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•Total syntheses of 4-methylthio-3-butenylisothiocyanate and raphanusanin.•MTBI and raphanusanin are phototropism-regulating substances of radish hypocotyls.•Mechanisms of ...phototropism: Cholodny–Went theory and Bruinsma–Hasegawa theory.
Total syntheses of 4-methylthio-3-butenylisothiocyanate (MTBI, 1) and raphanusanin (2), which are growth inhibitors involved in the phototropism of radish (Raphanus sativus) hypocotyls, were achieved from commercially available thiolane in four and five steps, respectively. MTBI (1) was prepared via the ring opening of thiolane with sodium azide, double bond introduction by oxidation, and isothiocyanation. Cyclization of MTBI to raphanusanin (2) was achieved under mild conditions using sauer Al2O3. Synthetic MTBI (1) and raphanusanin (2) showed potent bioactivity in a unilateral administration test and a segment elongation test using radish hypocotyls.
As a result of the research activities of the Japan Agency for Medical Research and Development (AMED), this document aims to show an approach to establishing control strategy for continuous ...manufacturing of oral solid dosage forms. The methods of drug development, technology transfer, process control, and quality control used in the current commercial batch manufacturing would be effective also in continuous manufacturing, while there are differences in the process development using continuous manufacturing and batch manufacturing. This document introduces an example of the way of thinking for establishing a control strategy for continuous manufacturing processes.
Background
Cholesterol efflux from cells to apolipoprotein A‐I (apoA‐I) acceptors via the ATP‐binding cassette transporters ABCA1 and ABCG1 is thought to be central in the antiatherogenic mechanism. ...MicroRNA (miR)‐33 is known to target ABCA1 and ABCG1 in vivo.
Methods and Results
We assessed the impact of the genetic loss of miR‐33 in a mouse model of atherosclerosis. MiR‐33 and apoE double‐knockout mice (miR‐33−/−Apoe−/−) showed an increase in circulating HDL‐C levels with enhanced cholesterol efflux capacity compared with miR‐33+/+Apoe−/− mice. Peritoneal macrophages from miR‐33−/−Apoe−/− mice showed enhanced cholesterol efflux to apoA‐I and HDL‐C compared with miR‐33+/+Apoe−/− macrophages. Consistent with these results, miR‐33−/−Apoe−/− mice showed reductions in plaque size and lipid content. To elucidate the roles of miR‐33 in blood cells, bone marrow transplantation was performed in these mice. Mice transplanted with miR‐33−/−Apoe−/− bone marrow showed a significant reduction in lipid content in atherosclerotic plaque compared with mice transplanted with miR‐33+/+Apoe−/− bone marrow, without an elevation of HDL‐C. Some of the validated targets of miR‐33 such as RIP140 (NRIP1) and CROT were upregulated in miR‐33−/−Apoe−/− mice compared with miR‐33+/+Apoe−/− mice, whereas CPT1a and AMPKα were not.
Conclusions
These data demonstrate that miR‐33 deficiency serves to raise HDL‐C, increase cholesterol efflux from macrophages via ABCA1 and ABCG1, and prevent the progression of atherosclerosis. Many genes are altered in miR‐33‐deficient mice, and detailed experiments are required to establish miR‐33 targeting therapy in humans.
Background
The impact of catheter ablation (CA) on the long-term clinical outcomes in atrial fibrillation (AF) are unclear due to limited cohort investigations.
Methods
The Fushimi AF Registry is a ...community-based prospective survey of patients with AF in Fushimi-ku, Kyoto, Japan. Of 4465 patients enrolled between March 2011 and July 2019, analyses were performed on 2639 patients (492 patients who underwent CA and 2147 patients who received standard rhythm- and/or rate-control drug therapy at baseline). We compared the baseline characteristics and the incidence of major adverse cardiovascular events (MACE: the composite of cardiovascular death, heart failure hospitalization, myocardial infarction, ischemic stroke or systemic embolism), and all-cause mortality during the follow-up using propensity score matching.
Results
After entering 20 covariates in the current matching analysis, 342 patients who underwent CA and 342 matched patients who received drug therapy, with a median follow-up of 1865 days, were included. The patients who underwent CA were significantly associated with lower incidence of MACE (hazard ratio (HR) 0.56, 95% confidential interval (CI) 0.36–0.86;
P
= 0.0077), and all-cause mortality (HR 0.47, 95% CI 0.29–0.75;
P
= 0.0016).
Conclusion
CA was associated with lower incidences of MACE and all-cause mortality for patients with AF as compared with those who received drug therapy. The most common event of MACE in patients who underwent CA was heart failure hospitalization.
Clinical trial registration
URL:
http://www.umin.ac.jp/ctr/index.htm
Unique identifier
UMIN000005834.
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.
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.
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.
GLUT4 shows decreased levels in failing human adult hearts. We speculated that GLUT4 expression in cardiac muscle may be fine-tuned by microRNAs. Forced expression of miR-133 decreased GLUT4 ...expression and reduced insulin-mediated glucose uptake in cardiomyocytes. A computational miRNA target prediction algorithm showed that KLF15 is one of the targets of miR-133. It was confirmed that over-expression of miR-133 reduced the protein level of KLF15, which reduced the level of the downstream target GLUT4. Cardiac myocytes infected with lenti-decoy, in which the 3′UTR with tandem sequences complementary to miR-133 was linked to the luciferase reporter gene, had decreased miR-133 levels and increased levels of GLUT4. The expression levels of KLF15 and GLUT4 were decreased at the left ventricular hypertrophy and congestive heart failure stage in a rat model. The present results indicated that miR-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiomyocytes.
Background:There is a growing burden of valvular heart disease (VHD) and atrial fibrillation (AF) due to population aging, but data regarding the characteristics and outcomes of patients with AF and ...concomitant VHD are lacking.Methods and Results:The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto. Among 3,566 patients with available echocardiographic data, 20% had VHD, consisting of 131 valvular AF (VAF: 3.7%) and 583 nonvalvular AF with VHD (NVAF-VHD: 16.3%). Here, VAF was defined as AF with mitral stenosis or a prosthetic heart valve. AF patients with VHD were older, had more comorbidities with a higher CHADS2 score, and were prescribed oral anticoagulants more frequently than those without VHD. After adjusting for confounders, VHD was not associated with stroke or systemic embolism, all-cause mortality, or cardiac death. NVAF-VHD was significantly associated with an increased risk of hospitalization for heart failure (adjusted hazard ratio HR, 1.44; 95% confidence interval CI, 1.16–1.78), whereas VAF was not (HR, 1.28; 95% CI, 0.86–1.92). Among all types of VHD, aortic valve diseases were associated with a higher risk of cardiac events, whereas mitral valve diseases were not.Conclusions:Although VHD did not significantly affect thromboembolism or mortality, it affected cardiac events depending on type, with aortic valve diseases having higher risk, in Japanese patients with AF.
Elevated neutrophil/lymphocyte ratio (NLR) has been reported as a sensitive marker for predicting poor prognosis in chronic inflammation-based diseases such as stroke, heart failure, cancers, and ...diabetes, as well as acute inflammatory diseases such as bacterial and viral infections, including COVID-19. NLR is also known to increase with age and is considered to be an aging marker. We conducted a double-blind, placebo-controlled trial in elderly volunteers to examine the effect of a newly developed, highly bioavailable curcumin formulation (curcuRougeTM) on NLR. Both the white blood cell count and the neutrophil rate decreased significantly, and the lymphocyte rate increased significantly from baseline to after curcuRougeTM administration for 4 wk. curcuRougeTM significantly reduced the NLR (p=0.020). On the other hand, in the placebo group, there were no changes in white blood cell count, neutrophil ratio, lymphocyte ratio, or NLR. The present study demonstrates for the first time, in elderly volunteers, that administration of curcuRougeTM significantly reduces NLR, an indicator of prognosis in cardiovascular diseases, cancer, infectious diseases, and aging. Thus, curcuRougeTM might be expected to improve the prognosis of these diseases as well as exhibit anti-aging effects.
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