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Chronic pain, along with comorbid psychiatric disorders, is a common problem worldwide. A growing number of studies have focused on non-opioid-based medicines, and billions of funds have been put into digging new analgesic mechanisms. Peripheral inflammation is one of the critical causes of chronic pain, and drugs with anti-inflammatory effects usually alleviate pain hypersensitivity. Sophoridine (SRI), one of the most abundant alkaloids in Chinese herbs, has been proved to exert antitumor, antivirus and anti-inflammation effects. Here, we evaluated the analgesic effect of SRI in an inflammatory pain mouse model induced by complete Freund’s adjuvant (CFA) injection. SRI treatment significantly decreased pro-inflammatory factors release after LPS stimuli in microglia. Three days of SRI treatment relieved CFA-induced mechanical hypersensitivity and anxiety-like behavior, and recovered abnormal neuroplasticity in the anterior cingulate cortex of mice. Therefore, SRI may be a candidate compound for the treatment of chronic inflammatory pain and may serve as a structural basis for the development of new drugs.

Flemingia macrophylla (Willd.) Prain is an ethnomedicinal plant with high nutritional and medicinal values. In this study, we report the complete chloroplast genome of F. macrophylla. The chloropla...

objective: 1. Two class of spiro[4H-pyran-3,3’-oxindole] derivatives were prepared via the one-pot reaction of chain diketones (1-phenyl-1,3-butanedione or dibenzoyl methane), substituted isatins and malononitrile successfully and which effectively catalyzed by a Tröger’s base derivative 1b (5,12-dimethyl-3,10-diphenyl-bis-1H-pyrazol[b,f][4,5]-1,5-diazadicyclo[3.3.1]-2,6-octadiene). 2. The anti-bacterial activity of products against three wild-type bacteria (B. subtilis, S. aureus and E. coli) and two resistant strain (Methicillin-resistant S. aureus (18H8) and E. coli carrying the BlaNDM-1 gene (18H5) was evaluated using the minimum inhibitory concentration (MIC) method. Methods: 1. 1-Phenyl-1,3-butanedione 2 or dibenzoylmethane 2' (0.42 mmol), substituted isatin 3 (0.4 mmol), malononitrile 4 (0.8 mmol), Tröger's base derivative 1b (0.08 mmol) and 10 mL of acetonitrile were added to a 50 mL round bottom flask and refluxed. After the completion (TLC monitoring), poured water (10 mL) into the reaction mixture, adjusted the pH = 7 with saturated NaHCO3 (aq.), then extracted the mixture with CH2Cl2 (50 mL × 3). Combined and dried the organic layers with anhydrous Na2SO4, removed the solvent under vacuum, purified the residue by column chromatography (VDCM : V MeOH = 80 : 1) to give product 5. 2. The evaluation of anti-bacterial activity was carried out by MTT method. Result: 1. Seventeen spiro[4H-pyran-3,3’-oxindole] derivatives were synthesized through the reaction of chain diketones (1-phenyl-1,3-butanedione or dibenzoyl methane), substituted isatins and malononitrile in one-pot in medium to high yields. 2. Four compounds showed antibacterial activity, and two of them showed the same activity as the positive control Ceftazidime on S. aureus (MIC = 12.5 μg/mL). Conclusion: Two class of spiro[4H-pyran-3,3’-oxindole] derivatives were prepared and their anti-bacterial activity was evaluated. Tröger’s base derivative 1b (5,12-dimethyl-3,10-diphenyl-bis-1H-pyrazol[b,f][4,5]-1,5-diazadicyclo[3,3,1]-2,6-octadiene) was used as efficient organocatalyst for the reaction of low reactive chain diketones (1-phenyl-1,3-butanedione or dibenzoyl methane), substituted isatins and malononitrile in one-pot successfully and effectively by providing multiple active sites and alkaline environment. By the theoretical calculation, we explained the possible reaction sequence and the possible reaction mechanism. Due to the superiority and high efficiency of the TB framework as organocatalyst, the reaction showed many advantages including mild reaction conditions, low catalyst loading and wide substrate range. It expanded the application of Tröger’s base to the multicomponent reaction in organocatalysis. Some products were screened out due to their high anti-bacterial activity in vitro, which showed their potential in new anti-bacterial drug development.

An enantiomeric pair of rare cyperane-type sesquiterpenoids, (+)- and (-)-gracilistones C (1a, 1b), together with a novel norsesquiterpenoid, gracilistone D (2), bearing a bicyclic lactone system were isolated from the root bark of Acanthopanax gracilistylus using LC-MS-IT-TOF analyses. The structures and absolute configurations of 1a, 1b, and 2 were elucidated by 1D and 2D NMR spectroscopy, X-ray diffraction, and ECD spectroscopic methods. Intermediate 1b suggests a possible biosynthesis process involving compound 2. The bioassay results showed that compounds 1a, 1b, and 2 exhibited significant inhibitory effects against lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells, with IC50 values of 7.7 ± 0.6, 6.8 ± 1.5, and 2.6 ± 0.4 μM, respectively. Additional docking analyses provided some perspective of this activity in human inducible nitric oxide synthase.

Polysaccharide from Ma-chi-xian (Portulacae oleracea L., POLP) was prepared and the therapeutic effect on dextran sodium sulfate-induced colitis mice was investigated in this study. The results of clinical activity score and H&E staining confirmed the therapeutic effect of POLP. POLP could diminished the symptoms of colitis and improve colon histopathological structure of the colitis mice. The expression levels of four cytokines were determined. The concentrations of PGE2 and IL-6 were downregulated by POLP treatment. The COX-2 protein expression levels and the STAT3 phosphorylation levels were detected. The results showed that these two protein levels were all increased in colitis and decreased after POLP treatment, indicating that these two proteins were closely related with the protective effect of POLP. Because the synthesis of PGE2 is catalyzed by COX-2 and phosphorylation of STAT3 can induce the expression of COX-2, it was concluded that STAT3 was a key protein related to the POLP exerting its activity in colitis.

Gracilistones A (1) and B (2), two new eudesmane-type sesquiterpenoids with an unusual tetrahydrofuran-fused 6/6/5 tricyclic ring system, were obtained from Acanthopanax gracilistylus under the guidance of LC-MS investigation. Their structures and absolute configurations were assigned by extensive spectroscopic analyses and quantum calculation methods. Compounds 1 and 2 showed potent inhibitory activity against LPS-induced nitric oxide production in RAW 264.7 macrophages, compared with the positive control L-NMMA. In addition, compounds 1 and 2 were also evaluated for their antioxidant (DPPH• and ABTS•+) and xanthine oxidase (XO) inhibitory activities, and they exhibited weak inhibitory effects at 100 μM.

In traditional Chinese Medicine (TCM), the licorice-yuanhua herbal pair is one of the most representative incompatible herbal pairs recorded in the “eighteen incompatible herbal pairs” theory. Previous studies of our research group have demonstrated several gut-related side-effects induced by the licorice-yuanhua herbal pair. In this study, we investigated whether and why this incompatible herbal pair could induce gut tissue damage. After licorice-yuanhua treatment, the duodenum, ileum, and colon and serum biomarkers of mice were examined by pathological staining, Western blot, and ELISA assays. The IEC-6 cells and LS174T cells were treated with licorice saponins, yuanhua flavonoids, and di-terpenes; iTRAQ-labeled proteomic technology was then used to explore their synergistic effects on mucosa cells, followed by verification of ZO-1 and MUC-2 protein expressions. The results showed that the licorice-yuanhua herbal pair induced ileum tissue injuries, including epithelial integrity loss, inflammation, and edema. These injuries were verified to be related to epithelial and mucous barrier weakening, such as downregulated ileum ZO-1 and MUC-2 protein expressions. Proteomic analysis also suggested that glycyrrhizic acid and genkwanin synergistically influence tight junction pathways in LS174T cells. Furthermore, licorice saponins, yuanhua flavonoids, and di-terpenes dose/structure-dependently downregulate ZO-1 and MUC-2 protein expressions in mucosa cells. Our study provides different insights into the incompatibility mechanisms and material basis of the licorice-yuanhua herbal pair, especially that besides toxic di-terpenes, licorice saponins and yuanhua flavonoids, which are commonly known to be non-toxic compounds, can also take part in the gut damage induced by the licorice-yuanhua herbal pair.

An enantiomeric pair of rare cyperane-type sesquiterpenoids, (+)- and (-)-gracilistones C (

With digital satellite remote sensing image data of GF-1,in 2018 the object-oriented classification method was used to extract Zizyphus jujuba planting area in Jia county of Shaanxi province. The results showed that the remote sensing classification method based on rule set could extract and reckon Z. jujube planting area in the study area effectively. The planting area of Z. jujube in Jia county was about 5. 34×104 hm2 and the area of consistent accuracy was 97. 92%. The method used in this study could provide a technical reference for the area extraction of the same type of medicinal materials. And it is of great significance to provide decision support for the protection and utilization of Z. jujube resources.

Indigo naturalis (IN) is a traditional Chinese medicine, named Qing-Dai, which is extracted from indigo plants and has been used to treat patients with inflammatory bowel disease (IBD) in China and Japan. Though there are notable effects of IN on colitis, the mechanisms remain elusive. Regarding the significance of alterations of intestinal flora related to IBD and the poor water solubility of the blue IN powder, we predicted that the protective action of IN on colitis may occur through modifying gut microbiota. To investigate the relationships of IN, colitis, and gut microbiomes, a dextran sulfate sodium (DSS)-induced mice colitis model was tested to explore the protective effects of IN on macroscopic colitis symptoms, the histopathological structure, inflammation cytokines, and gut microbiota, and their potential functions. Sulfasalazine (SASP) was used as the positive control. Firstly, because it was a mixture, the main chemical compositions of indigo and indirubin in IN were detected by ultra-performance liquid chromatography (UPLC). The clinical activity score (CAS), hematoxylin and eosin (H&amp, E) staining results, and enzyme-linked immunosorbent assay (ELISA) results in this study showed that IN greatly improved the health conditions of the tested colitis mice, ameliorated the histopathological structure of the colon tissue, down-regulated pro-inflammatory cytokines, and up-regulated anti-inflammatory cytokines. The results of 16S rDNA sequences analysis with the Illumina MiSeq platform showed that IN could modulate the balance of gut microbiota, especially by down-regulating the relative quantity of Turicibacter and up-regulating the relative quantity of Peptococcus. The therapeutic effect of IN may be closely related to the anaerobic gram-positive bacteria of Turicibacter and Peptococcus. The inferred metagenomes from 16S data using PICRUSt demonstrated that decreased metabolic genes, such as through biosynthesis of siderophore group nonribosomal peptides, non-homologous end-joining, and glycosphingolipid biosynthesis of lacto and neolacto series, may maintain microbiota homeostasis during inflammation from IN treatment in DSS-induced colitis.

A pair of new

A pair of new neo-clerodane diterpenoid epimers, 3S-methoxyl-teucvin (1) and 3R-methoxyl-teucvin (2), were isolated from the Roots of Croton crassifolius. Their structures were completely established on the basis of spectroscopic methods, and the absolute configurations were determined by analysis of electronic circular dichroism (ECD) spectroscopy and X-ray diffraction analysis. Compounds 1 and 2 exhibited anti-inflammatory activities with IC50 values of 0.82 and 0.54 μM, respectively, while the IC50 value of dexamethasone as a positive control was found to be 0.14 μM.

Ethnopharmacological relevance Guchang Zhixie Wan (GC) is a traditional Chinese patent medicine used in the treatment of colitis in clinical trials. Though the notable effect of GC on colitis, the concrete mechanism of GC remain elusive. Emerging evidence showed that the imbalances of inflammatory cytokines and gut microbiota were both closely related to the initiation and progression of colitis. Aim of the study To elucidate the relationship between the protective effects of GC on colitis and gut microbiota. Materials and methods Male Kunming (KM) mice were enrolled in our work to establish colitis model induced by dextran sulfate sodium (DSS). The colitis mice were randomly divided into different groups and treated orally with 125 mg/kg of sulfasalazine (positive control) and 25, 50, 100 mg/kg of GC for 7 days, respectively. Inflammation cytokines of IL-1β, IL-4, IL-6, IL-8, IL-11, IL-12 and TNF-α were detected by ELISA analysis and the histological changes were detected by H&E staining. Gut microbiota diversity was analyzed by 16S rDNA sequencing. Metagenomes analysis were also conducted to reflect the protective effects of GC on colitis. Results The results of CAS (Clinical Activity Score) confirmed the protective effects of GC on colitis. After administration of GC, the levels of pro-inflammatory cytokines IL-1β, IL-6, IL-8, IL-11, IL-12 and TNF-α were all decreased while the anti-inflammatory cytokines IL-4 was slightly increased, indicating that GC could down regulate pro-inflammatory cytokines. H&E staining revealed that GC could improve the histopathological structure of the colon tissue. The results of 16S rDNA sequences analysis showed that GC could decrease the relative abundance of Turicibacter and increase the relative abundance of Ruminococcaceae_UCG-005. Conclusion GC greatly improve the health condition of colitis mice induced by DSS through improving the imbalances of inflammatory cytokines and gut microbiota.

The 1,4-addition Ugi reaction can provide complex, novel and bioactive structures. However, Ugi reaction involving the 1,4-addition process has rarely been reported due to the Michael addition of amine to α,β-unsaturated ketones or aldehydes prevents the formation of the key intermediate iminium ion. In this paper, a Schiff base catalyst derived from Troger's base-NH2 and (R)-BINOL-CHO was used successfully to promote the four-component 1,4-addition Ugi reaction of α,β-unsaturated cyclic ketones, carboxylic acids, aromatic amines and isocyanides to afford an α,β-keto amide 2-arylformyl-3-(arylamino)cyclopent-2-enecarboxamides in high yield (6, 83–96%) under mild condition. A variety of aromatic amines participated in the reaction efficiently, which showed the high efficiency of the catalyst. A reasonable catalysis and formation mechanism were come up with.

To study the chemical constituents of Rubus stans.The chemical constituents were isolated and purified by silica gel and Sephadex LH-20 column chromatography. The structures were identified on the basis of spectroscopic analysis and physicochemical properties.Eleven compounds were isolated and purified from the ethanol extract of Rubus stans. They were identified as β-sitosterol( 1),betulinic acid( 2),euscaphic acid( 3),ursolic acid( 4),corosolic acid( 5),kaempferol( 6),quercetin( 7),2α,3β,19α,23-tetrahydroxy-urs-12-en-28-oic acid( 8),β-daucosterol( 9),quercetin-3-O-β-D-glucoside( 10) and kaempferol-3-O-β-D-6-O-( p-hydroxycinnamoyl)-glucopyranoside( 11).All the compounds are isolated from this plant for the first time.

To study the chemical constituents from the whole plant of Delphinium caeruleum.The chemical constituents were isolated and purified by silica gel and Sephadex LH-20 column chromatography. The structures of the isolated compounds were elucidated by spectroscopic analysis and physicochemical properties.Twelve compounds were isolated and purified from the ethanol extract of Delphinium caeruleum. They were identified as β-sitosterol( 1),kaempferol( 2),quercetin( 3),isovanillic acid( 4),apigenin( 5),luteolin( 6),8-methoxy-5,7,3’,4’-tetrahydroxy-flavone( 7),β-daucosterol( 8),kaempferol-3-O-β-D-glucoside( 9),3,5-dihydroxy-4’-methoxyflavone-7-yl-O-β-D-glucopyranosyl-( 1→4)-α-L-rhamnopyranoside( 10),rutin( 11) and sucrose( 12).Compounds 1 ~ 12 are isolated from this plant for the first time.

Inflammatory bowel disease (IBD) is a notable health problem and may considerably affect the quality of human life. Previously, the protective roles of tryptanthrin (TRYP) against dextran sulfate sodium (DSS) induced colitis has been proved, but the concrete mechanism remained elusive. It has been suggested that TRYP could diminish the weight loss and improve the health conditions of mice with DSS induced colitis. Hematoxylin and eosin staining revealed that TRYP could improve the histopathological structure of the colon tissue. Two signaling pathways (TNF-α/NF-κBp65 and IL-6/STAT3) were investigated using immunochemistry and western blot. The detected concentrations of the two cytokines TNF-α and IL-6 showed that their levels decreased after TRYP treatment of the colitis. The protein expression level of NF-κBp65 in cytoplasm increased after TRYP treatment of the induced colitis. However, the protein level of NF-κBp65 in the nucleus decreased after administration of TRYP. The expression level of IκBα, the inhibitory protein of NF-κBp65, was tested and the results suggested that TRYP could inhibit the degradation of IκBα. The phosphorylation level of STAT3 was inhibited by TRYP and the expression level of STAT3 and p-STAT3 decreased after administration of TRYP. We conclude that TRYP improves the health condition of mice with DSS induced colitis by regulating the TNF-α/NF-κBp65 and IL-6/STAT3 signaling pathways via inhibiting the degradation of IκBα and the phosphorylation of STAT3.

To assess the role of the lateral triazine group of 2,6-bis(1,2,4-triazin-3-yl) pyridine (BTP) when coordinated to Am(III), three tridentate N-donor ligands, i.e. BTP, 6-(-2-pyridyl)-2-pyridyl (hemi-BTP), and 2,2′:6′2′′-terpyridine (TPY), have been used to construct coordination complexes with Am(III), and the structures and binding modes of these complexes have been investigated using the B3LYP functional. The 1 : 1 and 1 : 2 (metal : ligand) type complexes, based on our calculations, form mainly via reactions Am(H2O)3(NO3)3 + L → AmL(NO3)3 + 3H2O and [Am(H2O)6(NO3)2]+ + 2L → [AmL2(NO3)2]+ + 6H2O. The Gibbs free energy changes were in the order of TPY > hemi-BTP > BTP, independent of the presence of nitrate ions in the complexes. We show that in 1 : 1 type complexes substitution of electron-donating groups to the three ligands can enhance their binding ability. From analysis of NPA charge and Mayer Bond Order, it is found that the value of binding free energy is correlated with charge transfers between the central metal and the ligand: the larger the ligand-to-metal charge transfer, the more negative the binding energy, and meanwhile, the smaller the Mayer bond order of the Am–N bonds. This suggests that the interaction between Am(III) and the tridentate ligands has a strong ionic feature, which is confirmed by the quantum theory of atoms-in-molecules (QTAIM) topological analysis. According to our calculations, the presence of the triazine group in BTP and hemi-BTP does not improve the binding affinity of the ligand to Am(III), compared to TPY, but facilitates the ligand to adopt a conformation that favors to coordinate with Am3+ than others via a dynamic isomerization process, and the electron-donating groups on the triazine group may enhance the charge transfer between Am(III) and the ligand, and thus stabilize the complex. We tentatively propose that the facile conversion between the conformations of BTP, which is more difficult for TPY and hemi-BTP, may significantly contribute to its higher affinity towards binding with Am(III).

Ethnopharmacological relevance Ligularia przewalskii (Maxim.) Diels (LP) (called zhangyetuowu in Chinese), is generally found in moist forest areas in the western regions of China. The root, leaves and flower of LP are utilized as a common traditional medicine in China. It has been utilized conventionally in herbal remedies for the remedy of haemoptysis, asthma, pulmonary phthisis, jaundice hepatitis, food poisoning, bronchitis, cough, fever, wound healing, measles, carbuncle, swelling and phlegm diseases. Aim of the study The review aims to provide a systematic summary of LP and to reveal the correlation between the traditional uses and pharmacological activities in order to provide updated, comprehensive and categorized information and identify the therapeutic potential for its use as a new medicine. Materials and methods The relevant data were searched by using the keywords “Ligularia przewalskii” “phytochemistry”, “pharmacology”, “Traditional uses”, and “Toxicity” in “Scopus”, “Scifinder”, “Springer”, “Pubmed”, “Wiley”, “Web of Science”, “China Knowledge Resource Integrated databases (CNKI)”, “Ph.D.” and “M.Sc. dissertations”, and a hand-search was done to acquire peer-reviewed articles and reports about LP. The plant taxonomy was validated by the databases “The Plant List”, “Flora Reipublicae Popularis Sinicae”, “A Collection of Qinghai Economic Plants”, “Inner Mongolia plant medicine Chi”, Zhonghua-bencao and the Standard of Chinese herbal medicine in Gansu. Results Based on the traditional uses, the chemical nature and biological effects of LP have been the focus of research. In modern research, approximately seventy-six secondary metabolites, including thirty-eight terpenoids, nine benzofuran derivatives, seven flavonoids, ten sterols and others, were isolated from this plant. They exhibit anti-inflammatory, antioxidative, anti-bacterial and anti-tumour effects, and so on. Currently, there is no report on the toxicity of LP, but hepatotoxic pyrrolizidine alkaloids (HPA) were first detected with LC/MSn in LP, and they have potential hepatotoxicity. Conclusions The lung-moistening, cough-relieving and phlegm-resolving actions of the root of LP are attributed to the anti-inflammatory properties of flavonoids and terpenoids. The heat-clearing, dampness-removing and gallbladder-normalizing (to cure jaundice) actions of the flowers of LP are based on the anti-inflammatory, antioxidant and hepatoprotective activity properties of terpenoids, flavonoids and sterols. The Traditional Chinese Medicine (TCM) characteristics of LP (bitter flavour) corroborate its potent anti-inflammatory effects. In addition, the remarkable anti-inflammatory and antioxidant capacities of LP contribute to its anti-tumour and antitussive activities. Many conventional uses of LP have now been validated by modernized pharmacological research. For future research, further phytochemical and biological studies need to be conducted on LP, In particular, the safety, mechanism of action and efficacy of LP could be of future research interest before beginning clinical trials. More in vivo experiments and clinical studies are encouraged to further clarify the relation between traditional uses and modern applications. Regarding the roots, leaves and flowers of LP, their chemical compositions and clinical effects should be compared. The information on LP will be helpful in providing and identifying its therapeutic potential and economic value for its use as a new medicine in the future.

Cordycepin is an active component of the traditional Chinese medicine Cordyceps sinensis and Cordyceps militaris with notable anticancer activity. Though the prominent inhibitory activity was reported in different kinds of cancer cell lines, the concrete mechanisms remain elusive. It was reported that cordycepin could be converted into tri-phosphates in vivo to confuse a number of enzymes and interfere the normal cell function. For the inhibitory mechanism of EGFR inhibitors and the structure similarity of ATP and tri-phosphated cordycepin, human lung cancer cell line H1975 was employed to investigate the inhibitory effect of cordycepin. The results showed that cordycepin could inhibit cell proliferation and induce apoptosis in a dose-dependent manner. Cell cycle analysis revealed that H1975 cells could be arrested at the G0/G1 phase after cordycepin treatment. The expression levels of apoptosis-related protein Caspase-3 and Bcl-2 and phosphorylated expression levels of EGFR, AKT and ERK1/2 were all decreased compared with the control group stimulated with EGF. However, the protein expression levels of proapoptotic protein Bax and cleaved caspase-3 were increased. These results implied that cordycepin could inhibit cell proliferation and induce apoptosis via the EGFR signaling pathway. Our results indicated that there was potential to seek a novel EGFR inhibitor from cordycepin and its chemical derivatives.

Acute lymphoblastic leukemia (ALL) is characterized by the accumulation of abnormal lymphoblasts in the bone marrow and blood. Though great progress has been made for improvement in clinical treatment during the past decades, some children with ALL still relapsed. Glucocorticoid (GC) resistance is an important clinical problem for ALL treatment failure. Therefore, further understanding of the mechanism of GC resistance and exploring novel therapeutic strategies are crucial for improving treatment outcome. The reported involvement of microRNAs (miRNAs) in drug resistance implied that deregulated miRNA expression might contribute to GC treatment response of ALL. However, individual miRNAs and their functional mechanisms potentially involved in the GC response are still largely unknown. In the present study, we found that miR-124 was up-regulated in prednisone insensitive human ALL cell line and prednisone-poor response ALL patients. Furthermore, it was found that miR-124 might contribute to GC resistance by promoting proliferation and inhibiting apoptosis of ALL cells. Importantly, we validated that miR-124, targeted and decreased the expression of glucocorticoid receptor (NR3C1), prevented the inhibitory effect of GC in ALL. These findings strongly suggest that miR-124 is critical in poor GC response and may serve as a potential therapeutic target in ALL with poor GC resistance.

// Yan-Lai Tang 1, * , Li-Bin Huang 1, * , Wen-Hao Lin 1, * , Li-Na Wang 1 , Yun Tian 2 , Dingbo Shi 2 , Jingshu Wang 2 , Ge Qin 2 , Anchuan Li 3 , Yan-Ni Liang 1 , Huan-Juan Zhou 1 , Zhi-Yong Ke 1 , Wenlin Huang 2, 4 , Wuguo Deng 2, 4 , Xue-Qun Luo 1 1 Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China 2 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China 3 Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, China 4 State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China * These authors have contributed equally to this work Correspondence to: Xue-Qun Luo, e-mail: l-xuequn@126.com Wuguo Deng, e-mail: dengwg@sysucc.org.cn Keywords: butein, acute lymphoblastic leukemia, FOXO3a, p27kip1 Received: November 22, 2015 Accepted: February 14, 2016 Published: February 23, 2016 ABSTRACT Acute lymphoblastic leukemia (ALL) is a common hematological malignancy characterized by the uncontrolled proliferation of leukemia cells in children. Discovering and developing effective chemotherapeutic drugs are needed for ALL. In this study, we investigated the anti-leukemic activity of butein and its action mechanisms in ALL. Butein was found to significantly suppress the cellular proliferation of ALL cell lines and primary ALL blasts in a dose-dependent manner. It also induced cell cycle arrest by decreasing the expression of cyclin E and CDK2. We also found that butein promoted nuclear Forkhead Class box O3a (FOXO3a) localization, enhanced the binding of FOXO3a on the p27kip1 gene promoter and then increased the expression of p27kip1. Moreover, we showed that FOXO3a knockdown significantly decreased the proliferation inhibition by butein, whereas overexpression of FOXO3a enhanced the butein-mediated proliferation inhibition. However, overexpression of FOXO3a mutation (C-terminally truncated FOXO3a DNA-binding domain) decreased the proliferation inhibition by butein through decreasing the expression of p27kip1. Our results therefore demonstrate the therapeutic potential of butein for ALL via FOXO3a/p27kip1 pathway.

The present theoretical study provides a realistic bonding characteristics of a variety of neptunyl complexes evaluation of the equilibrium structure, reaction modes, and formed with bis(triazinyl) N-donor extractants, which differ in their bridging groups such as pyridine, bipyridines, and orthophenanthroline, corresponding to the ligands (L) of tridentate bis(triazinyl)pyridines and tetradentate bis(triazinyl)-bipyridines and bis(triazinyl)-1,10-phenanthrolines (BTPhens), respectively. Our calculations show that coordination of [NpO2](+) to tetradentate ligands is more favorable than that to tridentate ones no matter in a gas, aqueous, or organic phase. The presence of nitrate ions can enhance the coordination ability of neptunyl and stabilize the neutral NpO2L(NO3) complexes in thermodynamics. Our studies indicate that the complexation reaction mode [NpO2(H2O)(n)](+) + L + NO3-) NpO2L(NO3) + nH(2)O is the most probable at the interface between water and the organic phase. The contribution of an orthophenanthroline bridging group is relatively more pronounced compared to its pyridine counterpart in ligand-exchange reaction. Complexation reactions of hydrated neptunyl with C2-BTPhen and BTPhen assisted by a nitrate ion are favorable thermodynamically, resulting from the least deformation of the ligand and strong complexation stability. The quantum theory of atoms-in-molecules and charge decomposition analysis suggest that electron delocalization and charge transfer are the main reasons responsible for stabilization of the tetradentate complexes and reveal a strong ionic feature of the Np-ligand bonds. Inspection of the frontier molecular orbitals reveals a distinct Sf orbital (Np) interaction with ligand atoms, implying the extent of f-based covalenc-y. Our study may facilitate the rational design of ligands toward the improvement of their binding ability with Np-V and more efficient separation of Np in spent nuclear fuels.

Low-lying states of Ga2P and Ga2As are investigated with the equation-of-motion coupled-cluster approach for ionized states at the singles and doubles level (EOMIP-CCSD) as well as at the CCSDT-3 level together with CCSD, CCSD(T), and DFT. Except for the asymmetric stretching b2 mode of the (2)B2 and (2)A1 states, all these approaches provide structures, frequencies and adiabatic electron affinities that are in reasonable agreement with each other. According to our results, the lowest-energy state of these two molecules is the (2)A' state of C(s) symmetry and the (2)B2 state is the ground electronic state with C(2v) symmetry. As for the b2 mode, CCSD and CCSD(T) afford real frequencies for the (2)B2 state, while EOM approaches and DFT with most exchange-correlation functionals give rise to imaginary frequencies. The (2)B2 and (2)A1 states couple with each other due to distortion along b2 mode through the pseudo-Jahn-Teller effect. Analysis on results shows that EOM approaches afford reasonable b2 frequencies for the two states and DFT approaches, except for BP86 and PBE, provide qualitatively correct b2 frequencies for the (2)B2 state. In addition, a potential matrix is introduced to describe the vibronic coupling between the (2)B2 and (2)A1 states and parameters in the matrix are fitted to the adiabatic potential curves from EOMIP-CCSD results.

To provide insight on the reaction mechanism of the methyperoxy (CH(3)O(2)•) self-reaction, stationary points on both the spin-singlet and the spin-triplet potential energy surfaces of 2(CH(3)O(2)•) have been searched at the B3LYP/6-311++G(2df,2p) level. The relative energies, enthalpies, and free energies of these stationary points are calculated using CCSD(T)/cc-pVTZ. Our theoretical results indicate that reactions on a spin-triplet potential energy surface are kinetically unfavorable due to high free energy barriers, while they are more complicated on the spin-singlet surface. CH(3)OOCH(3) + O(2)(1) can be produced directly from 2(CH(3)O(2)•), while in other channels, three spin-singlet chain-structure intermediates are first formed and subsequently dissociated to produce different products. Besides the dominant channels producing 2CH(3)O• + O(2) and CH(3)OH + CH(2)O + O(2) as determined before, the channels leading to CH(3)OOOH + CH(2)O and CH(3)O• + CH(2)O + HO(2)• are also energetically favorable in the self-reaction of CH(3)O(2)• especially at low temperature according to our results.

To screen childhood ALL related microRNAs (miRNAs), analyze association of miRNAs expression profiles with prognosis and relapse in childhood acute lymphoblastic leukemia (ALL) and explore new indicator for predicting relapse and prognosis.miRNAs expression profile was analyzed by gene chip in 49 newly diagnosed childhood ALL and 12 primary immune thrombocytopenia (ITP) cases (as control group). Abnormal expression of miRNAs was verified by qRT-PCR. The correlation of miRNAs expression pattern with indicators predicting early prednisone response and relapse within a year was analyzed.Specific expression of miRNAs profiles associated with prednisone response and early relapse in childhood ALL was identified. Eight miRNAs (miR-18a, miR-532, miR-218, miR-625, miR-193a, miR-638, miR-550 and miR-633) could distinguish prednisone sensitive from insensitive. The early relapse of newly diagnosed patients with either high-risk or non-high-risk clinical types had some characteristics of abnormal expression of miRNAs, including miR-7, miR-216 and let-7i upregulated, while miR-486, miR-191, miR-150, miR-487 and miR-342 downregulated.The initial screening reveals miRNAs differentially expressed from normal in ALL suggesting the potential roles of them in leukemogenesis. MiRNAs expression signatures may be useful for predicting prognosis and relapse in childhood ALL and directing personalized treatment.

In this work, the equation-of-motion coupled-cluster approach with spin-orbit coupling (SOC) for ionization potentials (IP) at the singles and doubles level (EOMIP-CCSD) is employed to calculate spectroscopic constants of low-lying states of rare gas dimer ions Kr2(+), Xe2(+), and Rn2(+). Two approaches are proposed to include contributions of triples: (1) energies of these states are calculated by adding the IPs from EOMIP-CCSD and the CCSD(T) energy of the rare gas dimers and (2) CCSD(T) energies without SOC for Rg2(+) are first calculated and energies of these states with SOC are determined subsequently using the SOC matrix between these states. The first approach can provide accurate results for the three most stable states, while overestimates bond lengths for the other states. The second approach has been adopted previously and the SOC matrix element between (2)Σ1∕2 (+) and (2)Π1∕2 states was set to be 1/2 times that of the SOC constant. In our work, the SOC matrix elements are determined from the calculated IPs and reasonable results for these states can be achieved with this approach, which could be useful for experimental works.

Background Leukemia is the most common malignant proliferative disease in children. Our previous study found that miR-99a was up-regulated in pediatric primary AML using microRNA expression profiles. Up to date, although there is a certain number of reports on microRNA expression features and functions in pediatric acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), the expression and function of miR-99a in these diseases remain to be investigated. Methods qRT-PCR was performed to measure the expression level of miR-99a in 88 samples including 68 pediatric acute myeloid leukemia patients, 8 chronic myeloid leukemia patients and 12 pediatric controls. MTT assay, apoptosis assay, dual-luciferase reporter transfection assay and western blot analysis were used to investigate the function of miR-99a. Results MiR-99a was highly expressed in pediatric-onset AML (M1-M5) and CML, while significantly lowly expressed during complete remission of these diseases. MTT assay indicated that the proliferations of K562 and HL60 cells were significantly promoted by miR-99a, and apoptosis assessment by Annexin V/propidium iodide staining demonstrated that the apoptosis of these cells was inhibited by miR-99a. Additionally, dual-luciferase reporter transfection assay and western blot analysis indicated that miR-99a may target CTDSPL and TRIB2, which are two tumor suppressor genes. Conclusions This study revealed that miR-99a may play a potential oncogenic role in pediatric myeloid leukemia including AML and CML via regulating tumor suppressors CTDSPL and TRIB2, suggesting that these two leukemias might share some common biological pathways involved in the generation and development of disease and miR-99a could be a common therapeutic target for myeloid leukemias treatment.