The thermodynamics of micelle formation of ionic surfactants, sodium dodecyl sulfate (SDS), cetyl pyridinium chloride (CPC), and sodium salt of dioctyl sulfosuccinate (Aerosol OT or AOT) have been thoroughly assessed from microcalorimetric, conductometric, and tensiometric measurements, and the results have been rationalized in terms of physicochemical concepts and relations. The past and recent critical micellar concentration (CMC) data on SDS have been considered and compared; the CMCs of SDS, CPC, and AOT determined in this and earlier studies have been processed to evaluate the energetic parameters (free energy, enthalpy, entropy, and heat capacity) of micellization. The effect of the salt, NaCl, on the CMC and energetics of micellization of the surfactants has been also examined.

SUMMARY Malignant cells exhibit aerobic glycolysis (the Warburg effect) and become dependent on de novo lipogenesis, which sustains rapid proliferation and resistance to cellular stress. The nuclear receptor liver-X-receptor (LXR) directly regulates expression of key glycolytic and lipogenic genes. To disrupt these oncogenic metabolism pathways, we designed an LXR inverse agonist SR9243 that induces LXR-corepressor interaction. In cancer cells, SR9243 significantly inhibited the Warburg effect and lipogenesis by reducing glycolytic and lipogenic gene expression. SR9243 induced apoptosis in tumors without inducing weight loss, hepatotoxicity, or inflammation. Our results suggest that LXR inverse agonists may be an effective cancer treatment approach.

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Mixed lineage kinase 7 (MLK7) is a mitogen-activated protein kinase kinase kinase (MAPKKK) that activates the pro-apoptotic signaling pathways p38 and JNK. A library of potential kinase inhibitors was screened, and a series of dihydropyrrolopyrazole quinolines was identified as highly potent inhibitors of MLK7 in vitro catalytic activity. Of this series, an aryl-substituted dihydropyrrolopyrazole quinoline (DHP-2) demonstrated an IC 50 of 70 nM for inhibition of pJNK formation in COS-7 cell MLK7/JNK co-transfection assays. In stimulated cells, DHP-2 at 200 nM or MLK7 small interfering RNA completely blocked anisomycin and UV induced but had no effect on interleukin-1␤ or tumor necrosis factor-␣-induced p38 and JNK activation. Additionally, the compound blocked anisomycin and UV-induced apoptosis in COS-7 cells. Heart tissue homogenates from MLK7 transgenic mice treated with DHP-2 at 30 mg/kg had reduced JNK and p38 activation with no apparent effect on ERK activation, demonstrating that this compound can be used to block MLK7-driven MAPK pathway activation in vivo. Taken together, these data demonstrate that MLK7 is the MAPKKK required for modulation of the stressactivated MAPKs downstream of anisomycin and UV stimulation and that DHP-2 can be used to block MLK7 pathway activation in cells as well as in vivo.The mitogen-activated protein kinases (MAPK) 1 are a highly conserved family of signal transduction molecules that transmits extracellular signals from the membrane to the nucleus. There are three major branches of MAPK signaling that include ERK, c-Jun N-terminal kinase (JNK) and p38. The JNK and p38 branches of the MAPK family are activated by stress stimuli including cytokines, osmotic stress, mitogens, UV irradiation, chemotherapeutic agents, and anisomycin (1, 2). There are three kinases that form a MAPK signaling module where a MAPK is activated by a MAPK kinase (MAPKK), which in turn is regulated by a MAPKK kinase (MAPKKK) (Fig. 1). The upstream activation of JNK and p38 is complex, allowing for activation of this pathway in multiple cells and by multiple stimuli. Cellular and receptor specificity of the pathway is conferred by protein-protein interactions where the MAPK and a MAPKK assemble with a specific MAPKKK on scaffold proteins such as JNK-interacting protein (3, 4) or ␤-arrestin (5). The resulting signaling module acts as a bridge joining the appropriate receptor to the downstream effectors, enabling activation of the stress-activated MAPK.The most distal point at which signal and cell specificity for JNK and p38 activation is conferred is at the MAPKKK level. Mixed lineage kinases (MLKs) are a family of MAPKKKs activating JNK and p38. There are currently seven mammalian kinases belonging to the MLK family that have recently been reviewed (6, 7). These kinases can be divided into three subclasses based on sequence similarity and domain structure, and they include MLK1-4, dual leucine zipper kinases, and the zipper sterile ␣-motif kinases (ZAKs). Although much is known about the mechanisms re...

The micellization characteristics of N-cetyl-N-ethanolyl-N,N-dimethyl and N-cetyl-N,N-diethanolyl-N-methyl ammonium bromides have been investigated by microcalorimetric, conductometric, and fluorimetric techniques. The critical micellar concentration (cmc), counterion binding of micelles, their aggregation number, and thermodynamics of micellization have been evaluated at eight different temperatures in the range of 288-323 K. The Gibbs free energy, enthalpy, entropy, and specific heat of the micellization process have been evaluated by the direct calorimetric method as well as by the indirect method of van't Hoff by processing the cmc results of microcalorimetry and conductometry at different temperatures. The differences of the results obtained by these two procedures have been discussed. The thermodynamic results have been compared with values for the parent compound, N-cetyl-N,N,Ntrimethylammonium bromide, and the effect of the substitution of the ethanolyl group in place of the methyl group on the surfactant head has been rationalized. The effects of the salt NaBr on the thermodynamics of micellization of the studied surfactants have been also studied from the microcalorimetric measurements.