No abstract

We introduce the reactive force field (ReaxFF) simulation to predict the hydrolysis reactions and water stability of metal-organic frameworks (MOFs) where the simulation showed that MOF-74 has superior water-resistance compared with isoreticular IRMOF-1 and IRMOF-10.

Cellular oxygen sensing is required for hypoxia-inducible factor-1␣ stabilization, which is important for tumor cell survival, proliferation, and angiogenesis. Here we find that terpestacin, a small molecule previously identified in a screen of microbial extracts, binds to the 13.4-kDa subunit (UQCRB) of mitochondrial Complex III, resulting in inhibition of hypoxia-induced reactive oxygen species generation. Consequently, such inhibition blocks hypoxia-inducible factor activation and tumor angiogenesis in vivo, without inhibiting mitochondrial respiration. Overexpression of UQCRB or its suppression using RNA interference demonstrates that it plays a crucial role in the oxygen sensing mechanism that regulates responses to hypoxia. These findings provide a novel molecular basis of terpestacin targeting UQCRB of Complex III in selective suppression of tumor progression.Progression of many solid tumors requires angiogenesis (1). Mitochondrial function has been linked to angiogenesis, because mitochondria are the primary sites of oxygen consumption, and angiogenesis is an oxygen concentration-sensitive process (2). Reports suggest that reactive oxygen species (ROS) 3 generation at mitochondrial Complex III is necessary and sufficient to trigger HIF-1␣ stabilization during hypoxia, and cells lacking mitochondrial DNA and electron transport activity ( cells) fail to exhibit increased ROS or up-regulation of HIF-1␣ target genes during hypoxia (3-5). Inhibitors of Complex III such as myxothiazol and stigmatellin also block mitochondrial ROS generation and inhibit the stabilization and transcriptional activity of HIF-1␣ during hypoxia. These findings suggest that the generation of ROS from mitochondrial Complex III is a critical event in the signaling of cellular hypoxia (6, 7). However, details regarding which of the components of Complex III contribute to this signaling remain to be described.Biological screening tools are useful for identifying naturally occurring small molecules capable of inducing a specific phenotype change (8, 9). We performed a large scale screen of microbial extracts in an attempt to identify small molecules that could inhibit the angiogenic response to pro-angiogenic stimuli, such as hypoxia, in endothelial cells. We identified terpestacin as a small molecule with unique bicyclo sesterterpene structure capable of inhibiting the angiogenic response at concentrations below the toxic threshold (10). Terpestacin strongly inhibits the functional response to hypoxia of human umbilical vein endothelial cells in vitro and angiogenesis within the embryonic chick chorioallantoic membrane in vivo. In addition to this anti-angiogenic activity, terpestacin has previously been reported to inhibit syncytium formation during human immunodeficiency virus infection and has been chemically synthesized (11-13). However, neither the molecular target of this compound nor the cellular mechanism of its anti-angiogenic activity has been identified.In the present study we identified the binding protein of terpestacin and...

CD13/aminopeptidase N (APN) is a membrane-bound, zinc-dependent metalloproteinase that plays a key role in tumor invasion and angiogenesis. Here, we show that curcumin, a phenolic natural product, binds to APN and irreversibly inhibits its activity. The direct interaction between curcumin with APN was confirmed both in vitro and in vivo by surface plasmon resonance analysis and an APN-specific antibody competition assay, respectively. Moreover, curcumin and other known APN inhibitors strongly inhibited APN-positive tumor cell invasion and basic fibroblast growth factor-induced angiogenesis. However, curcumin did not inhibit the invasion of APN-negative tumor cells, suggesting that the antiinvasive activity of curcumin against tumor cells is attributable to the inhibition of APN. Taken together, our study revealed that curcumin is a novel irreversible inhibitor of APN that binds to curcumin resulting in inhibition of angiogenesis.

Among recently synthesized isoreticular metal-organic frameworks (IRMOFs), interpenetrating IRMOFs show high hydrogen adsorption capacities at low temperature and under ambient pressure. However, little is known about the molecular basis of their hydrogen binding properties. In this work, we performed grand canonical Monte Carlo (GCMC) simulations to investigate the effect of catenation on the interactions between hydrogen molecules and IRMOFs. We identified the adsorption sites and analyzed the adsorption energy distributions. The simulation results show that the small pores generated by catenation can play a role to confine the hydrogen molecules more densely, so that the capacity of the interpenetrating IRMOFs could be higher than that of the non-interpenetrating IRMOFs.

Apoptosis, also called programmed cell death, is morphologically characterized by cell shrinkage, membrane remodeling, cell blebbing, chromatin condensation and DNA fragmentation with apoptotic bodies.1-3) Apoptosis activation has been considered a good target in cancer therapies. 4,5) In general, apoptosis is regulated by pro-apoptotic and antiapoptotic proteins of the Bcl-2 family and executed through caspases (or cysteine-aspartic proteases), chiefly via two major and inter-related pathways, i.e., the mitochondria-dependent "intrinsic" cytochrome c/caspase-9 pathway and the death receptor-mediated "extrinsic" caspase-8 pathway. [6][7][8] Additionally, apoptosis is controlled by various cell signaling pathways such as the phosphoinositide 3-kinase (PI3K)/AKT survival pathway, regulating apoptosis chiefly by blocking caspase-9 and the mitochondria damaging Bcl-2 family protein, Bad, through phosphorylative inactivation. 9)Tanshinone IIA (Tan IIA,14,6,8,13, Fig. 1A), one of the phytochemical compounds isolated from the Chinese medicinal herb Danshen (root of Salvia miltiorrhiza BUNGE), has been reported to exert diverse biological properties including anti-oxidative, 3,10,11) anti-angiogenic, 12) and anti-inflammatory activities.13) More importantly, anti-cancer activities have been reported including human hepatoma, [14][15][16][17] breast cancer 18) and leukemia. 19) However, there is no report of anticancer activity of Tan IIA on prostate cancer cells. Thus, in the present study, we investigated the cytocidal/apoptosis effect against prostate cancer cell lines of different pathogenetic make-up: LNCaP (p53 null, phosphate and tensin homolog (PTEN) null-high AKT, androgen sensitive) and PC-3 (p53 null, PTEN null-high AKT, androgen receptor null). Our mechanistic investigations suggested an involvement of mitochondria-intrinsic caspase activation cascade and inhibition of PI3K/AKT pathway. MATERIALS AND METHODSTanshinone IIA Isolation The procedure of Tan IIA (Fig. 1A) isolation is as reported by Choi and colleagues. 20)Cell Culture Human prostate cancer cells LNCaP (ATCC CRL 1740, p53 wild type, PTEN mutant-high AKT) and PC3 (ATCC CRL 1435, p53 null, PTEN null-high AKT), and breast cancer cells MDA-MB-231 (ATCC HTB 26, p53 mutant, wild type PTEN-low AKT) were obtained from American Type Culture Collection (ATCC) and maintained in RPMI 1640 supplemented with 10% fetal bovine serum (FBS) and 2 mmol/l L-glutamine, 10 mmol/l N-(2-hydroxyethyl)piperazine-NЈ-2-ethanesulfonic acid (HEPES), 1 mmol/l sodium pyruvate, and 4.5% D-glucose without antibiotics.Cytotoxicity Assay The cytotoxicity of Tan IIA was assessed by a tetrazolium salt, 2,3-bis[2-methyloxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide (XTT) assay. LNCaP or PC3 cells were seeded onto 96-well microplates at a density of 1ϫ10 4 cells per well in 100 ml of complete medium. After incubation for 24 h, cells were exposed to var- IIA; 14,16-epoxy-20-nor-5(10),6,8,13,15-abietapentaene-11,12-dione), a phytochemical derived from the roots of Salvia miltio...

Due to process parameter variations, a large variability in circuit delay occurs in scaled technologies affecting the yield. In this paper, we propose a sizing algorithm to ensure the speed of a circuit under process variation with a certain degree of confidence while maintaining the area and power budget within a limit. This algorithm estimates the variation in circuit delay using statistical timing analysis considering both interand intra-die process variation and resizes the circuit to achieve a desired yield. Experimental results on several benchmark circuits show that one can achieve up to 19% savings in area (power) using our algorithm compared to the worst-case design.

BackgroundSignal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various cellular processes such as cell survival, angiogenesis and proliferation. In the present study, we examined that betulinic acid (BA), a triterpene from the bark of white birch, had the inhibitory effects on hypoxia-mediated activation of STAT3 in androgen independent human prostate cancer PC-3 cells.Methodology/Principal FindingsBA inhibited the protein expression and the transcriptional activities of hypoxia-inducible factor-1α (HIF-1α) under hypoxic condition. Consistently, BA blocked hypoxia-induced phosphorylation, DNA binding activity and nuclear accumulation of STAT3. In addition, BA significantly reduced cellular and secreted levels of vascular endothelial growth factor (VEGF), a critical angiogenic factor and a target gene of STAT3 induced under hypoxia. Furthermore, BA prevented in vitro capillary tube formation in human umbilical vein endothelial cells (HUVECs) maintained in conditioned medium of hypoxic PC-3 cells, implying anti-angiogenic activity of BA under hypoxic condition. Of note, chromatin immunoprecipitation (ChiP) assay revealed that BA inhibited binding of HIF-1α and STAT3 to VEGF promoter. Furthermore, silencing STAT3 using siRNA transfection effectively enhanced the reduced VEGF production induced by BA treatment under hypoxia.Conclusions/SignificanceTaken together, our results suggest that BA has anti-angiogenic activity by disturbing the binding of HIF-1α and STAT3 to the VEGF promoter in hypoxic PC-3 cells.