Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy

A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7), nuclear factor-kappa B (NF-κB) was activated and could result in up-regulated interleukin (IL)-6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT₁ receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion.published_or_final_versio

Inhibition of prostate cancer cell growth by human secreted PDZ domain-containing protein 2, a potential autocrine prostate tumor suppressor

A possible role of the PDZ domain-containing protein 2 (PDZD2) in prostate tumorigenesis has been suggested. Besides, PDZD2 is posttranslationally cleaved by a caspase-dependent mechanism to form a secreted PDZ domain-containing protein 2 (sPDZD2) with unknown functions in humans. In this study, we demonstrate the endogenous expression of PDZD2 and secretion of sPDZD2 in cancerous DU145, PC-3, 22Rv1, LNCaP, and immortalized RWPE-1 prostate epithelial cells. Inhibition of endogenous sPDZD2 production and secretion by DU145, PC-3, 22Rv1, and RWPE-1 cells via the caspase-3 inhibitor Z-DEVD-FMK resulted in increased cell proliferation, which was abrogated by treatment with exogenous recombinant sPDZD2. Whereas sPDZD2-induced antiproliferation in DU145, PC-3, and 22Rv1 cells, it induced apoptosis in LNCaP cells. The data suggest that endogenous sPDZD2, produced by caspase-3-mediated cleavage from PDZD2, may function as a novel autocrine growth suppressor for human prostate cancer cells. The antiproliferative effect of sPDZD2 was apparently mediated through slowing the entry of DU145, PC-3, and 22Rv1 cells into the S phase of the cell cycle. In DU145 cells, this can be attributed to stimulated p53 and p21 CIP1/WAF1 expression by sPDZD2. On the other hand, the apoptotic effect of sPDZD2 on LNCaP cells was apparently mediated via p53-independent Bad stimulation. Together our results indicate the presence of p53-dependent and p53-independent PDZD2/sPDZD2 autocrine growth suppressive signaling pathways in human prostate cancer cells and suggest a novel therapeutic approach of harnessing the latent tumor-suppressive potential of an endogenous autocrine signaling protein like sPDZD2 to inhibit prostate cancer growth. Copyright © 2006 by The Endocrine Society.postprin

Ginkgo biloba extract (EGb761) inhibits mitochondria-dependent caspase pathway and prevents apoptosis in hypoxia-reoxygenated cardiomyocytes

Background: EGb761 is a standard extract from the leaves of Ginkgo biloba (Yinxing) containing ginkgo-flavone glycosides and terpenoid. The flavonoid components of EGb761 scavenge free radicals and protect myocardia from ischemia-reperfusion injury. The present study aims to determine the effects of the active compounds of EGb761 on mitochondria-dependent caspase pathway.Methods: Cardiomyocytes were exposed to 24 hours of hypoxia and four hours of reoxygenation, and pretreated with EGb761, bilobalide and quertcetin. By using immunoblot, immunofluorescent, biochemical and flow cytometry techniques, we compared the effects of EGb761 and its representative constituents including quercetin and bilobalides on regulating mitochondria-dependent caspases signal pathway and apoptotic cell death in the hypoxia-reoxygenated cardiomyocytes.Results: Pretreatment with EGb761 significantly inhibited the release of cytochrome c from mitochondria, the expression of caspase-3, cleavage activities of caspases and attenuated apoptotic cell death. The effects of quercetin on the release of cytochrome c, the cleavage activities of caspases and cell death were similar to those of EGb761 but better than those of bilobalide.Conclusion: The antioxidant constituents of EGb761 such as quercetin contribute to the cardioprotective effects of EGb761 and inhibit the mitochondria-dependent caspase pathway. It is possible that the mitochondria-dependent caspase pathway may be one of the molecular targets of EGb761 against myocardial ischemia-reperfusion injury. © 2011 Shen et al; licensee BioMed Central Ltd.published_or_final_versio

Resummation of heavy jet mass and comparison to LEP data

The heavy jet mass distribution in e+e- collisions is computed to next-to-next-to-next-to leading logarithmic (NNNLL) and next-to-next-to leading fixed order accuracy (NNLO). The singular terms predicted from the resummed distribution are confirmed by the fixed order distributions allowing a precise extraction of the unknown soft function coefficients. A number of quantitative and qualitative comparisons of heavy jet mass and the related thrust distribution are made. From fitting to ALEPH data, a value of alpha_s is extracted, alpha_s(m_Z)=0.1220 +/- 0.0031, which is larger than, but not in conflict with, the corresponding value for thrust. A weighted average of the two produces alpha_s(m_Z) = 0.1193 +/- 0.0027, consistent with the world average. A study of the non-perturbative corrections shows that the flat direction observed for thrust between alpha_s and a simple non-perturbative shape parameter is not lifted in combining with heavy jet mass. The Monte Carlo treatment of hadronization gives qualitatively different results for thrust and heavy jet mass, and we conclude that it cannot be trusted to add power corrections to the event shape distributions at this accuracy. Whether a more sophisticated effective field theory approach to power corrections can reconcile the thrust and heavy jet mass distributions remains an open question.Comment: 33 pages, 14 figures. v2 added effect of lower numerical cutoff with improved extraction of the soft function constants; power correction discussion clarified. v3 small typos correcte

HI-Tree: Mining High Influence Patterns Using External and Internal Utility Values

We propose an efficient algorithm, called HI-Tree, for mining high influence patterns for an incremental dataset. In traditional pattern mining, one would find the complete set of patterns and then apply a post-pruning step to it. The size of the complete mining results is typically prohibitively large, despite the fact that only a small percentage of high utility patterns are interesting. Thus it is inefficient to wait for the mining algorithm to complete and then apply feature selection to post-process the large number of resulting patterns. Instead of generating the complete set of frequent patterns we are able to directly mine patterns with high utility values in an incremental manner. In this paper we propose a novel utility measure called an influence factor using the concepts of external utility and internal utility of an item. The influence factor for an item takes into consideration its connectivity with its neighborhood as well as its importance within a transaction. The measure is especially useful in problem domains utilizing network or interaction characteristics amongst items such as in a social network or web click-stream data. We compared our technique against state of the art incremental mining techniques and show that our technique has better rule generation and runtime performance

Observation of discrete time-crystalline order in a disordered dipolar many-body system

Understanding quantum dynamics away from equilibrium is an outstanding challenge in the modern physical sciences. It is well known that out-of-equilibrium systems can display a rich array of phenomena, ranging from self-organized synchronization to dynamical phase transitions. More recently, advances in the controlled manipulation of isolated many-body systems have enabled detailed studies of non-equilibrium phases in strongly interacting quantum matter. As a particularly striking example, the interplay of periodic driving, disorder, and strong interactions has recently been predicted to result in exotic "time-crystalline" phases, which spontaneously break the discrete time-translation symmetry of the underlying drive. Here, we report the experimental observation of such discrete time-crystalline order in a driven, disordered ensemble of $\sim 10^6$ dipolar spin impurities in diamond at room-temperature. We observe long-lived temporal correlations at integer multiples of the fundamental driving period, experimentally identify the phase boundary and find that the temporal order is protected by strong interactions; this order is remarkably stable against perturbations, even in the presence of slow thermalization. Our work opens the door to exploring dynamical phases of matter and controlling interacting, disordered many-body systems.Comment: 6 + 3 pages, 4 figure

Uncoupling Protein-2 Mediates DPP-4 Inhibitor-Induced Restoration of Endothelial Function in Hypertension Through Reducing Oxidative Stress

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Effects of Erxian decoction, a Chinese medicinal formulation, on serum lipid profile in a rat model of menopause

<p>Abstract</p> <p>Background</p> <p>The prevalence and risk of cardiovascular disease increase after menopause in correlation with the progression of abnormality in the serum lipid profile and the deprivation of estrogen. <it>Erxian </it>decoction (EXD), a Chinese medicinal formulation for treating menopausal syndrome, stimulates ovarian estrogen biosynthesis. This study investigates whether EXD improves the serum lipid profile in a menopausal rat model.</p> <p>Methods</p> <p>Twenty-month-old female Sprague Dawley rats were treated with EXD and its constituent fractions. Premarin was administered for comparison. After eight weeks of treatment, rats were sacrificed and the serum levels of total cholesterol, triglyceride, high-density-lipoprotein cholesterol and low-density-lipoprotein cholesterol were determined. The hepatic protein levels of 3-hydroxy-3-methyl-glutaryl-CoA reductase and low-density-lipoprotein receptor were assessed with Western blot.</p> <p>Results</p> <p>The serum levels of total cholesterol and low-density-lipoprotein cholesterol were significantly lower in the EXD-treated group than in the constituent fractions of EXD or premarin groups. However, the serum levels of triglyceride and high-density-lipoprotein cholesterol were not significantly different from the control groups. Results from Western blot suggest that EXD significantly down-regulated the protein level of 3-hydroxy-3-methyl-glutaryl-CoA reductase and up-regulated low-density-lipoprotein receptor. <b>Conclusion </b>EXD improves serum lipid profile in a menopausal rat model through the suppression of the serum levels of total cholesterol and low-density-lipoprotein cholesterol, possibly through the down-regulation of the 3-hydroxy-3-methyl-glutaryl-CoA and up-regulation of the low-density-lipoprotein receptor.</p

Oxidative stress-dependent cyclooxygenase-2-derived prostaglandin F2α impairs endothelial function in renovascular hypertensive rats

Abstract Aims: The role of endothelium-derived contracting factors (EDCFs) in regulating renovascular function is yet to be elucidated in renovascular hypertension (RH). The current study investigated whether oxidative stress-dependent cyclooxygenase (COX)-2-derived prostaglandin F(2alpha) (PGF(2alpha)) impairs endothelial function in renal arteries of renovascular hypertensive rats (RHR). Results: Renal hypertension was induced in rats by renal artery stenosis of both kidneys using the 2-kidney 2-clip model. Acute treatment with reactive oxygen species (ROS) scavengers, COX-2 inhibitors, and thromboxane-prostanoid receptor antagonists, but not COX-1 inhibitors, improved endothelium-dependent relaxations and eliminated endothelium-dependent contractions in RHR renal arteries. Five weeks of treatment with celecoxib or tempol reduced blood pressure, increased renal blood flow, and restored endothelial function in RHRs. Increased ROS production in RHR arteries was inhibited by ROS scavengers, but unaffected by COX-2 inhibitors; whereas increased PGF(2alpha) release was reduced by both ROS scavengers and COX-2 inhibitors. ROS also induced COX-2-dependent contraction in RHR renal arteries, which was accompanied by the release of COX-2-derived PGF(2alpha). Further, chronic tempol treatment reduced COX-2 and BMP4 upregulation, p38MAPK phosphorylation, and the nitrotyrosine level in RHR renal arteries. Conclusion: These findings demonstrate the functional importance of oxidative stress, which serves as an initiator of increased COX-2 activity, and that COX-2-derived PGF(2alpha) plays an important role in mediating endothelial dysfunction in RH. Innovation: The current study, thus, suggests that drugs targeting oxidative stress-dependent COX-2-derived PGF(2alpha) may be useful in the prevention and management of RH. Antioxid. Redox Signal. 16, 363-373.published_or_final_versio