ABSTRACT
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.
Subject(s)
Cardiomegaly , Curcumin/analogs & derivatives , Heart Failure , Myocytes, Cardiac , Animals , Cardiomegaly/drug therapy , Cardiomegaly/metabolism , Cardiomegaly/pathology , Curcumin/chemical synthesis , Curcumin/chemistry , Curcumin/pharmacology , Heart Failure/drug therapy , Heart Failure/metabolism , Heart Failure/pathology , Male , Mice , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Rats , Rats, Sprague-DawleyABSTRACT
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 RelationshipABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthralgia/diet therapy , Bacillus subtilis , Fermented Foods , Myalgia/diet therapy , Soy Foods , Synbiotics/administration & dosage , Adult , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Arthralgia/complications , Arthralgia/immunology , Arthralgia/physiopathology , Cross-Over Studies , Developed Countries , Double-Blind Method , Female , Fermented Foods/adverse effects , Headache/complications , Headache/immunology , Headache/physiopathology , Headache/prevention & control , Humans , Japan , Male , Middle Aged , Myalgia/complications , Myalgia/immunology , Myalgia/physiopathology , Neck , Pain Measurement , Severity of Illness Index , Shoulder , Skin Temperature , Soy Foods/adverse effects , Synbiotics/adverse effectsABSTRACT
[This corrects the article on p. 107 in vol. 12, PMID: 30416577.].
