.

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-ß) 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-ß-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-ß-induced increases in L-proline incorporation, mRNA levels (POSTN and alpha-smooth muscle actin (α-SMA)), and myofibroblast differentiation. Additionally, it significantly inhibited TGF-ß-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.

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.

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.

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.

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/m2) 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.

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

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.

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

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.

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

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.

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

The zinc finger protein GATA4 is a transcription factor involved in cardiomyocyte hypertrophy. It forms a functional complex with the intrinsic histone acetyltransferase (HAT) p300. The HAT activity of p300 is required for the acetylation and transcriptional activity of GATA4, as well as for cardiomyocyte hypertrophy and the development of heart failure. In the present study, we have identified Receptor for Activated Protein Kinase C1 (RACK1) as a novel GATA4-binding protein using tandem affinity purification and mass spectrometry analyses. We found that exogenous RACK1 repressed phenylephrine (PE)-induced hypertrophic responses, such as myofibrillar organization, increased cell size, and hypertrophy-associated gene transcription, in cultured cardiomyocytes. RACK1 physically interacted with GATA4 and the overexpression of RACK1 reduced PE-induced formation of the p300/GATA4 complex and the acetylation and DNA binding activity of GATA4. In response to hypertrophic stimulation in cultured cardiomyocytes and in the hearts of hypertensive heart disease model rats, the tyrosine phosphorylation of RACK1 was increased, and the binding between GATA4 and RACK1 was reduced. In addition, the tyrosine phosphorylation of RACK1 was required for the disruption of the RACK1/GATA4 complex and for the formation of the p300/GATA4 complex. These findings demonstrate that RACK1 is involved in p300/GATA4-dependent hypertrophic responses in cardiomyocytes and is a promising therapeutic target for heart failure.

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

Statins, 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, are potential drugs for chronic heart failure treatment in clinical studies. However, there may be differences in the effects on heart failure between lipophilic and hydrophilic statins. In this study, we investigated whether hydrophilic rosuvastatin (RSV) and lipophilic pitavastatin (PTV) exert different effects on the left ventricular diastolic function. Subjects were hypercholesterolemia patients with left ventricular diastolic dysfunction. This was an open-label, randomized, parallel, comparative, prospective study. The subjects received treatment with RSV or PTV for 24 weeks, and their low density lipoprotein (LDL)-cholesterol levels were controlled by these statins according to the guideline. The primary endpoint was defined as the change in left ventricle (LV) diastolic function (E/E') estimated by echocardiography, and the secondary endpoint was the plasma B-type natriuretic peptide (BNP) level. No serious adverse effects were observed during the entire study period in any patient, nor were there any significant differences in changes in the body mass index, blood pressure, or heart rate. Statin treatment did not significantly alter the primary endpoint, E/E'. The change ratio of BNP was not significantly different between PTV and RSV groups. However, BNP was significantly increased in the RSV (p=0.030) but not the PTV (p>0.999) group. This study revealed that although neither RSV nor PTV improved LV diastolic dysfunction, BNP, a biomarker of LV wall stress, was increased in the RSV but not the PTV group. Observation for a longer period is necessary to clarify the different effects of these statins on LV diastolic dysfunction. (UMIN-ID: UMIN000003571).

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

A natural p300-specific histone acetyltransferase inhibitor, curcumin, may have a therapeutic potential for heart failure. However, a study of curcumin to identify an appropriate dose for heart failure has yet to be performed. Rats were subjected to a left coronary artery ligation. One week later, rats with a moderate severity of myocardial infarction (MI) were randomly assigned to 4 groups receiving the following: a solvent as a control, a low dose of curcumin (0.5 mg∙kg(-1)∙day(-1)), a medium dose of curcumin (5 mg∙kg(-1)∙day(-1)), or a high dose of curcumin (50 mg∙kg(-1)∙day(-1)). Daily oral treatment was continued for 6 weeks. After treatment, left ventricular (LV) fractional shortening was dose-dependently improved in the high-dose (25.2% ± 1.6%, P < 0.001 vs. vehicle) and medium-dose (19.6% ± 2.4%) groups, but not in the low-dose group (15.5% ± 1.4%) compared with the vehicle group (15.1% ± 0.8%). The histological cardiomyocyte diameter and perivascular fibrosis as well as echocardiographic LV posterior wall thickness dose-dependently decreased in the groups receiving high and medium doses. The beneficial effects of oral curcumin on the post-MI LV systolic function are lower at 5 compared to 50 mg∙kg(-1)∙day(-1) and disappear at 0.5 mg∙kg(-1)∙day(-1). To clinically apply curcumin therapy for heart failure patients, a precise, optimal dose-setting study is required.

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

Protein arginine methyltransferase 5 (PRMT5) is a well-known epigenetic regulatory enzyme. However, the role of PRMT5-mediated arginine methylation in gene transcription related to cardiac fibrosis is unknown. Here we show that fibroblast-specific deletion of PRMT5 significantly reduces pressure overload-induced cardiac fibrosis and improves cardiac dysfunction in male mice. Both the PRMT5-selective inhibitor EPZ015666 and knockdown of PRMT5 suppress α-smooth muscle actin (α-SMA) expression induced by transforming growth factor-ß (TGF-ß) in cultured cardiac fibroblasts. TGF-ß stimulation promotes the recruitment of the PRMT5/Smad3 complex to the promoter site of α-SMA. It also increases PRMT5-mediated H3R2 symmetric dimethylation, and this increase is inhibited by Smad3 knockdown. TGF-ß stimulation increases H3K4 tri-methylation mediated by the WDR5/MLL1 methyltransferase complex, which recognizes H3R2 dimethylation. Finally, treatment with EPZ015666 significantly improves pressure overload-induced cardiac fibrosis and dysfunction. These findings suggest that PRMT5 regulates TGF-ß/Smad3-dependent fibrotic gene transcription, possibly through histone methylation crosstalk, and plays a critical role in cardiac fibrosis and dysfunction.

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

Aims: Initiating smoking in early adolescence results in challenges with smoking cessation and is associated with high risk of cardiovascular disease. Recently, the initiation of smoking has transitioned from adolescence to young adulthood. However, there are few reports on the impact of initiating smoking at a later age. This study investigated the impact of the age of smoking initiation on nicotine dependency, smoking cessation rates, and cardiovascular risk factors, using a cut-off point of 20 years, within the Japanese population. Methods and results: This retrospective cohort study encompassed 1382 smokers who sought smoking cessation treatment at Kyoto Medical Centre Hospital between 2007 and 2019. Clinical indicators were evaluated by adjusting for age at the time of hospital visit and sex. The smoking cessation rate was further adjusted for treatment medication. The group with a smoking initiation age of <20 years reported a higher number of cigarettes/day (P = 0.002), higher respiratory carbon monoxide levels (P < 0.001), a higher Fagerström Test for Nicotine Dependence (FTND) score (P < 0.001), and a higher Self-rating Depression Scale score (P = 0.014). They also reported lower diastolic blood pressure (P = 0.020) and a lower successful smoking cessation rate [odds ratio: 0.736, 95% confidence interval (0.569, 0.951)] than the group with a smoking initiation age of ≥20 years. When smokers were divided into four groups based on the age they started smoking, the FTND score for those who started at 20-21 years was significantly higher than the score for those who started at 22 years or older. Conclusion: In young adulthood, initiating smoking later (beyond 20 years old) was associated with lower nicotine dependency and fewer depressive tendencies, as well as a higher success rate in smoking cessation among Japanese smokers. The results might suggest that raising the legal smoking initiation age from 20 to 22 years old or older could be effective in reducing nicotine dependency in smokers.

[A new attempt of integrated practice of basic medicine in Tokushima University].

The Japan Accreditation Council for Medical Education has strengthened the promotion of horizontal and vertical integration of medical education, assuring the quality of medical education in Japan from an international perspective. Pharmacology plays an important role as a central hub that connects basic medical education with clinical medical education. As part of promoting horizontal integration of medical education, Tokushima University has started a joint practice with three basic medical subjects such as Biochemistry, Physiology, and Pharmacology for 2nd grade medical students in 2019. Each subject is in charge of two or four items of practice, and a total 8 of items are performed for 10 days in integrated practice every year. This joint practice has become an official subject in 2022. We introduce our experiences of unique practices based on their advantages and limitations.

Roles of histone acetylation sites in cardiac hypertrophy and heart failure.

Heart failure results from various physiological and pathological stimuli that lead to cardiac hypertrophy. This pathological process is common in several cardiovascular diseases and ultimately leads to heart failure. The development of cardiac hypertrophy and heart failure involves reprogramming of gene expression, a process that is highly dependent on epigenetic regulation. Histone acetylation is dynamically regulated by cardiac stress. Histone acetyltransferases play an important role in epigenetic remodeling in cardiac hypertrophy and heart failure. The regulation of histone acetyltransferases serves as a bridge between signal transduction and downstream gene reprogramming. Investigating the changes in histone acetyltransferases and histone modification sites in cardiac hypertrophy and heart failure will provide new therapeutic strategies to treat these diseases. This review summarizes the association of histone acetylation sites and histone acetylases with cardiac hypertrophy and heart failure, with emphasis on histone acetylation sites.