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Peroxisomes play an essential role in a number of important metabolic pathways including β-oxidation of fatty acids and their derivatives. Therefore, peroxisomes possess various β-oxidation enzymes and specialized fatty acid transport systems. However, the molecular mechanisms of these proteins, especially in terms of substrate binding, are still unknown. In this study, to identify the substrate-binding sites of these proteins, we synthesized a photoreactive palmitic acid analogue bearing a diazirine moiety as a photophore, and performed photoaffinity labeling of purified rat liver peroxisomes. As a result, an 80-kDa peroxisomal protein was specifically labeled by the photoaffinity ligand, and the labeling efficiency competitively decreased in the presence of palmitoyl-CoA. Mass spectrometric analysis identified the 80-kDa protein as peroxisomal multifunctional enzyme type 2 (MFE2), one of the peroxisomal β-oxidation enzymes. Recombinant rat MFE2 was also labeled by the photoaffinity ligand, and mass spectrometric analysis revealed that a fragment of rat MFE2 (residues Trp249 to Arg251) was labeled by the ligand. MFE2 mutants bearing these residues, MFE2(W249A) and MFE2(R251A), exhibited decreased labeling efficiency. Furthermore, MFE2(W249G), which corresponds to one of the disease-causing mutations in human MFE2, also exhibited a decreased efficiency. Based on the crystal structure of rat MFE2, these residues are located on the top of a hydrophobic cavity leading to an active site of MFE2. These data suggest that MFE2 anchors its substrate around the region from Trp249 to Arg251 and positions the substrate along the hydrophobic cavity in the proper direction toward the catalytic center.
Fatty Acid, Fatty Acid-binding Protein, Fatty Acid Oxidation, Peroxisomes, Photoaffinity Labeling
Identification of a Substrate-binding Site in a Peroxisomal β-Oxidation Enzyme by Photoaffinity Labeling with a Novel Palmitoyl Derivative*An external file that holds a picture, illustration, etc. Object name is sbox.jpg
Yoshinori Kashiwayama,‡,1 Takenori Tomohiro,§,1 Kotomi Narita,‡ Miyuki Suzumura,§ Tuomo Glumoff,¶ J. Kalervo Hiltunen,¶ Paul P. Van Veldhoven,‖ Yasumaru Hatanaka,§,2 and Tsuneo Imanaka‡,3
2010 Aug 20;
Stress-related mental disorders (SRMD), which correspond to the diagnostic code F43 in the International Classification of Diseases, version 10, rank among the leading causes of sickness absence in several European countries. Despite the size of this health problem, research on risk factors for severe medical outcomes, like suicidal behavior, is lacking to date. The aim of this study was to investigate predictors of suicide attempt and suicide among sickness absentees with SRMD.
A cohort of 36,304 non-retired individuals, aged 16-64 years on 31.12.2004, with at least one sickness absence spell due to SRMD, initiated in 2005, was followed up with regard to suicide attempt (2006-2009) and suicide (2006-2008). Univariate and multivariate hazard ratios (HR) with 95% confidence intervals (CI) were estimated for a number of predictors.
During the follow-up period, 266 individuals attempted suicide and 34 committed suicide. In the multivariate analyses, the following factors increased the risk of suicide attempt: =< 25 years of age, low educational level, lone parenthood, > 1 sickness absence spell, long duration of the first spell of sickness absence due to SRMD (> 180 days), > 4 and > 8 days of inpatient care due to somatic or mental diagnoses (2000-2005), and > 4 and > 1 outpatient visits due to somatic or mental diagnoses (2001-2005), respectively. Hazard ratios ranged from 1.4 to 4.2. Health care due to mental diagnoses and > 1 spell of sickness absence regardless of diagnosis were predictive of suicide.
Several predictors related to socio-demographics, sickness absence and health-care consumption were identified as risk factors for suicidal behavior. Consideration of these risk factors is of both clinical and public health importance.
Suicide attempt, Suicide, Stress-related mental disorders, Sickness absence
Predictors of suicidal behaviour in 36,304 individuals sickness absent due to stress-related mental disorders - a Swedish register linkage cohort study
Kazi Ishtiak-Ahmed,1,2 Aleksander Perski,3 and Ellenor Mittendorfer-Rutzcorresponding author1
The number of patients with diabetes is increasing particularly in Asia-Pacific region. Many of them are treated with antidiabetics. As the basis of the studies on the benefit and harm of antidiabetic drugs in the region, the information on patterns of market penetration of new classes of antidiabetic medications is important in providing context for subsequent research and analyzing and interpreting results.
We compared penetration patterns of dipeptidyl peptidase-4 (DPP-4) inhibitors in Taiwan, Hong Kong, Japan, and the United States. We used the Taiwan National Health Insurance Research Database, a random sample of the Hong Kong Clinical Data Analysis and Reporting System, the Japan Medical Data Center database, and a 5% random sample of the US Medicare database converted to the Observational Medical Outcomes Partnership’s Common Data Model to identify new users of oral antidiabetic medications. We standardized prevalence and incidence rates of medication use by age and sex to those in the 2010 Taiwanese population. We compared age, sex, comorbid conditions, and concurrent medications between new users of DPP-4 inhibitors and biguanides.
Use of DPP-4 inhibitors 1 year after market entry was highest in Japan and lowest in Hong Kong. New users had more heart failure, hyperlipidemia, and renal failure than biguanide users in Taiwan, Hong Kong, and the United States while the proportions were similar in Japan. In a country with low penetration of DPP-4 inhibitors (eg, Hong Kong), users had diabetes with multiple comorbid conditions compared with biguanidine users. In a country with high penetration (eg, Japan), the proportion of users with comorbid conditions was similar to that of biguanide users.
We observed a marked difference of the penetration patterns of newly marketed antidiabetics in different countries in Asia. Those results will provide the basic information useful in the future studies.
Penetration of new antidiabetic medications in East Asian countries and the United States: A cross-national comparative study
Kiyoshi Kubota, Formal analysis, Writing - original draft, Writing - review & editing,1,* Yukari Kamijima, Data curation, Writing - review & editing,1 Yea-Huei Kao Yang, Data curation, Supervision, Writing - review & editing,2 Shinya Kimura, Data curation, Writing - review & editing,3 Edward Chia-Cheng Lai, Data curation, Formal analysis, Project administration, Writing - review & editing,4 Kenneth K. C. Man, Data curation, Writing - review & editing,5,6 Patrick Ryan, Methodology, Supervision, Writing - review & editing,7 Martijn Schuemie, Methodology, Writing - review & editing,7 Paul Stang, Methodology, Writing - review & editing,7 Chien-Chou Su, Data curation, Writing - review & editing,2 Ian C. K. Wong, Data curation, Writing - review & editing,5,6 Yinghong Zhang, Formal analysis, Writing - review & editing,4 and Soko Setoguchi, Conceptualization, Funding acquisition, Supervision, Writing - review & editing4,8 Stephen L. Atkin, Editor