Dysregulation of lipid homeostasis is intimately associated with obesity, type 2 diabetes, and cardiovascular diseases. Sterol regulatory-element binding proteins (SREBPs) are the master regulators of lipid biosynthesis. Previous studies have shown that the conserved transcriptional cofactor Mediator complex is critically required for the SREBP transcriptional activity, and recruitment of the Mediator complex to the SREBP transactivation domains (TADs) is through the MED15-KIX domain. Recently, we have synthesized several boron-containing small molecules. Among these novel compounds, BF175 can specifically block the binding of MED15-KIX to SREBP1a-TAD in vitro, resulting in an inhibition of the SREBP transcriptional activity and a decrease of SREBP target gene expression in cultured hepatocytes. Furthermore, BF175 can improve lipid homeostasis in the mouse model of diet-induced obesity. Compared with the control, BF175 treatment decreased the expression of SREBP target genes in mouse livers and decreased hepatic and blood levels of lipids. These results suggest that blocking the interaction between SREBP-TADs and the Mediator complex by small molecules may represent a novel approach for treating diseases with aberrant lipid homeostasis.
Dysregulation of lipid homeostasis is a risk factor for cardiovascular disease (CVD). Thus, understanding the molecular mechanisms of maintaining lipid homeostasis may aid the discovery of novel targets for treating CVD. MED15 and Cyclin-dependent kinase-8 (CDK8) are subunits of the Mediator complex, which contains multiple proteins and functions as a transcriptional cofactor. Mediator can positively or negatively regulate gene expression, depending on the contexts and its associated transcription factors. Recent studies revealed a critical role of MED15 and CDK8 in regulating sterol regulatory element-binding protein (SREBP) transcription factors, which are master activators for genes that are responsible for lipid biosynthesis. Here, we review the function of MED15 and CDK8 in regulating lipid homeostasis and discuss the implications for CVD.
The SD-HRM method was able to effectively detect common NCAs in 1550 prenatal samples. We propose that SD-HRM could serve as an effective alternative option to the currently used prenatal RAD methods.
Through the fluorescence and ultravioletvisible spectrophotometry we have studied the action of cefoperazone sodium and worfloxacin, two kinds of medicine with albumin, and examined the equal efficiency quality of fluorescence enhancement and fluorescence quenching equation. The result shows the equal efficiency of calculating dissociation constant. In this article, we obtain the dissociation constants of the action of the two kinds of medicine with bovine serum albumin, energy-transfer efficiency, the distance of donor-acceptor and quenching constants. The above shows that the action is not caused by dynamic collision but by the binding of medicine and albumin. This article specially points out that the [M t ]/[P t ], which is the ratio of the maximum mol concentration of the quenching agent (medicine) to fluorescent (albumin) mol concentration when the quenching ends, is very important because it is the maximum binding number of quenching agent molecule to a fluorescent molecule. There is no more quenching after adding more quenching agent beyond this quantity to fluorescent solution. This quantity is determined directly and strictly by experiment, so is also of important significance when discussing quenching efficiency and binding situation of donor-acceptor.Keywords: fluorescence quenching and enhancement, bovine serum albumin, cefoperazone, worfloxacin.The interaction of little dynamic biological molecule with biomacromolecule is a basic problem of chemicobiology medicine chemistry and many other subjects. To the corresponding liquid system, because of single crystal diffraction's incapability and NMR spectroscopy's complexity, chemists usually like to study the interaction of medicine or metallic ions with biomacromolecules by fluorescence probe method that is relatively simple.About fluorescence probe method, a few years ago we had deduced a new equation respectively from fluorescence enhancement [1] and fluorescence quenching [2] , which was broadly quoted by colleages [3][4][5][6][7][8] . Ten years' experience [9][10][11][12][13][14][15][16][17] made us think whether it is possible to regard fluorescence quenching as a negative fluorescence enhancement or not. To this kind of phenomenon such as quenching, can we get the two kinds of theories dually dealt with and the same or similar (because of the difference of supposition in the deduction of the two theories) result? In this article, we select cefoperazone sodium of cephalosporin class and worfloxacin sodium to act with BSA as an example, and then examine the equal-efficiency of fluorescence quenching and enhancement equation. Finally we have studied their quenching effect.
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