Masafumi Funamoto

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

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.

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.

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.

Noble Heart Failure Therapy Using Food Compositions

　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 curcumins 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.

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.

Curcumin Analogue GO-Y030 Significantly Improves Pressure Overload-induced Heart Failure in Vivo

Signals activated by increased hemodynamic overload to the heart finally reach the nuclei of cardiac myocytes and induce maladaptive hypertrophy in them. Nuclear acetylation, which is controlled by histone deacetylases and the intrinsic histone acetyltransferase p300, is a critical event in this process. We previously found that a natural p300 HAT inhibitor, curcumin, can inhibit cardiomyocyte hypertrophy and the development of heart failure in vivo. However, curcumin is insoluble in water, and its bioavailability is low. Therefore, a more efficient system for heart failure therapy is desirable for actual clinical practice. To overcome this limitation, we recently synthesized a curcumin analog, GO-Y030, which possesses stronger anti-cancer activity than curcumin. However, the effect of GO-Y030 on heart failure is still unclear. The purpose of this study was to determine whether GO-Y030 inhibits p300-HAT activity and can be used as a therapeutic agent for heart failure.

A Novel Target Molecule of Nobiletin Derived from Citrus Peels has a Therapeutic Potency Against the Development of Heart Failure

Maladaptive hypertrophy is being recognized as a critical event during the development of heart failure. In a previous study, we demonstrated that a natural compound, curcumin, prevented cardiomyocyte hypertrophy and the development of heart failure in two different model animals.[1–4] Recently, we screened a natural compound library and found that nobiletin, a poly-methoxy flavonoid derived from Citrus unshu, repressed phenylephrine (PE)-induced hypertrophic responses in cardiomyocytes and prevented the deterioration of systolic function and LV pathological hypertrophy in animals with myocardial infarction and pressure-overload. Thus, nobiletin is expected as an attractive pharmacological agent for the treatment of heart failure. However, the target molecule of nobiletin in cardiomyocytes is still unclear. To solve this problem, we attempted to identify novel nobiletin-binding proteins by a proteomics approach and investigate its functional mechanism in mice.

Nobiletin a Citrus Flavonoid, Exerts Additional Effects with Angiotensin II Receptor Blocker on Systolic Function in Salt-sensitive Dahl Rats

Introduction and Objectives Maladaptive hypertrophy is being recognized as a critical event during the development of heart failure. We screened natural compounds purified from fruits library and found that Nobiletin, contained in the peel of Citrus depressa, represses phenylephrine-induced hypertrophic responses in cardiomyocytes. Nobiletin has various useful effects such as anti-cancer, anti-inflammation, and anti-oxidant. In previous study, we demonstrated that Nobiletin suppresses phenylephrine-induced hypertrophic responses in cardiomyocytes in a dose-dependent manner in cultured cardiomyocytes and oral administration of Nobiletin prevented systolic dysfunction and development of heart failure after myocardial infarction in rats. Thus, Nobiletin is expected as an effective agent for heart failure. To clinically apply this novel therapy to humans, it should be clarified whether or not Nobiletin exhibits additional effects on conventional heart failure therapy, such as Candesartan, an angiotensin II receptor antagonist (ARB). Thus, we examined the effects of Nobiletin / Candesartan combination therapy on heart failure in vivo.

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

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.