Withaferin A Targets Hsp90 in Pancreatic Cancer Cells.

Pancreatic cancer is one of the most challenging cancers to treat. This study was aimed to examine the in vitro and in vivo anticancer efficacy and mechanism of Hsp90 inhibition of withaferin A (WA), a natural product purified from the Indian medicinal plant Withania somnifera, in pancreatic cancer cells.. Withaferin A exhibited potent antiproliferative activity against pancreatic cancer cells in vitro with IC50 values below 3 microM in the three pancreatic cancer cell lines Panc-1, MiaPaca-2 and BxPc-3. Withaferin A induced Hsp90 client protein (Akt, Cdk4 and glucocorticoid receptor) degradation mediated by proteasome. WA-Biotin pull-down assay showed that WA-biotin bound directly to the C-terminus of Hsp90, which could be competitively blocked by unlabeled WA. Co-immunoprecipitation demonstrated that WA disrupted the Hsp90-Cdc37 interaction, but not the Hsp90-P23 association and ATP binding to Hsp90. Finally, WA significantly decreased tumor growth in a mouse xenograft model of pancreatic cancer.. As WA induced Hsp70 upregulation, which has potent anti-apoptotic activity, we further examined whether inhibition of Hsp70 by myricetin (MY) would sensitize pancreatic cancer cells to WA. Combined treatment of MY and WA exhibited a much higher anticancer effect against pancreatic cancer cells in vitro compared to MY or WA treatment alone. . MY co-treatment (10 microM) with 1 microM WA decreased WA-induced Hsp70 expression by 3-fold compared to WA treatment alone. In addition, WA and MY acted synergistically in downregulating Hsp90 client proteins, including mutated P53, Akt, and Cdk4. Combined WA and MY treatment also showed significant advantage in tumor growth inhibition in pancreatic cancer mouse xenografts compared to a single treatment. Finally, the structure-activity relationship (SAR) of withanolides for inhibition of Hsp90 and anti-proliferative activities in pancreatic cancer cells was investigated. WA and the three analogues withanolide E (WE), 4β-hydroxywithanolide E (HWE), 3-aziridinylwithaferin A (AzWA) were examined for their anticancer and Hsp90 inhibitory activities in pancreatic cancer cells. SAR analysis showed that the C-5, 6 epoxy functional group was responsible for Hsp90 inhibition whereas, the hydroxyl group at C-4 might enhance the Hsp90 inhibitory activity of withanolide. In contrast, the steric bulk substitution at C-3 may reduce activity.Ph.D.Pharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/89629/1/yorkyu_1.pd

In-depth understanding of the morphology effect of α-Fe2O3 on catalytic ethane destruction

Shape effects of nanocrystal catalysts in different reactions have attracted remarkable attention. In the present work, three types of α-Fe2O3 oxides with different micromorphologies were rationally synthesized via a facile solvothermal method and adopted in deep oxidation of ethane. The physicochemical properties of prepared materials were characterized by XRD, N2 sorption, FE-SEM, HR-TEM, FTIR, in situ DRIFTS, XPS, Mössbauer spectroscopy, in situ Raman, electron energy loss spectroscopy, and H2-TPR. Moreover, the formation energy of oxygen vacancy and surface electronic structure on various crystal faces of α-Fe2O3 were explored by DFT calculations. It is shown that nanosphere-like α-Fe2O3 exhibits much higher ethane destruction activity and reaction stability than nanocube-like α-Fe2O3 and nanorod-like α-Fe2O3 due to larger amounts of oxygen vacancies and lattice defects, which greatly enhance the concentration of reactive oxygen species, oxygen transfer speed, and material redox property. In addition to this, DFT results reveal that nanosphere-like α-Fe2O3 has the lowest formation energy of oxygen vacancy on the (110) facet (Evo (110) = 1.97 eV) and the strongest adsorption energy for ethane (−0.26 eV) and O2 (−1.58 eV), which can accelerate the ethane oxidation process. This study has deepened the understanding of the face-dependent activities of α-Fe2O3 in alkane destruction

Finite-Time Stabilization of Uncertain Switched Positive Linear Systems with Time-Varying Delays

This paper is concerned with finite-time stabilization (FTS) analysis for a class of uncertain switched positive linear systems with time-varying delays. First, a new definition of finite-time boundedness (FTB) is introduced for switched positive system. This definition can simplify FTS analysis. Taking interval and polytopic uncertainties into account, a robust state feedback controller is built such that the switched positive linear system is finite-time bounded. Finally, an example is employed to illustrate the validities of obtained results

Atomic-scale insights into the low-temperature oxidation of methanol over a single-atom Pt1-Co3O4 catalyst

Heterogeneous catalysts with single‐atom active sites offer a means of expanding the industrial application of noble metal catalysts. Herein, an atomically dispersed Pt1‐Co3O4 catalyst is presented, which exhibits an exceptionally high efficiency for the total oxidation of methanol. Experimental and theoretical investigations indicate that this catalyst consists of Pt sites with a large proportion of occupied high electronic states. These sites possess a strong affinity for inactive Co2+ sites and anchor over the surface of (111) crystal plane, which increases the metal–support interaction of the Pt1‐Co3O4 material and accelerates the rate of oxygen vacancies regeneration. In turn, this is determined to promote the coadsorption of the probe methanol molecule and O2. Density functional theory calculations confirm that the electron transfer over the oxygen vacancies reduces both the methanol adsorption energy and activation barriers for methanol oxidation, which is proposed to significantly enhance the dissociation of the CH bond in the methanol decomposition reaction. This investigation serves as a solid foundation for characterizing and understanding single‐atom catalysts for heterogeneous oxidation reactions

The remarkable promotional effect of SO 2 on Pb-poisoned V 2 O 5 -WO 3 /TiO 2 catalysts: An in-depth experimental and theoretical study

Currently, Pb poisoning of heterogeneous catalysts is considered to be a key area of interest in research involved with industrial NOx reduction. As such, a series of Pb-poisoned V2O5-WO3/TiO2 catalysts were prepared by a wet impregnation method and the influence of SO2 on the performance of these poisoned catalysts for NOx reduction was assessed both experimentally and using theoretical calculations. As expected, the incorporation of Pb in these materials resulted in a significant reduction in their catalytic performance. The conversion of NOx over the Pb-V2O5-WO3/TiO2 catalyst increased from approximately 50% to 90% in presence of SO2 (2000 ppm) at 350 °C. It was postulated that in the absence of SO2, Pb reacts with surface V-OH species, which ultimately results in the destruction of Brønsted acid sites; considered to be crucial for the catalytic conversion of NOx. In the presence of SO2 however, enhanced catalytic activity was observed which was suggested to be a result of the formation of additional Brønsted sites (S-OH) via a surface bidentate sulfate intermediate species. The formation of these species was attributed to the interaction of Pb with SO2 and O2 on the surface of the catalyst. Density functional theory (DFT) calculations based on a monolayer V model on TiO2 (0 0 1) showed that SO2 absorbed selectively onto Pb sites rather than V or Ti oxides. It was subsequently determined that NH3 absorption proceeds through the formation of Pb-N species with Pb atom and H-O with SO2. We believe that the present work provides new insights into the design and application of SCR catalysts with specific relevance for application in flue gas streams which contain high quantities of Pb content

MORIN MITIGATES OXIDATIVE STRESS, APOPTOSIS AND INFLAMMATION IN CEREBRAL ISCHEMIC RATS

Background: Morin is a flavanoid which exhibits potent antioxidant activity in various oxidative stress related diseases. The current study was attempted to scrutinize the preclinical bio-efficacy of morin on focal ischemia. Methods: The animal model of focal cerebral ischemic injury was done by midbrain carotid artery occlusion (MCAO) method, followed by Morin (30mg/kg) administration for seven days. Results: The outcome of the study showed that treatment with morin displayed positive effects in reducing the focal cerebral ischemia. This effect was evident with the improvements in neurological deficits, reduction in MDA content and elevation of antioxidant levels (SOD, GSH and Gpx). Furthermore, protein expression of Bax and caspase-3 were effectively down-regulated, whilst the expression of Bcl-2 was significantly elevated. On the other hand, the mRNA expression of proinflammatory cytokines was significantly reduced in focal cerebral ischemic rats upon morin intervention. Conclusion: Thus, the beneficial effects of morin on cerebral ischemia assault may result from the reduction of oxidative stress, inhibition of apoptosis and inflammation

SO2 promoted in situ recovery of thermally deactivated Fe2(SO4)3/TiO2 NH3-SCR catalysts: from experimental work to theoretical study

Due to high catalytic activity and excellent resistance to SO2 and H2O, sulfate materials are considered to be promising vanadium-free catalysts for selective catalytic reduction of NOx with NH3 (NH3-SCR). Despite this, investigations about thermal stability of sulfate SCR catalysts are limited, which is surprising given that sulfates are typically susceptible to thermal decomposition. In this work, the thermal stability of Fe2(SO4)3/TiO2 catalysts was investigated. It was determined that the thermal decomposition of Fe2(SO4)3 resulted in NOx conversion decreased from 90% to 60% at 350 °C. Interestingly however, the introduction of SO2 into the gas stream was found to reverse the effects of the thermal deactivation and the NOx conversion of 90% (350 °C) was once again observed. Extensive characterization of each catalyst sample and density functional theory (DFT) calculations were subsequently conducted. The reduction in catalytic activity after the thermal treatment was attributed to the transformation of Fe2(SO4)3 to α-Fe2O3, which reduced the quantity of Brønsted acid sites on the catalyst. The presence of SO2 in the gas stream was found to reverse this phase transformation which ultimately led to the recovery of Brønsted acid sites. DFT calculations indicated that SO2 adsorbed selectively on Fe atoms of the thermal deactivated catalysts and S-Fe bond should mainly be formed by electrons from p orbitals of S and Fe atoms. Then NH3 could be adsorbed on the surface by N-S bond with SO2. The recoverable property of this catalyst provides a promising outlook for the commercial application, especially given that industrial flue gas streams regularly contain SO2