ABSTRACT
BACKGROUND: Auraptene derived from the peel of Citrus hassaku possesses anti-tumor, anti-inflammatory, and neuroprotective activities. Thus, it could be a valuable pharmacological alternative to treat some diseases. However, the therapeutic value of auraptene for heart failure (HF) is unknown. STUDY DESIGN/METHODS: In cultured cardiomyocytes from neonatal rats, the effect of auraptene on phenylephrine-induced hypertrophic responses and peroxisome proliferator-activated receptor-alpha (PPARα)-dependent gene transcriptions. To investigate whether auraptene prevents the development of heart failure after myocardial infarction (MI) in vivo, Sprague-Dawley rats with moderate MI (fractional shortening < 40%) were randomly assigned for treatment with low- or high-dose auraptene (5 or 50 mg/kg/day, respectively) or vehicle for 6 weeks. The effects of auraptene were evaluated by echocardiography, histological analysis, and the measurement of mRNA levels of hypertrophy, fibrosis, and PPARα-associated genes. RESULTS: In cultured cardiomyocytes, auraptene repressed phenylephrine-induced hypertrophic responses, such as increases in cell size and activities of atrial natriuretic factor and endothelin-1 promoters. Auraptene induced PPARα-dependent gene activation by enhancing cardiomyocyte peroxisome proliferator-responsive element reporter activity. The inhibition of PPARα abrogated the protective effect of auraptene on phenylephrine-induced hypertrophic responses. In rats with MI, auraptene significantly improved MI-induced systolic dysfunction and increased posterior wall thickness compared to the vehicle. Auraptene treatment also suppressed MI-induced increases in myocardial cell diameter, perivascular fibrosis, and expression of hypertrophy and fibrosis response markers at the mRNA level compared with vehicle treatment. MI-induced decreases in the expression of PPARα-dependent genes were improved by auraptene treatment. CONCLUSIONS: 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.
Subject(s)
Biological Products , Citrus , Heart Failure , Myocardial Infarction , Animals , Rats , Atrial Natriuretic Factor , Biological Products/therapeutic use , Cardiomegaly/drug therapy , Coumarins , Endothelin-1 , Fibrosis , Heart Failure/drug therapy , Heart Failure/etiology , Myocardial Infarction/drug therapy , Peroxisome Proliferators/therapeutic use , Phenylephrine , PPAR alpha/metabolism , Rats, Sprague-Dawley , RNA, MessengerABSTRACT
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.
Subject(s)
Heart Failure , Myocardial Infarction , Phaeophyceae , Animals , Myocardial Infarction/complications , Myocardial Infarction/drug therapy , Myocytes, Cardiac , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , RatsABSTRACT
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 Porphyromonas gingivalis (P. gingivalis) 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 (n = 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 P. gingivalis and Fusobacterium nucleatum (F. nucleatum) bacteria, which was the primary endpoint in this study, was not impacted by TF intake. The change ratio of Prevotella intermedia was significantly decreased by TF intake (P = .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).
Subject(s)
Fusobacterium nucleatum , Porphyromonas gingivalis , Aggregatibacter actinomycetemcomitans , Biflavonoids , Catechin , Double-Blind Method , Humans , Japan , Pilot ProjectsABSTRACT
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-ß)-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-ß-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.
Subject(s)
Cardiomegaly , Ventricular Remodeling , Animals , Cardiomegaly/drug therapy , Cardiomegaly/pathology , Fibrosis , Male , Mice , Mice, Inbred C57BL , Myocardium/pathology , Myocytes, Cardiac/pathology , Rats , SesquiterpenesABSTRACT
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.
Subject(s)
Cacao , Heart Failure , Animals , Cardiomegaly/drug therapy , Disease Models, Animal , Heart Failure/drug therapy , Humans , Hypertrophy, Left Ventricular , Male , Mice , Mice, Inbred C57BL , Myocytes, Cardiac , Polyphenols/pharmacology , RatsABSTRACT
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.
Subject(s)
Cardiovascular Diseases/prevention & control , Catechin/pharmacology , Obesity/diet therapy , Tea , Adult , Body Weight , Female , Functional Food , Humans , Male , Middle Aged , Pilot Projects , Risk FactorsABSTRACT
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.
ABSTRACT
ãHemodynamic 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 ß-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.
Subject(s)
Curcumin/administration & dosage , Drug Compounding/methods , Heart Failure/drug therapy , Heart Failure/prevention & control , Nanoparticles , Nanotechnology , Phytotherapy , Administration, Oral , Animals , Biological Availability , Curcumin/pharmacokinetics , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/prevention & control , Disease Models, Animal , Humans , Life Style , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/prevention & control , Rats , SolubilityABSTRACT
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.
Subject(s)
Curcumin/analogs & derivatives , Curcumin/pharmacology , Myocytes, Cardiac/pathology , p300-CBP Transcription Factors/antagonists & inhibitors , Animals , Cattle , Cells, Cultured , Curcuma/chemistry , Curcumin/chemistry , Curcumin/isolation & purification , Diarylheptanoids , Heart Failure/drug therapy , Humans , Hypertrophy , Phytotherapy , Rabbits , Structure-Activity RelationshipSubject(s)
Functional Food , Hypertension/diet therapy , Acetic Acid , Animals , Antihypertensive Agents/therapeutic use , Catechin/therapeutic use , Dioxoles/therapeutic use , Diterpenes, Kaurane/therapeutic use , Docosahexaenoic Acids/therapeutic use , Eicosapentaenoic Acid/therapeutic use , Garlic , Glucosides/therapeutic use , Humans , Lignans/therapeutic use , Onions , gamma-Aminobutyric Acid/therapeutic useABSTRACT
Curcumin is a major constituent of the spice turmeric and has various biological activities, including anticancer, antioxidant, and anti-inflammatory properties, as well as alcohol detoxification. However, because of its poor absorption efficiency, it is difficult for orally administered curcumin to reach blood levels sufficient to exert its bioactivities. To overcome this problem, several curcumin preparations with a drug-delivery system (DDS) have been developed to increase the bioavailability of curcumin after oral administration, and tested as functional foods and potential medical agents in humans. We have also produced capsules containing Theracurmin, curcumin dispersed with colloidal submicron-particles. To evaluate the absorption efficiency of three types of DDS curcumin, we performed a double-blind, 3-way crossover study. We compared plasma curcumin levels after the administration of Theracurmin and 2 other capsule types of curcumin with DDS, BCM-95 (micronized curcumin with turmeric essential oils) and Meriva (curcumin-phospholipid). Nine healthy subjects (male/female=5/4, age: 24-32 y old) were administered these 3 preparations of DDS curcumin, at commonly used dosages. Six capsules of Theracurmin, 1 capsule of BCM-95, and 2 capsules of Meriva contain 182.4 ± 1.0, 279.3 ± 10.7, and 152.5 ± 20.3 mg of curcumin, respectively. The maximal plasma curcumin concentration (0-24 h) of Theracurmin was 10.7 to 5.6 times higher than those of BCM-95 and Meriva, respectively. Moreover, the area under the blood concentration-time curve at 0-24 h was found to be 11.0- and 4.6-fold higher with Theracurmin than BCM-95 and Meriva, respectively. These data indicate that Theracurmin exhibits a much higher absorption efficiency than other curcumin DDS preparations.
Subject(s)
Curcuma/chemistry , Curcumin/administration & dosage , Intestinal Absorption , Particle Size , Plant Extracts/administration & dosage , Administration, Oral , Adult , Area Under Curve , Biological Availability , Capsules , Colloids , Cross-Over Studies , Curcumin/pharmacokinetics , Dose-Response Relationship, Drug , Double-Blind Method , Drug Delivery Systems , Female , Humans , Male , Phytotherapy , Plant Extracts/blood , Plant Extracts/pharmacokinetics , Young AdultABSTRACT
Heart failure is one of the leading causes of death throughout the world. During the development and deterioration processes of heart failure, cardiomyocytes undergo maladaptive hypertrophy by altering hypertrophy-related gene expression. The zinc finger protein GATA4 is one of the transcription factors involved in the regulation of cardiomyocyte hypertrophy. In response to hypertrophic stimuli such as the synaptic nervous and rennin-angiotensin systems, GATA4 forms a large complex with various functional proteins including an intrinsic histone acetyltransferase, p300, and the disruption of this complex results in the inhibition of hypertrophic responses in cardiomyocytes. While such a transcriptional signal pathway is recognized as a critical event during cardiomyocyte hypertrophy, pharmacological heart failure therapy that targets this pathway has not been established. In order to develop novel heart failure therapy targeting the pathway in cardiomyocytes, we have studied the potential of curcumin, a p300 histone acetyltransferase inhibitor, as an agent for novel heart failure therapy. In this review, we describe a recent study on the cardiac transcriptional signal pathway, especially p300/GATA4 pathway, and a novel heart failure therapy using curcumin.
Subject(s)
Cardiotonic Agents/therapeutic use , Curcumin/therapeutic use , Heart Failure/drug therapy , Animals , Cardiomegaly/genetics , Cardiotonic Agents/pharmacology , Curcumin/pharmacology , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Heart Failure/genetics , Humans , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Transcription, Genetic/drug effectsABSTRACT
Curcumin is an inhibitor of p300 histone acetyltransferase activity, which is associated with the deterioration of heart failure. We reported that native curcumin, at a dosage of 50 mg/kg, prevented deterioration of the systolic function in rat models of heart failure. To achieve more efficient oral pharmacological therapy against heart failure by curcumin, we have developed a novel drug delivery system (DDS) which markedly increases plasma curcumin levels. At the dosage of 0.5 mg/kg, DDS curcumin but not native curcumin restored left ventricular fractional shortening in post-myocardial infarction rats. Thus, our DDS strategy will be applicable to the clinical setting in humans.