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Myxobacteria are renowned for their genuine prowess to deliver multifarious bioactive natural products. Genome mining ofMyxococcussp. SDU36 identified a hybrid PKS-NRPS BGC (mpd) that presumably specified previously uncharacterized molecules. The expression ofmpdwas activated by exchanging the innate promoter of core PKS-NRPS genes with our recently characterized strong constitutive promoter BBa_J23104. Comparative metabolic profiling allowed facile isolation of the elicited compounds1–5designated myxopyromides A–E, a group of structurally related polyketidic amides. Especially, myxopyromides D was appended with an uncommon pyrrolinone warhead at the carboxylic terminus, whereas myxopyromide C was instead decorated with a rare structural unit of aminobutanone. Although myxopyromides basically follow a textbook modular PKS-NRPS biosynthetic trajectory, an anteriorly unappreciated flexible chain release strategy is adopted to enrich the chemical repertoire ofmpdBGC. Interestingly, myxopyromides were associated with the predation ofMyxococcussp. SDU36.Abstract Figure

Two pairs of diastereoisomeric isoindoline alkaloids, xylarins A-D (1-4), were isolated from the endolichenic fungus Xylaria sp. Xylarins A and B (1 and 2) possess a previously undescribed 5/6/5-5/6 polycyclic scaffold, featuring a combination of a novel dihydrobenzofurone unit and an isoindoline unit, while xylarins C and D (3 and 4) contain an additional N,N-dimethylaniline at the C-3' position. Their structures were elucidated by comprehensive spectroscopic analyses combined with single-crystal X-ray diffraction and electronic circular dichroism calculations. The plausible biosynthetic pathways and gene clusters for 1-4 were proposed. Compound 1 exhibited significant antithrombotic activity.

Background: The hypothalamic paraventricular nucleus (PVN) is an important nucleus in the brain that plays a key role in regulating sympathetic nerve activity (SNA) and blood pressure. Silent mating-type information regulation 2 homolog-1 (sirtuin1, SIRT1) not only protects cardiovascular function but also reduces inflammation and oxidative stress in the periphery. However, its role in the central regulation of hypertension remains unknown. It is hypothesized that SIRT1 activation by resveratrol may reduce SNA and lower blood pressure through the regulation of intracellular reactive oxygen species (ROS) and neurotransmitters in the PVN. Methods: The two-kidney one-clip (2K1C) method was used to induce renovascular hypertension in male Sprague-Dawley rats. Then, bilaterally injections of vehicle (artificial cerebrospinal fluid, aCSF, 0.4 μL) or resveratrol (a SIRT1 agonist, 160 μmol/L, 0.4 μL) into rat PVN were performed for four weeks. Results: PVN SIRT1 expression was lower in the hypertension group than the sham surgery (SHAM) group. Activated SIRT1 within the PVN lowered systolic blood pressure and plasma norepinephrine (NE) levels. It was found that PVN of 2K1C animals injected with resveratrol exhibited increased expression of SIRT1, copper-zinc superoxide dismutase (SOD1), and glutamic acid decarboxylase (GAD67), as well as decreased activity of nuclear factor-kappa B (NF-κB) p65 and NAD(P)H oxidase (NOX), particularly NOX4. Treatment with resveratrol also decreased expression of ROS and tyrosine hydroxylase (TH). Conclusion: Resveratrol within the PVN attenuates hypertension via the SIRT1/NF-κB pathway to decrease ROS and restore the balance of excitatory and inhibitory neurotransmitters.

Background: Aerobic exercise training (ExT) is beneficial for hypertension, however, its central mechanisms in improving hypertension remain unclear. Since the importance of the up-regulation of angiotensin II type 1 receptor (AT-1R) in the paraventricular nucleus (PVN) of the hypothalamic in sympathoexcitation and hypertension has been shown, we testified the hypothesis that aerobic ExT decreases blood pressure in hypertensive rats by down-regulating the AT-1R through reactive oxygen species (ROS)/mitogen-activated protein kinase (MAPK)/nuclear factors κB (NF-κB) pathway within the PVN. Methods: Forty-eight male Sprague-Dawley (SD) rats were assigned to the following groups: sham operation (SHAM) + kept sedentary (Sed), SHAM + exercise training (ExT), two kidney-one clamp (2K1C) + Sed, and 2K1C + ExT groups. Results: The 2K1C + Sed hypertensive rats showed higher systolic blood pressure (SBP), upregulated ROS, phosphorylated (p-) p44/42 MAPK, p-p38 MAPK, NF-κB p65 activity, and AT-1R expression in the PVN, and increased circulating norepinephrine (NE) than those of SHAM rats. After eight weeks of aerobic ExT, the 2K1C + ExT hypertensive rats showed attenuated NE and SBP levels, suppressed NF-κB p65 activity, and reduced expression of ROS, p-p44/42 MAPK, p-p38 MAPK, and AT-1R in the PVN, relatively to the 2K1C + Sed group. Conclusions: These data are suggestive of beneficial effects of aerobic ExT in decreasing SBP in hypertensive rats, via down-regulating the ROS/MAPK/NF-κB pathway that targets AT-1R in the PVN, and eventually ameliorating 2K1C-induced hypertension.

Jing Liu,1,* Shimei Huang,2,* Xin Liao,1 Zhongsheng Chen,3 Lianghe Li,3 Lei Yu,4 Wei Zhan,5 Rui Li6 1Imaging Department, Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 2Forensic Clinical Teaching and Research Office, Guizhou Medical University, Guiyang, People’s Republic of China; 3Surgery, Guizhou Medical University, Guiyang, People’s Republic of China; 4Department of Pathology, Guiyang Maternal and Child Health Hospital, Guiyang, People’s Republic of China; 5General Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 6Department of Traditional Chinese Medicine, Guizhou Provincial People’s Hospital, Guiyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rui LiDepartment of Traditional Chinese Medicine, Guizhou Provincial People’s Hospital, Zhongshan East Road 83, Guiyang 550002, People’s Republic of ChinaEmail ruilidoctor@126.comBackground: Ewing sarcoma-associated transcript 1 (EWSAT1) has been reported to be a pivotal modulator in a series of cancers. However, the function of EWSAT1 in colorectal cancer (CRC) has not been elaborated. This study aimed to explore the role of EWSAT1 in CRC progression and the underlying mechanisms.Methods: The expression patterns of EWSAT1, miR-326 and FBXL20 were examined by qCRCR. Si-EWSAT1 was transfected to study the effects of EWSAT1 on cell proliferation and metastasis. Rescue experiments were performed to investigate the underlying mechanisms in vitro. Xenograft models were used to evaluate the role of EWSAT1 in vivo.Results: We found that EWSAT1 was highly expressed in CRC tissues and cell lines and associated with poor overall survival. In vitro, knockdown of EWSAT1 suppressed the cell proliferation, migration and invasion. Moreover, miR-326 was found to be a target of EWSAT1, and miR-326 inhibitor could partially reverse the effects on CRC cell progression induced by si-EWSAT1. Subsequently, we validated FBXL20 as a vital downstream target for miR-326, and EWSAT1 positively regulated FBXL20 via miR-326 in vitro. In addition, these findings were confirmed by in vivo experiments.Conclusion: Taken together, the data showed that EWSAT1 promoted CRC progression via targeting miR-326/FBXL20 pathway, which might provide a novel therapeutic target for CRC treatment.Keywords: lncRNA EWSAT1, colorectal cancer, CRC, miR-326, FBXL20

In 2006, Sullivan stated the conjectures: (1) every oriented graph has a vertex x such that d++(x) ≥ d−(x); (2) every oriented graph has a vertex x such that d++(x)+d+(x) ≥ 2d− (x); (3) every oriented graph has a vertex x such that d++(x) + d+(x) ≥ 2 · min{d+(x), d− (x)}. A vertex x in D satisfying Conjecture (i) is called a Sullivan-i vertex, i = 1, 2, 3. A digraph D is called quasi-transitive if for every pair xy, yz of arcs between distinct vertices x, y, z, xz or zx (“or” is inclusive here) is in D. In this paper, we prove that the conjectures hold for quasi-transitive oriented graphs, which is a superclass of tournaments and transitive acyclic digraphs. Furthermore, we show that a quasi-transitive oriented graph with no vertex of in-degree zero has at least three Sullivan-1 vertices and a quasi-transitive oriented graph has at least three Sullivan-3 vertices unless it belongs to an exceptional class of quasi-transitive oriented graphs. For Sullivan-2 vertices, we show that an extended tournament, a subclass of quasi-transitive oriented graphs and a superclass of tournaments, has at least two Sullivan-2 vertices unless it belongs to an exceptional class of extended tournaments.

To detect the expression of CRLF2 in bone marrow mononuclear cells from children with newly diagnosed acute lymphoblastic leukemia(ALL) and to explore its clinical significance in pediatric ALL.A total of 218 children with newly diagnosed ALL who achieveal the complete remission and had the complete follow-up information were selected, and the expression level of CRLF2 in bone marrow mononuclear cells of these children was detected by real-time fluorescent quantitative PCR, and the significance of CRLF2 expression level in clinical prognosis of ALL children was analyzed by using statistical method.28 cases in 218 children with complete data showed high expression of CRLF2. The cumulative recurrence rate in the CRLF2 high expression group was significantly higher than that in the low expression group (53.6% vs 12.6%) (P＜0.01). The predicted 5-year recurrence-free survival rate (RFS) of ALL children with CRLF2 high expression was significantly higher than that of low expression group (P＜0.01). There was no significant difference in the predicted 5-year RFS between ALL children with CRLF2 low and high expression in the standard-risk(SR) group (P＞0.05). The predicted 5-year RFS of ALL children with CRLF2 low expression was higher than that of ALL children with CRLF2 high expression in the intermediate-risk (IR) and high-risk (HR) groups. (P＜0.05). Cox analysis showed that CRLF2 high expression is an independent risk factor for the relapse of children with ALL.The recurrence rate of pediatric ALL with CRLF2 high expression is high, and CRLF2 high expression is an important prognostic factor for high risk of relapse in ALL children with IR and HR. It is necessary to use CRLF2 expression as an indicator of risk stratification in pediatric ALL.急性淋巴细胞白血病儿童骨髓单个核细胞CRLF2 高表达的临床意义.检测初诊急性淋巴细胞白血病（ALL）儿童的骨髓单个核细胞CRLF2 表达水平，并探讨其在儿童ALL中的临床意义.对第一疗程化疗获得完全缓解且有完整随访信息的218例初诊ALL儿童，采用实时荧光定量PCR 方法检测骨髓单个核细胞CRLF2 表达水平；分析CRLF2 表达水平在ALL儿童临床预后中的意义.有完整资料的218例儿童ALL中有28例CRLF2 高表达。CRLF2高表达组累计复发率明显高于低表达组（53.6％vs 12.6％）（P＜0.01），CRLF2 高表达组预计5年无复发生存率明显高于低表达组（P＜0.01）。标危组中的CRLF2高表达和低表达患儿预计5年无复发生存率的差异无统计学意义（P＞0.05），中危组和高危组中CRLF2低表达的患儿预计5年无复发生存率均高于高表达组的儿童（P＜0.05）。Cox法分析显示，CRLF2高表达是影响ALL儿童复发的独立危险因素.CRLF2高表达的ALL儿童复发率高，CRLF2高表达是中高危ALL儿童复发高风险的重要预后因素。有必要将CRLF2表达水平作为ALL儿童的危险分层的指标.

Numerous studies implicated the relationship between the sinus node dysfunction (SND) and atrial arrhythmias, but the pacemaker activities of sinoatrial node (SAN) during the atrial reentry before ...

Chemical and antioxidant responses of the water-deficit tolerant Chinese liverwort, Plagiochasma appendiculatum, to water-deficit stress were investigated in this study. The results showed that water-deficit stress could increase the accumulation of the main bisbibenzyl, riccardin D (RD), and the level of the expression of genes related to production of RD. Activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), soluble protein and malondialdehyde (MDA) content could be used as indicators of the degree of damage to plants under different water-deficit stresses. Among these indicators, SOD played a significant role in defense against water stress when humidity is higher than 40 ± 5% RH (relative humidity), while the activities of POD and CAT were inhibited. However, when humidity is lower than 40 ± 5% RH, POD and CAT activities were accelerated, and if water-deficit reached serious levels (≤ 20 ± 5% RH), POD activity was inhibited, while CAT activity was long-lasting and enhanc...

Five new α-pyrone derivatives, necpyrones A–E (1–5), together with seven known compounds (6–12), were isolated from the extract of an endolichenic fungus Nectria sp. Chemical structures of these compounds were elucidated by spectroscopic analyses (HRESIMS and NMR). The absolute configurations of C-6 in the pyrone ring as well as the chiral carbons at the aliphatic side chain resulted from hydroxyl substitute were finally determined on the basis of measurement of ECD and Kusumi–Mosher method.

Many exceptional labdane-type diterpenoids have been exclusively found in liverworts, which serve as taxonomic molecules or play important ecological roles in interactions among organisms. Three unprecedented labdane-type diterpenoids hapmnioides A (1), B (2), and C (3) formed through cascade rearrangement from the Chinese liverwort Haplomitrium mnioides are reported. Their structures were established by comprehensive spectroscopic analysis coupled with single-crystal X-ray diffraction, and their anti-inflammatory activities were also preliminarily tested.

Human umbilical cord mesenchymal stem cells (hUC-MSCs) are potential stromal cells which are regarded as the most feasible stem cell group in cell therapy. The maintenance of cell survival without differentiation is important in cell transplantation and stem cell therapy. However, negative factors exist in cell transplantation. Lysophosphatidic acid (LPA) is a non-antigenic small molecule phospholipid which induced several fundamental cellular responses, such as cell proliferation, apoptosis and migration. In this study we aimed to explore the effects of LPA on the survival and differentiation of MSCs and its availability in cell therapy. We found that LPA stimulated hUC-MSC proliferation and protected hUC-MSCs from lipopolysaccharide (LPS) induced apoptosis. We also observed that CD29, CD44, CD73, CD90 and CD105 were expressed, whereas CD34 and CD45 were not expressed in hUC-MSCs, and these makers have no change in LPA containing medium, which indicated that LPA accelerated the survival of hUC-MSCs in an undifferentiating status. We also demonstrated that higher expressed LPAR1 involved in LPA stimulated cell survival action. LPA stimulated cell proliferation was associated with LPAR1 mediated Gi/o-proteins/ERK1/2 pathway. On the other hand, LPA protected hUC-MSCs from LPS-induced apoptosis through suppressing caspase-3 activation by LPAR1 coupled with a G protein, but not Gi/o or Gq/11 in hUC-MSC. Collectively, this study demonstrated that LPA increased the proliferation and survival of hUC-MSCs without differentiation through LPAR1 mediated manner. Our findings provide that LPA as a anti-apoptotic agent having potential application prospect in cell transplantation and stem cell therapy. Electronic supplementary material The online version of this article (doi:10.1007/s10495-017-1399-6) contains supplementary material, which is available to authorized users.

To investigate the effect of icaritin on the proliferation and apoptosis of THP-1 cells and its mechanism.After treated with various concentrations of icaritin, cell proliferation was detected by MTS method, and apoptosis was measured with flow cytometry and Hoechst 33258 staining. Expression of BCL-2, BAX and Caspase-3 protein in THP-1 cell was detected by Western blot.After treatment with various concentrations (4-32 µmol/L) of icaritin for 24, 48, 72 h, the inhibition rate of cell growth significantly increased (P0.05) in time-dose dependent manner(r=0.946); and the apoptotic rate of cells significantly increased (P0.05) in time-dose dependent manner(r= 0.924). The expression of BCL-2 protein at 48 h decreased significantly in icaritin-treated group, compared with that in control group (P0.05), while the expression of BAX and Caspase3 protein at 48 h increased significantly in icaritin-treated group, compared with that in control group (P0.05).Icaritin can inhibit proliferation and induce apoptosis of THP-1 in vitro, Icaritin may induce apoptosis in THP-1 cells through the mitochondrial pathway.

Five cis-clerodane diterpenoids, stephanialides A−E, along with seven known cis-clerodanes, scaparvins A−C, parvitexins B and C, 3-chloro-4-hydroxy-parvitexin A, and scapanialide B, were isolated from the Chinese liverwort Scapania stephanii. Their structures were established unequivocally on the basis of spectroscopic data. The absolute configuration of stephanialide A was determined by analysis of CD data using the octant rule. Phytotoxic activity evaluation showed that this type of diterpenoids can significantly inhibit root elongation of the seeds of Arabidopsis thaliana, Lepidium sativum and Brassica pekinensis.

p21-Activated kinase 4 (PAK4) is a serine/threonine protein kinase that plays important roles in a wide variety of human diseases including cancer. Targeting this kinase with specific inhibitors is of great interest in the treatment of cancer. In this study, PAK4 and its interaction with ATP-competitive inhibitors was investigated by a combined ligand- and structure-based approach. First, a ligand-based pharmacophore model was generated, consisting of five chemical features: a positive ionizable center, two hydrophobic groups, a hydrogen bond donor, and a hydrogen bond acceptor, which is consistent with available SAR information. The characteristics of the active site were then described as a topological region and used in docking of nine selected inhibitors. Combination of the pharmacophore model and results from the docking studies allowed us to weigh the various pharmacophore features and to identify the positive ionizable center as a spacer rather than an essential point. This research led to the proposal of an interaction model inside the PAK4 active site and provided guidance for the design of more potent PAK4 inhibitors.

Sixteen new clerodane diterpenoids, cephaloziellins A-P (1-16), and two known analogues (17 and 18) were isolated from an EtOH extract of the Chinese liverwort Cephaloziella kiaeri. The structures of the new compounds were elucidated from extensive spectroscopic data (IR, UV, HRESIMS, 1D NMR, and 2D NMR), and the structures of 5, 9, and 15 were confirmed by single-crystal X-ray diffraction analyses. The absolute configurations of all new compounds were established by comparing experimental and calculated electronic circular dichroism spectra.

Three new xanthone derivatives, including two first reported containing sulfur as natural products: sydoxanthone A ( 1 ) and sydoxanthone B ( 2 ), and 13- O -acetylsydowinin B ( 3 ) were isolated from an endophytic fungus Aspergillus sydowii , occurring in the livewort Scapania ciliata S. Lac, together with seven known biosynthetically related compounds ( 4–10 ). Their structures were established primarily by NMR, UV and MS data. In vitro suppression test on the Con A- and LPS-induced proliferations of mouse splenic lymphocytes showed that compounds 7 and 8 displayed moderate immunosuppressive activities.

In our continuing program to find new bioactive compounds from the Chinese liverworts, four new kaurane-type diterpenoids, (6β)-kaur-16-ene-6,9-diol (1), (6β,12β)-kaur-16-ene-6,9,12-triol (2), (6β)-kaur-16-ene-5,6,9-triol (3), and kaur-16-ene-9,19-diol (4), have been isolated from the Chinese liverwort Jungermannia comata Nees. Five known kaurane-type diterpenoids (5 - 9) and four known trachylobane-type diterpenoids (10 - 13) were also obtained. The structures of the new compounds were established unequivocally on the basis of spectroscopic data. The absolute configuration of compound 1 was established by comparing experimental and calculated electronic circular dichroism spectra.

A new flavonoid glycoside, rhamnazin-3-O-β-D-apiosyl-(1→2)-β-D-[6″-(3-hydroxy-3-methylglutaric methyl ester)]-glucoside (1), was isolated together with seven known flavonoid compounds from mistletoe transformed by Rhodobacter sphaeroides (PSBT). Its structure was elucidated on the basis of MS, 1D, and 2D NMR techniques. All of the eight compounds were subjected to antioxidant activity screening.

As a specific type of acid phosphatses, phytases play diverse roles in plants by catalazing the degradation of phytic acid and its derivatives. In this study, a rice phytase gene referred to OsPHY1 has been functionally characterized. OsPHY1 contains a 1 620 bp of open reading frame, encoding a 539-aa polypeptide. A conserve domain metallophosphatase (MPP) (MPP_PAPs), generally harbored in phytase and purple acid phosphatases (PAP), was identified in OsPHY1 (residue 194-398). Phylogenetic analysis revealed that OsPHY1 shares high similarities with phytase genes and PAP-type genes that derived from diverse plant species. The OsPHY1 transcripts were detected to be abundant in germinating seeds, suggesting that this gene plays potential roles on degradation of seed phytic acid and its derivatives during the germination process. Biochemical analysis confirmed that OsPHY1 possesses strong catalytic activities on phytic acid-Na2, with optimal temperature of 57°C and suitable pH of 3.5. Based on transgene analysis, the putative role of OsPHY1 in plants on utilization of phytate was assessed. Under the condition that phytic acid-Na2 was used as sole P source, the OsPHY1-overexpressing tobacco plants behaved higher phytase activities, higher concentrations of Pi, more accumulative amount of total phosphorus, and much more improved growth traits than those of the control plants. Therefore, OsPHY1 is acted as an important component on degradation of the phytins during the seed germination process in rice. Also, OsPHY1 has a potential use on generation of elite crop germplasms with improved use efficiencies on phytate and its derivatives.

The impact of two types of natural organic matters (NOM), humic acid (HA) and lipid, on char properties and sorption affinities for phenanthrene was studied. Char was coated with HA and lipid at a concentration of 0.060, 0.250 and 0.500 g/g char. HA, lipid, char and coated char were characterized and their sorption behaviors for phenanthrene were compared. Coating with NOM increased the polarity and aliphaticity, and reduced the specific surface area (SSA) of char, depending on the coated amount and the type of NOM. At the lower HA and lipid loading there was a strong attenuation of N(2)-assessible SSA. The SSA attenuation was less pronounced at larger HA and lipid loadings, which was most likely due to the preferential sorption at reactive sites and formation of clusters. The sorption isotherms of phenanthrene on char and coated char fitted Freundlich equation well, suggesting that all sorption isotherms were nonlinear, with N values in the range of 0.495-0.873. Coated char with HA and lipid decreased the organic carbon-normalized sorption coefficients K(Foc) and increased the N values. Lipid was more effective than HA in decreasing SSA. phenanthrene sorption capacity and sorption isotherm nonlinearity. The N values were correlated positively with the aliphaticity and negatively with pore volume of sorbents. The results of this investigation demonstrated that different NOM plays a different role in attenuating the SSA and sorption affinity of char for phenanthrene. (C) 2009 Elsevier B.V. All rights reserved.

Surimi gel was made from silver carp (hypophthalmichthys molitrix). Texture analyzer was adopted to measure stress-relaxation curve to study the effects of water, Na+ and Ca2+ on relaxation properties of surimi gel, so as to provide the basic data for development of surimi gel products. Micromodel of gel based on continuous phase of protein network with water embed and dispersed phase of myofibril was established. Stress-relaxation properties of the gel were imitated by use of five-element relaxation mathematical model, with high fitted precision. The results show that addition of water can reduce hardness of gel; Na+ and Ca2+ can improve the viscoelasticity of gel.

As the electrical source of hearts, sino-atrial node cells (SANCs) play significant roles in rhythmic firings. Due to the complex structure and function of SANCs, electrical interactions of SAN and its surrounding atrium has not yet been fully understood. The aim of the present study is to investigate effects of coupling conductance between SAN and atrial cells as well as the ectopic beats in atrium on automaticity of the SAN by computer simulation methods. On the basis of a dynamic mathematical single cell model considering the heterogeneity of central and peripheral SANCs, a two-dimensional inhomogeneous tissue slice including SAN and atrium was developed. The operator splitting method was used to integrate the tissue model. The results demonstrated that the coupling conductance between SAN and atrium had effects on the direction of spontaneous action potential conduction in SAN. Weak coupling resulted in a shift of the earliest pacemaker site from central to peripheral SANCs. Additionally, the ectopic beat-induced excitation in atrium was found to be able to enter into and overdrive suppress the automaticity of SAN. Even if the ectopic beat was delivered after the spontaneous firing had started in central SANCs, the spontaneous conduction toward the periphery could also be suppressed by the retrograde activation from the entering atrial depolarization wave. These findings suggested a direct link between sinus node dysfunction and atrial arrhythmias, and therefore were helpful in explaining the role of atrium in sinus node dysfunction.

Background The aim of the present study is to investigate the effects of two structurally divergent coumarins, calipteryxin (1) and (3’S,4’S)-3’,4’-disenecioyloxy-3’,4’-dihydroseselin (2) from Seseli recinosum, in lipopolysaccharide (LPS)-stimulated murine macrophages. Methods The nitrite production was evaluated using Griess reagent. The protein and mRNA expression levels were investigated through Western blot and quantitative real time-PCR analyses. The NF-κB and AP-1 DNA-binding activities were assessed using an electrophoretic mobility shift assay. The docking studies were performed with Glide XP in Schrödinger suite (version 2013). Results The results of the present study revealed that calipteryxin (1) and (3’S,4’S)-3’,4’-disenecioyloxy-3’,4’-dihydroseselin (2) treatment showed potent inhibitory effects on pro-inflammatory enzymes and cytokines associated with molecular signaling pathways. Treatment with calipteryxin and (3’S,4’S)-3’,4’-disenecioyloxy-3’,4’-dihydroseselin also decreased the production of nitric oxide (NO), tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) in a dose-dependent manner. Additionally, both coumarins inhibited the LPS-induced protein and mRNA expression levels of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in RAW264.7 cells. To explore the potential mechanisms underlying the inhibitory activity of coumarin derivatives, the protein signaling pathways for NF-κB, mitogen-activated protein kinase (MAPK) and Akt were examined. Calipteryxin and (3’S,4’S)-3’,4’-disenecioyloxy-3’,4’-dihydroseselin markedly reduced the LPS-stimulated phosphorylation of IKKα/β, p-IκBα and IκBα degradation as well as the nuclear translocation of the p65 subunit of pro-inflammatory transcription factor NF-κB. In addition, calipteryxin and (3’S,4’S)-3’,4’-disenecioyloxy-3’,4’-dihydroseselin) considerably inhibited the LPS-induced expression of ERK, c-Jun N-terminal kinase (JNK), p38 and Akt proteins. Furthermore, both coumarins significantly inhibited c-Jun expression in the nucleus. Conclusions Taken together, these results support the therapeutic potential and molecular mechanism of calipteryxin and (3’S,4’S)-3’,4’-disenecioyloxy-3’,4’-dihydroseselin associated with inflammatory diseases. Electronic supplementary material The online version of this article (doi:10.1186/s12950-015-0087-y) contains supplementary material, which is available to authorized users.

A new and efficient total synthesis has been developed to obtain plagiochin G (22), a macrocyclic bisbibenzyl, and four derivatives. The key 16-membered ring containing biphenyl ether and biaryl units was closed via an intramolecular SNAr reaction. All synthesized macrocyclic bisbibenzyls inhibited Epstein–Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells and, thus, are potential cancer chemopreventive agents.

Aim To study the chemical constituents of the Chinese liverwort Porella acutifolia subsp. tosana . Methods The compounds were isolated and purified with column chromatography and their structures were determined on the basis of 1D- and 2D-NMR analysis. Results Three compounds were obtained and identified as guaian-3-en-2α, 14-6α, 12-diolide ( 1 ), (20 R )-6β-hydroxystigmasta-4, 22-dien-3-one ( 2 ), and (20 R )-3β-hydroxystigmasta-5, 22-dien-7-one ( 3 ). Conclusion Compound 1 is a new guaiane-type sesquiterpene lactone. Compounds 2 and 3 are known steroids.

The important goal of cancer drug discovery is to develop therapeutic agents that are effective, safe, and affordable. In the present study, we demonstrated that alantolactone, which is a sesquiterpene lactone, has potential activity against triple-negative breast cancer MDA-MB-231 cells by suppressing the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Alantolactone effectively suppressed both constitutive and inducible STAT3 activation at tyrosine 705. Alantolactone decreased STAT3 translocation to the nucleus, its DNA-binding, and STAT3 target gene expression. Alantolactone significantly inhibits STAT3 activation with a marginal effect on MAPKs and on NF-κB transcription; however, this effect is notmediated by inhibiting STAT3 upstream kinases. Although SHP-1, SHP-2, and PTEN, which are protein tyrosine phosphatases (PTPs), were not affected by alantolactone, the treatment with a PTP inhibitor reversed the alantolactone-induced suppression of STAT3 activation, indicating that PTP plays an important role in the action of alantolactone. Finally, alantolactone treatment resulted in the inhibition of migration, invasion, adhesion, and colony formation. The in vivo administration of alantolactone inhibited the growth of human breast xenograft tumors. These results provide preclinical evidence to continue the development of alantolactone as a STAT3 inhibitor and as a potential therapeutic agent against breast cancer. ©

A new and efficient total synthesis has been developed to obtain plagiochin G (22), a macrocyclic bisbibenzyl, and four derivatives. The key 16-membered ring containing biphenyl ether and biaryl units was closed via an intramolecular SNAr reaction. All synthesized macrocyclic bisbibenzyls inhibited Epstein–Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells and, thus, are potential cancer chemopreventive agents.

Six new cembrane-type diterpenoids (1–6) were isolated from two species of Chandonanthus: Chandonanones A, B, and D–F (1, 2, and 4–6) were isolated from C. hirtellus, and chandonanones B, C, E, and F (2, 3, 5, and 6) from C. birmensis. Five known diterpenoids, (8E)-4α-acetoxy-12α,13α-epoxycembra-1(15),8-diene (7), isochandonanthone (8), chandonanthone (9), anadensin (10), and 2,10,14-triacetoxy-7,8,18,19-diepoxydolabell-3(E)-ene (11), were also obtained. The structures of the new metabolites were established by analyses of their spectroscopic data (1D NMR, 2D NMR, HRESIMS, and IR). The absolute configurations of compounds 1 and 2 were unequivocally confirmed using single-crystal X-ray diffraction analysis with Cu Kα radiation. Cytotoxicity tests of the isolated diterpenoids against seven cancer cell lines (DU145, PC3, A549, PC12, NCI-H292, NCI-H1299, and A172) revealed that some of the diterpenoids had weak activity.

isolation, structure determination and cytotoxicity of four new cis-clerodane lactones, ciliatolides A—D (I), (II)

Ten new dolabrane-type diterpenoids, notolutesins A-J (1-10), were isolated from the Chinese liverwort Notoscyphus lutescens, along with four known compounds. The structures of the new compounds were established on the basis of extensive spectroscopic data, and that of 1 was confirmed by single-crystal X-ray crystallography. The absolute configuration of 1 was determined by comparing its experimental and calculated electronic circular dichroism spectra. All of the isolates were evaluated for their cytotoxicity against a small panel of human cancer cell lines, and compound 1 exhibited an IC50 value of 6.2 μM against the PC3 human prostate cancer cell line.

Two new cadinane-type sesquiterpenes, frullanic acid (1) and frullanic acid methyl ester (2), together with four known bibenzyls, brittonin B (3), 3,3′-dimethoxy-4,5-methylenedioxybibenzyl (4), 3,4,5,3′,4′-penlamethoxybibenzyl (5) and ( ± )-3-(4′-methoxybenzyl)-5,6-dimethoxyphtbalide (6), were isolated from the Chinese liverwort Frullania serrata. The structures of the new metabolites were elucidated by analysing the spectroscopic data (1D NMR, 2D NMR, HR-ESI-MS and IR). The absolute configurations of compounds 1 and 2 were determined by comparing the experimental and calculated electronic circular dichroism spectra predicted by using time-dependent density functional theory as well as the CD exciton chirality method.

To detect the disparity of three cytokines interleukin-6 (IL-6), interferon-inducible protein 10 (IP-10) and interleukin-17 (IL-17) in peripheral blood (PB) and synovial fluid (SF) of patients with juvenile idiopathic arthritis (JIA).Serum concentrations of the three cytokines were measured in 27 patients with 13 systemic-onset JIA (sJIA), 14 polyarticular JIA (pJIA) and 28 healthy controls using enzyme-linked immunosorbent assay (ELISA). Nineteen patients with no marked arthritis symptom or only temporary arthralgia were enrolled in probable sJIA group. SF from 18 patients with 7 sJIA, 11 pJIA were examined for cytokine levels.(1) The statistically significant difference in serum IL-6 was detected between sJIA and healthy control group [28.0(4.2-59.2) ng/L vs. 12.3 (2.1-13.8) ng/L, P0.05], but no significant difference between probable sJIA and healthy control group [11.8(7.7-39.2) ng/L vs. 12.3 (2.1-13.8) ng/L, P0.05] was found. There were statistically significant differences between sJIA group and healthy control group in serum concentrations of IL-17 [14.0(9.8-34.3) ng/L vs. 9.8 (7.9-16.2) ng/L, P0.05], yet compared to healthy control group, no significant difference in concentration level of IL-17 was found in pJIA Group [14.2(9.9-16.9) ng/L vs. 9.8(7.9-16.2) ng/L, P0.05].(2) In sJIA and pJIA SF, the median IP-10 level was significantly higher compared to respective PB levels [619.7 (160.9, 873.1) ng/L vs. 64.8 (27.4-111.9) ng/L;660.9 (401.9, 1349.8) ng/L vs. 97.4 (41.9-222.1) ng/L, P0.01, respectively], but there was only significant difference in IL-17 between pJIA SF and PB [22.9 (17.1, 45.8) ng/L vs. 14.2 (9.9-16.9) ng/L, P0.01].IL-6 may play more important role in the pathogenesis of sJIA. Moreover, IL-6 may be the biomarker associated with arthritis in early JIA stage. Both autoinflammation and autoimmune response may be involved in the pathogenesis of sJIA. IL-17 enrichment may only occur in local joint, the levels of IL-17 in PB may not be significantly increased. The prominent expression gradient between SF and PB of IP-10 maybe the basis of performing chemotaxis and further causing joint damage.

Three new pimarane-type diterpenoids, 7β,11α-dihydroxypimara-8(14),15-diene (1), 1β,11α-dihydroxypimara-8(14),15-diene (2), and 11α-hydroxypimara-8(14),15-diene (3), five 2,3-secoaromadendrane-type sesquiterpenoids, including a new one, ethyoxyplagiochiline A2 (4), and three known fusicoccane-type diterpenoids were isolated from the Chinese liverwort Plagiochila pulcherrima. Their structures were established on the basis of extensive spectroscopic analysis. Compounds 6 and 7 exhibited moderate inhibitory activity on the proliferation of human cancer cell lines Hela, A172, and H460. Moreover, the cytotoxicity of compound 6 to Hela cells was related to apoptotis as confirmed by DAPI nuclear staining and flow cytometry.

Chemical investigation of the Chinese liverwort Scapania ciliata led to the isolation of four new cis-clerodane lactones, named ciliatolides A-D (1-4, resp.), among which compound 1 was found to be a tetranorclerodanoid. Their structures were determined by extensive analysis of spectroscopic data, and, in the case of compound 1, together with a single-crystal X-ray diffraction analysis. The absolute configurations were established by analysis of the CD spectra and by quantum-chemical CD calculations. The cytotoxicities of compounds 1-4 were preliminarily tested against the PC3 and MCF-7 cell lines.

Mycobacterium tuberculosis FabH, an essential enzyme in the mycolic acid biosynthetic pathway, is an attractive target for novel anti-tubercolosis agents. Structure-based design and synthesis of 1-(4-carboxybutyl)-4-(4-(substituted benzyloxy)phenyl)-1H-pyrrole-2-carboxylic acid derivatives 7a–h, a subset of eight potential FabH inhibitors, is described in this paper. The Vilsmeier-Haack reaction was employed as a key step. The structures of all the newly synthesized compounds were identified by IR, 1H-NMR, 13C-NMR, ESI-MS and HRMS. The alamarBlue™ microassay was employed to evaluate the compounds 7a–h against Mycobacterium tuberculosis H37Rv. The results demonstrate that the compound 7d possesses good in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (Minimum Inhibitory Concentration value [MIC], 12.5 µg/mL).These compounds may prove useful in the discovery and development of new anti-tuberculosis drugs.

Purpose To explore the effects of Icaritin on chronic myeloid leukemia (CML) cells and underlying mechanisms. Method CML cells were incubated with various concentration of Icaritin for 48 hours, the cell proliferation was analyzed by MTT and the apoptosis was assessed with Annexin V and Hoechst 33258 staining. Cell hemoglobinization was determined. Western blotting was used to evaluate the expressions of MAPK/ERK/JNK signal pathway and Jak-2/Phorpho-Stat3/Phorsph-Akt network-related protein. NOD-SCID nude mice were applied to demonstrate the anti-leukemia effect of Icaritin in vivo. Results Icaritin potently inhibited proliferation of K562 cells (IC50 was 8 µM) and primary CML cells (IC50 was 13.4 µM for CML-CP and 18 µM for CML-BC), induced CML cells apoptosis and promoted the erythroid differentiation of K562 cells with time-dependent manner. Furthermore, Icaritin was able to suppress the growth of primary CD34+ leukemia cells (CML) and Imatinib-resistant cells, and to induce apoptosis. In mouse leukemia model, Icaritin could prolong lifespan of NOD-SCID nude mice inoculated with K562 cells as effective as Imatinib without suppression of bone marrow. Icaritin could up-regulate phospho-JNK or phospho-C-Jun and down-regulate phospho-ERK, phospho-P-38, Jak-2, phospho-Stat3 and phospho-Akt expression with dose- or time-dependent manner. Icaritin had no influence both on c-Abl and phospho-c-Abl protein expression and mRNA levels of Bcr/Abl. Conclusion Icaritin from Chinese herb medicine may be a potential anti-CML agent with low adverse effect. The mechanism of anti-leukemia for Icaritin is involved in the regulation of Bcr/Abl downstream signaling. Icaritin may be useful for an alternative therapeutic choice of Imatinib-resistant forms of CML.

A new bakkenolide and a known one were isolated from Petasites tatewakianus. The structure of the new compound was elucidated on the basis of spectroscopic methods including IR, EIMS, HRESIMS, 1D and 2D NMR, and the known compound was established by single crystal X-ray structural analysis. The in vitro cytotoxic activity of these two compounds against cultured human cervical carcinoma (HeLa), human breast cancer (MCF-7) and murine Lewis lung carcinoma (LLC) cell lines was also evaluated.

In this study, three pentachlorophenol (PCP) laboratory-spiked and one field-contaminated soil were amended with 2.0% char, humic acid (HA) and peat, respectively. The amended soils were aged for either 7 or 250 days. After amendment, CaCl(2) extractability of PCP was significantly decreased. Desorption kinetics indicated that the proposed amendment could lead to a strong binding and slow desorption of PCP in soils. Amendment with char reduced the bioaccumulation factor (BAF) of PCP most significantly for earthworms (Eisenia fetida) in all soils studied. The results of both physicochemical and biological tests suggested that amendment reduced PCP bioavailability quickly and enduringly, implying that carbonaceous material amendment, especially char amendment, was a potentially attractive in situ remediation method for sequestration of PCP in contaminated soil.

This study was aimed to investigate the efficiency of 4 different culture media for in vitro culture and expanding adult human bone marrow mesenchymal stem cells (ahBM-MSCs) so as to establish a protocol of culturing and expanding hBM-MSCs and provide exprimental basis for hematopoietic blood stem cell transplantation combined with BM-MSCs. BM-MSCs were obtained from 16 fresh adult human bone marrow aspirate by gradient centrifugation with Ficoll Paque, then cultured in DMEM/F12 with 10% umbilical cord blood serum, 10% fetal calf serum (FCS), human blood serum, and MesenCult culture medium. The surface antigens of BM-MSCs were detected by flow cytometry. BM-MSCs were differentiated into osteoblasts and adipocytes under culture in the conditioned medium special for osteogenesis, and adipogenesis and the differentiated MSCs were identified by morphological observation, immunophenotype and immunohistochemical staining. The results showed that BM-MSCs could be isolated from adult human bone marrow and cultured by all culture media. The effect of umbilical cord blood serum on BM-MSC proliferation and their purity were similar to that of MesenCult culture medium, but better than that of FCS and human blood serum. The positive rate of CD29, CD73, CD105 on BM-MSCs cultured in umbilical cord serum and MesenCult medium was higher than that in FCS and adult human serum (p0.05), and the positive rate of CD31 was lower than that in FCS and adult human serum (p0.05). The positive rate of BM-MSCs differentiated into osteoblasts and adipocytes under culture in the conditioned medium for osteogenesis and adipogenesis with umbilical cord blood serum and MesenCult culture medium was also higher than that in FCS and adult human serum (p0.05). It is concluded that BM-MSCs can be obtained by all the four methods. DMEM/F12 with 10% umbilical cord blood serum and MesenCult culture medium are better than the others for the purification and differentiation potency of BM-MSCs in vitro. The medium with umbilical cord serum is valuable for clinical application in HSCT.

To explore the effects of Celecoxib on cell growth, early apoptosis, PRb and P27(Kip) protein expression of human leukemic cells of the line K562 and to determine its synergistic effects in combination of Imatinib.K562 cel1s were incubated with Celecoxib of the concentrations of 0, 10, 20, 40, 80, and 160 micromol/L for 36 hours, the cell vitality was determined by MTT assay, the early apoptosis was examined by flow cytometry (FC). The percentage of annexin V positive was detected by FC so as to evaluate the early apoptosis. The expression of PRb and P27(Kip) protein was detected by Western blotting. Another K562 cells were incubated with Celecoxib of the concentration of 40 micromol/L, Imatinib of the concentration of 0.2 micromol/L, or Celecoxib 40 micromol/L + Imatinib 0.2 micromol/L for 36 hours. Then the cell vitality and early apoptosis of the cells were detected so as to evaluate the synergistic effects of the combination of Celecoxib and Imatinib.Celecoxib inhibited the K562 cells vitality significantly in a dose-dependent manner. The apoptotic rate of K562 cells was elevated with the increasing Celecoxib concentration. Celecoxib down-regulated the expression of PRb protein and up-regulated the expression of P27(Kip) protein in the K562 cells. The combination of Celecoxib and Imatinib exhibited evidently synergistic effects in terms of anti-proliferation on K562 cells.Celecoxib inhibits the proliferation and induces apoptosis on leukemic cells in a dose-dependent fashion. The anti-proliferation effect of Celecoxib may be associated with the down-regulation of PRb expression and up-regulation of P27(Kip) expression. Combination of Celecoxib and Imatinib has obviously synergistic effects in terms of anti-proliferation on K562 cells.