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Two new guaiane-type sesquiterpenes, wenyujinolides A (1) and B (2), were isolated from the ethanol extract of Curcuma wenyujin, together with 10 known compounds. Their structures were established by extensive spectroscopic methods (IR, ESIMS, HRESIMS, ECD, 1D and 2D NMR) and comparison of their NMR data with literatures. Compounds 1 and 2 were evaluated for the inhibition of NO production in LPS induced RAW 264.7 macrophages. [ABSTRACT FROM AUTHOR]

Abstract: A two-sublattice Ising metamagnet in both uniform and random fields is studied within the mean-field approach based on Bogoliubov’s inequality for the Gibbs free energy. We show that the qualitative features of the phase diagrams are dependent on the parameters of the model and the uniform field values. The tricritical point and reentrant phenomenon can be observed on the phase diagram. The reentrance is due to the competition between uniform and random interactions. [Copyright &y& Elsevier]

Abstract: The mixed spin- 1/2 and spin- 3/2 transverse Ising model in a longitudinal magnetic field is studied within the framework of the effective-field theory with correlations. In this approach the effective-field equations are derived by using a probability distribution method based on the generalized but approximated van der Waerden identities. The total longitudinal and transverse magnetizations, the transverse susceptibility and longitudinal susceptibility and the critical temperatures are obtained. We find a number of interesting phenomena in these quantities, due to the applied transverse field and the longitudinal field. [Copyright &y& Elsevier]

Abstract: Phase diagrams and magnetization curves of a diluted spin-3/2 transverse Ising model in a random field on honeycomb lattices are investigated by the use of an effective-field theory with correlations. The tricritical point is found in the system, in contrast to the corresponding spin-1/2 Ising counterpart. The possible reentrant phenomena displayed by the system due to the competition effects that occur for appropriate ranges of the random and transverse fields are investigated. [Copyright &y& Elsevier]

Abstract: By applying the differential operator technology, magnetic properties (phase transition, tricritical points and magnetization) of a ferrimagnetic bilayer system with biaxial crystal-field are studied within the framework of the effective-field theory with correlations. The effects of the biaxial crystal-field constants on the magnetic properties of the ferrimagnetic bilayer system consisting of two ferromagnetically coupled monolayers (A and B) with different spins ( and 1, , 2) are discussed in detail for the case of simple cubic Ising-type structures. We find interesting phenomena in the system, such as two tricritical points exist on the curve in the system with a half integer spin (), while there is only one tricritical point in the system with an integer spin () at certain values of the biaxial crystal-field. The ferrimagnetic system can exhibit compensation behavior, depending on the competition between the interlayer interaction and the biaxial crystal-field when the intralayer interactions J 2 and J 1 are fixed. The results obtained may be related to experimental work on rare-earth/transition-metal multilayer films. [Copyright &y& Elsevier]

Abstract: The phase diagrams of a spin- transverse Ising model with a random field on honeycomb, square, and simple-cubic lattices, respectively, are investigated within the framework of an effective-field theory with correlations. We found that the behavior of the tricritical point and the reentrant phenomenon for the system with any coordination number , when the applied random field is bimodal. The behavior of the tricritical point is also examined as a function of applied transverse field. The reentrant phenomenon comes from the competition between the transverse field and the random field. [Copyright &y& Elsevier]

The magnetic properties of mixed Ising ferromagnetic and ferrimagnetic systems consisting of spin-1/2 and spin-3/2 and spin-3/2 with a longitudinal magnetic field are investigated within the framework of the effective-field theory with correlations. The thermal behaviors of magnetizations, magnetic susceptibilities and the phase diagrams are examined in detail. We find some interesting phenomena in these quantities, due to the applied longitudinal magnetic field. [Copyright &y& Elsevier]

In addition to its demethylating function, 5-aza-2'-deoxycytidine (5-aza-CdR) also plays an important role in inducing cell cycle arrest, differentiation, and cell death. However, the mechanism by which 5-aza-CdR induces antineoplastic activity is not clear. In this study, we found that 5-aza-CdR at limited concentrations (0.01-5 µM) induces inhibition of cell proliferation as well as increased p53/p21Waf1/Cip1 expression in A549 cells (wild-type p53) but not in H1299 (p53-null) and H719 cells (p53 mutant). The p53-dependent p21Waf1/Cip1 expression induced by 5-aza-CdR was not seen in A549 cells transfected with the wild-type human papilloma virus type-16 E6 gene that induces p53 degradation. Furthermore, deletion analysis and site-directed mutagenesis of the p21 promoter reveals that 5-aza-CdR induces p21Waf1/Cip1 expression through two p53 binding sites in the p21 promoter. Finally, 5-aza-CdR-induced p21Waf1/ Cip1 expression was dependent on DNA damage but not on DNA demethylation as demonstrated by comet assay and bisulfite sequencing, respectively. Our data provide useful clues for judging the therapeutic efficacy of 5-azaCdR in the treatment of human cancer cells. [ABSTRACT FROM AUTHOR]

The magnetic properties of the mixed ferro-ferrimagnetic compounds with (AaBbCc)yD, in which A, B, C and D are four different magnetic ions and form four different sublattices, are studied by using the Ising model. And the Ising model was dealt with standard mean-field approximation. The regions of concentration in which two compensation points or one compensation point exit are given in c–a, b–c and a–b planes. The phase diagrams of the transition temperature Tc and compensation temperature Tcomp are obtained. The temperature dependences of the magnetization are also investigated. Some of the result can be used to explain the experimental work of the molecule-based ferro-ferrimagnet (NiIIaMnIIbFeIIc)1.5[CrIII(CN)6]·zH2O. [Copyright &y& Elsevier]

A spin-3/2 random-field Ising model with a crystal field on the honeycomb lattice is studied within the framework of the effective-field theory with correlations. We have investigated the effect of the crystal field on the phase diagrams, magnetizations, quadrupolar moments of the system. The phase diagram exhibits a rich variety of behaviors: the reentrant phenomena and the existence of tricritical points. [Copyright &y& Elsevier]

The method of the effective-field theory with self-spin correlations and the differential operator technique is used to study the magnetic properties of the spin-3/2 Ising model with biaxial crystal-field on the honeycomb lattice. The effects of a biaxial crystal-field described by two uniaxial anisotropy parameters Dx and Dy on the phase transition and specific heat and susceptibility are studied analytically and numerically. Some characteristic phenomena are found in the system such as tricritical behavior depending sensitively on the strength of the biaxial crystal-field. [Copyright &y& Elsevier]

A spin-3/2 random-field Ising model with a crystal field on the honeycomb lattice is studied within the framework of the effective-field theory with correlations. We have investigated the effect of the crystal field on the phase diagrams, magnetizations, quadrupolar moments of the system. The phase diagram exhibits a rich variety of behaviors: the reentrant phenomena and the existence of tricritical points. [Copyright &y& Elsevier]

DNA methylation in the promoter of certain genes is associated with transcriptional silencing. Methylation affects gene expression directly by interfering with transcription factor binding and/or indirectly by recruiting histone deacetylases through methyl-DNA-binding proteins. In this study, we demonstrate that the human lung cancer cell line H719 lacks p53-dependent and -independent-p21[sup Cip1] expression, p53 response to treatment with gamma irradiation or etoposide is lost due to a mutation at codon 242 of p53 (C→W). Treatment with depsipeptide, an inhibitor of histone deacetylase, was unable to induce p53-independent p21[sup Cip1] expression because the promoter of p21[sup Cip1] in these cells is hypermethylated. By analyzing luciferase activity of transfected p21[cup Cip1] promoter vectors, we demonstrate that depsipeptide functions on Sp1-binding sites to induce p21[sup Cip1] expression. We hypothesize that hypermethylation may interfere with Sp1/Sp3 binding. By using an electrophoretic mobility shift assay, we show that, although methylation within the consensus Sp1-binding site did not reduce Sp1/Sp3 binding, methylation outside of the consensus Sp1 element induced a significant decrease in Sp1/Sp3 binding. Depsipeptide induced p21[sup Cip1] expression was reconstituted when cells were pretreated with 5-aza-2'-deoxycytidine. Our data suggest, for the first time, that hypermethylation around the consensus Sp1-binding sites may directly reduce Sp1/Sp3 binding, therefore leading to a reduced p21[sup Cip1] expression in response to depsipeptide treatment. [ABSTRACT FROM AUTHOR]

Compensation points of layer system consisting of mixed spin-2 and spin-5/2 ferrimagnetic honeycomb lattice layers which are coupled together with two kinds of positive interlayer coupling are examined by the use of the effective-field theory with correlations (EFT). In particular, the effects of interlayer coupling and a positive crystal-field constant of the spin-2 ions on the compensation temperature are investigated, in order to clarify the characteristic behavior of the temperature dependence of the total magnetization M. This is related to the experimental works of a molecular-based magnetic multilayer film, N(n-C4H9)4FeIIFeIII(C2O4)3. A comparison is made between the results in this paper and those in a previous work obtained by using Monte-Carlo simulations. [Copyright &y& Elsevier]

Within the framework of the effective-field theory with correlations, the ferromagnetic spin-1 Ising model with biaxial crystal-field on honeycomb lattice is studied. The effects of the biaxial anisotropy parameters on the phase diagrams, tricritical points are investigated. The results show that the tricritical points and reentrant phenomena may appear in certain ranges of the two transverse crystal-field interactions. [Copyright &y& Elsevier]

Phase diagrams of a ferromagnetic or ferrimagnetic bilayer system consisting of two magnetic monolayers (A and B) with different spins (SA=1/2, and SB=1,3/2, and SB=1,3/2) and different interaction constants coupled together in a transverse crystal field are studied. Within the framework of the effective-field theory with correlations, the effects of the transverse crystal field in the monolayer B on the magnetic properties are investigated in detail for the square lattice. We have obtained some interesting results that may potentially be related to experimental work on rare-earth/transition-metal multilayer films. [Copyright &y& Elsevier]

In this paper, we study the electron properties of an Aharonov-Bohm interferometer with an embedded quantum dot (QD) by considering the leads of spin bias. As a result, it is found that a local magnetic flux through the structure can efficiently induce spin accumulation in the QD, unaccompanied by any charge transfer, and it shows that the direction and magnitude of the spin accumulation are tightly dependent on the interplay between the magnetic flux and spin bias. Based on the calculated results, we propose such a structure to be a candidate of the spin-manipulating device. [ABSTRACT FROM AUTHOR]

The article explores the connection between SMYD2 inhibition, impaired nonhomologous end joining repair, and antitumor immunity. It investigates the role of SMYD2, a methyltransferase, in DNA damage repair and its implications for tumor cells' response to radiotherapy. The findings suggest that targeting SMYD2 could be a promising approach in cancer treatment.

Six new compounds, including two depsidones garciculendepsidones A and B (1 and 2), one prenylated xanthone garciculenxanthone (3) and three dimeric xanthones bigarciculenxanthones A–C (4 – 6), were isolated from the twigs and leaves of Garcinia esculenta Y. H. Li. Their structures were elucidated based on comprehensive analyses of spectral data, including HRESIMS, 1D and 2D NMR, and ECD calculation. All the isolates were tested for their cytotoxicity against five human cancer cell lines (myeloid leukemia HL-60, lung cancer A-549 cells, hepatocellular carcinoma SMMC-7721, breast cancer MDA-MB-231 and colon cancer SW480), among them, compounds 3 – 5 displayed cytotoxic potential, especially garciculenxanthone (3) had the lowest IC 50 value of 8.2 μm for lung cancer A-549 cells. [Display omitted] [ABSTRACT FROM AUTHOR]

Highlights: [•] Three structurally unusual alkaloids were isolated from Daphniphyllum longeracemosum. [•] Their structures were determined by extensive spectroscopic analysis. [•] Hybridaphniphyllines A and B represent a hitherto unknown class of natural product hybrids. [•] Hybridaphniphyllines A and B were possibly generated via Diels–Alder cycloaddition. [Copyright &y& Elsevier]

Ataxia telangiectasia and Rad3 related (ATR) activation after replication stress involves a cascade of reactions, including replication protein A (RPA) complex loading onto single-stranded DNA and ATR activator loading onto chromatin. The contribution of histone modifications to ATR activation, however, is unclear. Here, we report that H3K14 trimethylation responds to replication stress by enhancing ATR activation. First, we confirmed that H3K14 monomethylation, dimethylation, and trimethylation all exist in mammalian cells, and that both SUV39H1 and SETD2 methyltransferases can catalyze H3K14 trimethylation in vivo and in vitro. Interestingly, SETD2-mediated H3K14 trimethylation markedly increases in response to replication stress induced with hydroxyurea, a replication stress inducer. Under these conditions, SETD2- mediated H3K14me3 recruited the RPA complex to chromatin via a direct interaction with RPA70. The increase in H3K14me3 levels was abolished, and RPA loading was attenuated when SETD2 was depleted or H3K14 was mutated. Rather, the cells were sensitive to replication stress such that the replication forks failed to restart, and cell-cycle progression was delayed. These findings help us understand how H3K14 trimethylation links replication stress with ATR activation. [ABSTRACT FROM AUTHOR]

Abstract: Six eudesmane-type sesquiterpene lactones, named chlorantholides A–F, were isolated from the ethanol extract of Chloranthus elatior (Chloranthaceae) together with 12 known compounds. Their structures were elucidated on the basis of extensive spectroscopic analysis, and their absolute configurations were studied by the CD exciton chirality method. The structure of a recently reported eudesmanolide from Chloranthus anhuiensis: 8β-hydroxy-1-oxoeudesma-3,7(11)-dien-12,8-olide, was also revised as 8β-hydroxy-2-oxoeudesma-3,7(11)-dien-12,8-olide (chlorantholide D). [Copyright &y& Elsevier]

Two new water-soluble Cr(III) complexes [Cr(IP)2Cl2]+ and [Cr(PIP)2Cl2]+ (IP = imidazo[4,5- f][1,10]phenanthroline, PIP = 2-phenylimidazo[4,5- f][1,10]phenanthroline) were synthesized and characterized by elemental analysis, mass spectra, and ultraviolet-visible spectra. The DNA-binding properties of the two complexes were investigated by spectroscopic methods and viscosity measurements. The results indicate that both complexes bind to DNA via an intercalative mode with moderate strength. The fluorescence intensity of both complexes decreases with increasing DNA concentration, similar to those of [Cr(phen)3]3+ and [Cr(bpy)3]3+. Also, both complexes can cleave pBR-322 DNA in the presence of H2O2, and [Cr(PIP)2Cl2]+ exhibits more effective activity than [Cr(IP)2Cl2]+ under the same condition. [ABSTRACT FROM AUTHOR]

The tumour suppressor ARF is specifically required for p53 activation under oncogenic stress. Recent studies showed that p53 activation mediated by ARF, but not that induced by DNA damage, acts as a major protection against tumorigenesis in vivo under certain biological settings, suggesting that the ARF–p53 axis has more fundamental functions in tumour suppression than originally thought. Because ARF is a very stable protein in most human cell lines, it has been widely assumed that ARF induction is mediated mainly at the transcriptional level and that activation of the ARF–p53 pathway by oncogenes is a much slower and largely irreversible process by comparison with p53 activation after DNA damage. Here we report that ARF is very unstable in normal human cells but that its degradation is inhibited in cancerous cells. Through biochemical purification, we identified a specific ubiquitin ligase for ARF and named it ULF. ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF. ULF knockdown stabilizes ARF in normal human cells, triggering ARF-dependent, p53-mediated growth arrest. Moreover, nucleophosmin (NPM) and c-Myc, both of which are commonly overexpressed in cancer cells, are capable of abrogating ULF-mediated ARF ubiquitylation through distinct mechanisms, and thereby promote ARF stabilization in cancer cells. These findings reveal the dynamic feature of the ARF–p53 pathway and suggest that transcription-independent mechanisms are critically involved in ARF regulation during responses to oncogenic stress. [ABSTRACT FROM AUTHOR]

Abstract: Magnetic properties of a biaxial spin system on the honeycomb and square lattice have been studied based on the effective-field theory with the differential operator technique. The effects of the external longitudinal magnetic field on the magnetization and susceptibility are discussed in detail. Numerical results are performed and analyzed for the cases spin-1, and 2. [Copyright &y& Elsevier]

Two hitherto unknown highly modified abietane diterpenoids, namely salviapritin A (1) and salviapritin B (2), were isolated from the ethanol extract of Salvia prionitis, together with 17 known compounds. Their chemical structures were established by extensive spectroscopic methods (ESIMS, HRESIMS, 1D and 2D NMR) and by comparison of their NMR data with those of related analogues. Salviapritin A is the first example of a trinorabietane diterpenoid possessing an acenaphthylene skeleton from the Salvia genus. Additionally, a plausible biogenetic pathway for salviapritin B is proposed. [ABSTRACT FROM AUTHOR]

Werner syndrome protein (WRN) plays critical roles in DNA replication, recombination, and repair, as well as transcription and cellular senescence. Ubiquitination and degradation of WRN have been reported, however, the E3 ubiquitin ligase of WRN is little known. Here, we identify mindbomb E3 ubiquitin protein ligase 1 (MIB1) as a novel E3 ubiquitin ligase for WRN protein. MIB1 physically interacts with WRN in vitro and in vivo and induces ubiquitination and degradation of WRN in the ubiquitin-proteasome pathway. Camptothecin (CPT) enhances the interaction between MIB1 and WRN, and promotes WRN degradation in a MIB1-dependent manner. In addition, CPT-induced cellular senescence is facilitated by the expression of MIB1 and attenuated by WRN expression. Our results show that MIB1-mediated degradation of WRN promotes cellular senescence and reveal a novel model executed by MIB1 and WRN to regulate cellular senescence. [ABSTRACT FROM AUTHOR]

By introducing local Rashba spin-orbit interaction in a three-terminal quantum dot ring, we calculate the currents induced by thermoelectric effect. It shows that, when a temperature bias is applied between the source and drains, there emerge apparent spin currents in the two drains. We find, via adjusting the structure parameters, that an electron from the source will choose its drain according to its spin index. Due to the advances in nanodevice fabrication, this structure can be constructed, and then we believe that it can be a candidate of the spin-manipulating device. [ABSTRACT FROM AUTHOR]

Tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) plays a critical role in regulating cell survival, cell growth, and proliferation by antagonizing the PI3K-AKT-mTOR pathway. The regulatory mechanism of PTEN protein is still not completely understood. Here, we found that Sirtuin 4 (SIRT4) interacts with PTEN and regulates its stability. Overexpression of SIRT4 in cells causes down-regulation of PTEN. This regulation is independent of PTEN acetylation and ubiquitination. We further found that SIRT4 degrades PTEN through lysosome pathway mediated by insulin degrading enzyme (IDE). SIRT4 bridges PTEN and IDE for degradation in response to nutritional starvation stresses. Our results suggest that when cells were exposed to nutritional starvation, SIRT4 was induced and cooperated with IDE to degrade PTEN; low levels of PTEN promote cells to survive from cellular stress. Our findings provide a new regulation of PTEN in response to cellular stresses. [ABSTRACT FROM AUTHOR]

The histone transmethylase complex comprising WD repeat domain 77 (WDR77) and protein arginine methyltransferase 5 (PRMT5) catalyzes dimethylation of H4R3 (H4R3me2) and drives cancer cell proliferation and migration, but its regulation is not fully understood. Here, we report that sirtuin 7 (SIRT7) directly deacetylates WDR77 and that this deacetylation interferes with the WDR77-PRMT5 interaction and suppresses proliferation of human colon cancer HCT116 cells. Using co-expression in HEK293T cells and co-immunoprecipitation assays, we observed that SIRT7 deacetylates WDR77 at Lys-3 and Lys- 243, which reduced of WDR77's interaction with PRMT5. More importantly, this reduction suppressed the transmethylase activity of the WDR77/PRMT5 complex, resulting in a reduction of the H4R3me2 modification. Rescue of the WDR77-KO HCT116 cells with a WDR77-2KR (K3R and K243R) variant yielded cell migration and proliferation rates that were significantly lower than those of WDR77-KO HCT116 cells rescued withWTWDR77. In summary, SIRT7 is a major deacetylase for WDR77, and SIRT7-mediated deacetylation of WDR77 at Lys-3 and Lys-243 weakens the WDR77-PRMT5 interaction and activity and thereby suppresses growth of cancer cells. [ABSTRACT FROM AUTHOR]

Sirtuin 7 (SIRT7), a member of the NAD+-dependent class III histone deacetylases, is involved in the regulation of various cellular processes and in resisting various stresses, such as hypoxia, low glucose levels, and DNA damage. Interestingly, SIRT7 is linked to the control of glycolysis, suggesting a role in glucose metabolism. Given the important roles of SIRT7, it is critical to clarify how SIRT7 activity is potentially regulated. It has been reported that some transcriptional and post-transcriptional regulatory mechanisms are involved. However, little is known how SIRT7 is regulated by the post-translational modifications. Here, we identified ubiquitin-specific peptidase 7 (USP7), adeubiquitinase, as a negative regulator of SIRT7. We showed that USP7 interacts with SIRT7 both in vitro and in vivo, and we further demonstrated that SIRT7 undergoes endogenous Lys-63-linked polyubiquitination, which is removed by USP7. Although the USP7-mediated deubiquitination of SIRT7 had no effect on its stability, the deubiquitination repressed its enzymatic activity. We also showed that USP7 coordinates with SIRT7 to regulate the expression of glucose-6-phosphatase catalytic subunit (G6PC), a gluconeogenic gene. USP7 depletion by RNA interference increased both G6PC expression and SIRT7 enzymatic activity. Moreover, SIRT7 targeted the G6PC promoter through the transcription factor ELK4 but not through forkhead box O1 (FoxO1). In summary, SIRT7 is a USP7 substrate and has a novel role as a regulator of gluconeogenesis. Our study may provide the basis for new clinical approaches to treat metabolic disorders related to glucose metabolism. [ABSTRACT FROM AUTHOR]

Histone methyltransferase G9a has critical roles in promoting cancer-cell growth and gene suppression, but whether it is also associated with the DNA damage response is rarely studied. Here, we report that loss of G9a impairs DNA damage repair and enhances the sensitivity of cancer cells to radiation and chemotherapeutics. In response to DNA double-strand breaks (DSBs), G9a is phosphorylated at serine 211 by casein kinase 2 (CK2) and recruited to chromatin. The chromatin-enriched G9a can then directly interact with replication protein A (RPA) and promote loading of the RPA and Rad51 recombinase to DSBs. This mechanism facilitates homologous recombination (HR) and cell survival. We confirmed the interaction between RPA and G9a to be critical for RPA foci formation and HR upon DNA damage. Collectively, our findings demonstrate a regulatory pathway based on CK2-G9a-RPA that permits HR in cancer cells and provide further rationale for the use of G9a inhibitors as a cancer therapeutic. [ABSTRACT FROM AUTHOR]

Background: Lysine-specific histone demethylase 1 (LSD1) modulates chromatin status through demethylation of H3K4 and H3K9. It has been demonstrated that LSD1 is hyperphosphorylated and dissociates from chromatin during mitosis. However, the molecular mechanism of LSD1 detachment is unknown. Results: In this report, we found that polo-like kinase 1 (PLK1) directly interacted with LSD1 and phosphorylated LSD1 at Ser-126 . Nocodazole-induced metaphase arrest promoted release of LSD1 from chromatin, and the phosphorylation- defective mutant LSD1 (S126A) failed to dissociate from chromatin upon nocodazole treatment. Conclusions: Taken together, our findings demonstrate that phosphorylation of LSD1 at Ser-126 by PLK1 promotes its release from chromatin during mitosis. [ABSTRACT FROM AUTHOR]

The serine/threonine kinase Unc-51-like kinase-1 (Ulk1) is thought to be essential for induction of autophagy, an intracellular bulk degradation process that is activated by various stresses. Although several proteins have been suggested as Ulk1 substrates during autophagic process, it still remains largely unknown about Ulk1's physiological substrates. Here, by performing in vitro and in vivo phosphorylation assay, we report that the co-chaperone cell division cycle protein 37 (Cdc37) is a Ulk1 substrate. Ulk1-mediated phosphorylation of Ser-339 in Cdc37 compromised the recruitment of client kinases to a complex comprising Cdc37 and heat shock protein 90 (Hsp90) but only modestly affected Cdc37 binding to Hsp90. Because the recruitment of protein kinase clients to the Hsp90 complex is essential for their stability and functions, Ser-339 phosphorylation of Cdc37 disrupts its ability as a co-chaperone to coordinate Hsp90. Hsp90 inhibitors are cancer chemotherapeutic agents by inducing depletion of clients, many of which are oncogenes. Upon treatment with an Hsp90 inhibitor in cancer cells, Ulk1 promoted the degradation of Hsp90-Cdc37 client kinases, resulting in increased cellular sensitivity to Hsp90 inhibitors. Thus, our study provides evidence for an anti-proliferative role of Ulk1 in response to Hsp90 inhibition in cancer cells. [ABSTRACT FROM AUTHOR]

β-Catenin, which is a key mediator of the wingless-integration site (Wnt)/β-catenin signaling pathway, plays an important role in cell proliferation, cell fate determination, and tumorigenesis, by regulating the expression of a wide range of target genes. Although a variety of posttranslational modifications are involved in β-catenin activity, the role of lysine methylation in β-catenin activity is largely unknown. In this study, su(var)3-9, enhancer-of-zeste, trithorax (SET) domain-containing protein 7 (SET7/9), a lysine methyltransferase, interacted with and methylated β-catenin, as demonstrated both in vitro and in vivo. The interaction and methylation were significantly enhanced in response to H2O2 stimulation. A mutagenesis assay and mass spectrometric analyses revealed that β-catenin was monomethylated by SET7/9 at lysine residue 180. Methylated β-catenin was easily recognized by phosphokinase glycogen synthase kinase (GSK)-3β for degradation. Consistent with this finding, the mutated β-catenin (K180R) that cannot be methylated exhibited a longer half-life than did the methylated β-catenin. The consequent depletion of SET7/9 by shRNA or the mutation of the β-catenin (K180R) significantly enhanced the expression of Wnt/β-catenin target genes such as c-myc and cyclin D1 and promoted the growth of cancer cells. Together, these results provide a novel mechanism by which Wnt/β-catenin signaling is regulated in response to oxidative stress. [ABSTRACT FROM AUTHOR]

The key member of the MOZ (monocyticleukaemia zinc finger protein), Ybf2/Sas3, Sas2, and TIP60 acetyltransferases family, Tat-interactive protein, 60 kD (TIP60), tightly modulates a wide array of cellular processes, including chromatin remodeling, gene transcription, apoptosis, DNA repair, and cell cycle arrest. The function of TIP60 can be regulated by SIRT1 through deacetylation. Here we found that TIP60 can also be functionally regulated by HDAC3. We identified six lysine residues as its autoacetylation sites. Mutagenesis of these lysines to arginines completely abolishes the autoacetylation of TIP60. Overexpression of HDAC3 increases TIP60 ubiquitination levels. However, unlike SIRT1, HDAC3 increased the half-life of TIP60. Further study found that HDAC3 colocalized with TIP60 both in the nucleus and the cytoplasm, which could be the reason why HDAC3 can stabilize TIP60. The deacetylation of TIP60 by both SIRT1 and HDAC3 reduces apoptosis induced by DNA damage. Knockdown of HDAC3 in cells increased TIP60 acetylation levels and increased apoptosis after DNA damage. Together, our findings provide a better understanding of TIP60 regulation mechanisms, which is a significant basis for further studies of its cellular functions. [ABSTRACT FROM AUTHOR]

In mammalian cells, tumor suppressor p53 plays critical roles in the regulation of glucose metabolism, including glycolysis and oxidative phosphorylation, but whether and how p53 also regulates gluconeogenesis is less clear. Here, we report that p53 efficiently down-regulates the expression of phosphoenolpyruvate carboxy-kinase (PCK1) and glucose-6-phosphatase (G6PC), which encode rate-limiting enzymes in gluconeogenesis. Cell-based assays demonstrate the p53-dependent nuclear exclusion of forkhead box protein 01 (FoxOI), a key transcription factor that mediates activation of PCK1 and G6PC, with consequent alleviation of Fox01-dependent gluconeogenesis. Further mechanistic studies show that p53 directly activates expression of the NAD+-dependent histone deacetylase sirtuin 6 (SIRT6), whose interaction with Fox01 leads to Fox01 deacetylation and export to the cytoplasm. In support of these observations, p53-mediated Fox01 nuclear exclusion, down-regulation of PCK1 and G6PC expression, and regulation of glucose levels were confirmed in C57BL/J6 mice and in liver-specific Sirt6 conditional knockout mice. Our results provide insights into mechanisms of metabolism-related p53 functions that may be relevant to tumor suppression. [ABSTRACT FROM AUTHOR]

Phytochemical investigation of Lycopodium cernuum L. afforded seven undescribed serratene triterpenoids named 3 β, 21 β- dihydroxyserra-14-en-24-oic acid-3 β- (5′-hydroxybenzoate) (1), 3 β, 21 β , 24-trihydroxyserrat-14-en-3 β -(5′-hydroxyl benzoate) (2), 3 β , 14 α , 15 α , 21 β -tetrahydroxyserratane-24-methyl ester (3), 3 β , 14 α , 21 β -trihydroxyserratane-15 α -(4′-methoxy-5′-hydroxybenzoate)-24-methyl ester (4), 3 β , 14 α , 21 β -trihydroxyserratane-15 α -(4′-methoxy-5′-hydroxybenzoate) (5), 3 β -hydroxy-21 β -acetate-16-oxoserrat-14-en-24-oic acid (6), 3 β , 21 β -dihydroxy-16 α , 29-epoxyserrat-14-en-24-methyl ester (7), together with eleven known compounds (8 – 18), whose chemical structures were elucidated through spectroscopic analysis of HRESIMS, 1D NMR, 2D NMR and comparison between the literature. All compounds were evaluated for their α -glucosidase inhibitory activity for the first time. The results showed that compounds 1 , 2 , 4 , 5 , 6 , 10 , 13 , 15 , and 16 were among the most potent α-glucosidase inhibitors, with IC 50 values ranging from 23.22 ± 0.64 to 50.65 ± 0.82 μM. Structure – activity relationship (SAR) studies indicated that the combined properties of the 5-hydroxybenzoate moiety at C-3, β -OH at C-21, COOH- at C-24, and Δ14,15 groups enabled an increase in the α-glucosidase inhibitory effect. In addition, molecular docking studies showed that the potential inhibitors mainly interact with key amino acid residues in the active site of α -glucosidase through hydrogen bonds and hydrophobic forces. [Display omitted] • Seven undescribed serratene swere isolated from Lycopodium cernnum L. • Nine compounds showed significant inhibition against α-glucosidase for the first time. • The structure-activity relationship has been established. • The molecular docking studies of potential inhibitors were performed. [ABSTRACT FROM AUTHOR]

Suppressor of variegation 3-9 homolog 1 (SUV39H1), a histone methyltransferase, catalyzes histone 3 lysine 9 trimethylation and is involved in heterochromatin organization and genome stability. However, the mechanism for regulation of the enzymatic activity of SUV39H1 in cancer cells is not yet well known. In this study, we identified SET domain-containing protein 7 (SET7/9), a protein methyltransferase, as a unique regulator of SUV39H1 activity. In response to treatment with adriamycin, a DNA damage inducer, SET7/9 interacted with SUV39H1 in vivo, and a GST pull-down assay confirmed that the chromodomain-containing region of SUV39H1 bound to SET7/9. Western blot using antibodies specific for antimethylated SUV39H1 and mass spectrometry demonstrated that SUV39H1 was specifically methylated at lysines 105 and 123 by SET7/9. Although the half-life and localization of methylated SUV39H1 were not noticeably changed, the methyltransferase activity of SUV39H1 was dramatically down-regulated when SUV39H1 was methylated by SET7/ 9. Consequently, H3K9 trimethylation in the heterochromatin decreased significantly, which, in turn, led to a significant increase in the expression of satellite 2 (Sat2) and α-satellite (α-Sat), indicators of heterochromatin relaxation. Furthermore, a micrococcal nuclease sensitivity assay and an immunofluorescence assay demonstrated that methylation of SUV39H1 facilitated genome instability and ultimately inhibited cell proliferation. Together, our data reveal a unique interplay between SET7/9 and SUV39H1-two histone methyltransferases-that results in heterochromatin relaxation and genome instability in response to DNA damage in cancer cells. [ABSTRACT FROM AUTHOR]

Adiponectin, an abundant adipose tissue-derived protein, exerts protective effect against cardiovascular disease. Adiponectin receptors (AdipoR1 and AdipoR2) mediate the beneficial effects of adiponectin on the cardiovascular system. However, the alteration of AdipoRs in cardiac remodeling is not fully elucidated. Here, we investigated the effect of angiotensin II (AngII) on cardiac AdipoRs expression and explored the possible molecular mechanism. AngII infusion into rats induced cardiac hypertrophy, reduced AdipoR1 but not AdipoR2 expression, and attenuated the phosphorylations of adenosine monophosphate-activated protein kinase and acetyl coenzyme A carboxylase, and those effects were all reversed by losartan, an AngII type 1 (AT1) receptor blocker. AngII reduced expression of AdipoR1 mRNA and protein in cultured neonatal rat cardiomyocytes, which was abolished by losartan, but not by PD123319, an AT2 receptor antagonist. The antioxidants including reactive oxygen species (ROS) scavenger NAC, NADPH oxidase inhibitor apocynin, Nox2 inhibitor peptide gp91 ds-tat, and mitochondrial electron transport chain complex I inhibitor rotenone attenuated AngII-induced production of ROS and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. AngII-reduced AdipoR1 expression was reversed by pretreatment with NAC, apocynin, gp91 ds-tat, rotenone, and an ERK1/2 inhibitor PD98059. Chromatin immunoprecipitation assay demonstrated that AngII provoked the recruitment of c-Myc onto the promoter region of AdipoR1, which was attenuated by PD98059. Moreover, AngII-induced DNA binding activity of c-Myc was inhibited by losartan, NAC, apocynin, gp91 ds-tat, rotenone, and PD98059. c-Myc small interfering RNA abolished the inhibitory effect of AngII on AdipoR1 expression. Our results suggest that AngII inhibits cardiac AdipoR1 expression in vivo and in vitro and AT1 receptor/ROS/ERK1/2/c-Myc pathway is required for the downregulation of AdipoR1 induced by AngII. [ABSTRACT FROM AUTHOR]

The retinoblastoma protein (pRb) and the related proteins Rb2/p130 and 107 represent the "pocket protein" family of cell cycle regulators. A key function of these proteins is the cell cycle dependent modulation of E2F-regulated genes. The biological activity of these proteins is controlled by acetylation and phosphorylation in a cell cycle dependent manner. In this study we attempted to investigate the interdependence of acetylation and phosphorylation of Rb2/p130 in vitro. After having identified the acetyltransferase p300 among several acetyltransferases to be associated with Rb2/p130 during S-phase in NIH3T3 cells in vivo, we used this enzyme and the CDK4 protein kinase for in vitro modification of a variety of full length Rb2/p130 and truncated versions with mutations in the acetylatable lysine residues 1079, 128 and 130. Mutation of these residues results in the complete loss of Rb2/p130 acetylation. Replacement of lysines by arginines strongly inhibits phosphorylation of Rb2/p130 by CDK4; the inhibitory effect of replacement by glutamines is less pronounced. Preacetylation of Rb2/p130 strongly enhances CDK4-catalyzed phosphorylation, whereas deacetylation completely abolishes in vitro phosphorylation. In contrast, phosphorylation completely inhibits acetylation of Rb2/p130 by p300. These results suggest a mutual interdependence of modifications in a way that acetylation primes Rb2/p130 for phosphorylation and only dephosphorylated Rb2/p130 can be subject to acetylation. Human papillomavirus 16-E7 protein, which increases acetylation of Rb2/p130 by p300 strongly reduces phosphorylation of this protein by CDK4. This suggests that the balance between phosphorylation and acetylation of Rb2/p130 is essential for its biological function in cell cycle control. [ABSTRACT FROM AUTHOR]

Mapping DNase I hypersensitive sites (DHSs) within nuclear chromatin is a traditional and powerful method of identifying genetic regulatory elements. DHSs have been mapped by capturing the ends of long DNase I-cut fragments (>100,000 bp), or 100-1200 bp DNase I-double cleavage fragments (also called double-hit fragments). But next generation sequencing requires a DNA library containing DNA fragments of 100-500 bp. Therefore, we used short DNA fragments released by DNase I digestion to generate DNA libraries for next generation sequencing. The short segments are 100-300 bp and can be directly cloned and used for high- throughput sequencing. We identified 83,897 DHSs in 2,343,479 tags across the human genome. Our results indicate that the DHSs identified by this DHS assay are consistent with those identified by longer fragments in previous studies. We also found: (1) the distribution of DHSs in promoter and other gene regions of similarly expressed genes differs among different chromosomes; (2) silenced genes had a more open chromatin structure than previously thought; (3) DHSs in 3'untranslated regions (3'UTRs) are negatively correlated with level of gene expression. [ABSTRACT FROM AUTHOR]

Two new xanthones, angustins A and B (1 and 2), were isolated from the aerial parts of Swertia angustifolia together with six known compounds (3–8). The structures of these two xanthones were elucidated by extensive analysis of the spectroscopic data. In addition, compounds 3 and 6–8 were isolated from this plant for the first time. [ABSTRACT FROM PUBLISHER]

Not only does 5-aza-2'-deoxycytidine (5-aza-CdR) induce the reexpression of silenced genes through the demethylation of CpG islands, but it increases the expression of unmethylated genes. However, the mechanism by which 5-aza-CdR activates the expression of genes is not completely understood. Here, we report that the pRb pocket proteins pRb, p107, and p130 were degraded in various cancer cell lines in response to 5-aza-CdR treatment, and this effect was dependent on the proteasome pathway. Mouse double minute 2 (MDM2) played a critical role in this 5-aza-CdR-induced degradation of pRb. Furthermore, PP2A phosphatase-induced MDM2 dephosphorylation at S260 was found to be essential for MDM2 binding to pRb in the presence of 5-aza-CdR. pRb degradation resulted in the significant reexpression of several genes, including methylated CDKN2A, RASFF1A, and unmethylated CDKN2D. Finally, knockdown of pRb pocket proteins by either RNAi or 5-aza-CdR treatment induced a significant decrease in the recruitment of SUV39H1 and an increase in the enrichment of KDM3B and KDM4A to histones around the promoter of RASFF1A and thus reduced H3K9 di- and trimethylation, by which RASFF1A expression is activated. Our data reveal a novel mechanism by which 5-aza-CdR induces the expression of both methylated and unmethylated genes by degrading pRb pocket proteins. [ABSTRACT FROM AUTHOR]

POEMS syndrome is a rare clonal plasma cell disorder without standard treatment. Based on the efficacy and low toxicity of a combination of melphalan and dexamethasone (MDex) for light chain amyloidosis, we conducted a prospective study of MDex treatment for patients with newly diagnosed POEMS syndrome. Thirty-one patients (19 men) were enrolled and the median age at the time of diagnosis was 44 years (range, 32-68 years). All patients received 12 cycles of MDex treatment. Twenty-five patients (80.6%) achieved hematologic response including 12 (38.7%) complete remission and 13 (41.9%) partial remission. Of all 31 patients, the neurologic response rate was 100%, assessed by overall neuropathy limitation scale (ONLS). The initial neurologic response was observed in 24 patients (77.4%) at 3 months after treatment and the median time to maximal neurologic response was 12 months (range, 3-15 months). Moreover, MDex substantially improved the level of serum vascular endothelial growth factor and relieved organomegaly, extravascular volume overload, and pulmonary hypertension. Only 6 patients (19.3%) suffered from grade 3 adverse events during treatment. All patients are alive and free of neurologic relapse after the median follow-up time of 21 months. Therefore, MDex is an effective and well-tolerated treatment option for patients with newly diagnosed POEMS syndrome. [ABSTRACT FROM AUTHOR]

Numerous studies indicate that Sirtuin 1 (SIRT1), a mammalian nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase (HDAC), plays a crucial role in p53-mediated stress responses by deacetylating p53. Nevertheless, the acetylation levels of p53 are dramatically increased upon DNA damage, and it is not well understood how the SIRT1-p53 interaction is regulated during the stress responses. Here, we identified Set7/9 as a unique regulator of SIRT1. SIRT1 interacts with Set7/9 both in vitro and in vivo. In response to DNA damage in human cells, the interaction between Set7/9 and SIRT1 is significantly enhanced and coincident with an increase in p53 acetylation levels. Importantly, the interaction of SIRT1 and p53 is strongly suppressed in the presence of Set7/9. Consequently, SIRT1-mediated deacetylation of p53 is abrogated by Set7/9, and p53-mediated transactivation is increased during the DNA damage response. Of note, whereas SIRT1 can be methylated at multiple sites within its N terminus by Set7/9, a methylation-defective mutant of SIRT1 still retains its ability to inhibit p53 activity. Taken together, our results reveal that Set7/9 is a critical regulator of the SIRT1-p53 interaction and suggest that Set7/9 can modulate p53 function indirectly in addition to acting through a methylation-dependent mechanism. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2010; 40 (8): 669–677 Background A mutation in MEF2A (myocyte enhancer factor-2A) had been reported to be the first gene linked directly to coronary artery disease (CAD). However, an opposing opinion was proposed recently that MEF2A mutations are not a common cause of sporadic CAD. In this study, we screened exon 11 of the MEF2A gene in people of the Han nationality in China and finished some functional analysis of found variations. Materials and methods A gene structural investigation of MEF2A in 257 CAD patients and 154 control individuals were developed in this study. Subsequently, typical MEF2A variations were cloned and expressed in HeLa or 293T cell line to illustrate whether found structure changes could influence the main biological functions of these proteins. At last, another set of gene structural screen was initialized to get more reliable conclusions. Results Totally 16 different variations were detected in exon 11 of this gene in the first set of gene structural screen. By cloning and expressing typical MEF2A proteins in cultured cells, all the acquired MEF2A variations had transcriptional activation capabilities and subcellular localization patterns similar to those of the wild-type protein. Further larger scale genetic screening also revealed that the reported genetic variations of MEF2A did not differ significantly between CAD patients and healthy controls. Conclusions Our results reveal that structural changes of exon 11 in MEF2A are not involved in sporadic CAD in the Han population of China. [ABSTRACT FROM AUTHOR]