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Haematopoietic stem cell (HSC) homeostasis is tightly controlled by growth factors, signalling molecules and transcription factors. Definitive HSCs derived during embryogenesis in the aorta-gonad-mesonephros region subsequently colonize fetal and adult haematopoietic organs1,2. To identify new modulators of HSC formation and homeostasis, a panel of biologically active compounds was screened for effects on stem cell induction in the zebrafish aorta-gonad-mesonephros region. Here, we show that chemicals that enhance prostaglandin (PG) E2 synthesis increased HSC numbers, and those that block prostaglandin synthesis decreased stem cell numbers. The cyclooxygenases responsible for PGE2 synthesis were required for HSC formation. A stable derivative of PGE2 improved kidney marrow recovery following irradiation injury in the adult zebrafish. In murine embryonic stem cell differentiation assays, PGE2 caused amplification of multipotent progenitors. Furthermore, ex vivo exposure to stabilized PGE2 enhanced spleen colony forming units at day 12 post transplant and increased the frequency of long-term repopulating HSCs present in murine bone marrow after limiting dilution competitive transplantation. The conserved role for PGE2 in the regulation of vertebrate HSC homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of HSC number for therapeutic purposes.
Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis
Trista E. North,1,2 Wolfram Goessling,1,2 Carl R. Walkley,1,3 Claudia Lengerke,1 Kamden R. Kopani,1,2 Allegra M. Lord,1,2 Gerhard J. Weber,1,2 Teresa V. Bowman,1,2 Il-Ho Jang,1 Tilo Grosser,4 Garret A. FitzGerald,4 George Q. Daley,1 Stuart H. Orkin,1,2,3 and Leonard I. Zon1,2
2009 Nov 10.
As essential players in the field of diabetes treatment, resveratrol (RSV) has received much attention in recent years. However, it is unclear whether it can improve insulin resistance by regulating the long-chain non-coding RNA (lncRNA). The objective of this study was to investigate whether RSV improves high-fat diet-induced insulin resistance in mice by regulating thelncRNANONMMUT008655.2 in vivo and in vitro. To this end, animal and cell insulin resistance models were developed. Specifically, C57BL/6J mice were fed a high-fat diet (HFD) and administered RSV for eight weeks. Additionally, mouse Hepa cells were treated with palmitic acid, transfected with siRNA NONMMUT008655.2, and treated with RSV. Treated mice and cells were then compared to normal controls that were not exposed to RSV. In the animal model, RSV was found to decrease the levels of fasting blood glucose, triglycerides, and low-density lipoprotein cholesterol, as well as the insulin index and area under the curve; while increasing the insulin sensitivity index. Besides, RSV decreased the expression levels of SOCS3, G6PC, and FOXO1 yet increased that of p-Akt and p-FOXO1 in mice. The same results were observed following knockdown of NONMMUT008655.2 in cells. Overall, our results suggest that RSV may improve hepatic insulin resistance and control blood glucose levels by downregulating lncRNA NONMMUT008655.2.
Blood glucose, insulin resistance, resveratrol, long-chain non-coding RNA
Resveratrol improves high-fat diet-induced insulin resistance in mice by downregulating the lncRNA NONMMUT008655.2
Linyi Shu,1,2 Guangsen Hou,1,2 Hang Zhao,1,2 Wenli Huang,1,2 Guangyao Song,1,2 and Huijuan Ma1,2,3
Purpose: We aimed to estimate latent classes of concurrent polysubstance use and test for sexual orientation differences in latent class memberships with representative data from adolescents living in 19 U.S. states. We also tested whether sex, race/ethnicity, and age moderated the sexual identity differences in polysubstance use class memberships.
Methods: We analyzed data from 119,437 adolescents from 19 states who participated in the 2015 Youth Risk Behavior Survey. Latent class analysis characterized polysubstance use patterns based on self-reported frequency of lifetime and past-month use of alcohol (including heavy episodic drinking), tobacco (cigarettes, cigars, and smokeless tobacco), and marijuana. Multinomial logistic regression models tested differences in latent class memberships by sexual identity. Interaction terms tested whether sex, race/ethnicity, and age moderated the sexual identity differences in polysubstance use class memberships.
Results: A six-class model of polysubstance use fit the data best and included nonusers (61.5%), experimental users (12.2%), marijuana-alcohol users (14.8%), tobacco-alcohol users (3.8%), medium-frequency three-substance users (3.6%), and high-frequency three-substance users (4.1%). Gay/lesbian- and bisexual-identified adolescents had significantly higher odds than heterosexual-identified adolescents of being in all of the user classes compared with the nonuser class. These sexual identity differences in latent polysubstance use class memberships were generally larger for females than for males, varied occasionally by race/ethnicity, and were sometimes larger for younger ages.
Conclusion: Compared with their heterosexual peers, gay/lesbian and bisexual adolescents—especially females—are at heightened risk of engaging in multiple types of polysubstance use. Designing, implementing, and evaluating interventions will likely reduce these sexual orientation disparities.
adolescents, polysubstance use, sex, sexual minority youth, sexual orientation, YRBS
Latent Classes of Polysubstance Use Among Adolescents in the United States: Intersections of Sexual Identity with Sex, Age, and Race/Ethnicity
Robert W.S. Coulter, PhD, MPH,1,,2,,3,,4 Deanna Ware, MPH,5 Jessica N. Fish, PhD,6 and Michael W. Plankey, PhD5
2019 Apr 1